Allowing patients with a first episode to experience a second is unacceptable, Henry A. Nasrallah, MD, editor in chief of Current Psychiatry, said in his interview with Lorenzo Norris, MD, editor in chief of MDedge Psychiatry.

“It’s not too late to use injectables after the first episode, but my God, why are we letting them lose so much tissue and have so much suffering, so much PTSD, so much stigma, so much poverty, so much incarceration that comes from having repetitive psychotic episodes and deteriorating?” Dr. Nasrallah asked. “We can prevent all of that by utilizing, exploiting those agents.”

Dr. Nasrallah serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on the speakers bureaus of several companies. Dr. Norris has no disclosures.

Allowing patients with a first episode to experience a second is unacceptable, Henry A. Nasrallah, MD, editor in chief of Current Psychiatry, said in his interview with Lorenzo Norris, MD, editor in chief of MDedge Psychiatry.

“It’s not too late to use injectables after the first episode, but my God, why are we letting them lose so much tissue and have so much suffering, so much PTSD, so much stigma, so much poverty, so much incarceration that comes from having repetitive psychotic episodes and deteriorating?” Dr. Nasrallah asked. “We can prevent all of that by utilizing, exploiting those agents.”

Dr. Nasrallah serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on the speakers bureaus of several companies. Dr. Norris has no disclosures.

Allowing patients with a first episode to experience a second is unacceptable, Henry A. Nasrallah, MD, editor in chief of Current Psychiatry, said in his interview with Lorenzo Norris, MD, editor in chief of MDedge Psychiatry.

“It’s not too late to use injectables after the first episode, but my God, why are we letting them lose so much tissue and have so much suffering, so much PTSD, so much stigma, so much poverty, so much incarceration that comes from having repetitive psychotic episodes and deteriorating?” Dr. Nasrallah asked. “We can prevent all of that by utilizing, exploiting those agents.”

Dr. Nasrallah serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on the speakers bureaus of several companies. Dr. Norris has no disclosures.

LOS ANGELES – ALKS 8700, a novel prodrug of monomethyl fumarate, looks promising as an oral, disease-modifying treatment for relapsing forms of multiple sclerosis, according to interim findings from the phase 3 EVOLVE-MS-1 study.

The annualized relapse rate at a median follow-up of 0.93 patient-years (total, 497.1 patient-years) in 578 patients enrolled to date in the 2-year, open-label study was just 0.16, Robert T. Naismith, MD, reported during an emerging science session at the annual meeting of the American Academy of Neurology.

Further, a statistically significant 80% reduction from baseline was seen in the number of gadolinium-enhancing lesions in 374 patients who completed a 1-year MRI assessment (from a mean of 1.5 to 0.3), said Dr. Naismith of Washington University, St. Louis.

Patients enrolled in the ongoing study are adults aged 18-65 years (mean, 41 years) with confirmed relapsing-remitting MS (RRMS), Expanded Disability Status Scale score of 6.0 or less (mean, 2.7), and no evidence of relapse within 30 days prior to starting ALKS 8700. Those with progressive forms of MS are excluded, as are patients who are pregnant or breastfeeding, patients with a history of other clinically significant conditions, and those with clinically significant abnormal laboratory tests at screening or absolute lymphocyte counts less than 0.9 x 10³/mcL.

Of those enrolled so far, 72.5% received prior MS therapies, and their mean time since onset and diagnosis of MS was 9.7 and 7.6 years, respectively. The mean number of relapses in the prior year was 0.8.

ALKS 8700, also known as BIIB098, is given at a dose of 462 mg twice daily for up to 96 weeks; planned enrollment in EVOLVE-MS-1 is approximately 900 patients, Dr. Naismith said.

The preliminary findings from EVOLE-MS-1, which is limited by its single-arm, open-label design, “lend credence to ALKS 8700 as an oral treatment for patients with relapsing-remitting MS,” he said.

In addition to continued evaluation for long-term safety and tolerability in the current study, ALKS 8700 is also being evaluated in combination with 240 mg of twice daily dimethyl fumarate (DMF; Tecfidera) in the 5-week, randomized, double-blind EVOLVE-MS-2 study, which is looking at the gastrointestinal tolerability of the combination in patients with RRMS.

Oral DMF is approved for RRMS, and has been shown to significantly reduce clinical and MRI disease activity, but is commonly associated with GI events. Monomethyl fumarate is the active metabolite of DMF, and as a prodrug of monomethyl fumarate, ALKS 8700 is being developed to work in a manner similar to that of DMF, but with improved GI tolerability, Dr. Naismith explained.

EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.

sworcester@mdedge.com

SOURCE: Naismith R et al. AAN 2018 Emerging Science Abstract 006.

LOS ANGELES – ALKS 8700, a novel prodrug of monomethyl fumarate, looks promising as an oral, disease-modifying treatment for relapsing forms of multiple sclerosis, according to interim findings from the phase 3 EVOLVE-MS-1 study.

The annualized relapse rate at a median follow-up of 0.93 patient-years (total, 497.1 patient-years) in 578 patients enrolled to date in the 2-year, open-label study was just 0.16, Robert T. Naismith, MD, reported during an emerging science session at the annual meeting of the American Academy of Neurology.

Further, a statistically significant 80% reduction from baseline was seen in the number of gadolinium-enhancing lesions in 374 patients who completed a 1-year MRI assessment (from a mean of 1.5 to 0.3), said Dr. Naismith of Washington University, St. Louis.

Patients enrolled in the ongoing study are adults aged 18-65 years (mean, 41 years) with confirmed relapsing-remitting MS (RRMS), Expanded Disability Status Scale score of 6.0 or less (mean, 2.7), and no evidence of relapse within 30 days prior to starting ALKS 8700. Those with progressive forms of MS are excluded, as are patients who are pregnant or breastfeeding, patients with a history of other clinically significant conditions, and those with clinically significant abnormal laboratory tests at screening or absolute lymphocyte counts less than 0.9 x 10³/mcL.

Of those enrolled so far, 72.5% received prior MS therapies, and their mean time since onset and diagnosis of MS was 9.7 and 7.6 years, respectively. The mean number of relapses in the prior year was 0.8.

ALKS 8700, also known as BIIB098, is given at a dose of 462 mg twice daily for up to 96 weeks; planned enrollment in EVOLVE-MS-1 is approximately 900 patients, Dr. Naismith said.

The preliminary findings from EVOLE-MS-1, which is limited by its single-arm, open-label design, “lend credence to ALKS 8700 as an oral treatment for patients with relapsing-remitting MS,” he said.

In addition to continued evaluation for long-term safety and tolerability in the current study, ALKS 8700 is also being evaluated in combination with 240 mg of twice daily dimethyl fumarate (DMF; Tecfidera) in the 5-week, randomized, double-blind EVOLVE-MS-2 study, which is looking at the gastrointestinal tolerability of the combination in patients with RRMS.

Oral DMF is approved for RRMS, and has been shown to significantly reduce clinical and MRI disease activity, but is commonly associated with GI events. Monomethyl fumarate is the active metabolite of DMF, and as a prodrug of monomethyl fumarate, ALKS 8700 is being developed to work in a manner similar to that of DMF, but with improved GI tolerability, Dr. Naismith explained.

EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.

sworcester@mdedge.com

SOURCE: Naismith R et al. AAN 2018 Emerging Science Abstract 006.

LOS ANGELES – ALKS 8700, a novel prodrug of monomethyl fumarate, looks promising as an oral, disease-modifying treatment for relapsing forms of multiple sclerosis, according to interim findings from the phase 3 EVOLVE-MS-1 study.

The annualized relapse rate at a median follow-up of 0.93 patient-years (total, 497.1 patient-years) in 578 patients enrolled to date in the 2-year, open-label study was just 0.16, Robert T. Naismith, MD, reported during an emerging science session at the annual meeting of the American Academy of Neurology.

Further, a statistically significant 80% reduction from baseline was seen in the number of gadolinium-enhancing lesions in 374 patients who completed a 1-year MRI assessment (from a mean of 1.5 to 0.3), said Dr. Naismith of Washington University, St. Louis.

Patients enrolled in the ongoing study are adults aged 18-65 years (mean, 41 years) with confirmed relapsing-remitting MS (RRMS), Expanded Disability Status Scale score of 6.0 or less (mean, 2.7), and no evidence of relapse within 30 days prior to starting ALKS 8700. Those with progressive forms of MS are excluded, as are patients who are pregnant or breastfeeding, patients with a history of other clinically significant conditions, and those with clinically significant abnormal laboratory tests at screening or absolute lymphocyte counts less than 0.9 x 10³/mcL.

Of those enrolled so far, 72.5% received prior MS therapies, and their mean time since onset and diagnosis of MS was 9.7 and 7.6 years, respectively. The mean number of relapses in the prior year was 0.8.

ALKS 8700, also known as BIIB098, is given at a dose of 462 mg twice daily for up to 96 weeks; planned enrollment in EVOLVE-MS-1 is approximately 900 patients, Dr. Naismith said.

The preliminary findings from EVOLE-MS-1, which is limited by its single-arm, open-label design, “lend credence to ALKS 8700 as an oral treatment for patients with relapsing-remitting MS,” he said.

In addition to continued evaluation for long-term safety and tolerability in the current study, ALKS 8700 is also being evaluated in combination with 240 mg of twice daily dimethyl fumarate (DMF; Tecfidera) in the 5-week, randomized, double-blind EVOLVE-MS-2 study, which is looking at the gastrointestinal tolerability of the combination in patients with RRMS.

Oral DMF is approved for RRMS, and has been shown to significantly reduce clinical and MRI disease activity, but is commonly associated with GI events. Monomethyl fumarate is the active metabolite of DMF, and as a prodrug of monomethyl fumarate, ALKS 8700 is being developed to work in a manner similar to that of DMF, but with improved GI tolerability, Dr. Naismith explained.

EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.

sworcester@mdedge.com

SOURCE: Naismith R et al. AAN 2018 Emerging Science Abstract 006.

Meningiomas generally present as slow-growing, expanding intracranial lesions and are the most common benign intracranial tumor in adults.¹ Rarely, meningioma exhibits malignant potential and presents as an extracranial soft-tissue mass through extension or as a primary extracranial cutaneous neoplasm. The differential diagnosis of scalp neoplasms must be broadened to include uncommon tumors such as meningioma. We present a rare case of a 68-year-old woman with scalp metastasis of meningioma 11 years after initial resection of the primary tumor.

Case Report

A 68-year-old woman presented for evaluation of an asymptomatic nodule on the left parietal scalp of 2 years’ duration. She denied any headaches, difficulty with balance, vision changes, or changes in mentation. Her medical history was remarkable for a benign meningioma removed from the right parietal scalp 11 years prior without radiation therapy, as well as type 2 diabetes mellitus and arthritis. The patient’s son died from a brain tumor, but the exact tumor type and age at the time of death were unknown. Her current medications included metformin, insulin glargine, aspirin, and a daily multivitamin. She denied any allergies or history of smoking.

Physical examination of the scalp revealed 4 fixed, nontender, flesh-colored nodules: 2 on the left parietal scalp measuring 3.0 cm and 0.8 cm, respectively (Figure 1A); a 0.4-cm nodule on the right posterior occipital scalp; and a 1.6-cm sausage-shaped nodule on the right temple (Figure 1B). No positive lymph nodes were appreciated, and no additional lesions were noted. No additional atypical lesions were noted on full cutaneous examination.

A diagnostic 6-mm punch biopsy of the largest nodule was performed. Intraoperatively, there was no apparent cyst wall, but coiled, loose, stringlike, pink-yellow tissue was removed from the base of the wound before closing with sutures.

The primary histologic finding was cells within fibrous tissue containing delicate round-oval nuclei, inconspicuous nucleoli, and lightly eosinophilic cytoplasm with an indistinct border (Figure 2). Immunohistochemical studies for S100 protein were focal and limited to the cytoplasm of a subset of neoplastic cells (Figure 3). Tumor cells stained positive for epithelial membrane antigen (EMA) and were focally positive for progesterone receptor (Figure 4). Tumor cells were negative for CD31 and CD34. Based on the clinical and histologic findings, a diagnosis of metastatic meningioma of the scalp was made.

Magnetic resonance imaging and positron emission tomography of the head, neck, and chest demonstrated 3 residual subcutaneous nodules on the scalp and an indeterminate subcentimeter nodule in the right lung. The 0.4-cm nodule on the right posterior occipital scalp was removed without complication, and no radiation therapy was administered. The rest of the lesions were monitored. She remained under the close observation of a neurosurgeon and underwent repeat imaging of the scalp nodules and lungs, initially at 3 months and then routinely at the patient’s comfort. The patient currently denies any neurologic symptoms.

Comment

Meningiomas are derived from meningothelial cells found in the leptomeninges and in the choroid plexus of the ventricles of the brain.² They are common intracranial neoplasms that generally are associated with a benign course and present during the fourth to sixth decades of life. Meningiomas constitute 13% to 30% of intracranial neoplasms and usually are female predominant (3:1).^3,4 Rarely, malignant transformation can lead to local and distant metastasis to the lungs,^5,6 liver,⁷ and skeletal system.⁸ In cases of metastatic spread, there is an increased incidence in males versus females.^9-11

Risk Factors
Although many meningiomas are sporadic, numerous risk factors have been associated with the disease development. One study showed a link between exposure to ionizing radiation and subsequent development of meningioma.¹² Another study found a population link between a higher incidence of meningioma and nuclear exposure in Hiroshima, Japan, after the atomic bomb blast in 1980.¹³ There is an increased incidence of meningioma in patients exposed to radiography from frequent dental imaging, particularly when older machines with higher levels of radiation exposure are used.¹⁴Another study demonstrated a correlation between meningioma and hormonal factors (eg, estrogen for hormone therapy) and exacerbation of symptoms during pregnancy.¹⁵ There also is an increased incidence of meningioma in breast cancer patients.⁴ Genetic alterations also have been implicated in the development of meningioma. It was found that 50% of patients with a mutation in the neurofibromatosis 2 gene (which codes for the merlin protein) had associated meningiomas.^16,17 Scalp nodules in patients with neurofibromatosis type 2 increases suspicion of a scalp meningioma and necessitates biopsy.

Clinical Presentation
Cutaneous meningiomas typically present as firm, subcutaneous nodules. Scalp nodules ranging from alopecia^18,19 to hypertrichosis²⁰ have been reported. These neoplasms can be painless or painful, depending on mass effect and location.

Classification
The primary clinical classification system of metastatic meningioma was first described in 1974.²¹ Type 1 meningioma refers to congenital lesions that tend to cluster closer to the midline. Type 2 refers to ectopic soft-tissue lesions that extend to the skin from likely remnants of arachnoid cells. These lesions are more likely to be found around the eyes, ears, nose, and mouth. Type 3 meningiomas extend from intracranial tumors that secondarily involve the skin through proliferation through bone or anatomic defects. Type 3 is the result of direct extension and the location of the cutaneous presentation depends on the location of the intracranial lesion.^4,22,23

Pathology
Meningiomas exhibit a range of morphologic appearances on histopathology. In almost all meningiomas, tumor cells are concentrically wrapped in tight whorls with round-oval nuclei and delicate chromatin, central clearing, and pale pseudonuclear inclusions. Lamellate calcifications known as psammoma bodies are a common finding. Immunohistochemical studies show that most meningiomas are positive for EMA, vimentin, and progesterone receptor. S100 protein expression, if present, usually is focal.

Differential Diagnosis
Asymptomatic nodules on the scalp may present a diagnostic challenge to physicians. Most common scalp lesions tend to be cystic or lipomatous. In children, a broad differential diagnosis should be considered, including dermoid and epidermoid tumors, dermal sinus tumors, hemangiomas, metastasis of another tumor, aplasia cutis congenita, pilomatricoma, and lipoma. In adults, the differential should focus on epidermoid cysts, lipomas, metastasis of other tumors, osteomas, arteriovenous fistulae, and heterotopic brain tissue. Often, microscopic examination is necessary, along with additional immunohistochemical staining (eg, EMA, vimentin).

Treatment
Treatment options for meningioma include observation, surgical resection, radiotherapy, and systemic therapy, as well as a combination of these modalities. The choice of therapy depends on such variables as patient age; performance status; comorbidities; presence or absence of symptoms (including focal neurologic deficits); and tumor location, size, and grade. It is important to note that there is limited knowledge looking at the results of various treatment modalities, and no consensus approach has been established.

Conclusion

Our patient’s medical history was remarkable for an intracranial meningioma 11 years prior to the current presentation, and she was found to have biopsy-proven metastatic meningioma without recurrence of the initial tumor. Patients presenting with a scalp nodule warrant a thorough medical history and consideration beyond common cysts and lipomas.

Meningiomas generally present as slow-growing, expanding intracranial lesions and are the most common benign intracranial tumor in adults.¹ Rarely, meningioma exhibits malignant potential and presents as an extracranial soft-tissue mass through extension or as a primary extracranial cutaneous neoplasm. The differential diagnosis of scalp neoplasms must be broadened to include uncommon tumors such as meningioma. We present a rare case of a 68-year-old woman with scalp metastasis of meningioma 11 years after initial resection of the primary tumor.

Case Report

A 68-year-old woman presented for evaluation of an asymptomatic nodule on the left parietal scalp of 2 years’ duration. She denied any headaches, difficulty with balance, vision changes, or changes in mentation. Her medical history was remarkable for a benign meningioma removed from the right parietal scalp 11 years prior without radiation therapy, as well as type 2 diabetes mellitus and arthritis. The patient’s son died from a brain tumor, but the exact tumor type and age at the time of death were unknown. Her current medications included metformin, insulin glargine, aspirin, and a daily multivitamin. She denied any allergies or history of smoking.

Physical examination of the scalp revealed 4 fixed, nontender, flesh-colored nodules: 2 on the left parietal scalp measuring 3.0 cm and 0.8 cm, respectively (Figure 1A); a 0.4-cm nodule on the right posterior occipital scalp; and a 1.6-cm sausage-shaped nodule on the right temple (Figure 1B). No positive lymph nodes were appreciated, and no additional lesions were noted. No additional atypical lesions were noted on full cutaneous examination.

A diagnostic 6-mm punch biopsy of the largest nodule was performed. Intraoperatively, there was no apparent cyst wall, but coiled, loose, stringlike, pink-yellow tissue was removed from the base of the wound before closing with sutures.

The primary histologic finding was cells within fibrous tissue containing delicate round-oval nuclei, inconspicuous nucleoli, and lightly eosinophilic cytoplasm with an indistinct border (Figure 2). Immunohistochemical studies for S100 protein were focal and limited to the cytoplasm of a subset of neoplastic cells (Figure 3). Tumor cells stained positive for epithelial membrane antigen (EMA) and were focally positive for progesterone receptor (Figure 4). Tumor cells were negative for CD31 and CD34. Based on the clinical and histologic findings, a diagnosis of metastatic meningioma of the scalp was made.

Magnetic resonance imaging and positron emission tomography of the head, neck, and chest demonstrated 3 residual subcutaneous nodules on the scalp and an indeterminate subcentimeter nodule in the right lung. The 0.4-cm nodule on the right posterior occipital scalp was removed without complication, and no radiation therapy was administered. The rest of the lesions were monitored. She remained under the close observation of a neurosurgeon and underwent repeat imaging of the scalp nodules and lungs, initially at 3 months and then routinely at the patient’s comfort. The patient currently denies any neurologic symptoms.

Comment

Meningiomas are derived from meningothelial cells found in the leptomeninges and in the choroid plexus of the ventricles of the brain.² They are common intracranial neoplasms that generally are associated with a benign course and present during the fourth to sixth decades of life. Meningiomas constitute 13% to 30% of intracranial neoplasms and usually are female predominant (3:1).^3,4 Rarely, malignant transformation can lead to local and distant metastasis to the lungs,^5,6 liver,⁷ and skeletal system.⁸ In cases of metastatic spread, there is an increased incidence in males versus females.^9-11

Risk Factors
Although many meningiomas are sporadic, numerous risk factors have been associated with the disease development. One study showed a link between exposure to ionizing radiation and subsequent development of meningioma.¹² Another study found a population link between a higher incidence of meningioma and nuclear exposure in Hiroshima, Japan, after the atomic bomb blast in 1980.¹³ There is an increased incidence of meningioma in patients exposed to radiography from frequent dental imaging, particularly when older machines with higher levels of radiation exposure are used.¹⁴Another study demonstrated a correlation between meningioma and hormonal factors (eg, estrogen for hormone therapy) and exacerbation of symptoms during pregnancy.¹⁵ There also is an increased incidence of meningioma in breast cancer patients.⁴ Genetic alterations also have been implicated in the development of meningioma. It was found that 50% of patients with a mutation in the neurofibromatosis 2 gene (which codes for the merlin protein) had associated meningiomas.^16,17 Scalp nodules in patients with neurofibromatosis type 2 increases suspicion of a scalp meningioma and necessitates biopsy.

Clinical Presentation
Cutaneous meningiomas typically present as firm, subcutaneous nodules. Scalp nodules ranging from alopecia^18,19 to hypertrichosis²⁰ have been reported. These neoplasms can be painless or painful, depending on mass effect and location.

Classification
The primary clinical classification system of metastatic meningioma was first described in 1974.²¹ Type 1 meningioma refers to congenital lesions that tend to cluster closer to the midline. Type 2 refers to ectopic soft-tissue lesions that extend to the skin from likely remnants of arachnoid cells. These lesions are more likely to be found around the eyes, ears, nose, and mouth. Type 3 meningiomas extend from intracranial tumors that secondarily involve the skin through proliferation through bone or anatomic defects. Type 3 is the result of direct extension and the location of the cutaneous presentation depends on the location of the intracranial lesion.^4,22,23

Pathology
Meningiomas exhibit a range of morphologic appearances on histopathology. In almost all meningiomas, tumor cells are concentrically wrapped in tight whorls with round-oval nuclei and delicate chromatin, central clearing, and pale pseudonuclear inclusions. Lamellate calcifications known as psammoma bodies are a common finding. Immunohistochemical studies show that most meningiomas are positive for EMA, vimentin, and progesterone receptor. S100 protein expression, if present, usually is focal.

Differential Diagnosis
Asymptomatic nodules on the scalp may present a diagnostic challenge to physicians. Most common scalp lesions tend to be cystic or lipomatous. In children, a broad differential diagnosis should be considered, including dermoid and epidermoid tumors, dermal sinus tumors, hemangiomas, metastasis of another tumor, aplasia cutis congenita, pilomatricoma, and lipoma. In adults, the differential should focus on epidermoid cysts, lipomas, metastasis of other tumors, osteomas, arteriovenous fistulae, and heterotopic brain tissue. Often, microscopic examination is necessary, along with additional immunohistochemical staining (eg, EMA, vimentin).

Treatment
Treatment options for meningioma include observation, surgical resection, radiotherapy, and systemic therapy, as well as a combination of these modalities. The choice of therapy depends on such variables as patient age; performance status; comorbidities; presence or absence of symptoms (including focal neurologic deficits); and tumor location, size, and grade. It is important to note that there is limited knowledge looking at the results of various treatment modalities, and no consensus approach has been established.

Conclusion

Our patient’s medical history was remarkable for an intracranial meningioma 11 years prior to the current presentation, and she was found to have biopsy-proven metastatic meningioma without recurrence of the initial tumor. Patients presenting with a scalp nodule warrant a thorough medical history and consideration beyond common cysts and lipomas.

Meningiomas generally present as slow-growing, expanding intracranial lesions and are the most common benign intracranial tumor in adults.¹ Rarely, meningioma exhibits malignant potential and presents as an extracranial soft-tissue mass through extension or as a primary extracranial cutaneous neoplasm. The differential diagnosis of scalp neoplasms must be broadened to include uncommon tumors such as meningioma. We present a rare case of a 68-year-old woman with scalp metastasis of meningioma 11 years after initial resection of the primary tumor.

Case Report

A 68-year-old woman presented for evaluation of an asymptomatic nodule on the left parietal scalp of 2 years’ duration. She denied any headaches, difficulty with balance, vision changes, or changes in mentation. Her medical history was remarkable for a benign meningioma removed from the right parietal scalp 11 years prior without radiation therapy, as well as type 2 diabetes mellitus and arthritis. The patient’s son died from a brain tumor, but the exact tumor type and age at the time of death were unknown. Her current medications included metformin, insulin glargine, aspirin, and a daily multivitamin. She denied any allergies or history of smoking.

Physical examination of the scalp revealed 4 fixed, nontender, flesh-colored nodules: 2 on the left parietal scalp measuring 3.0 cm and 0.8 cm, respectively (Figure 1A); a 0.4-cm nodule on the right posterior occipital scalp; and a 1.6-cm sausage-shaped nodule on the right temple (Figure 1B). No positive lymph nodes were appreciated, and no additional lesions were noted. No additional atypical lesions were noted on full cutaneous examination.

A diagnostic 6-mm punch biopsy of the largest nodule was performed. Intraoperatively, there was no apparent cyst wall, but coiled, loose, stringlike, pink-yellow tissue was removed from the base of the wound before closing with sutures.

The primary histologic finding was cells within fibrous tissue containing delicate round-oval nuclei, inconspicuous nucleoli, and lightly eosinophilic cytoplasm with an indistinct border (Figure 2). Immunohistochemical studies for S100 protein were focal and limited to the cytoplasm of a subset of neoplastic cells (Figure 3). Tumor cells stained positive for epithelial membrane antigen (EMA) and were focally positive for progesterone receptor (Figure 4). Tumor cells were negative for CD31 and CD34. Based on the clinical and histologic findings, a diagnosis of metastatic meningioma of the scalp was made.

Magnetic resonance imaging and positron emission tomography of the head, neck, and chest demonstrated 3 residual subcutaneous nodules on the scalp and an indeterminate subcentimeter nodule in the right lung. The 0.4-cm nodule on the right posterior occipital scalp was removed without complication, and no radiation therapy was administered. The rest of the lesions were monitored. She remained under the close observation of a neurosurgeon and underwent repeat imaging of the scalp nodules and lungs, initially at 3 months and then routinely at the patient’s comfort. The patient currently denies any neurologic symptoms.

Comment

Meningiomas are derived from meningothelial cells found in the leptomeninges and in the choroid plexus of the ventricles of the brain.² They are common intracranial neoplasms that generally are associated with a benign course and present during the fourth to sixth decades of life. Meningiomas constitute 13% to 30% of intracranial neoplasms and usually are female predominant (3:1).^3,4 Rarely, malignant transformation can lead to local and distant metastasis to the lungs,^5,6 liver,⁷ and skeletal system.⁸ In cases of metastatic spread, there is an increased incidence in males versus females.^9-11

Risk Factors
Although many meningiomas are sporadic, numerous risk factors have been associated with the disease development. One study showed a link between exposure to ionizing radiation and subsequent development of meningioma.¹² Another study found a population link between a higher incidence of meningioma and nuclear exposure in Hiroshima, Japan, after the atomic bomb blast in 1980.¹³ There is an increased incidence of meningioma in patients exposed to radiography from frequent dental imaging, particularly when older machines with higher levels of radiation exposure are used.¹⁴Another study demonstrated a correlation between meningioma and hormonal factors (eg, estrogen for hormone therapy) and exacerbation of symptoms during pregnancy.¹⁵ There also is an increased incidence of meningioma in breast cancer patients.⁴ Genetic alterations also have been implicated in the development of meningioma. It was found that 50% of patients with a mutation in the neurofibromatosis 2 gene (which codes for the merlin protein) had associated meningiomas.^16,17 Scalp nodules in patients with neurofibromatosis type 2 increases suspicion of a scalp meningioma and necessitates biopsy.

Clinical Presentation
Cutaneous meningiomas typically present as firm, subcutaneous nodules. Scalp nodules ranging from alopecia^18,19 to hypertrichosis²⁰ have been reported. These neoplasms can be painless or painful, depending on mass effect and location.

Classification
The primary clinical classification system of metastatic meningioma was first described in 1974.²¹ Type 1 meningioma refers to congenital lesions that tend to cluster closer to the midline. Type 2 refers to ectopic soft-tissue lesions that extend to the skin from likely remnants of arachnoid cells. These lesions are more likely to be found around the eyes, ears, nose, and mouth. Type 3 meningiomas extend from intracranial tumors that secondarily involve the skin through proliferation through bone or anatomic defects. Type 3 is the result of direct extension and the location of the cutaneous presentation depends on the location of the intracranial lesion.^4,22,23

Pathology
Meningiomas exhibit a range of morphologic appearances on histopathology. In almost all meningiomas, tumor cells are concentrically wrapped in tight whorls with round-oval nuclei and delicate chromatin, central clearing, and pale pseudonuclear inclusions. Lamellate calcifications known as psammoma bodies are a common finding. Immunohistochemical studies show that most meningiomas are positive for EMA, vimentin, and progesterone receptor. S100 protein expression, if present, usually is focal.

Differential Diagnosis
Asymptomatic nodules on the scalp may present a diagnostic challenge to physicians. Most common scalp lesions tend to be cystic or lipomatous. In children, a broad differential diagnosis should be considered, including dermoid and epidermoid tumors, dermal sinus tumors, hemangiomas, metastasis of another tumor, aplasia cutis congenita, pilomatricoma, and lipoma. In adults, the differential should focus on epidermoid cysts, lipomas, metastasis of other tumors, osteomas, arteriovenous fistulae, and heterotopic brain tissue. Often, microscopic examination is necessary, along with additional immunohistochemical staining (eg, EMA, vimentin).

Treatment
Treatment options for meningioma include observation, surgical resection, radiotherapy, and systemic therapy, as well as a combination of these modalities. The choice of therapy depends on such variables as patient age; performance status; comorbidities; presence or absence of symptoms (including focal neurologic deficits); and tumor location, size, and grade. It is important to note that there is limited knowledge looking at the results of various treatment modalities, and no consensus approach has been established.

Conclusion

Our patient’s medical history was remarkable for an intracranial meningioma 11 years prior to the current presentation, and she was found to have biopsy-proven metastatic meningioma without recurrence of the initial tumor. Patients presenting with a scalp nodule warrant a thorough medical history and consideration beyond common cysts and lipomas.

Eccrine carcinomas are uncommon cutaneous neoplasms demonstrating nonuniform histologic features, behavior, and nomenclature. Given the rarity of these tumors, no known criteria by which to diagnose the tumor or guidelines for treatment have been proposed. We report a rare case of an immunocompromised patient with a primary squamoid eccrine ductal carcinoma (SEDC) who was subsequently treated with radical resection and axillary dissection. It was later determined that the patient had distant metastasis of SEDC. A review of the literature on the diagnosis, treatment, and surveillance of SEDC also is provided.

Case Report

A 77-year-old man whose medical history was remarkable for chronic lymphocytic leukemia (CLL) and numerous previous basal cell carcinomas and squamous cell carcinomas (SCCs) presented with a 5-cm, stellate, sclerotic plaque on the left chest of approximately 2 years’ duration (Figure 1) and a 3-mm pink papule on the right nasal sidewall of 2 months’ duration. Initial histology of both lesions revealed carcinoma with squamous and ductal differentiation extending from the undersurface of the epidermis, favoring a diagnosis of SEDC (Figure 2). At the time of initial presentation, the patient also had a 6-mm pink papule on the right chest of several months duration that was consistent with a well-differentiated sebaceous carcinoma on histology.

Further analysis of the lesion on the left chest revealed positive staining for cytokeratin (CK) 5/14 and p63, suggestive of a cutaneous malignancy. Staining for S100 protein highlighted rare cells in the basal layer of tumor aggregates. The immunohistochemical profile showed negative staining for CK7, CK5D3, epithelial membrane antigen (EMA), estrogen receptor, progesterone receptor, and human epidermal growth factor 2.

Diagnosis of SEDC of the chest and nasal lesions was based on the morphologic architecture, which included ductal formation noted within the tumor. The chest lesion also had prominent squamoid differentiation. Another histologic feature consistent with SEDC was poorly demarcated, infiltrative neoplastic cells extending into the dermis and subcutis. Although there was some positive focal staining for carcinoembryonic antigen (CEA), variegation within the tumor and the prominent squamoid component might have contributed to this unexpected staining pattern.

The patient was admitted to the hospital for excision of the lesion on the chest wall. Initial workup revealed macrocytic anemia, which required transfusion, and an incidental finding of non–small-cell lung cancer. The chest lesion was unrelated to the non–small-cell lung cancer based on the staining profile. Material from the lung stained positive for thyroid transcription factor 1 (TTF-1) and exhibited rare staining for p63; however, the chest lesion did not stain positive for TTF-1 and had strong staining affinity for p63, indicative of a cutaneous malignancy.

The lesion on the chest wall was definitively excised. Pathologic analysis revealed a dermal-based infiltrative tumor of irregular nests and cords of squamoid cells with focal ductal formation in a fibromyxoid background stroma, suggestive of an adnexal carcinoma with a considerable degree of squamous differentiation and favoring a diagnosis of SEDC. Focal perineural invasion was noted, but no lymphovascular spread was identified; however, metastasis was identified in 1 of 26 axillary lymph nodes. The patient underwent 9 sessions of radiation therapy for the lung cancer and also was given cetuximab.

Three months later, the nasal tumor was subsequently excised in an outpatient procedure, and the final biopsy report indicated a diagnosis of basal cell carcinoma. One-and-a-half years later, in follow-up with surgery after removal of the chest lesion, a 2×3-cm mass was excised from the left neck that demonstrated lymph nodes consistent with metastatic SEDC. Careful evaluation of this patient, including family history and genetic screening, was considered. Our patient continues to follow-up with the dermatology department every 3 months. He has been doing well and has had multiple additional primary SCCs in the subsequent 5 years of follow-up.

Comment

Eccrine carcinoma is the most common subtype of adnexal carcinoma, representing 0.01% of all cutaneous tumors.¹ Squamoid eccrine ductal carcinoma is rare, with as few as 13 cases reported in the literature; 3 of these patients were treated with Mohs micrographic surgery (MMS).^1,2 Recently, two series of 7 and 30 cases, respectively, were longitudinally followed and described.^3,4 We report an additional rare case of SEDC in an immunocompromised patient with distant metastases that was treated with radical resection and axillary dissection.

Eccrine carcinoma is observed clinically as a slow-growing, nodular plaque on the scalp, arms, legs, or trunk in middle-aged and elderly individuals.¹ Squamoid eccrine ductal carcinoma also has been reported in a young woman.⁵ Another immunocompromised patient was identified in the literature with a great toe lesion that showed follicular differentiation along with the usual SEDC features of squamoid and ductal differentiation.⁶ The etiology of SEDC is controversial but is thought to be an SCC arising from eccrine glands, a subtype of eccrine carcinoma with extensive squamoid differentiation, or a biphenotypic carcinoma.^1,7

Histologically, SEDC is poorly circumscribed with an infiltrative growth pattern and deep extension into the dermis and subcutaneous tissue. The lesion is characterized by prominent squamous epithelial proliferation superficially with cellular atypia, keratinous cyst formation, squamous eddies, and eccrine ductal differentiation.¹

The differential diagnosis of SEDC includes SCC; metastatic carcinoma with squamoid features; and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma, and porocarcinoma with squamous differentiation.¹

Immunohistochemistry has a role in the diagnosis of SEDC. Findings include positive staining for S100 protein, EMA, CKs, and CEA. Glandular tissue stains positive for EMA and CEA, supporting an adnexal origin.¹ Positivity for p63 and CK5/6 supports the conclusion that this is a primary cutaneous malignancy, not a metastatic disease.¹

Squamoid eccrine ductal carcinoma has an indeterminate malignant potential. There is a disparity of clinical behavior between SCC and eccrine cancers; however, because squamous differentiation sometimes dominates the histological picture, eccrine carcinomas can be misdiagnosed as SCC.^1,8 Eccrine adnexal tumors are characterized by multiple local recurrences (70%–80% of cases); perineural invasion; and metastasis (50% of cases) to regional lymph nodes and viscera, including the lungs, liver, bones, and brain.¹ Squamous cell carcinoma, however, has a markedly lower recurrence rate (3.1%–18.7% of cases) and rate of metastasis (5.2%–37.8%).¹

Squamoid eccrine ductal carcinoma is classified as one of the less aggressive eccrine tumors, although the low number of cases makes it a controversial conclusion.¹ To our knowledge, no cases of SEDC metastasis have been reported with SEDC. Recurrence of SEDC has been reported locally, and perineural or perivascular invasion (or both) has been demonstrated in 3 cases.¹

Since SEDC has invasive and metastatic potential, as demonstrated in our case, along with elevated local recurrence rates, physicians must be able to properly diagnose this rare entity and recommend an appropriate surgical modality. Due to the low incidence of SEDC, there are no known randomized studies comparing treatment modalities.¹ Other works in the literature have suggested treating SEDC with the same approach as lesions with similar histologic features and behavior, such as eccrine carcinoma and SCC.^1,5-7

Surgical extirpation with complete margin examination is recommended, as SEDC tends to be underestimated in size, is aggressive in its infiltration, and is predisposed to perineural and perivascular invasion. The literature has shown that MMS has demonstrated lower recurrence rates (3.1%–5%) than other treatments at 5-year follow-up for SCC and (0%–5%) for eccrine carcinoma (average follow-up, 31 months).^1,5 Further studies are needed to understand the clinical progression of SEDC, and more experience is necessary with close follow-up of this subset of patients. Follow-up is determined at the present time from anecdotal experience and patient history.

Along with the rarity of SEDC in our patient, the simultaneous occurrence of 3 primary malignancies also is unusual. Patients with CLL have progressive defects of cell- and humoral-mediated immunity, causing immunosuppression. In a retrospective study, Tsimberidou et al⁹ reviewed the records of 2028 untreated CLL patients and determined that 27% had another primary malignancy, including skin (30%) and lung cancers (6%), which were two of the malignancies seen in our patient. The investigators concluded that patients with CLL have more than twice the risk of developing a second primary malignancy and an increased frequency of certain cancer types.⁹ Furthermore, treatment regimens for CLL have been considered to increase cell- and humoral-mediated immune defects at specific cancer sites,¹⁰ although the exact mechanism of this action is unknown. Development of a second primary malignancy (or even a third) in patients with SEDC is increasingly being reported in CLL patients.^9,10

A high index of suspicion with SEDC in the differential diagnosis should be maintained in elderly men with slow-growing, solitary, nodular lesions of the scalp, nose, arms, legs, or trunk.

Eccrine carcinomas are uncommon cutaneous neoplasms demonstrating nonuniform histologic features, behavior, and nomenclature. Given the rarity of these tumors, no known criteria by which to diagnose the tumor or guidelines for treatment have been proposed. We report a rare case of an immunocompromised patient with a primary squamoid eccrine ductal carcinoma (SEDC) who was subsequently treated with radical resection and axillary dissection. It was later determined that the patient had distant metastasis of SEDC. A review of the literature on the diagnosis, treatment, and surveillance of SEDC also is provided.

Case Report

A 77-year-old man whose medical history was remarkable for chronic lymphocytic leukemia (CLL) and numerous previous basal cell carcinomas and squamous cell carcinomas (SCCs) presented with a 5-cm, stellate, sclerotic plaque on the left chest of approximately 2 years’ duration (Figure 1) and a 3-mm pink papule on the right nasal sidewall of 2 months’ duration. Initial histology of both lesions revealed carcinoma with squamous and ductal differentiation extending from the undersurface of the epidermis, favoring a diagnosis of SEDC (Figure 2). At the time of initial presentation, the patient also had a 6-mm pink papule on the right chest of several months duration that was consistent with a well-differentiated sebaceous carcinoma on histology.

Further analysis of the lesion on the left chest revealed positive staining for cytokeratin (CK) 5/14 and p63, suggestive of a cutaneous malignancy. Staining for S100 protein highlighted rare cells in the basal layer of tumor aggregates. The immunohistochemical profile showed negative staining for CK7, CK5D3, epithelial membrane antigen (EMA), estrogen receptor, progesterone receptor, and human epidermal growth factor 2.

Diagnosis of SEDC of the chest and nasal lesions was based on the morphologic architecture, which included ductal formation noted within the tumor. The chest lesion also had prominent squamoid differentiation. Another histologic feature consistent with SEDC was poorly demarcated, infiltrative neoplastic cells extending into the dermis and subcutis. Although there was some positive focal staining for carcinoembryonic antigen (CEA), variegation within the tumor and the prominent squamoid component might have contributed to this unexpected staining pattern.

The patient was admitted to the hospital for excision of the lesion on the chest wall. Initial workup revealed macrocytic anemia, which required transfusion, and an incidental finding of non–small-cell lung cancer. The chest lesion was unrelated to the non–small-cell lung cancer based on the staining profile. Material from the lung stained positive for thyroid transcription factor 1 (TTF-1) and exhibited rare staining for p63; however, the chest lesion did not stain positive for TTF-1 and had strong staining affinity for p63, indicative of a cutaneous malignancy.

The lesion on the chest wall was definitively excised. Pathologic analysis revealed a dermal-based infiltrative tumor of irregular nests and cords of squamoid cells with focal ductal formation in a fibromyxoid background stroma, suggestive of an adnexal carcinoma with a considerable degree of squamous differentiation and favoring a diagnosis of SEDC. Focal perineural invasion was noted, but no lymphovascular spread was identified; however, metastasis was identified in 1 of 26 axillary lymph nodes. The patient underwent 9 sessions of radiation therapy for the lung cancer and also was given cetuximab.

Three months later, the nasal tumor was subsequently excised in an outpatient procedure, and the final biopsy report indicated a diagnosis of basal cell carcinoma. One-and-a-half years later, in follow-up with surgery after removal of the chest lesion, a 2×3-cm mass was excised from the left neck that demonstrated lymph nodes consistent with metastatic SEDC. Careful evaluation of this patient, including family history and genetic screening, was considered. Our patient continues to follow-up with the dermatology department every 3 months. He has been doing well and has had multiple additional primary SCCs in the subsequent 5 years of follow-up.

Comment

Eccrine carcinoma is the most common subtype of adnexal carcinoma, representing 0.01% of all cutaneous tumors.¹ Squamoid eccrine ductal carcinoma is rare, with as few as 13 cases reported in the literature; 3 of these patients were treated with Mohs micrographic surgery (MMS).^1,2 Recently, two series of 7 and 30 cases, respectively, were longitudinally followed and described.^3,4 We report an additional rare case of SEDC in an immunocompromised patient with distant metastases that was treated with radical resection and axillary dissection.

Eccrine carcinoma is observed clinically as a slow-growing, nodular plaque on the scalp, arms, legs, or trunk in middle-aged and elderly individuals.¹ Squamoid eccrine ductal carcinoma also has been reported in a young woman.⁵ Another immunocompromised patient was identified in the literature with a great toe lesion that showed follicular differentiation along with the usual SEDC features of squamoid and ductal differentiation.⁶ The etiology of SEDC is controversial but is thought to be an SCC arising from eccrine glands, a subtype of eccrine carcinoma with extensive squamoid differentiation, or a biphenotypic carcinoma.^1,7

Histologically, SEDC is poorly circumscribed with an infiltrative growth pattern and deep extension into the dermis and subcutaneous tissue. The lesion is characterized by prominent squamous epithelial proliferation superficially with cellular atypia, keratinous cyst formation, squamous eddies, and eccrine ductal differentiation.¹

The differential diagnosis of SEDC includes SCC; metastatic carcinoma with squamoid features; and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma, and porocarcinoma with squamous differentiation.¹

Immunohistochemistry has a role in the diagnosis of SEDC. Findings include positive staining for S100 protein, EMA, CKs, and CEA. Glandular tissue stains positive for EMA and CEA, supporting an adnexal origin.¹ Positivity for p63 and CK5/6 supports the conclusion that this is a primary cutaneous malignancy, not a metastatic disease.¹

Squamoid eccrine ductal carcinoma has an indeterminate malignant potential. There is a disparity of clinical behavior between SCC and eccrine cancers; however, because squamous differentiation sometimes dominates the histological picture, eccrine carcinomas can be misdiagnosed as SCC.^1,8 Eccrine adnexal tumors are characterized by multiple local recurrences (70%–80% of cases); perineural invasion; and metastasis (50% of cases) to regional lymph nodes and viscera, including the lungs, liver, bones, and brain.¹ Squamous cell carcinoma, however, has a markedly lower recurrence rate (3.1%–18.7% of cases) and rate of metastasis (5.2%–37.8%).¹

Squamoid eccrine ductal carcinoma is classified as one of the less aggressive eccrine tumors, although the low number of cases makes it a controversial conclusion.¹ To our knowledge, no cases of SEDC metastasis have been reported with SEDC. Recurrence of SEDC has been reported locally, and perineural or perivascular invasion (or both) has been demonstrated in 3 cases.¹

Since SEDC has invasive and metastatic potential, as demonstrated in our case, along with elevated local recurrence rates, physicians must be able to properly diagnose this rare entity and recommend an appropriate surgical modality. Due to the low incidence of SEDC, there are no known randomized studies comparing treatment modalities.¹ Other works in the literature have suggested treating SEDC with the same approach as lesions with similar histologic features and behavior, such as eccrine carcinoma and SCC.^1,5-7

Surgical extirpation with complete margin examination is recommended, as SEDC tends to be underestimated in size, is aggressive in its infiltration, and is predisposed to perineural and perivascular invasion. The literature has shown that MMS has demonstrated lower recurrence rates (3.1%–5%) than other treatments at 5-year follow-up for SCC and (0%–5%) for eccrine carcinoma (average follow-up, 31 months).^1,5 Further studies are needed to understand the clinical progression of SEDC, and more experience is necessary with close follow-up of this subset of patients. Follow-up is determined at the present time from anecdotal experience and patient history.

Along with the rarity of SEDC in our patient, the simultaneous occurrence of 3 primary malignancies also is unusual. Patients with CLL have progressive defects of cell- and humoral-mediated immunity, causing immunosuppression. In a retrospective study, Tsimberidou et al⁹ reviewed the records of 2028 untreated CLL patients and determined that 27% had another primary malignancy, including skin (30%) and lung cancers (6%), which were two of the malignancies seen in our patient. The investigators concluded that patients with CLL have more than twice the risk of developing a second primary malignancy and an increased frequency of certain cancer types.⁹ Furthermore, treatment regimens for CLL have been considered to increase cell- and humoral-mediated immune defects at specific cancer sites,¹⁰ although the exact mechanism of this action is unknown. Development of a second primary malignancy (or even a third) in patients with SEDC is increasingly being reported in CLL patients.^9,10

A high index of suspicion with SEDC in the differential diagnosis should be maintained in elderly men with slow-growing, solitary, nodular lesions of the scalp, nose, arms, legs, or trunk.

Eccrine carcinomas are uncommon cutaneous neoplasms demonstrating nonuniform histologic features, behavior, and nomenclature. Given the rarity of these tumors, no known criteria by which to diagnose the tumor or guidelines for treatment have been proposed. We report a rare case of an immunocompromised patient with a primary squamoid eccrine ductal carcinoma (SEDC) who was subsequently treated with radical resection and axillary dissection. It was later determined that the patient had distant metastasis of SEDC. A review of the literature on the diagnosis, treatment, and surveillance of SEDC also is provided.

Case Report

A 77-year-old man whose medical history was remarkable for chronic lymphocytic leukemia (CLL) and numerous previous basal cell carcinomas and squamous cell carcinomas (SCCs) presented with a 5-cm, stellate, sclerotic plaque on the left chest of approximately 2 years’ duration (Figure 1) and a 3-mm pink papule on the right nasal sidewall of 2 months’ duration. Initial histology of both lesions revealed carcinoma with squamous and ductal differentiation extending from the undersurface of the epidermis, favoring a diagnosis of SEDC (Figure 2). At the time of initial presentation, the patient also had a 6-mm pink papule on the right chest of several months duration that was consistent with a well-differentiated sebaceous carcinoma on histology.

Further analysis of the lesion on the left chest revealed positive staining for cytokeratin (CK) 5/14 and p63, suggestive of a cutaneous malignancy. Staining for S100 protein highlighted rare cells in the basal layer of tumor aggregates. The immunohistochemical profile showed negative staining for CK7, CK5D3, epithelial membrane antigen (EMA), estrogen receptor, progesterone receptor, and human epidermal growth factor 2.

Diagnosis of SEDC of the chest and nasal lesions was based on the morphologic architecture, which included ductal formation noted within the tumor. The chest lesion also had prominent squamoid differentiation. Another histologic feature consistent with SEDC was poorly demarcated, infiltrative neoplastic cells extending into the dermis and subcutis. Although there was some positive focal staining for carcinoembryonic antigen (CEA), variegation within the tumor and the prominent squamoid component might have contributed to this unexpected staining pattern.

The patient was admitted to the hospital for excision of the lesion on the chest wall. Initial workup revealed macrocytic anemia, which required transfusion, and an incidental finding of non–small-cell lung cancer. The chest lesion was unrelated to the non–small-cell lung cancer based on the staining profile. Material from the lung stained positive for thyroid transcription factor 1 (TTF-1) and exhibited rare staining for p63; however, the chest lesion did not stain positive for TTF-1 and had strong staining affinity for p63, indicative of a cutaneous malignancy.

The lesion on the chest wall was definitively excised. Pathologic analysis revealed a dermal-based infiltrative tumor of irregular nests and cords of squamoid cells with focal ductal formation in a fibromyxoid background stroma, suggestive of an adnexal carcinoma with a considerable degree of squamous differentiation and favoring a diagnosis of SEDC. Focal perineural invasion was noted, but no lymphovascular spread was identified; however, metastasis was identified in 1 of 26 axillary lymph nodes. The patient underwent 9 sessions of radiation therapy for the lung cancer and also was given cetuximab.

Three months later, the nasal tumor was subsequently excised in an outpatient procedure, and the final biopsy report indicated a diagnosis of basal cell carcinoma. One-and-a-half years later, in follow-up with surgery after removal of the chest lesion, a 2×3-cm mass was excised from the left neck that demonstrated lymph nodes consistent with metastatic SEDC. Careful evaluation of this patient, including family history and genetic screening, was considered. Our patient continues to follow-up with the dermatology department every 3 months. He has been doing well and has had multiple additional primary SCCs in the subsequent 5 years of follow-up.

Comment

Eccrine carcinoma is the most common subtype of adnexal carcinoma, representing 0.01% of all cutaneous tumors.¹ Squamoid eccrine ductal carcinoma is rare, with as few as 13 cases reported in the literature; 3 of these patients were treated with Mohs micrographic surgery (MMS).^1,2 Recently, two series of 7 and 30 cases, respectively, were longitudinally followed and described.^3,4 We report an additional rare case of SEDC in an immunocompromised patient with distant metastases that was treated with radical resection and axillary dissection.

Eccrine carcinoma is observed clinically as a slow-growing, nodular plaque on the scalp, arms, legs, or trunk in middle-aged and elderly individuals.¹ Squamoid eccrine ductal carcinoma also has been reported in a young woman.⁵ Another immunocompromised patient was identified in the literature with a great toe lesion that showed follicular differentiation along with the usual SEDC features of squamoid and ductal differentiation.⁶ The etiology of SEDC is controversial but is thought to be an SCC arising from eccrine glands, a subtype of eccrine carcinoma with extensive squamoid differentiation, or a biphenotypic carcinoma.^1,7

Histologically, SEDC is poorly circumscribed with an infiltrative growth pattern and deep extension into the dermis and subcutaneous tissue. The lesion is characterized by prominent squamous epithelial proliferation superficially with cellular atypia, keratinous cyst formation, squamous eddies, and eccrine ductal differentiation.¹

The differential diagnosis of SEDC includes SCC; metastatic carcinoma with squamoid features; and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma, and porocarcinoma with squamous differentiation.¹

Immunohistochemistry has a role in the diagnosis of SEDC. Findings include positive staining for S100 protein, EMA, CKs, and CEA. Glandular tissue stains positive for EMA and CEA, supporting an adnexal origin.¹ Positivity for p63 and CK5/6 supports the conclusion that this is a primary cutaneous malignancy, not a metastatic disease.¹

Squamoid eccrine ductal carcinoma has an indeterminate malignant potential. There is a disparity of clinical behavior between SCC and eccrine cancers; however, because squamous differentiation sometimes dominates the histological picture, eccrine carcinomas can be misdiagnosed as SCC.^1,8 Eccrine adnexal tumors are characterized by multiple local recurrences (70%–80% of cases); perineural invasion; and metastasis (50% of cases) to regional lymph nodes and viscera, including the lungs, liver, bones, and brain.¹ Squamous cell carcinoma, however, has a markedly lower recurrence rate (3.1%–18.7% of cases) and rate of metastasis (5.2%–37.8%).¹

Squamoid eccrine ductal carcinoma is classified as one of the less aggressive eccrine tumors, although the low number of cases makes it a controversial conclusion.¹ To our knowledge, no cases of SEDC metastasis have been reported with SEDC. Recurrence of SEDC has been reported locally, and perineural or perivascular invasion (or both) has been demonstrated in 3 cases.¹

Since SEDC has invasive and metastatic potential, as demonstrated in our case, along with elevated local recurrence rates, physicians must be able to properly diagnose this rare entity and recommend an appropriate surgical modality. Due to the low incidence of SEDC, there are no known randomized studies comparing treatment modalities.¹ Other works in the literature have suggested treating SEDC with the same approach as lesions with similar histologic features and behavior, such as eccrine carcinoma and SCC.^1,5-7

Surgical extirpation with complete margin examination is recommended, as SEDC tends to be underestimated in size, is aggressive in its infiltration, and is predisposed to perineural and perivascular invasion. The literature has shown that MMS has demonstrated lower recurrence rates (3.1%–5%) than other treatments at 5-year follow-up for SCC and (0%–5%) for eccrine carcinoma (average follow-up, 31 months).^1,5 Further studies are needed to understand the clinical progression of SEDC, and more experience is necessary with close follow-up of this subset of patients. Follow-up is determined at the present time from anecdotal experience and patient history.

Along with the rarity of SEDC in our patient, the simultaneous occurrence of 3 primary malignancies also is unusual. Patients with CLL have progressive defects of cell- and humoral-mediated immunity, causing immunosuppression. In a retrospective study, Tsimberidou et al⁹ reviewed the records of 2028 untreated CLL patients and determined that 27% had another primary malignancy, including skin (30%) and lung cancers (6%), which were two of the malignancies seen in our patient. The investigators concluded that patients with CLL have more than twice the risk of developing a second primary malignancy and an increased frequency of certain cancer types.⁹ Furthermore, treatment regimens for CLL have been considered to increase cell- and humoral-mediated immune defects at specific cancer sites,¹⁰ although the exact mechanism of this action is unknown. Development of a second primary malignancy (or even a third) in patients with SEDC is increasingly being reported in CLL patients.^9,10

A high index of suspicion with SEDC in the differential diagnosis should be maintained in elderly men with slow-growing, solitary, nodular lesions of the scalp, nose, arms, legs, or trunk.

Electrical stimulation in the lateral temporal cortex enhances verbal memory performance, according to two studies in patients with epilepsy.

“While electrical stimulation of the brain is emerging as potential therapy for a wide range of neurologic and psychiatric diseases, little is known about its effect on memory,” said Gregory Worrell, MD, PhD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and an author of the studies. Electrical stimulation may have the potential to treat memory deficits and cognitive dysfunction in brain disorders such as traumatic brain injury and Alzheimer’s disease, the researchers said.

Patients Were Tested During Seizure Monitoring

In the April issue of Brain, Michal T. Kucewicz, PhD, a researcher at the Mayo Clinic, and colleagues described a study of patients with epilepsy who were undergoing evaluation for resective surgery. As part of the evaluations, patients had intracranial subdural and depth electrode arrays implanted in cortical and subcortical brain regions.

After implantation, patients completed delayed free-recall memory tasks in which they learned lists of words for subsequent recall. Twelve words appeared one at a time on a laptop screen for 1.6 seconds each. Participants then solved a series of arithmetic problems. Afterward, participants had 30 seconds to verbally recall as many words as possible from the list in any order. Patients completed this procedure 25 times during each testing session. Twenty of the lists in each session were learned with stimulation (ie, with stimulation applied for two words and then turned off for two words throughout the list), and five lists were learned without stimulation. Participants completed at least two control sessions with no stimulation to reduce potential learning effects.

The investigators focused on 22 patients (nine males) who had electrodes implanted in four brain regions known to support declarative memory: the hippocampus (n = 6), the parahippocampal cortex (n = 7), the prefrontal cortex (n = 6), and the temporal cortex (n = 4). One subject received stimulation in two of the brain regions (ie, the temporal cortex and the parahippocampal cortex).

The number of sessions that patients completed was determined by the length of seizure monitoring (range, two days to 14 days) and patients’ willingness to participate in the study. The subjects were blinded to the stimulation site.

Within-Individual and Between-Group Effects

Stimulation in the lateral temporal cortex enhanced memory performance, whereas stimulation in other brain regions did not. “The positive effect of [lateral cortex] stimulation was reported in individual patients tested across multiple days of stimulation sessions, on the level of the group of patients stimulated in the temporal cortex, and between the four groups stimulated in different brain regions,” the researchers said.

Two of the four patients stimulated in the lateral temporal cortex had significantly improved recall with stimulation, and the other two patients showed a positive trend.

In the subject who received stimulation in two brain regions, stimulation in the dominant lateral temporal neocortex increased the number of remembered words above the normal range, whereas stimulation in the parahippocampal region did not.

Among the participants who received temporal cortex stimulation, memory performance within each session on the stimulated word lists was consistently higher than on the control lists without stimulation.

For the stimulated lists, memory enhancement was observed on the level of the entire list, with no difference in recall between stimulated and nonstimulated words. This finding suggests that the positive effect of stimulation lasted beyond the period of electrical current administration, the researchers said.

The study’s limitations include the small number of participants and their variable clinical characteristics (eg, epilepsy pathologies, medications, and baseline cognition). It is unclear whether electrical stimulation modulates memory processing, attention, perception, or other related processes, the researchers noted. It also is not known whether the positive effect generalizes to other verbal and nonverbal memory functions, or whether stimulation in the nondominant hemisphere would have a different effect.

The data “might provide a hint as to why some patients undergoing surgical removal of this region complain about verbal memory deficits,” Dr. Kucewicz and colleagues said.

“The next step for this project is to determine how to best apply electrical current in terms of the exact location within this area of the brain, timing, and parameters of stimulation,” said study author Brent Berry, MD, PhD, a Mayo Clinic researcher in the Department of Physiology and Biomedical Engineering.

A Closed-Loop Approach

In a study published February 6 in Nature Communications, Youssef Ezzyat, PhD, a senior data scientist at the University of Pennsylvania in Philadelphia, and colleagues found that a closed-loop stimulation system may identify periods of poor memory encoding and apply targeted stimulation to the lateral temporal cortex to compensate.

The investigators recruited 25 neurosurgical patients undergoing clinical monitoring for epilepsy to participate in sessions of a delayed free-recall memory task. Subjects completed at least three record-only sessions of free recall with which the researchers trained a system to use intracranial EEG activity during encoding to predict the likelihood of later word recall.

During subsequent sessions, if the system predicted that the probability of recall was less than 0.5, it triggered 500 ms of bipolar stimulation. The researchers found that lateral temporal cortex stimulation increased the relative probability of item recall by 15%.

“By developing patient-specific, personalized, machine-learning models, we could program our stimulator to deliver pulses only when memory was predicted to fail, giving this technology the best chance of restoring memory function,” said Michael Kahana, PhD, Professor of Psychology at the University of Pennsylvania and principal investigator of the Restoring Active Memory program. “This [approach] was important, because we knew from earlier work that stimulating the brain during periods of good function was likely to make memory worse.”

—Jake Remaly

Suggested Reading

Ezzyat Y, Wanda PA, Levy DF, et al. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 2018;9(1):365.

Hampson RE, Song D, Robinson BS, et al. Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall. J Neural Eng. 2018;15(3):036014.

Inman CS, Manns JR, Bijanki KR, et al. Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci U S A. 2018;115(1):98-103.

Kucewicz MT, Berry BM, Kremen V, et al. Electrical stimulation modulates high γ activity and human memory performance. eNeuro. 2018;5(1).

Kucewicz MT, Berry BM, Miller LR, et al. Evidence for verbal memory enhancement with electrical brain stimulation in the lateral temporal cortex. Brain. 2018;141(4):971-978.

Electrical stimulation in the lateral temporal cortex enhances verbal memory performance, according to two studies in patients with epilepsy.

“While electrical stimulation of the brain is emerging as potential therapy for a wide range of neurologic and psychiatric diseases, little is known about its effect on memory,” said Gregory Worrell, MD, PhD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and an author of the studies. Electrical stimulation may have the potential to treat memory deficits and cognitive dysfunction in brain disorders such as traumatic brain injury and Alzheimer’s disease, the researchers said.

Patients Were Tested During Seizure Monitoring

In the April issue of Brain, Michal T. Kucewicz, PhD, a researcher at the Mayo Clinic, and colleagues described a study of patients with epilepsy who were undergoing evaluation for resective surgery. As part of the evaluations, patients had intracranial subdural and depth electrode arrays implanted in cortical and subcortical brain regions.

After implantation, patients completed delayed free-recall memory tasks in which they learned lists of words for subsequent recall. Twelve words appeared one at a time on a laptop screen for 1.6 seconds each. Participants then solved a series of arithmetic problems. Afterward, participants had 30 seconds to verbally recall as many words as possible from the list in any order. Patients completed this procedure 25 times during each testing session. Twenty of the lists in each session were learned with stimulation (ie, with stimulation applied for two words and then turned off for two words throughout the list), and five lists were learned without stimulation. Participants completed at least two control sessions with no stimulation to reduce potential learning effects.

The investigators focused on 22 patients (nine males) who had electrodes implanted in four brain regions known to support declarative memory: the hippocampus (n = 6), the parahippocampal cortex (n = 7), the prefrontal cortex (n = 6), and the temporal cortex (n = 4). One subject received stimulation in two of the brain regions (ie, the temporal cortex and the parahippocampal cortex).

The number of sessions that patients completed was determined by the length of seizure monitoring (range, two days to 14 days) and patients’ willingness to participate in the study. The subjects were blinded to the stimulation site.

Within-Individual and Between-Group Effects

Stimulation in the lateral temporal cortex enhanced memory performance, whereas stimulation in other brain regions did not. “The positive effect of [lateral cortex] stimulation was reported in individual patients tested across multiple days of stimulation sessions, on the level of the group of patients stimulated in the temporal cortex, and between the four groups stimulated in different brain regions,” the researchers said.

Two of the four patients stimulated in the lateral temporal cortex had significantly improved recall with stimulation, and the other two patients showed a positive trend.

In the subject who received stimulation in two brain regions, stimulation in the dominant lateral temporal neocortex increased the number of remembered words above the normal range, whereas stimulation in the parahippocampal region did not.

Among the participants who received temporal cortex stimulation, memory performance within each session on the stimulated word lists was consistently higher than on the control lists without stimulation.

For the stimulated lists, memory enhancement was observed on the level of the entire list, with no difference in recall between stimulated and nonstimulated words. This finding suggests that the positive effect of stimulation lasted beyond the period of electrical current administration, the researchers said.

The study’s limitations include the small number of participants and their variable clinical characteristics (eg, epilepsy pathologies, medications, and baseline cognition). It is unclear whether electrical stimulation modulates memory processing, attention, perception, or other related processes, the researchers noted. It also is not known whether the positive effect generalizes to other verbal and nonverbal memory functions, or whether stimulation in the nondominant hemisphere would have a different effect.

The data “might provide a hint as to why some patients undergoing surgical removal of this region complain about verbal memory deficits,” Dr. Kucewicz and colleagues said.

“The next step for this project is to determine how to best apply electrical current in terms of the exact location within this area of the brain, timing, and parameters of stimulation,” said study author Brent Berry, MD, PhD, a Mayo Clinic researcher in the Department of Physiology and Biomedical Engineering.

A Closed-Loop Approach

In a study published February 6 in Nature Communications, Youssef Ezzyat, PhD, a senior data scientist at the University of Pennsylvania in Philadelphia, and colleagues found that a closed-loop stimulation system may identify periods of poor memory encoding and apply targeted stimulation to the lateral temporal cortex to compensate.

The investigators recruited 25 neurosurgical patients undergoing clinical monitoring for epilepsy to participate in sessions of a delayed free-recall memory task. Subjects completed at least three record-only sessions of free recall with which the researchers trained a system to use intracranial EEG activity during encoding to predict the likelihood of later word recall.

During subsequent sessions, if the system predicted that the probability of recall was less than 0.5, it triggered 500 ms of bipolar stimulation. The researchers found that lateral temporal cortex stimulation increased the relative probability of item recall by 15%.

“By developing patient-specific, personalized, machine-learning models, we could program our stimulator to deliver pulses only when memory was predicted to fail, giving this technology the best chance of restoring memory function,” said Michael Kahana, PhD, Professor of Psychology at the University of Pennsylvania and principal investigator of the Restoring Active Memory program. “This [approach] was important, because we knew from earlier work that stimulating the brain during periods of good function was likely to make memory worse.”

—Jake Remaly

Suggested Reading

Ezzyat Y, Wanda PA, Levy DF, et al. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 2018;9(1):365.

Hampson RE, Song D, Robinson BS, et al. Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall. J Neural Eng. 2018;15(3):036014.

Inman CS, Manns JR, Bijanki KR, et al. Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci U S A. 2018;115(1):98-103.

Kucewicz MT, Berry BM, Kremen V, et al. Electrical stimulation modulates high γ activity and human memory performance. eNeuro. 2018;5(1).

Kucewicz MT, Berry BM, Miller LR, et al. Evidence for verbal memory enhancement with electrical brain stimulation in the lateral temporal cortex. Brain. 2018;141(4):971-978.

Electrical stimulation in the lateral temporal cortex enhances verbal memory performance, according to two studies in patients with epilepsy.

“While electrical stimulation of the brain is emerging as potential therapy for a wide range of neurologic and psychiatric diseases, little is known about its effect on memory,” said Gregory Worrell, MD, PhD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and an author of the studies. Electrical stimulation may have the potential to treat memory deficits and cognitive dysfunction in brain disorders such as traumatic brain injury and Alzheimer’s disease, the researchers said.

Patients Were Tested During Seizure Monitoring

In the April issue of Brain, Michal T. Kucewicz, PhD, a researcher at the Mayo Clinic, and colleagues described a study of patients with epilepsy who were undergoing evaluation for resective surgery. As part of the evaluations, patients had intracranial subdural and depth electrode arrays implanted in cortical and subcortical brain regions.

After implantation, patients completed delayed free-recall memory tasks in which they learned lists of words for subsequent recall. Twelve words appeared one at a time on a laptop screen for 1.6 seconds each. Participants then solved a series of arithmetic problems. Afterward, participants had 30 seconds to verbally recall as many words as possible from the list in any order. Patients completed this procedure 25 times during each testing session. Twenty of the lists in each session were learned with stimulation (ie, with stimulation applied for two words and then turned off for two words throughout the list), and five lists were learned without stimulation. Participants completed at least two control sessions with no stimulation to reduce potential learning effects.

The investigators focused on 22 patients (nine males) who had electrodes implanted in four brain regions known to support declarative memory: the hippocampus (n = 6), the parahippocampal cortex (n = 7), the prefrontal cortex (n = 6), and the temporal cortex (n = 4). One subject received stimulation in two of the brain regions (ie, the temporal cortex and the parahippocampal cortex).

The number of sessions that patients completed was determined by the length of seizure monitoring (range, two days to 14 days) and patients’ willingness to participate in the study. The subjects were blinded to the stimulation site.

Within-Individual and Between-Group Effects

Stimulation in the lateral temporal cortex enhanced memory performance, whereas stimulation in other brain regions did not. “The positive effect of [lateral cortex] stimulation was reported in individual patients tested across multiple days of stimulation sessions, on the level of the group of patients stimulated in the temporal cortex, and between the four groups stimulated in different brain regions,” the researchers said.

Two of the four patients stimulated in the lateral temporal cortex had significantly improved recall with stimulation, and the other two patients showed a positive trend.

In the subject who received stimulation in two brain regions, stimulation in the dominant lateral temporal neocortex increased the number of remembered words above the normal range, whereas stimulation in the parahippocampal region did not.

Among the participants who received temporal cortex stimulation, memory performance within each session on the stimulated word lists was consistently higher than on the control lists without stimulation.

For the stimulated lists, memory enhancement was observed on the level of the entire list, with no difference in recall between stimulated and nonstimulated words. This finding suggests that the positive effect of stimulation lasted beyond the period of electrical current administration, the researchers said.

The study’s limitations include the small number of participants and their variable clinical characteristics (eg, epilepsy pathologies, medications, and baseline cognition). It is unclear whether electrical stimulation modulates memory processing, attention, perception, or other related processes, the researchers noted. It also is not known whether the positive effect generalizes to other verbal and nonverbal memory functions, or whether stimulation in the nondominant hemisphere would have a different effect.

The data “might provide a hint as to why some patients undergoing surgical removal of this region complain about verbal memory deficits,” Dr. Kucewicz and colleagues said.

“The next step for this project is to determine how to best apply electrical current in terms of the exact location within this area of the brain, timing, and parameters of stimulation,” said study author Brent Berry, MD, PhD, a Mayo Clinic researcher in the Department of Physiology and Biomedical Engineering.

A Closed-Loop Approach

In a study published February 6 in Nature Communications, Youssef Ezzyat, PhD, a senior data scientist at the University of Pennsylvania in Philadelphia, and colleagues found that a closed-loop stimulation system may identify periods of poor memory encoding and apply targeted stimulation to the lateral temporal cortex to compensate.

The investigators recruited 25 neurosurgical patients undergoing clinical monitoring for epilepsy to participate in sessions of a delayed free-recall memory task. Subjects completed at least three record-only sessions of free recall with which the researchers trained a system to use intracranial EEG activity during encoding to predict the likelihood of later word recall.

During subsequent sessions, if the system predicted that the probability of recall was less than 0.5, it triggered 500 ms of bipolar stimulation. The researchers found that lateral temporal cortex stimulation increased the relative probability of item recall by 15%.

“By developing patient-specific, personalized, machine-learning models, we could program our stimulator to deliver pulses only when memory was predicted to fail, giving this technology the best chance of restoring memory function,” said Michael Kahana, PhD, Professor of Psychology at the University of Pennsylvania and principal investigator of the Restoring Active Memory program. “This [approach] was important, because we knew from earlier work that stimulating the brain during periods of good function was likely to make memory worse.”

—Jake Remaly

Suggested Reading

Ezzyat Y, Wanda PA, Levy DF, et al. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 2018;9(1):365.

Hampson RE, Song D, Robinson BS, et al. Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall. J Neural Eng. 2018;15(3):036014.

Inman CS, Manns JR, Bijanki KR, et al. Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci U S A. 2018;115(1):98-103.

Kucewicz MT, Berry BM, Kremen V, et al. Electrical stimulation modulates high γ activity and human memory performance. eNeuro. 2018;5(1).

Kucewicz MT, Berry BM, Miller LR, et al. Evidence for verbal memory enhancement with electrical brain stimulation in the lateral temporal cortex. Brain. 2018;141(4):971-978.

Case Report

A 62-year-old black man presented for examination of a dark longitudinal streak located adjacent to the lateral nail fold on the third finger of the left hand. The lesion had been present for several months, during which time it had slowly expanded in size. The fingertip had recently become tender, which interfered with the patient’s ability to work. His past medical history was remarkable for end-stage renal disease secondary to glomerulonephritis with nephrotic syndrome of unclear etiology. He initially was treated by an outside physician using peritoneal dialysis for 3 years until he underwent renal transplantation in 2004 with a cadaveric organ. Other remarkable medical conditions included posttransplantation diabetes, hyperlipidemia, and gout. His multidrug regimen included 2 immunosuppressive medications: oral cyclosporine 125 mg twice daily and oral mycophenolate mofetil 250 mg twice daily.

A broad, irregular, black, pigmented, subungual band was noted on the left third finger. The lesion appeared to emanate from below the nail cuticle and traveled along the nail longitudinally toward the distal tip. The band appeared darker at the edge adjacent to the lateral nail fold and grew lighter near the middle of the nail where its free edge was noted to be irregular. A slightly thickened lateral nail fold with an irregular, small, sawtoothlike hyperkeratosis and hyperpigmentation also was noted (Figure 1).

Subungual melanoma, onychomycosis, squamous cell carcinoma (SCC), and a verruca copresenting with onychomycosis were considered in the differential diagnosis. The patient underwent nail avulsion and biopsy of the nail bed as well as the nail matrix. Histopathology was notable for malignant dyskeratosis with a lack of nuclear maturation, occasional mitoses, multinucleation, and individual cell keratinization (Figure 2). Immunostaining for S100 was negative, while staining for cytokeratins AE1/AE3 was positive. Deposition of melanin pigment in the malignant dyskeratotic cells was noted. Periodic acid–Schiff staining identified pseudohyphae without invasion of the nail plate. A diagnosis of pigmented SCC (pSCC) was made. The patient’s nail also was sent for fungal cultures that later grew Candida glabrata and Candida parapsilosis.

The patient underwent Mohs micrographic surgery for removal of the pSCC, which was found to be more extensive than originally suspected and required en bloc excision of the nail repaired with a full-thickness skin graft from the left forearm. The area healed well with some hyperpigmentation (Figure 3).

Comment

Among the various types of skin cancer, an estimated 700,000 patients are diagnosed with SCC annually, making it the second most common form of skin cancer in the United States.¹ Basal cell carcinoma (BCC) is the most common skin cancer among whites in the United States, while in contrast SCC is the most common skin cancer in patients with skin of color.² Only an estimated 2% to 5% of all SCCs are pigmented, and this variant is more commonly seen in patients with skin of color.^3-5 One analysis of 52 cases of pSCC showed that common features included a flat or slightly raised appearance and hyperpigmentation with varying levels of scaling.⁶ Studies have shown an altered presentation of pSCC in black skin with increased melanin production and thickness of the stratum corneum in contrast with cases seen in white patients.⁷ Other potential features include scaling, erosive changes, and sharply demarcated borders. Squamous cell carcinoma typically occurs in sun-exposed areas, reflecting its association with UV light damage; however, SCC in skin of color patients has been noted to occur in sun-protected areas and in areas of chronic scarring.⁸ Pigmented SCC also appears to follow this distribution, as affected areas are not necessarily in direct exposure to the sun. Pigmented SCCs have been associated with pruritus and/or burning pain, which also was seen in our case when our patient complained of tenderness at the site.

We describe the case of a subungual pSCC clinically presenting as longitudinal melanonychia. Pigmented SCC presenting as longitudinal melanonychia was first described by Baran and Simon in 1988.⁹ Since that time, it has been reported that approximately 10% of subungual pSCCs clinically present as longitudinal melanonychia.^10,11 A retrospective study reviewing 35 cases of SCC of the nail apparatus found that 5 (14.3%) cases presented as longitudinal melanonychia.¹⁰ Another retrospective study found that 6 of 51 (11.8%) cases of SCCs affecting the nail unit presented as the warty type of SCC in association with longitudinal melanonychia.¹² Cases of pSCC in situ appearing as longitudinal melanonychia also have been reported.^13,14

Risk factors for the development of pSCC include advanced age, male sex, presence of human papilloma virus, and use of immunosuppressants.¹⁵ Male predominance and advanced age at the time of diagnosis (mean age, 67 years) have been observed in pSCC cases.¹⁶ It is now well established that renal transplant recipients have an increased risk of SCC, with a reported incidence rate of 5% to 6%.¹⁶ When these patients develop an SCC, they typically follow a more aggressive course. Renal transplantation has a higher ratio than cardiac transplantation for SCC development (2.37:1), whereas cardiac transplantation is associated with a higher risk of BCC development.¹⁷ A study of 384 transplant recipients found that 96 (25.0%) had a postsurgical nonmelanoma skin cancer (NMSC), with a ratio of SCC to BCC of 1.2:1.¹⁶ The calculated incidence of NMSC at 10 and 20 years posttransplantation was 24.2% and 54.4%, respectively. Another study also determined that SCC rates (50.0%) in postrenal transplant recipients were approximately twice that of BCC (27.0%).¹⁸

A daily regimen of immunosuppressive medications such as cyclosporine and mycophenolate mofetil showed an increased risk for development of NMSC.¹⁵ Immunosuppressive medications play an important role in the pathogenesis of SCC due to a direct oncogenic effect as well as impairment of the immune system’s ability to fight precancerous developments.¹⁵ A 4-year study of 100 renal transplant recipients using mycophenolate mofetil as part of an immunosuppressive regimen reported 22% NMSC findings among 9 patients.¹⁹ On average, patients developed an NMSC approximately 61 months posttransplantation, with a wide range from 2 to 120 months.

Advanced age was another important risk factor, with each decade of life producing a 60% increase in instantaneous risk of SCC development for transplant recipients.¹⁵ A steady increase in risk was related to the length of time adhering to an immunosuppressive regimen, especially from 2 to 6 years, and then remaining constant in subsequent years. For older patients on immunosuppressant regimens for more than 8 years, the calculated relative risk was noted to be over 200 times greater than the normal population’s development of skin cancers.¹⁸

Conclusion

Although cases of pSCC presenting as longitudinal melanonychia have previously been reported,^9-14,20 our case is unique in that it describes pSCC in a renal transplant recipient. Our patient had many of the known risk factors for the development of pSCC including male sex, advanced age, skin of color, history of renal transplantation, and immunosuppressive therapy. Although regular full-body skin examinations are an accepted part of renal transplantation follow-up due to SCC risk, our case emphasizes the need to remain vigilant due to possible atypical presentations among the immunosuppressed. The nail unit should not be overlooked during the clinical examination of renal transplant recipients as demonstrated by our patient’s rare presentation of pSCC in the nail.

Case Report

A 62-year-old black man presented for examination of a dark longitudinal streak located adjacent to the lateral nail fold on the third finger of the left hand. The lesion had been present for several months, during which time it had slowly expanded in size. The fingertip had recently become tender, which interfered with the patient’s ability to work. His past medical history was remarkable for end-stage renal disease secondary to glomerulonephritis with nephrotic syndrome of unclear etiology. He initially was treated by an outside physician using peritoneal dialysis for 3 years until he underwent renal transplantation in 2004 with a cadaveric organ. Other remarkable medical conditions included posttransplantation diabetes, hyperlipidemia, and gout. His multidrug regimen included 2 immunosuppressive medications: oral cyclosporine 125 mg twice daily and oral mycophenolate mofetil 250 mg twice daily.

A broad, irregular, black, pigmented, subungual band was noted on the left third finger. The lesion appeared to emanate from below the nail cuticle and traveled along the nail longitudinally toward the distal tip. The band appeared darker at the edge adjacent to the lateral nail fold and grew lighter near the middle of the nail where its free edge was noted to be irregular. A slightly thickened lateral nail fold with an irregular, small, sawtoothlike hyperkeratosis and hyperpigmentation also was noted (Figure 1).

Subungual melanoma, onychomycosis, squamous cell carcinoma (SCC), and a verruca copresenting with onychomycosis were considered in the differential diagnosis. The patient underwent nail avulsion and biopsy of the nail bed as well as the nail matrix. Histopathology was notable for malignant dyskeratosis with a lack of nuclear maturation, occasional mitoses, multinucleation, and individual cell keratinization (Figure 2). Immunostaining for S100 was negative, while staining for cytokeratins AE1/AE3 was positive. Deposition of melanin pigment in the malignant dyskeratotic cells was noted. Periodic acid–Schiff staining identified pseudohyphae without invasion of the nail plate. A diagnosis of pigmented SCC (pSCC) was made. The patient’s nail also was sent for fungal cultures that later grew Candida glabrata and Candida parapsilosis.

The patient underwent Mohs micrographic surgery for removal of the pSCC, which was found to be more extensive than originally suspected and required en bloc excision of the nail repaired with a full-thickness skin graft from the left forearm. The area healed well with some hyperpigmentation (Figure 3).

Comment

Among the various types of skin cancer, an estimated 700,000 patients are diagnosed with SCC annually, making it the second most common form of skin cancer in the United States.¹ Basal cell carcinoma (BCC) is the most common skin cancer among whites in the United States, while in contrast SCC is the most common skin cancer in patients with skin of color.² Only an estimated 2% to 5% of all SCCs are pigmented, and this variant is more commonly seen in patients with skin of color.^3-5 One analysis of 52 cases of pSCC showed that common features included a flat or slightly raised appearance and hyperpigmentation with varying levels of scaling.⁶ Studies have shown an altered presentation of pSCC in black skin with increased melanin production and thickness of the stratum corneum in contrast with cases seen in white patients.⁷ Other potential features include scaling, erosive changes, and sharply demarcated borders. Squamous cell carcinoma typically occurs in sun-exposed areas, reflecting its association with UV light damage; however, SCC in skin of color patients has been noted to occur in sun-protected areas and in areas of chronic scarring.⁸ Pigmented SCC also appears to follow this distribution, as affected areas are not necessarily in direct exposure to the sun. Pigmented SCCs have been associated with pruritus and/or burning pain, which also was seen in our case when our patient complained of tenderness at the site.

We describe the case of a subungual pSCC clinically presenting as longitudinal melanonychia. Pigmented SCC presenting as longitudinal melanonychia was first described by Baran and Simon in 1988.⁹ Since that time, it has been reported that approximately 10% of subungual pSCCs clinically present as longitudinal melanonychia.^10,11 A retrospective study reviewing 35 cases of SCC of the nail apparatus found that 5 (14.3%) cases presented as longitudinal melanonychia.¹⁰ Another retrospective study found that 6 of 51 (11.8%) cases of SCCs affecting the nail unit presented as the warty type of SCC in association with longitudinal melanonychia.¹² Cases of pSCC in situ appearing as longitudinal melanonychia also have been reported.^13,14

Risk factors for the development of pSCC include advanced age, male sex, presence of human papilloma virus, and use of immunosuppressants.¹⁵ Male predominance and advanced age at the time of diagnosis (mean age, 67 years) have been observed in pSCC cases.¹⁶ It is now well established that renal transplant recipients have an increased risk of SCC, with a reported incidence rate of 5% to 6%.¹⁶ When these patients develop an SCC, they typically follow a more aggressive course. Renal transplantation has a higher ratio than cardiac transplantation for SCC development (2.37:1), whereas cardiac transplantation is associated with a higher risk of BCC development.¹⁷ A study of 384 transplant recipients found that 96 (25.0%) had a postsurgical nonmelanoma skin cancer (NMSC), with a ratio of SCC to BCC of 1.2:1.¹⁶ The calculated incidence of NMSC at 10 and 20 years posttransplantation was 24.2% and 54.4%, respectively. Another study also determined that SCC rates (50.0%) in postrenal transplant recipients were approximately twice that of BCC (27.0%).¹⁸

A daily regimen of immunosuppressive medications such as cyclosporine and mycophenolate mofetil showed an increased risk for development of NMSC.¹⁵ Immunosuppressive medications play an important role in the pathogenesis of SCC due to a direct oncogenic effect as well as impairment of the immune system’s ability to fight precancerous developments.¹⁵ A 4-year study of 100 renal transplant recipients using mycophenolate mofetil as part of an immunosuppressive regimen reported 22% NMSC findings among 9 patients.¹⁹ On average, patients developed an NMSC approximately 61 months posttransplantation, with a wide range from 2 to 120 months.

Advanced age was another important risk factor, with each decade of life producing a 60% increase in instantaneous risk of SCC development for transplant recipients.¹⁵ A steady increase in risk was related to the length of time adhering to an immunosuppressive regimen, especially from 2 to 6 years, and then remaining constant in subsequent years. For older patients on immunosuppressant regimens for more than 8 years, the calculated relative risk was noted to be over 200 times greater than the normal population’s development of skin cancers.¹⁸

Conclusion

Although cases of pSCC presenting as longitudinal melanonychia have previously been reported,^9-14,20 our case is unique in that it describes pSCC in a renal transplant recipient. Our patient had many of the known risk factors for the development of pSCC including male sex, advanced age, skin of color, history of renal transplantation, and immunosuppressive therapy. Although regular full-body skin examinations are an accepted part of renal transplantation follow-up due to SCC risk, our case emphasizes the need to remain vigilant due to possible atypical presentations among the immunosuppressed. The nail unit should not be overlooked during the clinical examination of renal transplant recipients as demonstrated by our patient’s rare presentation of pSCC in the nail.

Case Report

A 62-year-old black man presented for examination of a dark longitudinal streak located adjacent to the lateral nail fold on the third finger of the left hand. The lesion had been present for several months, during which time it had slowly expanded in size. The fingertip had recently become tender, which interfered with the patient’s ability to work. His past medical history was remarkable for end-stage renal disease secondary to glomerulonephritis with nephrotic syndrome of unclear etiology. He initially was treated by an outside physician using peritoneal dialysis for 3 years until he underwent renal transplantation in 2004 with a cadaveric organ. Other remarkable medical conditions included posttransplantation diabetes, hyperlipidemia, and gout. His multidrug regimen included 2 immunosuppressive medications: oral cyclosporine 125 mg twice daily and oral mycophenolate mofetil 250 mg twice daily.

A broad, irregular, black, pigmented, subungual band was noted on the left third finger. The lesion appeared to emanate from below the nail cuticle and traveled along the nail longitudinally toward the distal tip. The band appeared darker at the edge adjacent to the lateral nail fold and grew lighter near the middle of the nail where its free edge was noted to be irregular. A slightly thickened lateral nail fold with an irregular, small, sawtoothlike hyperkeratosis and hyperpigmentation also was noted (Figure 1).

Subungual melanoma, onychomycosis, squamous cell carcinoma (SCC), and a verruca copresenting with onychomycosis were considered in the differential diagnosis. The patient underwent nail avulsion and biopsy of the nail bed as well as the nail matrix. Histopathology was notable for malignant dyskeratosis with a lack of nuclear maturation, occasional mitoses, multinucleation, and individual cell keratinization (Figure 2). Immunostaining for S100 was negative, while staining for cytokeratins AE1/AE3 was positive. Deposition of melanin pigment in the malignant dyskeratotic cells was noted. Periodic acid–Schiff staining identified pseudohyphae without invasion of the nail plate. A diagnosis of pigmented SCC (pSCC) was made. The patient’s nail also was sent for fungal cultures that later grew Candida glabrata and Candida parapsilosis.

The patient underwent Mohs micrographic surgery for removal of the pSCC, which was found to be more extensive than originally suspected and required en bloc excision of the nail repaired with a full-thickness skin graft from the left forearm. The area healed well with some hyperpigmentation (Figure 3).

Comment

Among the various types of skin cancer, an estimated 700,000 patients are diagnosed with SCC annually, making it the second most common form of skin cancer in the United States.¹ Basal cell carcinoma (BCC) is the most common skin cancer among whites in the United States, while in contrast SCC is the most common skin cancer in patients with skin of color.² Only an estimated 2% to 5% of all SCCs are pigmented, and this variant is more commonly seen in patients with skin of color.^3-5 One analysis of 52 cases of pSCC showed that common features included a flat or slightly raised appearance and hyperpigmentation with varying levels of scaling.⁶ Studies have shown an altered presentation of pSCC in black skin with increased melanin production and thickness of the stratum corneum in contrast with cases seen in white patients.⁷ Other potential features include scaling, erosive changes, and sharply demarcated borders. Squamous cell carcinoma typically occurs in sun-exposed areas, reflecting its association with UV light damage; however, SCC in skin of color patients has been noted to occur in sun-protected areas and in areas of chronic scarring.⁸ Pigmented SCC also appears to follow this distribution, as affected areas are not necessarily in direct exposure to the sun. Pigmented SCCs have been associated with pruritus and/or burning pain, which also was seen in our case when our patient complained of tenderness at the site.

We describe the case of a subungual pSCC clinically presenting as longitudinal melanonychia. Pigmented SCC presenting as longitudinal melanonychia was first described by Baran and Simon in 1988.⁹ Since that time, it has been reported that approximately 10% of subungual pSCCs clinically present as longitudinal melanonychia.^10,11 A retrospective study reviewing 35 cases of SCC of the nail apparatus found that 5 (14.3%) cases presented as longitudinal melanonychia.¹⁰ Another retrospective study found that 6 of 51 (11.8%) cases of SCCs affecting the nail unit presented as the warty type of SCC in association with longitudinal melanonychia.¹² Cases of pSCC in situ appearing as longitudinal melanonychia also have been reported.^13,14

Risk factors for the development of pSCC include advanced age, male sex, presence of human papilloma virus, and use of immunosuppressants.¹⁵ Male predominance and advanced age at the time of diagnosis (mean age, 67 years) have been observed in pSCC cases.¹⁶ It is now well established that renal transplant recipients have an increased risk of SCC, with a reported incidence rate of 5% to 6%.¹⁶ When these patients develop an SCC, they typically follow a more aggressive course. Renal transplantation has a higher ratio than cardiac transplantation for SCC development (2.37:1), whereas cardiac transplantation is associated with a higher risk of BCC development.¹⁷ A study of 384 transplant recipients found that 96 (25.0%) had a postsurgical nonmelanoma skin cancer (NMSC), with a ratio of SCC to BCC of 1.2:1.¹⁶ The calculated incidence of NMSC at 10 and 20 years posttransplantation was 24.2% and 54.4%, respectively. Another study also determined that SCC rates (50.0%) in postrenal transplant recipients were approximately twice that of BCC (27.0%).¹⁸

A daily regimen of immunosuppressive medications such as cyclosporine and mycophenolate mofetil showed an increased risk for development of NMSC.¹⁵ Immunosuppressive medications play an important role in the pathogenesis of SCC due to a direct oncogenic effect as well as impairment of the immune system’s ability to fight precancerous developments.¹⁵ A 4-year study of 100 renal transplant recipients using mycophenolate mofetil as part of an immunosuppressive regimen reported 22% NMSC findings among 9 patients.¹⁹ On average, patients developed an NMSC approximately 61 months posttransplantation, with a wide range from 2 to 120 months.

Advanced age was another important risk factor, with each decade of life producing a 60% increase in instantaneous risk of SCC development for transplant recipients.¹⁵ A steady increase in risk was related to the length of time adhering to an immunosuppressive regimen, especially from 2 to 6 years, and then remaining constant in subsequent years. For older patients on immunosuppressant regimens for more than 8 years, the calculated relative risk was noted to be over 200 times greater than the normal population’s development of skin cancers.¹⁸

Conclusion

Although cases of pSCC presenting as longitudinal melanonychia have previously been reported,^9-14,20 our case is unique in that it describes pSCC in a renal transplant recipient. Our patient had many of the known risk factors for the development of pSCC including male sex, advanced age, skin of color, history of renal transplantation, and immunosuppressive therapy. Although regular full-body skin examinations are an accepted part of renal transplantation follow-up due to SCC risk, our case emphasizes the need to remain vigilant due to possible atypical presentations among the immunosuppressed. The nail unit should not be overlooked during the clinical examination of renal transplant recipients as demonstrated by our patient’s rare presentation of pSCC in the nail.

Cutaneous manifestations of systemic lupus erythematosus (SLE) can be classified as lupus-specific or lupus-nonspecific skin lesions. Lupus-specific lesions commonly are photodistributed, with involvement of the malar region, arms, and trunk. The development of discoid lupus erythematosus (DLE) in areas of trauma, including sun-exposed skin, is not uncommon and may be associated with an isomorphic response. We present a rare case of an isomorphic response following herpes zoster (HZ) in a young woman undergoing treatment with immunosuppressive agents for SLE and DLE. Potential prophylactic therapy also is discussed.

Case Report

A 19-year-old woman initially presented to an outside dermatologist for evaluation of new-onset scarring alopecia, crusted erythematous plaques on the face and arms, and arthralgia. A punch biopsy of a lesion on the left arm demonstrated a lichenoid and perivascular lymphocytic infiltrate with scattered necrotic keratinocytes, perifollicular inflammation, and focally thickened basement membrane at the dermoepidermal junction consistent with discoid lupus erythematosus (DLE). A laboratory workup for SLE revealed 1:1280 antinuclear antibodies (reference range, negative <1:80) with elevated titers of double-stranded DNA, Smith, ribonucleoprotein, Sjögren syndrome A, and Sjögren syndrome B autoantibodies with low complement levels. Based on these findings, a diagnosis of SLE and DLE was made.

At that time, the patient was started on hydroxychloroquine 200 mg twice daily for SLE. Four days later she developed swelling in both hands and feet, and hydroxychloroquine was stopped due to a presumed adverse reaction; however, her symptoms subsequently were determined to be polyarthritis secondary to a lupus flare. Prednisone 10 mg once daily was then initiated. The patient was encouraged to restart hydroxychloroquine, but she declined.

Over the next 13 months, the patient developed severe photosensitivity, oral ulcers, Raynaud phenomenon, anemia, and nephrotic-range proteinuria. She ultimately was diagnosed by the nephrology department at our institution with mixed diffuse proliferative and membranous glomerulonephritis. Induction therapy with oral mycophenolate mofetil 1000 mg twice daily and prednisone 60 mg once daily was started, followed by the addition of tacrolimus 1 mg twice daily. Despite immunosuppressive therapy, she continued to develop new discoid lesions on the face, chest, and arms. The disease course also was complicated by a pulmonary embolism and deep venous thrombosis, for which the hematology department initiated treatment with warfarin for anticoagulation. Anticardiolipin antibodies were negative at presentation and again 12 weeks later.

After 4 weeks of treatment with mycophenolate mofetil, prednisone, and tacrolimus, the patient developed a painful vesicular rash on the left breast with extension over the left axilla and scapula in a T3 to T4 dermatomal distribution. A clinical diagnosis of HZ was made, and she was started on intravenous acyclovir 10 mg/kg in dextrose 5% every 8 hours for 4 days followed by oral valacyclovir 1000 mg every 8 hours for 14 days, which led to resolution of the eruption.

Over the next 4 months, the patient continued to experience pain confined to the same dermatomal area as the HZ, which was consistent with postherpetic neuralgia. Mycophenolate mofetil was discontinued after she developed acute liver toxicity attributed to the drug. Upon discontinuation, the patient developed a new pruritic rash on both arms and the back. Physical examination by the dermatology department at our institution revealed diffuse, scaly, hyperpigmented papules and annular plaques with central pink hypopigmentation on the face, ears, anterior chest, arms, hands, and back. On the left anterior chest and back, the distribution was strikingly unilateral and multidermatomal (Figure 1). Upon further questioning, the patient confirmed that the areas of the new rash coincided with areas previously affected by HZ. Histologic examination of a representative lesion from the left lateral breast revealed hyperkeratosis, follicular plugging, a patchy lichenoid and perivascular mononuclear cell infiltrate, and pigment incontinence (Figure 2A). These histologic features were subtle and were not diagnostic for lupus; however, direct immunofluorescence demonstrated a continuous granular band of IgG and C3 along the dermoepidermal junction, confirming the diagnosis of DLE (Figure 2B). The histologic findings and clinical presentation were consistent with the development of DLE in areas of previous trauma from HZ. The patient continues to follow-up with the rheumatology and nephrology departments but was lost to dermatology follow-up.

Comment

The pathogenesis of DLE is poorly understood but is thought to be multifactorial, involving genetics, sun exposure, and immune dysregulation.¹ Development of DLE lesions in skin traumatized by tattoos, scratches, scars, and prolonged heat exposure has been reported.² Clarification of the mechanism(s) underlying these traumatized areas may provide insight into the pathophysiology of DLE.

The isomorphic response, also known as the Köbner phenomenon, is the development of a preexisting skin condition at a site of trauma. This phenomenon has been observed in several dermatologic conditions including psoriasis, lichen planus, systemic sclerosis, dermatomyositis, sarcoidosis, vitiligo, and DLE.³ Koebnerization may result from trauma to the skin caused by scratches, sun exposure, radiography, prolonged heat and cold exposure, pressure, tattoos, scars, and inflammatory dermatoses.^2,4 Ueki⁴ suggested that localized trauma to the skin stimulates an immune response that makes the traumatized site a target for a preexisting skin condition. Inflammatory mediators such as IL-1, tumor necrosis factor α, IL-6, and interferon γ have been implicated in the pathophysiology of the isomorphic response.⁴

Wolf isotopic response is a similar entity that refers to the development of a novel skin condition at the site of a distinct, previously resolved skin disorder. This phenomenon was described by Wolf et al⁵ in 1995, and since then over 170 cases have been reported.^5-7 In most cases the initial skin condition is HZ, although herpes simplex virus has also been implicated. The common resulting skin conditions include granulomatous reactions, malignant tumors, lichen planus, morphea, and infections. The notion that the antecedent skin disease alters the affected site and causes it to be more susceptible to autoimmunity has been proposed as a mechanism for the isotopic response.^7,8 While one might consider our presentation of DLE following HZ to be an isotopic response, we believe this case is best classified as an isomorphic response, as the patient already had an established diagnosis of DLE.

The development of DLE at the site of a previous HZ eruption has been described in 2 other cases of young women with SLE.^9,10 Unique to our case is the development of a multidermatomal eruption, which may be an indication of her degree of immunosuppression, as immunosuppressed patients are more likely to present with multidermatomal reactivation of varicella zoster virus and postherpetic neuralgia.¹¹ The similarities between our case and the 2 prior reports—including the patients’ age, sex, history of SLE, and degree of immunosuppression—are noteworthy in that they may represent a subset of SLE patients who are predisposed to developing koebnerization following HZ. Physicians should be aware of this phenomenon and consider being proactive in preventing long-term damage.

When feasible, physicians should consider administering the HZ vaccine to reduce the course and severity of HZ before prescribing immunosuppressive agents. When HZ presents in young, immunosuppressed women with a history of SLE, we suggest monitoring the affected sites closely for any evidence of DLE. Topical corticosteroids should be applied to involved areas of the face or body at the earliest appearance of such lesions, which may prevent the isomorphic response and its potentially scarring DLE lesions. This will be our therapeutic approach if we encounter a similar clinical situation in the future. Further studies are warranted to assess the efficacy and optimal duration of this approach, which to our knowledge has not been reported in the literature. It may be that aggressive treatment for a few weeks can preclude the further development of DLE lesions; however, DLE lesions may appear in susceptible skin months after the HZ has resolved.

Acknowledgment
We thank Carolyn E. Grotkowski, MD, from the Department of Pathology, Cooper Medical School of Rowan University, Camden, New Jersey, for her assistance in photographing the pathology slides.

Cutaneous manifestations of systemic lupus erythematosus (SLE) can be classified as lupus-specific or lupus-nonspecific skin lesions. Lupus-specific lesions commonly are photodistributed, with involvement of the malar region, arms, and trunk. The development of discoid lupus erythematosus (DLE) in areas of trauma, including sun-exposed skin, is not uncommon and may be associated with an isomorphic response. We present a rare case of an isomorphic response following herpes zoster (HZ) in a young woman undergoing treatment with immunosuppressive agents for SLE and DLE. Potential prophylactic therapy also is discussed.

Case Report

A 19-year-old woman initially presented to an outside dermatologist for evaluation of new-onset scarring alopecia, crusted erythematous plaques on the face and arms, and arthralgia. A punch biopsy of a lesion on the left arm demonstrated a lichenoid and perivascular lymphocytic infiltrate with scattered necrotic keratinocytes, perifollicular inflammation, and focally thickened basement membrane at the dermoepidermal junction consistent with discoid lupus erythematosus (DLE). A laboratory workup for SLE revealed 1:1280 antinuclear antibodies (reference range, negative <1:80) with elevated titers of double-stranded DNA, Smith, ribonucleoprotein, Sjögren syndrome A, and Sjögren syndrome B autoantibodies with low complement levels. Based on these findings, a diagnosis of SLE and DLE was made.

At that time, the patient was started on hydroxychloroquine 200 mg twice daily for SLE. Four days later she developed swelling in both hands and feet, and hydroxychloroquine was stopped due to a presumed adverse reaction; however, her symptoms subsequently were determined to be polyarthritis secondary to a lupus flare. Prednisone 10 mg once daily was then initiated. The patient was encouraged to restart hydroxychloroquine, but she declined.

Over the next 13 months, the patient developed severe photosensitivity, oral ulcers, Raynaud phenomenon, anemia, and nephrotic-range proteinuria. She ultimately was diagnosed by the nephrology department at our institution with mixed diffuse proliferative and membranous glomerulonephritis. Induction therapy with oral mycophenolate mofetil 1000 mg twice daily and prednisone 60 mg once daily was started, followed by the addition of tacrolimus 1 mg twice daily. Despite immunosuppressive therapy, she continued to develop new discoid lesions on the face, chest, and arms. The disease course also was complicated by a pulmonary embolism and deep venous thrombosis, for which the hematology department initiated treatment with warfarin for anticoagulation. Anticardiolipin antibodies were negative at presentation and again 12 weeks later.

After 4 weeks of treatment with mycophenolate mofetil, prednisone, and tacrolimus, the patient developed a painful vesicular rash on the left breast with extension over the left axilla and scapula in a T3 to T4 dermatomal distribution. A clinical diagnosis of HZ was made, and she was started on intravenous acyclovir 10 mg/kg in dextrose 5% every 8 hours for 4 days followed by oral valacyclovir 1000 mg every 8 hours for 14 days, which led to resolution of the eruption.

Over the next 4 months, the patient continued to experience pain confined to the same dermatomal area as the HZ, which was consistent with postherpetic neuralgia. Mycophenolate mofetil was discontinued after she developed acute liver toxicity attributed to the drug. Upon discontinuation, the patient developed a new pruritic rash on both arms and the back. Physical examination by the dermatology department at our institution revealed diffuse, scaly, hyperpigmented papules and annular plaques with central pink hypopigmentation on the face, ears, anterior chest, arms, hands, and back. On the left anterior chest and back, the distribution was strikingly unilateral and multidermatomal (Figure 1). Upon further questioning, the patient confirmed that the areas of the new rash coincided with areas previously affected by HZ. Histologic examination of a representative lesion from the left lateral breast revealed hyperkeratosis, follicular plugging, a patchy lichenoid and perivascular mononuclear cell infiltrate, and pigment incontinence (Figure 2A). These histologic features were subtle and were not diagnostic for lupus; however, direct immunofluorescence demonstrated a continuous granular band of IgG and C3 along the dermoepidermal junction, confirming the diagnosis of DLE (Figure 2B). The histologic findings and clinical presentation were consistent with the development of DLE in areas of previous trauma from HZ. The patient continues to follow-up with the rheumatology and nephrology departments but was lost to dermatology follow-up.

Comment

The pathogenesis of DLE is poorly understood but is thought to be multifactorial, involving genetics, sun exposure, and immune dysregulation.¹ Development of DLE lesions in skin traumatized by tattoos, scratches, scars, and prolonged heat exposure has been reported.² Clarification of the mechanism(s) underlying these traumatized areas may provide insight into the pathophysiology of DLE.

The isomorphic response, also known as the Köbner phenomenon, is the development of a preexisting skin condition at a site of trauma. This phenomenon has been observed in several dermatologic conditions including psoriasis, lichen planus, systemic sclerosis, dermatomyositis, sarcoidosis, vitiligo, and DLE.³ Koebnerization may result from trauma to the skin caused by scratches, sun exposure, radiography, prolonged heat and cold exposure, pressure, tattoos, scars, and inflammatory dermatoses.^2,4 Ueki⁴ suggested that localized trauma to the skin stimulates an immune response that makes the traumatized site a target for a preexisting skin condition. Inflammatory mediators such as IL-1, tumor necrosis factor α, IL-6, and interferon γ have been implicated in the pathophysiology of the isomorphic response.⁴

Wolf isotopic response is a similar entity that refers to the development of a novel skin condition at the site of a distinct, previously resolved skin disorder. This phenomenon was described by Wolf et al⁵ in 1995, and since then over 170 cases have been reported.^5-7 In most cases the initial skin condition is HZ, although herpes simplex virus has also been implicated. The common resulting skin conditions include granulomatous reactions, malignant tumors, lichen planus, morphea, and infections. The notion that the antecedent skin disease alters the affected site and causes it to be more susceptible to autoimmunity has been proposed as a mechanism for the isotopic response.^7,8 While one might consider our presentation of DLE following HZ to be an isotopic response, we believe this case is best classified as an isomorphic response, as the patient already had an established diagnosis of DLE.

The development of DLE at the site of a previous HZ eruption has been described in 2 other cases of young women with SLE.^9,10 Unique to our case is the development of a multidermatomal eruption, which may be an indication of her degree of immunosuppression, as immunosuppressed patients are more likely to present with multidermatomal reactivation of varicella zoster virus and postherpetic neuralgia.¹¹ The similarities between our case and the 2 prior reports—including the patients’ age, sex, history of SLE, and degree of immunosuppression—are noteworthy in that they may represent a subset of SLE patients who are predisposed to developing koebnerization following HZ. Physicians should be aware of this phenomenon and consider being proactive in preventing long-term damage.

When feasible, physicians should consider administering the HZ vaccine to reduce the course and severity of HZ before prescribing immunosuppressive agents. When HZ presents in young, immunosuppressed women with a history of SLE, we suggest monitoring the affected sites closely for any evidence of DLE. Topical corticosteroids should be applied to involved areas of the face or body at the earliest appearance of such lesions, which may prevent the isomorphic response and its potentially scarring DLE lesions. This will be our therapeutic approach if we encounter a similar clinical situation in the future. Further studies are warranted to assess the efficacy and optimal duration of this approach, which to our knowledge has not been reported in the literature. It may be that aggressive treatment for a few weeks can preclude the further development of DLE lesions; however, DLE lesions may appear in susceptible skin months after the HZ has resolved.

Acknowledgment
We thank Carolyn E. Grotkowski, MD, from the Department of Pathology, Cooper Medical School of Rowan University, Camden, New Jersey, for her assistance in photographing the pathology slides.

Cutaneous manifestations of systemic lupus erythematosus (SLE) can be classified as lupus-specific or lupus-nonspecific skin lesions. Lupus-specific lesions commonly are photodistributed, with involvement of the malar region, arms, and trunk. The development of discoid lupus erythematosus (DLE) in areas of trauma, including sun-exposed skin, is not uncommon and may be associated with an isomorphic response. We present a rare case of an isomorphic response following herpes zoster (HZ) in a young woman undergoing treatment with immunosuppressive agents for SLE and DLE. Potential prophylactic therapy also is discussed.

Case Report

A 19-year-old woman initially presented to an outside dermatologist for evaluation of new-onset scarring alopecia, crusted erythematous plaques on the face and arms, and arthralgia. A punch biopsy of a lesion on the left arm demonstrated a lichenoid and perivascular lymphocytic infiltrate with scattered necrotic keratinocytes, perifollicular inflammation, and focally thickened basement membrane at the dermoepidermal junction consistent with discoid lupus erythematosus (DLE). A laboratory workup for SLE revealed 1:1280 antinuclear antibodies (reference range, negative <1:80) with elevated titers of double-stranded DNA, Smith, ribonucleoprotein, Sjögren syndrome A, and Sjögren syndrome B autoantibodies with low complement levels. Based on these findings, a diagnosis of SLE and DLE was made.

At that time, the patient was started on hydroxychloroquine 200 mg twice daily for SLE. Four days later she developed swelling in both hands and feet, and hydroxychloroquine was stopped due to a presumed adverse reaction; however, her symptoms subsequently were determined to be polyarthritis secondary to a lupus flare. Prednisone 10 mg once daily was then initiated. The patient was encouraged to restart hydroxychloroquine, but she declined.

Over the next 13 months, the patient developed severe photosensitivity, oral ulcers, Raynaud phenomenon, anemia, and nephrotic-range proteinuria. She ultimately was diagnosed by the nephrology department at our institution with mixed diffuse proliferative and membranous glomerulonephritis. Induction therapy with oral mycophenolate mofetil 1000 mg twice daily and prednisone 60 mg once daily was started, followed by the addition of tacrolimus 1 mg twice daily. Despite immunosuppressive therapy, she continued to develop new discoid lesions on the face, chest, and arms. The disease course also was complicated by a pulmonary embolism and deep venous thrombosis, for which the hematology department initiated treatment with warfarin for anticoagulation. Anticardiolipin antibodies were negative at presentation and again 12 weeks later.

After 4 weeks of treatment with mycophenolate mofetil, prednisone, and tacrolimus, the patient developed a painful vesicular rash on the left breast with extension over the left axilla and scapula in a T3 to T4 dermatomal distribution. A clinical diagnosis of HZ was made, and she was started on intravenous acyclovir 10 mg/kg in dextrose 5% every 8 hours for 4 days followed by oral valacyclovir 1000 mg every 8 hours for 14 days, which led to resolution of the eruption.

Over the next 4 months, the patient continued to experience pain confined to the same dermatomal area as the HZ, which was consistent with postherpetic neuralgia. Mycophenolate mofetil was discontinued after she developed acute liver toxicity attributed to the drug. Upon discontinuation, the patient developed a new pruritic rash on both arms and the back. Physical examination by the dermatology department at our institution revealed diffuse, scaly, hyperpigmented papules and annular plaques with central pink hypopigmentation on the face, ears, anterior chest, arms, hands, and back. On the left anterior chest and back, the distribution was strikingly unilateral and multidermatomal (Figure 1). Upon further questioning, the patient confirmed that the areas of the new rash coincided with areas previously affected by HZ. Histologic examination of a representative lesion from the left lateral breast revealed hyperkeratosis, follicular plugging, a patchy lichenoid and perivascular mononuclear cell infiltrate, and pigment incontinence (Figure 2A). These histologic features were subtle and were not diagnostic for lupus; however, direct immunofluorescence demonstrated a continuous granular band of IgG and C3 along the dermoepidermal junction, confirming the diagnosis of DLE (Figure 2B). The histologic findings and clinical presentation were consistent with the development of DLE in areas of previous trauma from HZ. The patient continues to follow-up with the rheumatology and nephrology departments but was lost to dermatology follow-up.

Comment

The pathogenesis of DLE is poorly understood but is thought to be multifactorial, involving genetics, sun exposure, and immune dysregulation.¹ Development of DLE lesions in skin traumatized by tattoos, scratches, scars, and prolonged heat exposure has been reported.² Clarification of the mechanism(s) underlying these traumatized areas may provide insight into the pathophysiology of DLE.

The isomorphic response, also known as the Köbner phenomenon, is the development of a preexisting skin condition at a site of trauma. This phenomenon has been observed in several dermatologic conditions including psoriasis, lichen planus, systemic sclerosis, dermatomyositis, sarcoidosis, vitiligo, and DLE.³ Koebnerization may result from trauma to the skin caused by scratches, sun exposure, radiography, prolonged heat and cold exposure, pressure, tattoos, scars, and inflammatory dermatoses.^2,4 Ueki⁴ suggested that localized trauma to the skin stimulates an immune response that makes the traumatized site a target for a preexisting skin condition. Inflammatory mediators such as IL-1, tumor necrosis factor α, IL-6, and interferon γ have been implicated in the pathophysiology of the isomorphic response.⁴

Wolf isotopic response is a similar entity that refers to the development of a novel skin condition at the site of a distinct, previously resolved skin disorder. This phenomenon was described by Wolf et al⁵ in 1995, and since then over 170 cases have been reported.^5-7 In most cases the initial skin condition is HZ, although herpes simplex virus has also been implicated. The common resulting skin conditions include granulomatous reactions, malignant tumors, lichen planus, morphea, and infections. The notion that the antecedent skin disease alters the affected site and causes it to be more susceptible to autoimmunity has been proposed as a mechanism for the isotopic response.^7,8 While one might consider our presentation of DLE following HZ to be an isotopic response, we believe this case is best classified as an isomorphic response, as the patient already had an established diagnosis of DLE.

The development of DLE at the site of a previous HZ eruption has been described in 2 other cases of young women with SLE.^9,10 Unique to our case is the development of a multidermatomal eruption, which may be an indication of her degree of immunosuppression, as immunosuppressed patients are more likely to present with multidermatomal reactivation of varicella zoster virus and postherpetic neuralgia.¹¹ The similarities between our case and the 2 prior reports—including the patients’ age, sex, history of SLE, and degree of immunosuppression—are noteworthy in that they may represent a subset of SLE patients who are predisposed to developing koebnerization following HZ. Physicians should be aware of this phenomenon and consider being proactive in preventing long-term damage.

When feasible, physicians should consider administering the HZ vaccine to reduce the course and severity of HZ before prescribing immunosuppressive agents. When HZ presents in young, immunosuppressed women with a history of SLE, we suggest monitoring the affected sites closely for any evidence of DLE. Topical corticosteroids should be applied to involved areas of the face or body at the earliest appearance of such lesions, which may prevent the isomorphic response and its potentially scarring DLE lesions. This will be our therapeutic approach if we encounter a similar clinical situation in the future. Further studies are warranted to assess the efficacy and optimal duration of this approach, which to our knowledge has not been reported in the literature. It may be that aggressive treatment for a few weeks can preclude the further development of DLE lesions; however, DLE lesions may appear in susceptible skin months after the HZ has resolved.

Acknowledgment
We thank Carolyn E. Grotkowski, MD, from the Department of Pathology, Cooper Medical School of Rowan University, Camden, New Jersey, for her assistance in photographing the pathology slides.

Not all younger patients with mantle cell lymphoma (MCL) are ideal candidates for conventional high-intensity upfront treatment, according to a recent review published in Best Practice & Research Clinical Haematology.

Use of high-dose cytarabine plus rituximab as frontline treatment is well established, with median overall survival now exceeding 10 years, said Rory McCulloch, MD, and Simon Rule, MD, of the department of Haematology, Derriford Hospital, Plymouth, England. However, there is no proven benefit to conventional therapy in patients with asymptomatic, non-bulky disease, making a watch-and-wait strategy appropriate for these patients, the authors said.

On the opposite end of the spectrum there is a subgroup of patients characterized by TP53 mutations and poor prognostic index scores that have poor outcomes in spite of conventional therapy.

These patients might have improved outcomes either with early allogeneic haematopoietic cell transplantation (allo-HCT), or, especially, clinical trials of novel agents in the upfront setting, the authors noted.

“There are a host of exciting novel agents, most prominently the BTK inhibitors, that are game changing with respect to their activity,” wrote Dr. McCulloch and Dr. Rule. “Based on the long-term results seen with conventional therapy, it is premature to be considering such new drugs in the frontline setting outside the context of a clinical trial, but it is hard to believe they will not become incorporated into treatment protocols in the future.”

Watch-and-wait treatment strategies for lower-risk patients are supported by the results of two single-center, retrospective studies published in 2009 that suggest the practice has no adverse impact on overall survival. More recent registry studies, published in 2016 and 2017, have shown that a significant proportion of patients can be managed according to the watch-and-wait strategy.

Although it’s been challenging to precisely define the group of patients for whom watch-and-wait is appropriate, enrollment criteria for studies have generally specified that patients be asymptomatic with non-bulky disease and non-blastoid morphology, they said.

For the minority of patients presenting with high-risk disease, allo-HCT may improve outcomes, according to Dr. McCulloch and Dr. Rule. One prospective study evaluating allogeneic transplants in frontline therapy showed favorable outcomes in younger patients, although few high-risk patients were enrolled.

However, a second prospective study of allo-HCT, involving 25 patients with untreated MCL in the United Kingdom, demonstrated a 2-year overall survival of 80%. “Although immature, the results are encouraging and provide data to support frontline allogeneic transplant for some patients,” Dr. McCulloch and Dr. Rule said in a comment on that study.

Novel agent studies have produced mixed results in treatment settings relevant to younger, high-risk MCL patients, though key trials are ongoing that could change practice.

One phase 2 study is evaluating obinituzumab, the fully humanized anti-CD20, as part of MCL induction and maintenance. Results of that study could challenge the role of rituximab in maintenance, the review authors noted. Likewise, the immune modulator lenalidomide has been evaluated as maintenance in an Italian phase 3 trial that recently closed to recruitment.

BTK inhibitors represent a “step change” in the management of MCL, according to the authors of this review.

“It has become clear that earlier use of ibrutinib leads to an improved outcome [in MCL] and it is logical to extend this into frontline treatment,” they wrote.

A randomized phase 3, multinational trial known as TRIANGLE, now open to recruitment, is designed to evaluate use of ibrutinib in both induction and maintenance. Investigators plan to enroll 870 patients into the three-arm study, which will also evaluate the use of ibrutinib as part of induction, but with no autologous stem cell transplant.

“The trial is the first to randomize to a non-ASCT arm since the introduction of rituximab and cytarabine to the induction regimen and the results have the potential to significantly reduce chemotherapy intensity and toxicity,” the authors said.

Dr. Rule reported consulting for Pharmacyclics, Napp, Sunesis, Acerta Pharma, Kite, AstraZeneca, Roche, Janssen, and Celgene, and research funding from Janssen, Celgene, and GSK. Dr. McCulloch reported having no financial disclosures.

SOURCE: McCulloch R et al. Best Pract Res Clin Haematol. 2018 Mar;31(1):90-8.

Not all younger patients with mantle cell lymphoma (MCL) are ideal candidates for conventional high-intensity upfront treatment, according to a recent review published in Best Practice & Research Clinical Haematology.

Use of high-dose cytarabine plus rituximab as frontline treatment is well established, with median overall survival now exceeding 10 years, said Rory McCulloch, MD, and Simon Rule, MD, of the department of Haematology, Derriford Hospital, Plymouth, England. However, there is no proven benefit to conventional therapy in patients with asymptomatic, non-bulky disease, making a watch-and-wait strategy appropriate for these patients, the authors said.

On the opposite end of the spectrum there is a subgroup of patients characterized by TP53 mutations and poor prognostic index scores that have poor outcomes in spite of conventional therapy.

These patients might have improved outcomes either with early allogeneic haematopoietic cell transplantation (allo-HCT), or, especially, clinical trials of novel agents in the upfront setting, the authors noted.

“There are a host of exciting novel agents, most prominently the BTK inhibitors, that are game changing with respect to their activity,” wrote Dr. McCulloch and Dr. Rule. “Based on the long-term results seen with conventional therapy, it is premature to be considering such new drugs in the frontline setting outside the context of a clinical trial, but it is hard to believe they will not become incorporated into treatment protocols in the future.”

Watch-and-wait treatment strategies for lower-risk patients are supported by the results of two single-center, retrospective studies published in 2009 that suggest the practice has no adverse impact on overall survival. More recent registry studies, published in 2016 and 2017, have shown that a significant proportion of patients can be managed according to the watch-and-wait strategy.

Although it’s been challenging to precisely define the group of patients for whom watch-and-wait is appropriate, enrollment criteria for studies have generally specified that patients be asymptomatic with non-bulky disease and non-blastoid morphology, they said.

For the minority of patients presenting with high-risk disease, allo-HCT may improve outcomes, according to Dr. McCulloch and Dr. Rule. One prospective study evaluating allogeneic transplants in frontline therapy showed favorable outcomes in younger patients, although few high-risk patients were enrolled.

However, a second prospective study of allo-HCT, involving 25 patients with untreated MCL in the United Kingdom, demonstrated a 2-year overall survival of 80%. “Although immature, the results are encouraging and provide data to support frontline allogeneic transplant for some patients,” Dr. McCulloch and Dr. Rule said in a comment on that study.

Novel agent studies have produced mixed results in treatment settings relevant to younger, high-risk MCL patients, though key trials are ongoing that could change practice.

One phase 2 study is evaluating obinituzumab, the fully humanized anti-CD20, as part of MCL induction and maintenance. Results of that study could challenge the role of rituximab in maintenance, the review authors noted. Likewise, the immune modulator lenalidomide has been evaluated as maintenance in an Italian phase 3 trial that recently closed to recruitment.

BTK inhibitors represent a “step change” in the management of MCL, according to the authors of this review.

“It has become clear that earlier use of ibrutinib leads to an improved outcome [in MCL] and it is logical to extend this into frontline treatment,” they wrote.

A randomized phase 3, multinational trial known as TRIANGLE, now open to recruitment, is designed to evaluate use of ibrutinib in both induction and maintenance. Investigators plan to enroll 870 patients into the three-arm study, which will also evaluate the use of ibrutinib as part of induction, but with no autologous stem cell transplant.

“The trial is the first to randomize to a non-ASCT arm since the introduction of rituximab and cytarabine to the induction regimen and the results have the potential to significantly reduce chemotherapy intensity and toxicity,” the authors said.

Dr. Rule reported consulting for Pharmacyclics, Napp, Sunesis, Acerta Pharma, Kite, AstraZeneca, Roche, Janssen, and Celgene, and research funding from Janssen, Celgene, and GSK. Dr. McCulloch reported having no financial disclosures.

SOURCE: McCulloch R et al. Best Pract Res Clin Haematol. 2018 Mar;31(1):90-8.

Not all younger patients with mantle cell lymphoma (MCL) are ideal candidates for conventional high-intensity upfront treatment, according to a recent review published in Best Practice & Research Clinical Haematology.

Use of high-dose cytarabine plus rituximab as frontline treatment is well established, with median overall survival now exceeding 10 years, said Rory McCulloch, MD, and Simon Rule, MD, of the department of Haematology, Derriford Hospital, Plymouth, England. However, there is no proven benefit to conventional therapy in patients with asymptomatic, non-bulky disease, making a watch-and-wait strategy appropriate for these patients, the authors said.

On the opposite end of the spectrum there is a subgroup of patients characterized by TP53 mutations and poor prognostic index scores that have poor outcomes in spite of conventional therapy.

These patients might have improved outcomes either with early allogeneic haematopoietic cell transplantation (allo-HCT), or, especially, clinical trials of novel agents in the upfront setting, the authors noted.

“There are a host of exciting novel agents, most prominently the BTK inhibitors, that are game changing with respect to their activity,” wrote Dr. McCulloch and Dr. Rule. “Based on the long-term results seen with conventional therapy, it is premature to be considering such new drugs in the frontline setting outside the context of a clinical trial, but it is hard to believe they will not become incorporated into treatment protocols in the future.”

Watch-and-wait treatment strategies for lower-risk patients are supported by the results of two single-center, retrospective studies published in 2009 that suggest the practice has no adverse impact on overall survival. More recent registry studies, published in 2016 and 2017, have shown that a significant proportion of patients can be managed according to the watch-and-wait strategy.

Although it’s been challenging to precisely define the group of patients for whom watch-and-wait is appropriate, enrollment criteria for studies have generally specified that patients be asymptomatic with non-bulky disease and non-blastoid morphology, they said.

For the minority of patients presenting with high-risk disease, allo-HCT may improve outcomes, according to Dr. McCulloch and Dr. Rule. One prospective study evaluating allogeneic transplants in frontline therapy showed favorable outcomes in younger patients, although few high-risk patients were enrolled.

However, a second prospective study of allo-HCT, involving 25 patients with untreated MCL in the United Kingdom, demonstrated a 2-year overall survival of 80%. “Although immature, the results are encouraging and provide data to support frontline allogeneic transplant for some patients,” Dr. McCulloch and Dr. Rule said in a comment on that study.

Novel agent studies have produced mixed results in treatment settings relevant to younger, high-risk MCL patients, though key trials are ongoing that could change practice.

One phase 2 study is evaluating obinituzumab, the fully humanized anti-CD20, as part of MCL induction and maintenance. Results of that study could challenge the role of rituximab in maintenance, the review authors noted. Likewise, the immune modulator lenalidomide has been evaluated as maintenance in an Italian phase 3 trial that recently closed to recruitment.

BTK inhibitors represent a “step change” in the management of MCL, according to the authors of this review.

“It has become clear that earlier use of ibrutinib leads to an improved outcome [in MCL] and it is logical to extend this into frontline treatment,” they wrote.

A randomized phase 3, multinational trial known as TRIANGLE, now open to recruitment, is designed to evaluate use of ibrutinib in both induction and maintenance. Investigators plan to enroll 870 patients into the three-arm study, which will also evaluate the use of ibrutinib as part of induction, but with no autologous stem cell transplant.

“The trial is the first to randomize to a non-ASCT arm since the introduction of rituximab and cytarabine to the induction regimen and the results have the potential to significantly reduce chemotherapy intensity and toxicity,” the authors said.

Dr. Rule reported consulting for Pharmacyclics, Napp, Sunesis, Acerta Pharma, Kite, AstraZeneca, Roche, Janssen, and Celgene, and research funding from Janssen, Celgene, and GSK. Dr. McCulloch reported having no financial disclosures.

SOURCE: McCulloch R et al. Best Pract Res Clin Haematol. 2018 Mar;31(1):90-8.

Although there currently are no formal guidelines for the treatment of refractory pityriasis rubra pilaris (PRP), successful off-label treatment of the condition with multiple biologics approved for psoriasis has been reported.^1,2 Secukinumab, an IL-17A antagonist, has shown particularly striking results in the treatment of PRP in 2 recent case reports.^3,4 We report 2 additional cases of severe refractory PRP that responded rapidly to treatment with secukinumab. In both cases, the patients’ erythematous plaques resolved or had nearly resolved by week 4 of treatment. Our findings suggest that IL-17 plays an important role in PRP pathogenesis and support future clinical trials of anti–IL-17 agents for treatment of this entity.

Case Reports

Patient 1
A 60-year-old man with a history of biopsy-proven PRP presented with persistent generalized erythema, scattered patches of normal skin, and hyperkeratotic plaques on the bilateral palms of 1 year’s duration. Previous therapies included topical steroids, topical calcipotriene, adalimumab 40 mg once every other week, infliximab 5 mg/kg once every 8 weeks, ustekinumab 90 mg once every 12 weeks, acitretin 25 mg once daily, and most recently cyclosporine 200 mg twice daily. Of these treatments, infliximab was the only treatment that provided minimal relief; however, the patient continued to have itching and painful plaques covering approximately 20% of body surface area (Figure 1A). Infliximab was therefore discontinued and treatment with cyclosporine was started. After failure on cyclosporine, the patient was started on secukinumab, with loading doses of 300 mg injected subcutaneously once weekly for 5 weeks.

At 4 weeks’ follow-up, there was a marked decrease in erythema and scaling. The body surface area affected had decreased to 5%, and improvement of palmar keratoderma was noted. The patient continued with maintenance dosing of secukinumab 300 mg once every 4 weeks. By week 8, the erythema had fully resolved (Figure 1B), and he remained clear at week 24. No adverse events were noted since initiation of therapy.

The patient had been maintained on ustekinumab and acitretin for 2 years with only mild improvement. Ustekinumab was then discontinued, and after 3 months treatment with secukinumab was added to the once-daily acitretin. Similar to Patient 1, loading doses of secukinumab 300 mg were administered once weekly for 5 weeks. The plaques on the trunk and arms had resolved by week 4, but the palmoplantar keratoderma persisted. The patient continued with the maintenance dose of secukinumab 300 mg once every 4 weeks and reported an increase in peeling of the palms and soles at week 8.

By week 12 of treatment, the palmar keratoderma had resolved, and debridement of the soles revealed patches of normal skin (Figure 2B). By week 52, no adverse events had been noted. The patient continued to experience mild keratoderma of the soles, making us reluctant to discontinue acitretin; however, she has maintained her maximal response, and her quality of life has significantly improved. The patient was continued on acitretin and secukinumab, and her condition remained stable.

Comment

Because there are no formal treatment guidelines for refractory PRP, case reports play an important role in clinical decision-making. When a patient is unresponsive to topical medications and first-line traditional systemic therapies (eg, methotrexate, cyclosporine, acitretin), biologic drugs effective in the treatment of psoriasis are widely accepted as the next therapeutic step.¹ The biologic medications that are most often reported in the treatment of PRP are the TNF-α antagonists, as they have been available the longest.^1-2 In a systematic review of 15 patients with PRP who were treated with TNF-α antagonists,² 80% of patients achieved complete response (mean time to maximal response, 5 months). There also are a number of reports of successful treatment of PRP with the IL-12/23 antagonist ustekinumab, which has been commercially available since 2009.^5-9 Although improvement was noted in most of these patients at the time of the second injection (week 4 of therapy), maximal response with ustekinumab typically occurs between weeks 12 and 28.¹⁰

In our cases of PRP treated with secukinumab as well as 2 others that were recently reported in the literature, resolution of erythema and plaques was rapid. This superiority of the response rate parallels the performance of secukinumab relative to ustekinumab in patients with psoriasis¹¹ In one case of a 67-year-old man with PRP treated with secukinumab, scaling and pruritus were reduced by week 3 of treatment and erythema had cleared by week 8.³ In another case of a 33-year-old woman with PRP, pruritus resolved after 1 week of treatment and erythematous plaques and palmoplantar keratoderma improved by week 2.⁴ In both of our cases, plaques had resolved or nearly resolved by week 4 of follow-up. Patient 1 achieved complete response at week 8 of therapy. Patient 2 never attained complete response, but by week 12 she achieved maximal response, which still resulted in markedly increased quality of life. We do not intend to make additions to her treatment plan because she is currently the clearest she has been since onset of symptoms and is happy with her present condition.

Although it is difficult to predict the long-term prognosis in our 2 patients, we will continue their current regimens indefinitely—as long as the response persists and no adverse events are experienced. This approach is consistent with guidelines for management of plaque psoriasis with secukinumab.¹²

This accumulation of evidence suggests the importance of the role of IL-17 in the pathogenesis of PRP. The serum level of IL-17 was not evaluated in our patients, but elevation of IL-17 has been reported in a case of PRP.¹³ Further studies are needed to clarify the role of IL-17 in this disease entity.

Conclusion

Given the refractory nature of PRP and the relative safety of targeted immunotherapy, trials of new biologics and potent small molecules approved for psoriasis treatment are worth exploring for PRP. In light of our reports and those in the literature and given the relative safety of anti–IL-17 agents, it may be reasonable to consider such agents as a first-line therapy for this predictably refractory disease.

Although there currently are no formal guidelines for the treatment of refractory pityriasis rubra pilaris (PRP), successful off-label treatment of the condition with multiple biologics approved for psoriasis has been reported.^1,2 Secukinumab, an IL-17A antagonist, has shown particularly striking results in the treatment of PRP in 2 recent case reports.^3,4 We report 2 additional cases of severe refractory PRP that responded rapidly to treatment with secukinumab. In both cases, the patients’ erythematous plaques resolved or had nearly resolved by week 4 of treatment. Our findings suggest that IL-17 plays an important role in PRP pathogenesis and support future clinical trials of anti–IL-17 agents for treatment of this entity.

Case Reports

Patient 1
A 60-year-old man with a history of biopsy-proven PRP presented with persistent generalized erythema, scattered patches of normal skin, and hyperkeratotic plaques on the bilateral palms of 1 year’s duration. Previous therapies included topical steroids, topical calcipotriene, adalimumab 40 mg once every other week, infliximab 5 mg/kg once every 8 weeks, ustekinumab 90 mg once every 12 weeks, acitretin 25 mg once daily, and most recently cyclosporine 200 mg twice daily. Of these treatments, infliximab was the only treatment that provided minimal relief; however, the patient continued to have itching and painful plaques covering approximately 20% of body surface area (Figure 1A). Infliximab was therefore discontinued and treatment with cyclosporine was started. After failure on cyclosporine, the patient was started on secukinumab, with loading doses of 300 mg injected subcutaneously once weekly for 5 weeks.

At 4 weeks’ follow-up, there was a marked decrease in erythema and scaling. The body surface area affected had decreased to 5%, and improvement of palmar keratoderma was noted. The patient continued with maintenance dosing of secukinumab 300 mg once every 4 weeks. By week 8, the erythema had fully resolved (Figure 1B), and he remained clear at week 24. No adverse events were noted since initiation of therapy.

The patient had been maintained on ustekinumab and acitretin for 2 years with only mild improvement. Ustekinumab was then discontinued, and after 3 months treatment with secukinumab was added to the once-daily acitretin. Similar to Patient 1, loading doses of secukinumab 300 mg were administered once weekly for 5 weeks. The plaques on the trunk and arms had resolved by week 4, but the palmoplantar keratoderma persisted. The patient continued with the maintenance dose of secukinumab 300 mg once every 4 weeks and reported an increase in peeling of the palms and soles at week 8.

By week 12 of treatment, the palmar keratoderma had resolved, and debridement of the soles revealed patches of normal skin (Figure 2B). By week 52, no adverse events had been noted. The patient continued to experience mild keratoderma of the soles, making us reluctant to discontinue acitretin; however, she has maintained her maximal response, and her quality of life has significantly improved. The patient was continued on acitretin and secukinumab, and her condition remained stable.

Comment

Because there are no formal treatment guidelines for refractory PRP, case reports play an important role in clinical decision-making. When a patient is unresponsive to topical medications and first-line traditional systemic therapies (eg, methotrexate, cyclosporine, acitretin), biologic drugs effective in the treatment of psoriasis are widely accepted as the next therapeutic step.¹ The biologic medications that are most often reported in the treatment of PRP are the TNF-α antagonists, as they have been available the longest.^1-2 In a systematic review of 15 patients with PRP who were treated with TNF-α antagonists,² 80% of patients achieved complete response (mean time to maximal response, 5 months). There also are a number of reports of successful treatment of PRP with the IL-12/23 antagonist ustekinumab, which has been commercially available since 2009.^5-9 Although improvement was noted in most of these patients at the time of the second injection (week 4 of therapy), maximal response with ustekinumab typically occurs between weeks 12 and 28.¹⁰

In our cases of PRP treated with secukinumab as well as 2 others that were recently reported in the literature, resolution of erythema and plaques was rapid. This superiority of the response rate parallels the performance of secukinumab relative to ustekinumab in patients with psoriasis¹¹ In one case of a 67-year-old man with PRP treated with secukinumab, scaling and pruritus were reduced by week 3 of treatment and erythema had cleared by week 8.³ In another case of a 33-year-old woman with PRP, pruritus resolved after 1 week of treatment and erythematous plaques and palmoplantar keratoderma improved by week 2.⁴ In both of our cases, plaques had resolved or nearly resolved by week 4 of follow-up. Patient 1 achieved complete response at week 8 of therapy. Patient 2 never attained complete response, but by week 12 she achieved maximal response, which still resulted in markedly increased quality of life. We do not intend to make additions to her treatment plan because she is currently the clearest she has been since onset of symptoms and is happy with her present condition.

Although it is difficult to predict the long-term prognosis in our 2 patients, we will continue their current regimens indefinitely—as long as the response persists and no adverse events are experienced. This approach is consistent with guidelines for management of plaque psoriasis with secukinumab.¹²

This accumulation of evidence suggests the importance of the role of IL-17 in the pathogenesis of PRP. The serum level of IL-17 was not evaluated in our patients, but elevation of IL-17 has been reported in a case of PRP.¹³ Further studies are needed to clarify the role of IL-17 in this disease entity.

Conclusion

Given the refractory nature of PRP and the relative safety of targeted immunotherapy, trials of new biologics and potent small molecules approved for psoriasis treatment are worth exploring for PRP. In light of our reports and those in the literature and given the relative safety of anti–IL-17 agents, it may be reasonable to consider such agents as a first-line therapy for this predictably refractory disease.

Although there currently are no formal guidelines for the treatment of refractory pityriasis rubra pilaris (PRP), successful off-label treatment of the condition with multiple biologics approved for psoriasis has been reported.^1,2 Secukinumab, an IL-17A antagonist, has shown particularly striking results in the treatment of PRP in 2 recent case reports.^3,4 We report 2 additional cases of severe refractory PRP that responded rapidly to treatment with secukinumab. In both cases, the patients’ erythematous plaques resolved or had nearly resolved by week 4 of treatment. Our findings suggest that IL-17 plays an important role in PRP pathogenesis and support future clinical trials of anti–IL-17 agents for treatment of this entity.

Case Reports

Patient 1
A 60-year-old man with a history of biopsy-proven PRP presented with persistent generalized erythema, scattered patches of normal skin, and hyperkeratotic plaques on the bilateral palms of 1 year’s duration. Previous therapies included topical steroids, topical calcipotriene, adalimumab 40 mg once every other week, infliximab 5 mg/kg once every 8 weeks, ustekinumab 90 mg once every 12 weeks, acitretin 25 mg once daily, and most recently cyclosporine 200 mg twice daily. Of these treatments, infliximab was the only treatment that provided minimal relief; however, the patient continued to have itching and painful plaques covering approximately 20% of body surface area (Figure 1A). Infliximab was therefore discontinued and treatment with cyclosporine was started. After failure on cyclosporine, the patient was started on secukinumab, with loading doses of 300 mg injected subcutaneously once weekly for 5 weeks.

At 4 weeks’ follow-up, there was a marked decrease in erythema and scaling. The body surface area affected had decreased to 5%, and improvement of palmar keratoderma was noted. The patient continued with maintenance dosing of secukinumab 300 mg once every 4 weeks. By week 8, the erythema had fully resolved (Figure 1B), and he remained clear at week 24. No adverse events were noted since initiation of therapy.

The patient had been maintained on ustekinumab and acitretin for 2 years with only mild improvement. Ustekinumab was then discontinued, and after 3 months treatment with secukinumab was added to the once-daily acitretin. Similar to Patient 1, loading doses of secukinumab 300 mg were administered once weekly for 5 weeks. The plaques on the trunk and arms had resolved by week 4, but the palmoplantar keratoderma persisted. The patient continued with the maintenance dose of secukinumab 300 mg once every 4 weeks and reported an increase in peeling of the palms and soles at week 8.

By week 12 of treatment, the palmar keratoderma had resolved, and debridement of the soles revealed patches of normal skin (Figure 2B). By week 52, no adverse events had been noted. The patient continued to experience mild keratoderma of the soles, making us reluctant to discontinue acitretin; however, she has maintained her maximal response, and her quality of life has significantly improved. The patient was continued on acitretin and secukinumab, and her condition remained stable.

Comment

Because there are no formal treatment guidelines for refractory PRP, case reports play an important role in clinical decision-making. When a patient is unresponsive to topical medications and first-line traditional systemic therapies (eg, methotrexate, cyclosporine, acitretin), biologic drugs effective in the treatment of psoriasis are widely accepted as the next therapeutic step.¹ The biologic medications that are most often reported in the treatment of PRP are the TNF-α antagonists, as they have been available the longest.^1-2 In a systematic review of 15 patients with PRP who were treated with TNF-α antagonists,² 80% of patients achieved complete response (mean time to maximal response, 5 months). There also are a number of reports of successful treatment of PRP with the IL-12/23 antagonist ustekinumab, which has been commercially available since 2009.^5-9 Although improvement was noted in most of these patients at the time of the second injection (week 4 of therapy), maximal response with ustekinumab typically occurs between weeks 12 and 28.¹⁰

In our cases of PRP treated with secukinumab as well as 2 others that were recently reported in the literature, resolution of erythema and plaques was rapid. This superiority of the response rate parallels the performance of secukinumab relative to ustekinumab in patients with psoriasis¹¹ In one case of a 67-year-old man with PRP treated with secukinumab, scaling and pruritus were reduced by week 3 of treatment and erythema had cleared by week 8.³ In another case of a 33-year-old woman with PRP, pruritus resolved after 1 week of treatment and erythematous plaques and palmoplantar keratoderma improved by week 2.⁴ In both of our cases, plaques had resolved or nearly resolved by week 4 of follow-up. Patient 1 achieved complete response at week 8 of therapy. Patient 2 never attained complete response, but by week 12 she achieved maximal response, which still resulted in markedly increased quality of life. We do not intend to make additions to her treatment plan because she is currently the clearest she has been since onset of symptoms and is happy with her present condition.

Although it is difficult to predict the long-term prognosis in our 2 patients, we will continue their current regimens indefinitely—as long as the response persists and no adverse events are experienced. This approach is consistent with guidelines for management of plaque psoriasis with secukinumab.¹²

This accumulation of evidence suggests the importance of the role of IL-17 in the pathogenesis of PRP. The serum level of IL-17 was not evaluated in our patients, but elevation of IL-17 has been reported in a case of PRP.¹³ Further studies are needed to clarify the role of IL-17 in this disease entity.

Conclusion

Given the refractory nature of PRP and the relative safety of targeted immunotherapy, trials of new biologics and potent small molecules approved for psoriasis treatment are worth exploring for PRP. In light of our reports and those in the literature and given the relative safety of anti–IL-17 agents, it may be reasonable to consider such agents as a first-line therapy for this predictably refractory disease.

LOS ANGELES – Transient epileptic amnesia is a rare but a treatable memory condition that usually occurs in late life and can be mistaken for neurodegenerative disease among patients presenting to a neurology or memory clinic.

Transient epileptic amnesia (TEA) is thought to be a focal epilepsy whose major clinical feature is the presence of recurrent spells of anterograde or retrograde amnesia lasting under an hour. The spells tend to occur on waking from sleep.

©Thinkstock

FDG-PET, however, revealed focal abnormalities in 11 of the 16 cases that underwent scanning. “Most of them had focal areas of hypometabolism; none of those metabolic patterns fit those of known neurodegenerative disorders, and more rarely they were entirely normal,” Dr. Ramanan said during a presentation of his findings.

The results suggest that FDG-PET “may be a more useful tool than EEG” in distinguishing TEA from other disorders, he said. “I think the fascinating question going forward is whether TEA has an underlying biomarker and if there’s a neuroimaging biomarker for this. From these data, I think FDG-PET could be a very promising avenue for that,” he said.

In most of these cases where there was an abnormality detected on EEG, he noted that the patient “had multiple or prolonged EEGs, so it’s not always an easy thing to catch.”

Dr. Ramanan stressed that it’s important for clinicians “to have your antennae up for this diagnosis, particularly as these patients will come in with chronic memory trouble, because this is something we can fix.” In his study, all of the 22 individuals followed up after treatment with antiepileptic drugs, most commonly lamotrigine or levetiracetam, improved on follow-up.

Dr. Ramanan and his colleagues disclosed no conflicts of interest related to their findings.

SOURCE: Ramanan V et al. Neurology. 2018 Apr 90(15 Suppl.):P3.035.

LOS ANGELES – Transient epileptic amnesia is a rare but a treatable memory condition that usually occurs in late life and can be mistaken for neurodegenerative disease among patients presenting to a neurology or memory clinic.

Transient epileptic amnesia (TEA) is thought to be a focal epilepsy whose major clinical feature is the presence of recurrent spells of anterograde or retrograde amnesia lasting under an hour. The spells tend to occur on waking from sleep.

©Thinkstock

FDG-PET, however, revealed focal abnormalities in 11 of the 16 cases that underwent scanning. “Most of them had focal areas of hypometabolism; none of those metabolic patterns fit those of known neurodegenerative disorders, and more rarely they were entirely normal,” Dr. Ramanan said during a presentation of his findings.

The results suggest that FDG-PET “may be a more useful tool than EEG” in distinguishing TEA from other disorders, he said. “I think the fascinating question going forward is whether TEA has an underlying biomarker and if there’s a neuroimaging biomarker for this. From these data, I think FDG-PET could be a very promising avenue for that,” he said.

In most of these cases where there was an abnormality detected on EEG, he noted that the patient “had multiple or prolonged EEGs, so it’s not always an easy thing to catch.”

Dr. Ramanan stressed that it’s important for clinicians “to have your antennae up for this diagnosis, particularly as these patients will come in with chronic memory trouble, because this is something we can fix.” In his study, all of the 22 individuals followed up after treatment with antiepileptic drugs, most commonly lamotrigine or levetiracetam, improved on follow-up.

Dr. Ramanan and his colleagues disclosed no conflicts of interest related to their findings.

SOURCE: Ramanan V et al. Neurology. 2018 Apr 90(15 Suppl.):P3.035.

LOS ANGELES – Transient epileptic amnesia is a rare but a treatable memory condition that usually occurs in late life and can be mistaken for neurodegenerative disease among patients presenting to a neurology or memory clinic.

Transient epileptic amnesia (TEA) is thought to be a focal epilepsy whose major clinical feature is the presence of recurrent spells of anterograde or retrograde amnesia lasting under an hour. The spells tend to occur on waking from sleep.

©Thinkstock

FDG-PET, however, revealed focal abnormalities in 11 of the 16 cases that underwent scanning. “Most of them had focal areas of hypometabolism; none of those metabolic patterns fit those of known neurodegenerative disorders, and more rarely they were entirely normal,” Dr. Ramanan said during a presentation of his findings.

The results suggest that FDG-PET “may be a more useful tool than EEG” in distinguishing TEA from other disorders, he said. “I think the fascinating question going forward is whether TEA has an underlying biomarker and if there’s a neuroimaging biomarker for this. From these data, I think FDG-PET could be a very promising avenue for that,” he said.

In most of these cases where there was an abnormality detected on EEG, he noted that the patient “had multiple or prolonged EEGs, so it’s not always an easy thing to catch.”

Dr. Ramanan stressed that it’s important for clinicians “to have your antennae up for this diagnosis, particularly as these patients will come in with chronic memory trouble, because this is something we can fix.” In his study, all of the 22 individuals followed up after treatment with antiepileptic drugs, most commonly lamotrigine or levetiracetam, improved on follow-up.

Dr. Ramanan and his colleagues disclosed no conflicts of interest related to their findings.

SOURCE: Ramanan V et al. Neurology. 2018 Apr 90(15 Suppl.):P3.035.