Cutis

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of the skin that is thought to arise from neural crest cells. It has an estimated annual incidence of 0.6 per 100,000 individuals, typically occurs in the elderly population, and is most common in white males.¹ The tumor presents as a rapidly growing, violaceous nodule in sun-exposed areas of the skin; early in the course, it can be mistaken for a benign entity such as an epidermal cyst.² Merkel cell carcinoma has a propensity to spread to regional lymph nodes, and in some cases, it occurs in the absence of skin findings.³ Histologically, MCC is nearly indistinguishable from small cell lung carcinoma (SCLC).⁴ The overall prognosis for patients with MCC is poor and largely dependent on the stage at diagnosis. Patients with regional and distant metastases have a 5-year survival rate of 26% to 42% and 18%, respectively.³

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic or autoimmune disorder of the neuromuscular junction that is found in 3% of cases of SCLC.⁴ Reported cases of LEMS in patients with MCC are exceedingly rare.^5-8 We provide a full report and longitudinal clinical follow-up of a case that was briefly discussed by Simmons et al,⁸ and we review the literature regarding paraneoplastic syndromes associated with MCC and other extrapulmonary small cell carcinomas (EPSCCs).

Case Report

A 63-year-old man was evaluated in the neurology clinic due to difficulty walking, climbing stairs, and performing push-ups over the last month. Prior to the onset of symptoms, he was otherwise healthy, walking 3 miles daily; however, at presentation he required use of a cane. Leg weakness worsened as the day progressed. In addition, he reported constipation, urinary urgency, dry mouth, mild dysphagia, reduced sensation below the knees, and a nasal quality in his speech. He had no ptosis, diplopia, dysarthria, muscle cramps, myalgia, or facial weakness. He denied fevers, chills, and night sweats but did admit to an unintentional 10- to 15-lb weight loss over the preceding few months.

The neurologic examination revealed mild proximal upper extremity weakness in the bilateral shoulder abductors, infraspinatus, hip extensors, and hip flexors (Medical Research Council muscle scale grade 4). All deep tendon reflexes, except the Achilles reflex, were present. Despite subjective sensory concerns, objective examination of all sensory modalities was normal. Cranial nerve examination was normal, except for a slight nasal quality to his voice.

A qualitative assay was positive for the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies. Other laboratory studies were within reference range, including acetylcholine-receptor antibodies (blocking, binding, and modulating) and muscle-specific kinase antibodies.

Lumbar and cervical spine magnetic resonance imaging revealed multilevel neuroforaminal stenosis without spinal canal stenosis or myelopathy. Computed tomography (CT) of the chest was notable for 2 pathologically enlarged lymph nodes in the left axilla and no evidence of primary pulmonary malignancy. Nerve-conduction studies (NCSs) in conjunction with other clinical findings were consistent with the diagnosis of LEMS.

Ultrasound-guided biopsy of the enlarged axillary lymph nodes demonstrated sheets and nests of small round blue tumor cells with minimal cytoplasm, high mitotic rate, and foci of necrosis (Figure 1). The tumor cells were positive for pancytokeratin (Lu-5) and cytokeratin (CK) 20 in a perinuclear dotlike pattern (Figure 2), as well as for the neuroendocrine markers synaptophysin (Figure 3), chromogranin A, and CD56. The tumor cells showed no immunoreactivity for CK7, thyroid transcription factor 1, CD3, CD5, or CD20. Flow cytometry demonstrated low cellularity, low specimen viability, and no evidence of an abnormal B-cell population. These findings were consistent with the diagnosis of MCC.

The patient underwent surgical excision of the involved lymph nodes. Four weeks after surgery, he reported dramatic improvement in strength, with complete resolution of the nasal speech, dysphagia, dry mouth, urinary retention, and constipation. Two months after surgery, his strength had normalized, except for slight persistent weakness in the bilateral shoulder abductors, trace weakness in the hip flexors, and a slight Trendelenburg gait. He was able to rise from a chair without using his arms and no longer required a cane for ambulation.

The patient underwent adjuvant radiation therapy after 2-month surgical follow-up with 5000-cGy radiation treatment to the left axillary region. Six months following primary definitive surgery and 4 months following adjuvant radiation therapy, he reported a 95% subjective return of physical strength. The patient was able to return to near-baseline physical activity. He continued to deny symptoms of dry mouth, incontinence, or constipation. Objectively, he had no focal neurologic deficits or weakness; no evidence of new skin lesions or lymphadenopathy was noted.

Comment

MCC vs SCLC
Merkel cell carcinoma is classified as a type of EPSCC. The histologic appearance of MCC is indistinguishable from SCLC. Both tumors are composed of uniform sheets of small round cells with a high nucleus to cytoplasm ratio, and both can express neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and synaptophysin.⁹ Immunohistochemical positivity for CK20 and neurofilaments in combination with negative staining for thyroid transcription factor 1 and CK7 effectively differentiate MCC from SCLC.⁹ In addition, MCC often displays CK20 positivity in a perinuclear dotlike or punctate pattern, which is characteristic of this tumor.^3,9,10 Negative immunohistochemical markers for B cells (CD20) and T cells (CD3) are important in excluding lymphoma.

LEMS Diagnosis
Lambert-Eaton myasthenic syndrome is a paraneoplastic or autoimmune disorder involving the neuromuscular junction. Autoantibodies to VGCC impair calcium influx into the presynaptic terminal, resulting in marked reduction of acetylcholine release into the synaptic cleft. The reduction in acetylcholine activity impairs production of muscle fiber action potentials, resulting in clinical weakness. The diagnosis of LEMS rests on clinical presentation, positive serology, and confirmatory neurophysiologic testing by NCS. Clinically, patients present with proximal weakness, hyporeflexia or areflexia, and autonomic dysfunction. Antibodies to P/Q-type VGCCs are found in 85% to 90% of cases of LEMS and are thought to play a direct causative role in the development of weakness.¹¹ The finding of postexercise facilitation on motor NCS is the neurophysiologic hallmark and is highly specific for the diagnosis.

Approximately 50% to 60% of patients who present with LEMS have an underlying tumor, the vast majority of which are SCLC.¹¹ There are a few reports of LEMS associated with other malignancies, including lymphoma; thymoma; neuroblastoma; and carcinoma of the breast, stomach, prostate, bladder, kidney, and gallbladder.¹² Patients with nontumor or autoimmune LEMS tend to be younger, and there is no male predominance, as there is in paraneoplastic LEMS.¹³ Given the risk of underlying malignancy in LEMS, Titulaer et al¹⁴ proposed a screening protocol for patients presenting with LEMS, recommending initial primary screening using CT of the chest. If the CT scan is negative, total-body fludeoxyglucose positron emission tomography should be performed to assess for fludeoxyglucose avid lesions. If both initial studies are negative, routine follow-up with CT of the chest at 6-month intervals for a minimum of 2 to 4 years after the initial diagnosis of LEMS was recommended. An exception to this protocol was suggested to allow consideration to stop screening after the first 6-month follow-up chest CT for patients younger than 45 years who have never smoked and who have an HLA 8.1 haplotype for which nontumor LEMS would be a more probable diagnosis.¹⁴

In addition to a screening protocol, a validated prediction tool, the Dutch-English LEMS Tumor Association prediction score, was developed. It uses common signs and symptoms of LEMS and risk factors for SCLC to help guide the need for further screening.¹⁵

Paraneoplastic Syndromes Associated With MCC
Other paraneoplastic syndromes have been reported in association with MCC. A patient with brainstem encephalitis associated with MCC was reported in a trial of a novel immunotherapy for paraneoplastic neurologic syndromes.^16,17 A syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported in a patient with N-type calcium channel antibodies.¹⁸ Two cases of paraneoplastic cerebellar degeneration have been reported; the first was associated with a novel 70-kD antibody,¹⁹ and the second was associated with the P/Q-type VGCC antibody.²⁰ Anti-Hu antibodies have been found in a handful of reports of neurologic deterioration in patients with MCC. Hocar et al²¹ reported a severe necrotizing myopathy; Greenlee et al²² described a syndrome of progressive sensorimotor and autonomic neuropathy with encephalopathy; and Lopez et al²³ described a constellation of vision changes, gait imbalance, and proximal weakness. Support for a pathophysiologic connection among these 3 cases is suggested by the finding of Hu antigen expression by MCC in 2 studies.^24,25 Because MCC can present with occult lymph node involvement in the absence of primary cutaneous findings,³ there are more cases of paraneoplastic neurologic syndromes that were not recognized.

Extrapulmonary small cell carcinomas such as MCC are morphologically indistinguishable from their pulmonary counterparts and have been reported in most anatomic regions of the body, including gynecologic organs (eg, ovaries, cervix), genitourinary organs (eg, bladder, prostate), the gastrointestinal tract (eg, esophagus), skin (eg, MCC), and the head and neck region. Extrapulmonary small cell carcinoma is a rare entity, with the most common form found in the gynecologic tract, representing only 2% of gynecologic malignancies.²⁶

Paraneoplastic syndromes of EPSCC are rare given the paucity of the malignancy. Several case reports discuss findings of SIADH in EPSCC of the cervix, as well as hypercalcemia, polyneuropathy, Cushing syndrome, limbic encephalitis, and peripheral neuropathy in EPSCC of the prostate.^27,28 In contrast, SCLC has long been associated with paraneoplastic syndromes. Numerous case reports have been published describing SCLC-associated paraneoplastic syndromes to include hypercalcemia, Cushing syndrome, SIADH, vasoactive peptide production, cerebellar degeneration, limbic encephalitis, visceral plexopathy, autonomic dysfunction, and LEMS.²⁹ As more cases of EPSCC with paraneoplastic syndromes are identified and reported, we might gain a better understanding of this interesting phenomenon.

Conclusion

Merkel cell carcinoma is an aggressive neuroendocrine malignancy associated with paraneoplastic neurologic syndromes, including LEMS. A thorough search for an underlying malignancy is highly recommended in patients with diagnosed LEMS without clear cause. Early identification and treatment of the primary tumor can lead to improvement of neurologic symptoms.

We present a case of LEMS with no clearly identifiable cause on presentation with later diagnosis of metastatic MCC of unknown primary origin. After surgical excision of affected lymph nodes and adjuvant radiation therapy, the patient had near-complete resolution of LEMS symptoms at 6-month follow-up, without additional findings of lymphadenopathy or skin lesions. Although this patient is not undergoing routine surveillance imaging to monitor for recurrence of MCC, a chest CT or positron emission tomography–CT for secondary screening would be considered if the patient experienced clinical symptoms consistent with LEMS.

In cases of LEMS without pulmonary malignancy, we recommend considering MCC in the differential diagnosis during the workup of an underlying malignancy

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of the skin that is thought to arise from neural crest cells. It has an estimated annual incidence of 0.6 per 100,000 individuals, typically occurs in the elderly population, and is most common in white males.¹ The tumor presents as a rapidly growing, violaceous nodule in sun-exposed areas of the skin; early in the course, it can be mistaken for a benign entity such as an epidermal cyst.² Merkel cell carcinoma has a propensity to spread to regional lymph nodes, and in some cases, it occurs in the absence of skin findings.³ Histologically, MCC is nearly indistinguishable from small cell lung carcinoma (SCLC).⁴ The overall prognosis for patients with MCC is poor and largely dependent on the stage at diagnosis. Patients with regional and distant metastases have a 5-year survival rate of 26% to 42% and 18%, respectively.³

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic or autoimmune disorder of the neuromuscular junction that is found in 3% of cases of SCLC.⁴ Reported cases of LEMS in patients with MCC are exceedingly rare.^5-8 We provide a full report and longitudinal clinical follow-up of a case that was briefly discussed by Simmons et al,⁸ and we review the literature regarding paraneoplastic syndromes associated with MCC and other extrapulmonary small cell carcinomas (EPSCCs).

Case Report

A 63-year-old man was evaluated in the neurology clinic due to difficulty walking, climbing stairs, and performing push-ups over the last month. Prior to the onset of symptoms, he was otherwise healthy, walking 3 miles daily; however, at presentation he required use of a cane. Leg weakness worsened as the day progressed. In addition, he reported constipation, urinary urgency, dry mouth, mild dysphagia, reduced sensation below the knees, and a nasal quality in his speech. He had no ptosis, diplopia, dysarthria, muscle cramps, myalgia, or facial weakness. He denied fevers, chills, and night sweats but did admit to an unintentional 10- to 15-lb weight loss over the preceding few months.

The neurologic examination revealed mild proximal upper extremity weakness in the bilateral shoulder abductors, infraspinatus, hip extensors, and hip flexors (Medical Research Council muscle scale grade 4). All deep tendon reflexes, except the Achilles reflex, were present. Despite subjective sensory concerns, objective examination of all sensory modalities was normal. Cranial nerve examination was normal, except for a slight nasal quality to his voice.

A qualitative assay was positive for the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies. Other laboratory studies were within reference range, including acetylcholine-receptor antibodies (blocking, binding, and modulating) and muscle-specific kinase antibodies.

Lumbar and cervical spine magnetic resonance imaging revealed multilevel neuroforaminal stenosis without spinal canal stenosis or myelopathy. Computed tomography (CT) of the chest was notable for 2 pathologically enlarged lymph nodes in the left axilla and no evidence of primary pulmonary malignancy. Nerve-conduction studies (NCSs) in conjunction with other clinical findings were consistent with the diagnosis of LEMS.

Ultrasound-guided biopsy of the enlarged axillary lymph nodes demonstrated sheets and nests of small round blue tumor cells with minimal cytoplasm, high mitotic rate, and foci of necrosis (Figure 1). The tumor cells were positive for pancytokeratin (Lu-5) and cytokeratin (CK) 20 in a perinuclear dotlike pattern (Figure 2), as well as for the neuroendocrine markers synaptophysin (Figure 3), chromogranin A, and CD56. The tumor cells showed no immunoreactivity for CK7, thyroid transcription factor 1, CD3, CD5, or CD20. Flow cytometry demonstrated low cellularity, low specimen viability, and no evidence of an abnormal B-cell population. These findings were consistent with the diagnosis of MCC.

The patient underwent surgical excision of the involved lymph nodes. Four weeks after surgery, he reported dramatic improvement in strength, with complete resolution of the nasal speech, dysphagia, dry mouth, urinary retention, and constipation. Two months after surgery, his strength had normalized, except for slight persistent weakness in the bilateral shoulder abductors, trace weakness in the hip flexors, and a slight Trendelenburg gait. He was able to rise from a chair without using his arms and no longer required a cane for ambulation.

The patient underwent adjuvant radiation therapy after 2-month surgical follow-up with 5000-cGy radiation treatment to the left axillary region. Six months following primary definitive surgery and 4 months following adjuvant radiation therapy, he reported a 95% subjective return of physical strength. The patient was able to return to near-baseline physical activity. He continued to deny symptoms of dry mouth, incontinence, or constipation. Objectively, he had no focal neurologic deficits or weakness; no evidence of new skin lesions or lymphadenopathy was noted.

Comment

MCC vs SCLC
Merkel cell carcinoma is classified as a type of EPSCC. The histologic appearance of MCC is indistinguishable from SCLC. Both tumors are composed of uniform sheets of small round cells with a high nucleus to cytoplasm ratio, and both can express neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and synaptophysin.⁹ Immunohistochemical positivity for CK20 and neurofilaments in combination with negative staining for thyroid transcription factor 1 and CK7 effectively differentiate MCC from SCLC.⁹ In addition, MCC often displays CK20 positivity in a perinuclear dotlike or punctate pattern, which is characteristic of this tumor.^3,9,10 Negative immunohistochemical markers for B cells (CD20) and T cells (CD3) are important in excluding lymphoma.

LEMS Diagnosis
Lambert-Eaton myasthenic syndrome is a paraneoplastic or autoimmune disorder involving the neuromuscular junction. Autoantibodies to VGCC impair calcium influx into the presynaptic terminal, resulting in marked reduction of acetylcholine release into the synaptic cleft. The reduction in acetylcholine activity impairs production of muscle fiber action potentials, resulting in clinical weakness. The diagnosis of LEMS rests on clinical presentation, positive serology, and confirmatory neurophysiologic testing by NCS. Clinically, patients present with proximal weakness, hyporeflexia or areflexia, and autonomic dysfunction. Antibodies to P/Q-type VGCCs are found in 85% to 90% of cases of LEMS and are thought to play a direct causative role in the development of weakness.¹¹ The finding of postexercise facilitation on motor NCS is the neurophysiologic hallmark and is highly specific for the diagnosis.

Approximately 50% to 60% of patients who present with LEMS have an underlying tumor, the vast majority of which are SCLC.¹¹ There are a few reports of LEMS associated with other malignancies, including lymphoma; thymoma; neuroblastoma; and carcinoma of the breast, stomach, prostate, bladder, kidney, and gallbladder.¹² Patients with nontumor or autoimmune LEMS tend to be younger, and there is no male predominance, as there is in paraneoplastic LEMS.¹³ Given the risk of underlying malignancy in LEMS, Titulaer et al¹⁴ proposed a screening protocol for patients presenting with LEMS, recommending initial primary screening using CT of the chest. If the CT scan is negative, total-body fludeoxyglucose positron emission tomography should be performed to assess for fludeoxyglucose avid lesions. If both initial studies are negative, routine follow-up with CT of the chest at 6-month intervals for a minimum of 2 to 4 years after the initial diagnosis of LEMS was recommended. An exception to this protocol was suggested to allow consideration to stop screening after the first 6-month follow-up chest CT for patients younger than 45 years who have never smoked and who have an HLA 8.1 haplotype for which nontumor LEMS would be a more probable diagnosis.¹⁴

In addition to a screening protocol, a validated prediction tool, the Dutch-English LEMS Tumor Association prediction score, was developed. It uses common signs and symptoms of LEMS and risk factors for SCLC to help guide the need for further screening.¹⁵

Paraneoplastic Syndromes Associated With MCC
Other paraneoplastic syndromes have been reported in association with MCC. A patient with brainstem encephalitis associated with MCC was reported in a trial of a novel immunotherapy for paraneoplastic neurologic syndromes.^16,17 A syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported in a patient with N-type calcium channel antibodies.¹⁸ Two cases of paraneoplastic cerebellar degeneration have been reported; the first was associated with a novel 70-kD antibody,¹⁹ and the second was associated with the P/Q-type VGCC antibody.²⁰ Anti-Hu antibodies have been found in a handful of reports of neurologic deterioration in patients with MCC. Hocar et al²¹ reported a severe necrotizing myopathy; Greenlee et al²² described a syndrome of progressive sensorimotor and autonomic neuropathy with encephalopathy; and Lopez et al²³ described a constellation of vision changes, gait imbalance, and proximal weakness. Support for a pathophysiologic connection among these 3 cases is suggested by the finding of Hu antigen expression by MCC in 2 studies.^24,25 Because MCC can present with occult lymph node involvement in the absence of primary cutaneous findings,³ there are more cases of paraneoplastic neurologic syndromes that were not recognized.

Extrapulmonary small cell carcinomas such as MCC are morphologically indistinguishable from their pulmonary counterparts and have been reported in most anatomic regions of the body, including gynecologic organs (eg, ovaries, cervix), genitourinary organs (eg, bladder, prostate), the gastrointestinal tract (eg, esophagus), skin (eg, MCC), and the head and neck region. Extrapulmonary small cell carcinoma is a rare entity, with the most common form found in the gynecologic tract, representing only 2% of gynecologic malignancies.²⁶

Paraneoplastic syndromes of EPSCC are rare given the paucity of the malignancy. Several case reports discuss findings of SIADH in EPSCC of the cervix, as well as hypercalcemia, polyneuropathy, Cushing syndrome, limbic encephalitis, and peripheral neuropathy in EPSCC of the prostate.^27,28 In contrast, SCLC has long been associated with paraneoplastic syndromes. Numerous case reports have been published describing SCLC-associated paraneoplastic syndromes to include hypercalcemia, Cushing syndrome, SIADH, vasoactive peptide production, cerebellar degeneration, limbic encephalitis, visceral plexopathy, autonomic dysfunction, and LEMS.²⁹ As more cases of EPSCC with paraneoplastic syndromes are identified and reported, we might gain a better understanding of this interesting phenomenon.

Conclusion

Merkel cell carcinoma is an aggressive neuroendocrine malignancy associated with paraneoplastic neurologic syndromes, including LEMS. A thorough search for an underlying malignancy is highly recommended in patients with diagnosed LEMS without clear cause. Early identification and treatment of the primary tumor can lead to improvement of neurologic symptoms.

We present a case of LEMS with no clearly identifiable cause on presentation with later diagnosis of metastatic MCC of unknown primary origin. After surgical excision of affected lymph nodes and adjuvant radiation therapy, the patient had near-complete resolution of LEMS symptoms at 6-month follow-up, without additional findings of lymphadenopathy or skin lesions. Although this patient is not undergoing routine surveillance imaging to monitor for recurrence of MCC, a chest CT or positron emission tomography–CT for secondary screening would be considered if the patient experienced clinical symptoms consistent with LEMS.

In cases of LEMS without pulmonary malignancy, we recommend considering MCC in the differential diagnosis during the workup of an underlying malignancy

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of the skin that is thought to arise from neural crest cells. It has an estimated annual incidence of 0.6 per 100,000 individuals, typically occurs in the elderly population, and is most common in white males.¹ The tumor presents as a rapidly growing, violaceous nodule in sun-exposed areas of the skin; early in the course, it can be mistaken for a benign entity such as an epidermal cyst.² Merkel cell carcinoma has a propensity to spread to regional lymph nodes, and in some cases, it occurs in the absence of skin findings.³ Histologically, MCC is nearly indistinguishable from small cell lung carcinoma (SCLC).⁴ The overall prognosis for patients with MCC is poor and largely dependent on the stage at diagnosis. Patients with regional and distant metastases have a 5-year survival rate of 26% to 42% and 18%, respectively.³

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic or autoimmune disorder of the neuromuscular junction that is found in 3% of cases of SCLC.⁴ Reported cases of LEMS in patients with MCC are exceedingly rare.^5-8 We provide a full report and longitudinal clinical follow-up of a case that was briefly discussed by Simmons et al,⁸ and we review the literature regarding paraneoplastic syndromes associated with MCC and other extrapulmonary small cell carcinomas (EPSCCs).

Case Report

A 63-year-old man was evaluated in the neurology clinic due to difficulty walking, climbing stairs, and performing push-ups over the last month. Prior to the onset of symptoms, he was otherwise healthy, walking 3 miles daily; however, at presentation he required use of a cane. Leg weakness worsened as the day progressed. In addition, he reported constipation, urinary urgency, dry mouth, mild dysphagia, reduced sensation below the knees, and a nasal quality in his speech. He had no ptosis, diplopia, dysarthria, muscle cramps, myalgia, or facial weakness. He denied fevers, chills, and night sweats but did admit to an unintentional 10- to 15-lb weight loss over the preceding few months.

The neurologic examination revealed mild proximal upper extremity weakness in the bilateral shoulder abductors, infraspinatus, hip extensors, and hip flexors (Medical Research Council muscle scale grade 4). All deep tendon reflexes, except the Achilles reflex, were present. Despite subjective sensory concerns, objective examination of all sensory modalities was normal. Cranial nerve examination was normal, except for a slight nasal quality to his voice.

A qualitative assay was positive for the presence of P/Q-type voltage-gated calcium channel (VGCC) antibodies. Other laboratory studies were within reference range, including acetylcholine-receptor antibodies (blocking, binding, and modulating) and muscle-specific kinase antibodies.

Lumbar and cervical spine magnetic resonance imaging revealed multilevel neuroforaminal stenosis without spinal canal stenosis or myelopathy. Computed tomography (CT) of the chest was notable for 2 pathologically enlarged lymph nodes in the left axilla and no evidence of primary pulmonary malignancy. Nerve-conduction studies (NCSs) in conjunction with other clinical findings were consistent with the diagnosis of LEMS.

Ultrasound-guided biopsy of the enlarged axillary lymph nodes demonstrated sheets and nests of small round blue tumor cells with minimal cytoplasm, high mitotic rate, and foci of necrosis (Figure 1). The tumor cells were positive for pancytokeratin (Lu-5) and cytokeratin (CK) 20 in a perinuclear dotlike pattern (Figure 2), as well as for the neuroendocrine markers synaptophysin (Figure 3), chromogranin A, and CD56. The tumor cells showed no immunoreactivity for CK7, thyroid transcription factor 1, CD3, CD5, or CD20. Flow cytometry demonstrated low cellularity, low specimen viability, and no evidence of an abnormal B-cell population. These findings were consistent with the diagnosis of MCC.

The patient underwent surgical excision of the involved lymph nodes. Four weeks after surgery, he reported dramatic improvement in strength, with complete resolution of the nasal speech, dysphagia, dry mouth, urinary retention, and constipation. Two months after surgery, his strength had normalized, except for slight persistent weakness in the bilateral shoulder abductors, trace weakness in the hip flexors, and a slight Trendelenburg gait. He was able to rise from a chair without using his arms and no longer required a cane for ambulation.

The patient underwent adjuvant radiation therapy after 2-month surgical follow-up with 5000-cGy radiation treatment to the left axillary region. Six months following primary definitive surgery and 4 months following adjuvant radiation therapy, he reported a 95% subjective return of physical strength. The patient was able to return to near-baseline physical activity. He continued to deny symptoms of dry mouth, incontinence, or constipation. Objectively, he had no focal neurologic deficits or weakness; no evidence of new skin lesions or lymphadenopathy was noted.

Comment

MCC vs SCLC
Merkel cell carcinoma is classified as a type of EPSCC. The histologic appearance of MCC is indistinguishable from SCLC. Both tumors are composed of uniform sheets of small round cells with a high nucleus to cytoplasm ratio, and both can express neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and synaptophysin.⁹ Immunohistochemical positivity for CK20 and neurofilaments in combination with negative staining for thyroid transcription factor 1 and CK7 effectively differentiate MCC from SCLC.⁹ In addition, MCC often displays CK20 positivity in a perinuclear dotlike or punctate pattern, which is characteristic of this tumor.^3,9,10 Negative immunohistochemical markers for B cells (CD20) and T cells (CD3) are important in excluding lymphoma.

LEMS Diagnosis
Lambert-Eaton myasthenic syndrome is a paraneoplastic or autoimmune disorder involving the neuromuscular junction. Autoantibodies to VGCC impair calcium influx into the presynaptic terminal, resulting in marked reduction of acetylcholine release into the synaptic cleft. The reduction in acetylcholine activity impairs production of muscle fiber action potentials, resulting in clinical weakness. The diagnosis of LEMS rests on clinical presentation, positive serology, and confirmatory neurophysiologic testing by NCS. Clinically, patients present with proximal weakness, hyporeflexia or areflexia, and autonomic dysfunction. Antibodies to P/Q-type VGCCs are found in 85% to 90% of cases of LEMS and are thought to play a direct causative role in the development of weakness.¹¹ The finding of postexercise facilitation on motor NCS is the neurophysiologic hallmark and is highly specific for the diagnosis.

Approximately 50% to 60% of patients who present with LEMS have an underlying tumor, the vast majority of which are SCLC.¹¹ There are a few reports of LEMS associated with other malignancies, including lymphoma; thymoma; neuroblastoma; and carcinoma of the breast, stomach, prostate, bladder, kidney, and gallbladder.¹² Patients with nontumor or autoimmune LEMS tend to be younger, and there is no male predominance, as there is in paraneoplastic LEMS.¹³ Given the risk of underlying malignancy in LEMS, Titulaer et al¹⁴ proposed a screening protocol for patients presenting with LEMS, recommending initial primary screening using CT of the chest. If the CT scan is negative, total-body fludeoxyglucose positron emission tomography should be performed to assess for fludeoxyglucose avid lesions. If both initial studies are negative, routine follow-up with CT of the chest at 6-month intervals for a minimum of 2 to 4 years after the initial diagnosis of LEMS was recommended. An exception to this protocol was suggested to allow consideration to stop screening after the first 6-month follow-up chest CT for patients younger than 45 years who have never smoked and who have an HLA 8.1 haplotype for which nontumor LEMS would be a more probable diagnosis.¹⁴

In addition to a screening protocol, a validated prediction tool, the Dutch-English LEMS Tumor Association prediction score, was developed. It uses common signs and symptoms of LEMS and risk factors for SCLC to help guide the need for further screening.¹⁵

Paraneoplastic Syndromes Associated With MCC
Other paraneoplastic syndromes have been reported in association with MCC. A patient with brainstem encephalitis associated with MCC was reported in a trial of a novel immunotherapy for paraneoplastic neurologic syndromes.^16,17 A syndrome of inappropriate antidiuretic hormone (SIADH) secretion was reported in a patient with N-type calcium channel antibodies.¹⁸ Two cases of paraneoplastic cerebellar degeneration have been reported; the first was associated with a novel 70-kD antibody,¹⁹ and the second was associated with the P/Q-type VGCC antibody.²⁰ Anti-Hu antibodies have been found in a handful of reports of neurologic deterioration in patients with MCC. Hocar et al²¹ reported a severe necrotizing myopathy; Greenlee et al²² described a syndrome of progressive sensorimotor and autonomic neuropathy with encephalopathy; and Lopez et al²³ described a constellation of vision changes, gait imbalance, and proximal weakness. Support for a pathophysiologic connection among these 3 cases is suggested by the finding of Hu antigen expression by MCC in 2 studies.^24,25 Because MCC can present with occult lymph node involvement in the absence of primary cutaneous findings,³ there are more cases of paraneoplastic neurologic syndromes that were not recognized.

Extrapulmonary small cell carcinomas such as MCC are morphologically indistinguishable from their pulmonary counterparts and have been reported in most anatomic regions of the body, including gynecologic organs (eg, ovaries, cervix), genitourinary organs (eg, bladder, prostate), the gastrointestinal tract (eg, esophagus), skin (eg, MCC), and the head and neck region. Extrapulmonary small cell carcinoma is a rare entity, with the most common form found in the gynecologic tract, representing only 2% of gynecologic malignancies.²⁶

Paraneoplastic syndromes of EPSCC are rare given the paucity of the malignancy. Several case reports discuss findings of SIADH in EPSCC of the cervix, as well as hypercalcemia, polyneuropathy, Cushing syndrome, limbic encephalitis, and peripheral neuropathy in EPSCC of the prostate.^27,28 In contrast, SCLC has long been associated with paraneoplastic syndromes. Numerous case reports have been published describing SCLC-associated paraneoplastic syndromes to include hypercalcemia, Cushing syndrome, SIADH, vasoactive peptide production, cerebellar degeneration, limbic encephalitis, visceral plexopathy, autonomic dysfunction, and LEMS.²⁹ As more cases of EPSCC with paraneoplastic syndromes are identified and reported, we might gain a better understanding of this interesting phenomenon.

Conclusion

Merkel cell carcinoma is an aggressive neuroendocrine malignancy associated with paraneoplastic neurologic syndromes, including LEMS. A thorough search for an underlying malignancy is highly recommended in patients with diagnosed LEMS without clear cause. Early identification and treatment of the primary tumor can lead to improvement of neurologic symptoms.

We present a case of LEMS with no clearly identifiable cause on presentation with later diagnosis of metastatic MCC of unknown primary origin. After surgical excision of affected lymph nodes and adjuvant radiation therapy, the patient had near-complete resolution of LEMS symptoms at 6-month follow-up, without additional findings of lymphadenopathy or skin lesions. Although this patient is not undergoing routine surveillance imaging to monitor for recurrence of MCC, a chest CT or positron emission tomography–CT for secondary screening would be considered if the patient experienced clinical symptoms consistent with LEMS.

In cases of LEMS without pulmonary malignancy, we recommend considering MCC in the differential diagnosis during the workup of an underlying malignancy

To the Editor:

A 56-year-old white woman with a history of melanoma and hypertension presented for evaluation of progressive hair loss of more than 1 year’s duration with associated pruritis. Scalp examination revealed diffuse erythema and scarring alopecia of the bilateral parietal and temporal regions. Physical examination also revealed nonscarring alopecia of the bilateral axillae, with associated thinning of the pubic hair, eyebrows, and eyelashes, as well as keratosis pilaris on the upper arms. Biopsy of the parietal scalp revealed mild scarring alopecia with isthmic fibroplasia consistent with early lichen planopilaris (LPP)(Figure). These histologic features combined with the patient’s clinical presentation were consistent with a diagnosis of Graham-Little-Piccardi-Lassueur syndrome (GLPL).

Graham-Little-Piccardi-Lassueur syndrome was first described by Piccardi in 1913.A second case was then described by Graham-Little in 1915 in a patient referred by Lassueur, resulting in the name it bears today.^1,2 The condition presents most commonly in middle-aged white women and is characterized by a triad of cicatricial alopecia of the scalp, nonscarring alopecia of the axillae and/or groin, and a rough follicular eruption on the body and/or scalp. Symptoms may not be present simultaneously. In GLPL, scarring alopecia of the scalp often precedes follicular eruptions of the trunk, arms, and legs by as much as years,² and the inverse also has been reported.¹ The inflammatory lesions of the scalp eventually resolve spontaneously, but the hair loss is by definition irreversible.

This rare condition is considered one of the 3 clinical variants of LPP. Other variants include classic LPP, also known as follicular lichen planus, and frontal fibrosing alopecia.³ More recently, fibrosing alopecia in a pattern distribution has gained some popularity as a fourth variant of LPP.⁴ All variants of LPP, including GLPL, result in a scarring alopecia. The classic scalp finding is an erythematous to violaceous, perifollicular, hyperkeratotic scale at the base of the terminal hairs. The population of inflamed follicles spreads outward, leaving behind a round to oval, central, atrophic scar that often is devoid of follicles. Few hairs may persist within zones of alopecia at presentation; however, these hairs are affected by inflammation and also will likely shed. A hair pull test will be positive at the margins during active disease, consisting of mostly anagen hairs on trichogram examination.^1,5 Patients may develop only a single foci of hair loss, but much more commonly, a patchy multifocal alopecia is noted.⁶ Sites often will coalesce. Onset of scalp alopecia may be insidious or fulminant.

The nonscarring alopecia of the axillae and groin may be described as subtle thinning to complete hair loss with no signs of atrophy or inflammation. Although not commonly reported, a case of nonscarring alopecia located on the shoulders has been seen.⁷

The follicular eruption that can be present on the trunk, arms, or legs in GLPL is most often but not limited to keratosis pilaris, as was seen in our patient. One reported case also described lichen spinulosus as a potential variant.⁸ Lichen planopilaris is separate from lichen planus (LP) because of its selective follicular involvement vs the nonselective mucocutaneous distribution of LP. The 2 processes also are histologically distinct; however, estimations have shown that more than 50% of patients with GLPL experience at least 1 episode of mucosal or cutaneous LP in their lifetime.⁹ Rarely, coexistence of GLPL and LP lesions has been described. One reported case of GLPL and concomitant hypertrophic LP could represent a severe form of the disease.⁹ Additionally, lichen planus pigmentosus, an uncommon variant of LP characterized by hyperpigmented brown macules in sun-exposed areas and flexural folds, was identified in a case report of an Asian woman with GLPL.¹⁰

As a general rule, the variants of LPP most commonly are seen in postmenopausal women aged 40 to 60 years; however, rare cases in a child and a teenager have been reported.¹¹ The GLPL variant of LPP is reported up to 4 times more frequently in females.⁵ Pruritus and pain are inconsistent findings, and there are no systemic signs of illness. A case of androgen insensitivity syndrome associated with GLPL suggested a potential influence of hormones in LPP.¹² Stress, vitamin A deficiency, and autoimmunity also have been proposed as triggers of GLPL.¹³ Furthermore, familial GLPL was described in a mother and daughter, though the association was uncertain.¹⁴ Our patient had no relevant family history.

Workups to reveal the etiology of GLPL have been inconclusive. Reports of laboratory testing including complete blood cell count, basic metabolic panel, liver function tests, testosterone and dehydroepiandrosterone levels, and chest radiograph have been normal.² Additional workup for viral triggers also has been negative.¹⁵ A case series of 29 patients with LPP and its variants, including GLPL, revealed positive antinuclear antibodies in 10% of patients and a thyroid disorder in 24% of patients, with Hashimoto thyroiditis being the most prevalent in 7% of cases.¹⁶ There may be a strong association between the comorbidities of thyroid dysfunction and GLPL, as documented in other studies.^10,17 A case-control study by Mesinkovska et al¹⁷ revealed a considerable increase in the prevalence of thyroid gland disease among patients with LPP vs controls. Human leukocyte antigen DR1 was found in a familial case of GLPL,⁴ and a case of GLPL following hepatitis B vaccination also has been described.¹⁸

Graham-Little-Piccardi-Lassueur syndrome most likely is a T-cell mediated autoimmune condition associated with one or multiple unknown keratinocyte antigens. Autoantibodies to the inner centromere protein were identified in a case that was positive on direct immunofluorescence, which may provide more insight into the disease pathophysiology.¹³ Interestingly, a study comparing the concentrations of inflammatory cells in LPP and traction alopecia found an elevation in the ratio of Langerhans cells to T lymphocytes within the follicular inflammatory infiltrate of LPP.¹⁹

Because the number of patients with GLPL is so few, therapy should mirror advances being made in treatments for other variants of LPP. More recent studies of LPP treatment with hydroxychloroquine showed opposing results, though the safety profile of this agent makes it an enticing treatment option.^22,23 Tetracyclines showed improvement in 4 of 15 (26.7%) patients in a retrospective study by Spencer et al.²⁴ Another retrospective study showed promising results with the potent 5-alpha reductase inhibitor dutasteride with 7 of 10 (70%) postmenopausal patients reporting stabilization over a mean duration of 28 months with no reported side effects.²⁵ Antimalarial medications also have been implemented as adjunct therapies with mixed results.⁵ A case of a 26-year-old man with GLPL from South India showed systemic disease improvement following treatment with pulsed systemic steroids, isotretinoin, and anxiolytics.⁷ Chloroquine phosphate at a daily dose of 150 mg for 3 to 9 months yielded a transient response in one postmenopausal patient with frontal fibrosing alopecia.⁶ Stabilization of hair loss was achieved with a combination of hydroxychloroquine and doxycycline in a woman with GLPL who was previously unresponsive to tacrolimus ointment.¹⁰ Thalidomide showed early promise in an isolated report claiming successful treatment of LPP,²⁶ but there is contradictory evidence, as thalidomide showed no benefit in a series of 4 patients with LPP.²⁷

Peroxisome proliferator–activated receptor gamma (PPAR-γ), a transcription factor that regulates genes, is downregulated in LPP.²⁸ Deletion of PPAR-γ within follicular stem cells in mice results in a phenotype similar to cicatricial alopecia. Data have supported the role of PPAR-γ in maintaining the pilosebaceous unit. A case report of pioglitazone (PPAR-γ agonist) therapy used at 15 mg daily for 8 months was successful in treating a patient with LPP.²⁸ Further investigation must be conducted to evaluate these treatments since early attenuation of the disease process is crucial to the reduction of permanent hair loss.

Advances in the early recognition and successful treatment of GLPL are dependent on continued research in all variants of LPP. Randomized controlled trials are necessary to establish standard of care. Further studies should target the association of GLPL and other autoimmune phenomena. Moreover, research into the etiology will provide direction in understanding disease progression and outcome.

To the Editor:

A 56-year-old white woman with a history of melanoma and hypertension presented for evaluation of progressive hair loss of more than 1 year’s duration with associated pruritis. Scalp examination revealed diffuse erythema and scarring alopecia of the bilateral parietal and temporal regions. Physical examination also revealed nonscarring alopecia of the bilateral axillae, with associated thinning of the pubic hair, eyebrows, and eyelashes, as well as keratosis pilaris on the upper arms. Biopsy of the parietal scalp revealed mild scarring alopecia with isthmic fibroplasia consistent with early lichen planopilaris (LPP)(Figure). These histologic features combined with the patient’s clinical presentation were consistent with a diagnosis of Graham-Little-Piccardi-Lassueur syndrome (GLPL).

Graham-Little-Piccardi-Lassueur syndrome was first described by Piccardi in 1913.A second case was then described by Graham-Little in 1915 in a patient referred by Lassueur, resulting in the name it bears today.^1,2 The condition presents most commonly in middle-aged white women and is characterized by a triad of cicatricial alopecia of the scalp, nonscarring alopecia of the axillae and/or groin, and a rough follicular eruption on the body and/or scalp. Symptoms may not be present simultaneously. In GLPL, scarring alopecia of the scalp often precedes follicular eruptions of the trunk, arms, and legs by as much as years,² and the inverse also has been reported.¹ The inflammatory lesions of the scalp eventually resolve spontaneously, but the hair loss is by definition irreversible.

This rare condition is considered one of the 3 clinical variants of LPP. Other variants include classic LPP, also known as follicular lichen planus, and frontal fibrosing alopecia.³ More recently, fibrosing alopecia in a pattern distribution has gained some popularity as a fourth variant of LPP.⁴ All variants of LPP, including GLPL, result in a scarring alopecia. The classic scalp finding is an erythematous to violaceous, perifollicular, hyperkeratotic scale at the base of the terminal hairs. The population of inflamed follicles spreads outward, leaving behind a round to oval, central, atrophic scar that often is devoid of follicles. Few hairs may persist within zones of alopecia at presentation; however, these hairs are affected by inflammation and also will likely shed. A hair pull test will be positive at the margins during active disease, consisting of mostly anagen hairs on trichogram examination.^1,5 Patients may develop only a single foci of hair loss, but much more commonly, a patchy multifocal alopecia is noted.⁶ Sites often will coalesce. Onset of scalp alopecia may be insidious or fulminant.

The nonscarring alopecia of the axillae and groin may be described as subtle thinning to complete hair loss with no signs of atrophy or inflammation. Although not commonly reported, a case of nonscarring alopecia located on the shoulders has been seen.⁷

The follicular eruption that can be present on the trunk, arms, or legs in GLPL is most often but not limited to keratosis pilaris, as was seen in our patient. One reported case also described lichen spinulosus as a potential variant.⁸ Lichen planopilaris is separate from lichen planus (LP) because of its selective follicular involvement vs the nonselective mucocutaneous distribution of LP. The 2 processes also are histologically distinct; however, estimations have shown that more than 50% of patients with GLPL experience at least 1 episode of mucosal or cutaneous LP in their lifetime.⁹ Rarely, coexistence of GLPL and LP lesions has been described. One reported case of GLPL and concomitant hypertrophic LP could represent a severe form of the disease.⁹ Additionally, lichen planus pigmentosus, an uncommon variant of LP characterized by hyperpigmented brown macules in sun-exposed areas and flexural folds, was identified in a case report of an Asian woman with GLPL.¹⁰

As a general rule, the variants of LPP most commonly are seen in postmenopausal women aged 40 to 60 years; however, rare cases in a child and a teenager have been reported.¹¹ The GLPL variant of LPP is reported up to 4 times more frequently in females.⁵ Pruritus and pain are inconsistent findings, and there are no systemic signs of illness. A case of androgen insensitivity syndrome associated with GLPL suggested a potential influence of hormones in LPP.¹² Stress, vitamin A deficiency, and autoimmunity also have been proposed as triggers of GLPL.¹³ Furthermore, familial GLPL was described in a mother and daughter, though the association was uncertain.¹⁴ Our patient had no relevant family history.

Workups to reveal the etiology of GLPL have been inconclusive. Reports of laboratory testing including complete blood cell count, basic metabolic panel, liver function tests, testosterone and dehydroepiandrosterone levels, and chest radiograph have been normal.² Additional workup for viral triggers also has been negative.¹⁵ A case series of 29 patients with LPP and its variants, including GLPL, revealed positive antinuclear antibodies in 10% of patients and a thyroid disorder in 24% of patients, with Hashimoto thyroiditis being the most prevalent in 7% of cases.¹⁶ There may be a strong association between the comorbidities of thyroid dysfunction and GLPL, as documented in other studies.^10,17 A case-control study by Mesinkovska et al¹⁷ revealed a considerable increase in the prevalence of thyroid gland disease among patients with LPP vs controls. Human leukocyte antigen DR1 was found in a familial case of GLPL,⁴ and a case of GLPL following hepatitis B vaccination also has been described.¹⁸

Graham-Little-Piccardi-Lassueur syndrome most likely is a T-cell mediated autoimmune condition associated with one or multiple unknown keratinocyte antigens. Autoantibodies to the inner centromere protein were identified in a case that was positive on direct immunofluorescence, which may provide more insight into the disease pathophysiology.¹³ Interestingly, a study comparing the concentrations of inflammatory cells in LPP and traction alopecia found an elevation in the ratio of Langerhans cells to T lymphocytes within the follicular inflammatory infiltrate of LPP.¹⁹

Because the number of patients with GLPL is so few, therapy should mirror advances being made in treatments for other variants of LPP. More recent studies of LPP treatment with hydroxychloroquine showed opposing results, though the safety profile of this agent makes it an enticing treatment option.^22,23 Tetracyclines showed improvement in 4 of 15 (26.7%) patients in a retrospective study by Spencer et al.²⁴ Another retrospective study showed promising results with the potent 5-alpha reductase inhibitor dutasteride with 7 of 10 (70%) postmenopausal patients reporting stabilization over a mean duration of 28 months with no reported side effects.²⁵ Antimalarial medications also have been implemented as adjunct therapies with mixed results.⁵ A case of a 26-year-old man with GLPL from South India showed systemic disease improvement following treatment with pulsed systemic steroids, isotretinoin, and anxiolytics.⁷ Chloroquine phosphate at a daily dose of 150 mg for 3 to 9 months yielded a transient response in one postmenopausal patient with frontal fibrosing alopecia.⁶ Stabilization of hair loss was achieved with a combination of hydroxychloroquine and doxycycline in a woman with GLPL who was previously unresponsive to tacrolimus ointment.¹⁰ Thalidomide showed early promise in an isolated report claiming successful treatment of LPP,²⁶ but there is contradictory evidence, as thalidomide showed no benefit in a series of 4 patients with LPP.²⁷

Peroxisome proliferator–activated receptor gamma (PPAR-γ), a transcription factor that regulates genes, is downregulated in LPP.²⁸ Deletion of PPAR-γ within follicular stem cells in mice results in a phenotype similar to cicatricial alopecia. Data have supported the role of PPAR-γ in maintaining the pilosebaceous unit. A case report of pioglitazone (PPAR-γ agonist) therapy used at 15 mg daily for 8 months was successful in treating a patient with LPP.²⁸ Further investigation must be conducted to evaluate these treatments since early attenuation of the disease process is crucial to the reduction of permanent hair loss.

Advances in the early recognition and successful treatment of GLPL are dependent on continued research in all variants of LPP. Randomized controlled trials are necessary to establish standard of care. Further studies should target the association of GLPL and other autoimmune phenomena. Moreover, research into the etiology will provide direction in understanding disease progression and outcome.

To the Editor:

A 56-year-old white woman with a history of melanoma and hypertension presented for evaluation of progressive hair loss of more than 1 year’s duration with associated pruritis. Scalp examination revealed diffuse erythema and scarring alopecia of the bilateral parietal and temporal regions. Physical examination also revealed nonscarring alopecia of the bilateral axillae, with associated thinning of the pubic hair, eyebrows, and eyelashes, as well as keratosis pilaris on the upper arms. Biopsy of the parietal scalp revealed mild scarring alopecia with isthmic fibroplasia consistent with early lichen planopilaris (LPP)(Figure). These histologic features combined with the patient’s clinical presentation were consistent with a diagnosis of Graham-Little-Piccardi-Lassueur syndrome (GLPL).

Graham-Little-Piccardi-Lassueur syndrome was first described by Piccardi in 1913.A second case was then described by Graham-Little in 1915 in a patient referred by Lassueur, resulting in the name it bears today.^1,2 The condition presents most commonly in middle-aged white women and is characterized by a triad of cicatricial alopecia of the scalp, nonscarring alopecia of the axillae and/or groin, and a rough follicular eruption on the body and/or scalp. Symptoms may not be present simultaneously. In GLPL, scarring alopecia of the scalp often precedes follicular eruptions of the trunk, arms, and legs by as much as years,² and the inverse also has been reported.¹ The inflammatory lesions of the scalp eventually resolve spontaneously, but the hair loss is by definition irreversible.

This rare condition is considered one of the 3 clinical variants of LPP. Other variants include classic LPP, also known as follicular lichen planus, and frontal fibrosing alopecia.³ More recently, fibrosing alopecia in a pattern distribution has gained some popularity as a fourth variant of LPP.⁴ All variants of LPP, including GLPL, result in a scarring alopecia. The classic scalp finding is an erythematous to violaceous, perifollicular, hyperkeratotic scale at the base of the terminal hairs. The population of inflamed follicles spreads outward, leaving behind a round to oval, central, atrophic scar that often is devoid of follicles. Few hairs may persist within zones of alopecia at presentation; however, these hairs are affected by inflammation and also will likely shed. A hair pull test will be positive at the margins during active disease, consisting of mostly anagen hairs on trichogram examination.^1,5 Patients may develop only a single foci of hair loss, but much more commonly, a patchy multifocal alopecia is noted.⁶ Sites often will coalesce. Onset of scalp alopecia may be insidious or fulminant.

The nonscarring alopecia of the axillae and groin may be described as subtle thinning to complete hair loss with no signs of atrophy or inflammation. Although not commonly reported, a case of nonscarring alopecia located on the shoulders has been seen.⁷

The follicular eruption that can be present on the trunk, arms, or legs in GLPL is most often but not limited to keratosis pilaris, as was seen in our patient. One reported case also described lichen spinulosus as a potential variant.⁸ Lichen planopilaris is separate from lichen planus (LP) because of its selective follicular involvement vs the nonselective mucocutaneous distribution of LP. The 2 processes also are histologically distinct; however, estimations have shown that more than 50% of patients with GLPL experience at least 1 episode of mucosal or cutaneous LP in their lifetime.⁹ Rarely, coexistence of GLPL and LP lesions has been described. One reported case of GLPL and concomitant hypertrophic LP could represent a severe form of the disease.⁹ Additionally, lichen planus pigmentosus, an uncommon variant of LP characterized by hyperpigmented brown macules in sun-exposed areas and flexural folds, was identified in a case report of an Asian woman with GLPL.¹⁰

As a general rule, the variants of LPP most commonly are seen in postmenopausal women aged 40 to 60 years; however, rare cases in a child and a teenager have been reported.¹¹ The GLPL variant of LPP is reported up to 4 times more frequently in females.⁵ Pruritus and pain are inconsistent findings, and there are no systemic signs of illness. A case of androgen insensitivity syndrome associated with GLPL suggested a potential influence of hormones in LPP.¹² Stress, vitamin A deficiency, and autoimmunity also have been proposed as triggers of GLPL.¹³ Furthermore, familial GLPL was described in a mother and daughter, though the association was uncertain.¹⁴ Our patient had no relevant family history.

Workups to reveal the etiology of GLPL have been inconclusive. Reports of laboratory testing including complete blood cell count, basic metabolic panel, liver function tests, testosterone and dehydroepiandrosterone levels, and chest radiograph have been normal.² Additional workup for viral triggers also has been negative.¹⁵ A case series of 29 patients with LPP and its variants, including GLPL, revealed positive antinuclear antibodies in 10% of patients and a thyroid disorder in 24% of patients, with Hashimoto thyroiditis being the most prevalent in 7% of cases.¹⁶ There may be a strong association between the comorbidities of thyroid dysfunction and GLPL, as documented in other studies.^10,17 A case-control study by Mesinkovska et al¹⁷ revealed a considerable increase in the prevalence of thyroid gland disease among patients with LPP vs controls. Human leukocyte antigen DR1 was found in a familial case of GLPL,⁴ and a case of GLPL following hepatitis B vaccination also has been described.¹⁸

Graham-Little-Piccardi-Lassueur syndrome most likely is a T-cell mediated autoimmune condition associated with one or multiple unknown keratinocyte antigens. Autoantibodies to the inner centromere protein were identified in a case that was positive on direct immunofluorescence, which may provide more insight into the disease pathophysiology.¹³ Interestingly, a study comparing the concentrations of inflammatory cells in LPP and traction alopecia found an elevation in the ratio of Langerhans cells to T lymphocytes within the follicular inflammatory infiltrate of LPP.¹⁹

Because the number of patients with GLPL is so few, therapy should mirror advances being made in treatments for other variants of LPP. More recent studies of LPP treatment with hydroxychloroquine showed opposing results, though the safety profile of this agent makes it an enticing treatment option.^22,23 Tetracyclines showed improvement in 4 of 15 (26.7%) patients in a retrospective study by Spencer et al.²⁴ Another retrospective study showed promising results with the potent 5-alpha reductase inhibitor dutasteride with 7 of 10 (70%) postmenopausal patients reporting stabilization over a mean duration of 28 months with no reported side effects.²⁵ Antimalarial medications also have been implemented as adjunct therapies with mixed results.⁵ A case of a 26-year-old man with GLPL from South India showed systemic disease improvement following treatment with pulsed systemic steroids, isotretinoin, and anxiolytics.⁷ Chloroquine phosphate at a daily dose of 150 mg for 3 to 9 months yielded a transient response in one postmenopausal patient with frontal fibrosing alopecia.⁶ Stabilization of hair loss was achieved with a combination of hydroxychloroquine and doxycycline in a woman with GLPL who was previously unresponsive to tacrolimus ointment.¹⁰ Thalidomide showed early promise in an isolated report claiming successful treatment of LPP,²⁶ but there is contradictory evidence, as thalidomide showed no benefit in a series of 4 patients with LPP.²⁷

Peroxisome proliferator–activated receptor gamma (PPAR-γ), a transcription factor that regulates genes, is downregulated in LPP.²⁸ Deletion of PPAR-γ within follicular stem cells in mice results in a phenotype similar to cicatricial alopecia. Data have supported the role of PPAR-γ in maintaining the pilosebaceous unit. A case report of pioglitazone (PPAR-γ agonist) therapy used at 15 mg daily for 8 months was successful in treating a patient with LPP.²⁸ Further investigation must be conducted to evaluate these treatments since early attenuation of the disease process is crucial to the reduction of permanent hair loss.

Advances in the early recognition and successful treatment of GLPL are dependent on continued research in all variants of LPP. Randomized controlled trials are necessary to establish standard of care. Further studies should target the association of GLPL and other autoimmune phenomena. Moreover, research into the etiology will provide direction in understanding disease progression and outcome.

To the Editor:

A 30-year-old man with no notable medical history presented to the dermatology clinic with multiple subcutaneous nodules on the forehead of 5 years’ duration. He reported no history of forehead trauma or manipulation of the lesions, and there was no accompanying pruritis, pain, erythema, or purulent discharge. There was no family history of skin or gastrointestinal tract tumors. On physical examination, the patient had 5 firm, flesh-colored to yellow nodules measuring approximately 0.2 to 1.5 cm in diameter without central punctae scattered over the central forehead (Figure 1). Due to cosmetic concerns, the patient elected to pursue surgical excision of the lesions, which occurred over several office visits. During surgical excision, the lesions were found to be smooth, encapsulated, and mobile, and they were excised without surgical complication. Histopathologic examination showed subcutaneous cysts lined by squamous epithelium with associated sebaceous glands (Figure 2A) and hair follicles in the cyst lumen (Figure 2B). These findings confirmed the diagnosis of multiple subcutaneous dermoid cysts.

Dermoid cysts are relatively uncommon, benign tumors consisting of tissue derived from ectodermal and mesodermal germ cell layers. Dermoid cysts may be distinguished from teratomas, which may contain tissues derived from all 3 germ cell layers and typically consist of types of tissues foreign to the site of origin, such as dental, thyroid, gastrointestinal, or neural tissue.^1,2 The majority of dermoid cysts are congenitally developed along the lines of embryologic fusion due to an error in the division of the ectoderm and mesoderm^3,4; however, some dermoid cysts may be acquired from epidermal elements being traumatically implanted into the dermis.⁵

Our patient’s presentation with multiple dermoid cysts was atypical, as dermoid cysts are almost always solitary tumors. A similar case was reported in a 41-year-old man who developed multiple dermoid cysts on the forehead over a 20-year period.This patient also was otherwise healthy, denied prior trauma to the forehead, and reported no family history of skin or gastrointestinal tract tumors.⁵

Another unusual feature in our case was the location of the dermoid cysts on the central forehead. The most common location for dermoid cysts is the lateral third of the eyebrows (47%–70% of cases).^1,4,6-10 These cysts occur because of sequestration of the surface ectoderm during fusion along the naso-optic groove.² Dermoid cysts also have been noted in other anatomical areas such as the scalp, nose, anterior neck, and trunk.⁶

Dermoid cysts tend to be small, round, smooth, and slowly growing until sudden enlargement prompts surgical evaluation.^4,6 During surgical excision, they often are fixed to the underlying bone but also may be freely mobile, as in our patient.⁶ Histopathologic examination reveals a stratified squamous epithelium with associated adnexal structures such as sebaceous glands or hair follicles.¹ Smooth muscle fibers, prominent vascular stroma, small nerves, and collagen and elastic fibers also may be found within the lumen of dermoid cysts.²

In some cases, dermoid cysts may be invasive and carry the risk of bony erosion, intracranial extension, osteomyelitis, meningitis, or cerebral abscess. Imaging studies sometimes are needed to rule out intracranial or intraspinal extension, particularly for midline dermoid cysts.⁶ The standard of treatment for dermoid cysts is surgical excision and complete enucleation without disruption of the cyst wall; however, invasive dermoid cysts may require endoscopic excision, orbitotomy, or craniotomy.^4,6

To the Editor:

A 30-year-old man with no notable medical history presented to the dermatology clinic with multiple subcutaneous nodules on the forehead of 5 years’ duration. He reported no history of forehead trauma or manipulation of the lesions, and there was no accompanying pruritis, pain, erythema, or purulent discharge. There was no family history of skin or gastrointestinal tract tumors. On physical examination, the patient had 5 firm, flesh-colored to yellow nodules measuring approximately 0.2 to 1.5 cm in diameter without central punctae scattered over the central forehead (Figure 1). Due to cosmetic concerns, the patient elected to pursue surgical excision of the lesions, which occurred over several office visits. During surgical excision, the lesions were found to be smooth, encapsulated, and mobile, and they were excised without surgical complication. Histopathologic examination showed subcutaneous cysts lined by squamous epithelium with associated sebaceous glands (Figure 2A) and hair follicles in the cyst lumen (Figure 2B). These findings confirmed the diagnosis of multiple subcutaneous dermoid cysts.

Dermoid cysts are relatively uncommon, benign tumors consisting of tissue derived from ectodermal and mesodermal germ cell layers. Dermoid cysts may be distinguished from teratomas, which may contain tissues derived from all 3 germ cell layers and typically consist of types of tissues foreign to the site of origin, such as dental, thyroid, gastrointestinal, or neural tissue.^1,2 The majority of dermoid cysts are congenitally developed along the lines of embryologic fusion due to an error in the division of the ectoderm and mesoderm^3,4; however, some dermoid cysts may be acquired from epidermal elements being traumatically implanted into the dermis.⁵

Our patient’s presentation with multiple dermoid cysts was atypical, as dermoid cysts are almost always solitary tumors. A similar case was reported in a 41-year-old man who developed multiple dermoid cysts on the forehead over a 20-year period.This patient also was otherwise healthy, denied prior trauma to the forehead, and reported no family history of skin or gastrointestinal tract tumors.⁵

Another unusual feature in our case was the location of the dermoid cysts on the central forehead. The most common location for dermoid cysts is the lateral third of the eyebrows (47%–70% of cases).^1,4,6-10 These cysts occur because of sequestration of the surface ectoderm during fusion along the naso-optic groove.² Dermoid cysts also have been noted in other anatomical areas such as the scalp, nose, anterior neck, and trunk.⁶

Dermoid cysts tend to be small, round, smooth, and slowly growing until sudden enlargement prompts surgical evaluation.^4,6 During surgical excision, they often are fixed to the underlying bone but also may be freely mobile, as in our patient.⁶ Histopathologic examination reveals a stratified squamous epithelium with associated adnexal structures such as sebaceous glands or hair follicles.¹ Smooth muscle fibers, prominent vascular stroma, small nerves, and collagen and elastic fibers also may be found within the lumen of dermoid cysts.²

In some cases, dermoid cysts may be invasive and carry the risk of bony erosion, intracranial extension, osteomyelitis, meningitis, or cerebral abscess. Imaging studies sometimes are needed to rule out intracranial or intraspinal extension, particularly for midline dermoid cysts.⁶ The standard of treatment for dermoid cysts is surgical excision and complete enucleation without disruption of the cyst wall; however, invasive dermoid cysts may require endoscopic excision, orbitotomy, or craniotomy.^4,6

To the Editor:

A 30-year-old man with no notable medical history presented to the dermatology clinic with multiple subcutaneous nodules on the forehead of 5 years’ duration. He reported no history of forehead trauma or manipulation of the lesions, and there was no accompanying pruritis, pain, erythema, or purulent discharge. There was no family history of skin or gastrointestinal tract tumors. On physical examination, the patient had 5 firm, flesh-colored to yellow nodules measuring approximately 0.2 to 1.5 cm in diameter without central punctae scattered over the central forehead (Figure 1). Due to cosmetic concerns, the patient elected to pursue surgical excision of the lesions, which occurred over several office visits. During surgical excision, the lesions were found to be smooth, encapsulated, and mobile, and they were excised without surgical complication. Histopathologic examination showed subcutaneous cysts lined by squamous epithelium with associated sebaceous glands (Figure 2A) and hair follicles in the cyst lumen (Figure 2B). These findings confirmed the diagnosis of multiple subcutaneous dermoid cysts.

Dermoid cysts are relatively uncommon, benign tumors consisting of tissue derived from ectodermal and mesodermal germ cell layers. Dermoid cysts may be distinguished from teratomas, which may contain tissues derived from all 3 germ cell layers and typically consist of types of tissues foreign to the site of origin, such as dental, thyroid, gastrointestinal, or neural tissue.^1,2 The majority of dermoid cysts are congenitally developed along the lines of embryologic fusion due to an error in the division of the ectoderm and mesoderm^3,4; however, some dermoid cysts may be acquired from epidermal elements being traumatically implanted into the dermis.⁵

Our patient’s presentation with multiple dermoid cysts was atypical, as dermoid cysts are almost always solitary tumors. A similar case was reported in a 41-year-old man who developed multiple dermoid cysts on the forehead over a 20-year period.This patient also was otherwise healthy, denied prior trauma to the forehead, and reported no family history of skin or gastrointestinal tract tumors.⁵

Another unusual feature in our case was the location of the dermoid cysts on the central forehead. The most common location for dermoid cysts is the lateral third of the eyebrows (47%–70% of cases).^1,4,6-10 These cysts occur because of sequestration of the surface ectoderm during fusion along the naso-optic groove.² Dermoid cysts also have been noted in other anatomical areas such as the scalp, nose, anterior neck, and trunk.⁶

Dermoid cysts tend to be small, round, smooth, and slowly growing until sudden enlargement prompts surgical evaluation.^4,6 During surgical excision, they often are fixed to the underlying bone but also may be freely mobile, as in our patient.⁶ Histopathologic examination reveals a stratified squamous epithelium with associated adnexal structures such as sebaceous glands or hair follicles.¹ Smooth muscle fibers, prominent vascular stroma, small nerves, and collagen and elastic fibers also may be found within the lumen of dermoid cysts.²

In some cases, dermoid cysts may be invasive and carry the risk of bony erosion, intracranial extension, osteomyelitis, meningitis, or cerebral abscess. Imaging studies sometimes are needed to rule out intracranial or intraspinal extension, particularly for midline dermoid cysts.⁶ The standard of treatment for dermoid cysts is surgical excision and complete enucleation without disruption of the cyst wall; however, invasive dermoid cysts may require endoscopic excision, orbitotomy, or craniotomy.^4,6

The Diagnosis: Kaposi Sarcoma

A 4-mm punch biopsy from the border of an ulcerated nodular lesion on the hard palate demonstrated diffusely distributed spindle cells, cleftlike microvascularity with extravasated erythrocytes, and widespread human herpesvirus 8 immunoreactivity on histopathology (Figure 1). Serologic tests were positive for human immunodeficiency virus (HIV) infection; HIV RNA was 14,584 IU/mL and the CD4 count was 254/mm³. The patient was diagnosed with Kaposi sarcoma (KS) and referred to the infectious disease department for initiation of antiviral therapy. Marked regression was detected after 6 months of highly active antiretroviral therapy (HAART) without any additional treatment (Figure 2).  

Kaposi sarcoma is a human herpesvirus 8-associated angioproliferative disorder with low-grade malignant potential. There are 4 well-known clinical types: classic, endemic, iatrogenic, and AIDS associated.¹ Involvement of the oral cavity may be seen in all types but mostly is associated with the AIDS-associated type, which also could be a signal for undiagnosed asymptomatic HIV infection.² Oral KS most often affects the hard and soft palate, gingiva, and dorsal tongue, with plaques or tumors ranging from nonpigmented to brownish red or violaceous. AIDS-associated KS is known to be related to cytokine expression, which is induced by HIV infection causing immune dysregulation by altering the expression of cytokines, including IL-1, tumor necrosis factor α, and IL-6.¹ An in vitro study showed that cytokines secrete a number of angiogenic growth factors that, along with HIV proteins, induce and proliferate cells to become sarcoma cells. Integrins and the apoptosis process also are important in proliferation and neovascularization of KS tumor cells.³  

Bacillary angiomatosis (BA) is a rare manifestation of infection caused by Bartonella species, which leads to vasoproliferative lesions of the skin and other organs. Bacillary angiomatosis affects individuals with advanced HIV or other immunocompromised individuals and may clinically mimic KS, which is similarly characterized by red-purple papules, nodules, or plaques. Differentiating BA from KS largely depends on histopathologic examination, with BA demonstrating protuberant endothelial cells surrounded by clumps of bacilli that are visible on Warthin-Starry silver stain. 

Lymphangioma is a benign hamartomatous hyperplasia of the lymphatic vessels. The majority of lymphangiomas are superficial, but a few may extend deeply into the connective tissue. Intraoral lymphangiomas occur more frequently on the dorsum of the tongue, followed by the palate, buccal mucosa, gingiva, and lips. They may be differentiated with their soft quality, pebblelike surface, and translucent vesicles. 

Malignant tumors of the oral cavity are rare, representing only 5% of tumors occurring in the body.⁴ Among malignant tumors of the oral cavity, squamous cell carcinomas are the most frequent type (90%-98%), and lymphomas and melanoma are the most outstanding among the remaining 2% to 10%. Both for lymphoma and mucosal melanoma, the most common sites of involvement are the soft tissues of the oral cavity, palatal mucosa, gingiva, tongue, cheeks, floor of the mouth, and lips.⁴ Although mucosal melanoma lesions usually are characterized by pigmented and ulcerated lesions, amelanotic variants also should be kept in mind. Histopathologic examination is mandatory for diagnosis.   

Intralesional chemotherapy with vinblastine or bleomycin, radiotherapy, electrochemotherapy, systemic antiretroviral therapy (ie, HAART), and chemotherapy with daunorubicin and pegylated liposomal doxorubicin are the main treatment options.^5,6 The immune system activator role of HAART leads to an increased CD4 count and reduces HIV proteins, which helps induction of the proliferation and neovascularization of KS tumor cells.³ This effect may help resolution of KS with localized involvement and allows physicians to utilize HAART without any other additional local and systemic chemotherapy treatment. 

The Diagnosis: Kaposi Sarcoma

A 4-mm punch biopsy from the border of an ulcerated nodular lesion on the hard palate demonstrated diffusely distributed spindle cells, cleftlike microvascularity with extravasated erythrocytes, and widespread human herpesvirus 8 immunoreactivity on histopathology (Figure 1). Serologic tests were positive for human immunodeficiency virus (HIV) infection; HIV RNA was 14,584 IU/mL and the CD4 count was 254/mm³. The patient was diagnosed with Kaposi sarcoma (KS) and referred to the infectious disease department for initiation of antiviral therapy. Marked regression was detected after 6 months of highly active antiretroviral therapy (HAART) without any additional treatment (Figure 2).  

Kaposi sarcoma is a human herpesvirus 8-associated angioproliferative disorder with low-grade malignant potential. There are 4 well-known clinical types: classic, endemic, iatrogenic, and AIDS associated.¹ Involvement of the oral cavity may be seen in all types but mostly is associated with the AIDS-associated type, which also could be a signal for undiagnosed asymptomatic HIV infection.² Oral KS most often affects the hard and soft palate, gingiva, and dorsal tongue, with plaques or tumors ranging from nonpigmented to brownish red or violaceous. AIDS-associated KS is known to be related to cytokine expression, which is induced by HIV infection causing immune dysregulation by altering the expression of cytokines, including IL-1, tumor necrosis factor α, and IL-6.¹ An in vitro study showed that cytokines secrete a number of angiogenic growth factors that, along with HIV proteins, induce and proliferate cells to become sarcoma cells. Integrins and the apoptosis process also are important in proliferation and neovascularization of KS tumor cells.³  

Bacillary angiomatosis (BA) is a rare manifestation of infection caused by Bartonella species, which leads to vasoproliferative lesions of the skin and other organs. Bacillary angiomatosis affects individuals with advanced HIV or other immunocompromised individuals and may clinically mimic KS, which is similarly characterized by red-purple papules, nodules, or plaques. Differentiating BA from KS largely depends on histopathologic examination, with BA demonstrating protuberant endothelial cells surrounded by clumps of bacilli that are visible on Warthin-Starry silver stain. 

Lymphangioma is a benign hamartomatous hyperplasia of the lymphatic vessels. The majority of lymphangiomas are superficial, but a few may extend deeply into the connective tissue. Intraoral lymphangiomas occur more frequently on the dorsum of the tongue, followed by the palate, buccal mucosa, gingiva, and lips. They may be differentiated with their soft quality, pebblelike surface, and translucent vesicles. 

Malignant tumors of the oral cavity are rare, representing only 5% of tumors occurring in the body.⁴ Among malignant tumors of the oral cavity, squamous cell carcinomas are the most frequent type (90%-98%), and lymphomas and melanoma are the most outstanding among the remaining 2% to 10%. Both for lymphoma and mucosal melanoma, the most common sites of involvement are the soft tissues of the oral cavity, palatal mucosa, gingiva, tongue, cheeks, floor of the mouth, and lips.⁴ Although mucosal melanoma lesions usually are characterized by pigmented and ulcerated lesions, amelanotic variants also should be kept in mind. Histopathologic examination is mandatory for diagnosis.   

Intralesional chemotherapy with vinblastine or bleomycin, radiotherapy, electrochemotherapy, systemic antiretroviral therapy (ie, HAART), and chemotherapy with daunorubicin and pegylated liposomal doxorubicin are the main treatment options.^5,6 The immune system activator role of HAART leads to an increased CD4 count and reduces HIV proteins, which helps induction of the proliferation and neovascularization of KS tumor cells.³ This effect may help resolution of KS with localized involvement and allows physicians to utilize HAART without any other additional local and systemic chemotherapy treatment. 

The Diagnosis: Kaposi Sarcoma

A 4-mm punch biopsy from the border of an ulcerated nodular lesion on the hard palate demonstrated diffusely distributed spindle cells, cleftlike microvascularity with extravasated erythrocytes, and widespread human herpesvirus 8 immunoreactivity on histopathology (Figure 1). Serologic tests were positive for human immunodeficiency virus (HIV) infection; HIV RNA was 14,584 IU/mL and the CD4 count was 254/mm³. The patient was diagnosed with Kaposi sarcoma (KS) and referred to the infectious disease department for initiation of antiviral therapy. Marked regression was detected after 6 months of highly active antiretroviral therapy (HAART) without any additional treatment (Figure 2).  

Kaposi sarcoma is a human herpesvirus 8-associated angioproliferative disorder with low-grade malignant potential. There are 4 well-known clinical types: classic, endemic, iatrogenic, and AIDS associated.¹ Involvement of the oral cavity may be seen in all types but mostly is associated with the AIDS-associated type, which also could be a signal for undiagnosed asymptomatic HIV infection.² Oral KS most often affects the hard and soft palate, gingiva, and dorsal tongue, with plaques or tumors ranging from nonpigmented to brownish red or violaceous. AIDS-associated KS is known to be related to cytokine expression, which is induced by HIV infection causing immune dysregulation by altering the expression of cytokines, including IL-1, tumor necrosis factor α, and IL-6.¹ An in vitro study showed that cytokines secrete a number of angiogenic growth factors that, along with HIV proteins, induce and proliferate cells to become sarcoma cells. Integrins and the apoptosis process also are important in proliferation and neovascularization of KS tumor cells.³  

Bacillary angiomatosis (BA) is a rare manifestation of infection caused by Bartonella species, which leads to vasoproliferative lesions of the skin and other organs. Bacillary angiomatosis affects individuals with advanced HIV or other immunocompromised individuals and may clinically mimic KS, which is similarly characterized by red-purple papules, nodules, or plaques. Differentiating BA from KS largely depends on histopathologic examination, with BA demonstrating protuberant endothelial cells surrounded by clumps of bacilli that are visible on Warthin-Starry silver stain. 

Lymphangioma is a benign hamartomatous hyperplasia of the lymphatic vessels. The majority of lymphangiomas are superficial, but a few may extend deeply into the connective tissue. Intraoral lymphangiomas occur more frequently on the dorsum of the tongue, followed by the palate, buccal mucosa, gingiva, and lips. They may be differentiated with their soft quality, pebblelike surface, and translucent vesicles. 

Malignant tumors of the oral cavity are rare, representing only 5% of tumors occurring in the body.⁴ Among malignant tumors of the oral cavity, squamous cell carcinomas are the most frequent type (90%-98%), and lymphomas and melanoma are the most outstanding among the remaining 2% to 10%. Both for lymphoma and mucosal melanoma, the most common sites of involvement are the soft tissues of the oral cavity, palatal mucosa, gingiva, tongue, cheeks, floor of the mouth, and lips.⁴ Although mucosal melanoma lesions usually are characterized by pigmented and ulcerated lesions, amelanotic variants also should be kept in mind. Histopathologic examination is mandatory for diagnosis.   

Intralesional chemotherapy with vinblastine or bleomycin, radiotherapy, electrochemotherapy, systemic antiretroviral therapy (ie, HAART), and chemotherapy with daunorubicin and pegylated liposomal doxorubicin are the main treatment options.^5,6 The immune system activator role of HAART leads to an increased CD4 count and reduces HIV proteins, which helps induction of the proliferation and neovascularization of KS tumor cells.³ This effect may help resolution of KS with localized involvement and allows physicians to utilize HAART without any other additional local and systemic chemotherapy treatment. 

To the Editor:

Syringomas are small, benign, asymptomatic eccrine or apocrine tumors that present as multiple discrete flesh-colored papules. They are more common in females than males.¹ The etiology of eruptive syringomas is unclear, though an inflammatory process has been implicated in the abnormal proliferation of sweat glands.² However, a minority of tumors have been known to have an autosomal-dominant mode of transmission. Multiple or eruptive syringomas are associated with Down syndrome, Marfan syndrome, Ehlers-Danlos syndrome, and Blau syndrome.³ The clear cell variant has been found to be associated with diabetes mellitus.⁴ Syringomas most commonly appear on the lower eyelids, upper cheeks, neck, and upper chest; presentation on the penis is rare.⁵ We report a case of multiple eruptive syringomas located exclusively on the penis mimicking a sexually transmitted condition.

A 53-year-old man who was otherwise healthy presented with multiple flesh-colored papules on the penis that initially began to develop 30 years prior, but increased crops of lesions appeared 4 to 6 weeks prior to presentation. The patient described the lesions as rashlike, nonpruritic, and sensitive to the touch. He denied any discharge, oozing, crusting, or bleeding from the lesions. He did not report any high-risk sexual behaviors and stated that he was in a monogamous relationship with his wife. He had a medical history of molluscum contagiosum that was diagnosed and treated with cryotherapy 30 years prior; however, he did not have a history of any other sexually transmitted diseases. He also did not have a history of diabetes mellitus or thyroid disease.

Physical examination revealed multiple pink papules on the dorsal and ventral shaft of the penis, measuring 2 to 4 mm in diameter, with koebnerization (Figure 1). Based on clinical examination, the differential included condyloma, inflamed seborrheic keratosis, bowenoid papulosis, atypical molluscum contagiosum, or lichen planus. Consequently, a punch biopsy of the penile shaft was performed and histopathologic examination revealed proliferation of ducts focally that were tadpole shaped and embedded in a sclerotic stroma. The lining of the ducts was composed of cuboidal cells, some with clear cell change. The microscopic findings were consistent with penile syringomas (Figure 2). Laboratory results revealed the patient was negative for human immunodeficiency virus, hepatitis B, hepatitis C, and syphilis. The patient was given topical hydrocortisone butyrate and tacrolimus for symptomatic treatment. He declined further aggressive treatment.

To prevent misdiagnosis and unnecessary treatment, it is important to have syringomas as part of the differential diagnosis when patients present with multiple small flesh-colored papules on the penis. The lesions should be biopsied for accurate diagnosis and to provide reassurance to patients who usually come in for evaluation for fear of having acquired a sexually transmitted disease.

To the Editor:

Syringomas are small, benign, asymptomatic eccrine or apocrine tumors that present as multiple discrete flesh-colored papules. They are more common in females than males.¹ The etiology of eruptive syringomas is unclear, though an inflammatory process has been implicated in the abnormal proliferation of sweat glands.² However, a minority of tumors have been known to have an autosomal-dominant mode of transmission. Multiple or eruptive syringomas are associated with Down syndrome, Marfan syndrome, Ehlers-Danlos syndrome, and Blau syndrome.³ The clear cell variant has been found to be associated with diabetes mellitus.⁴ Syringomas most commonly appear on the lower eyelids, upper cheeks, neck, and upper chest; presentation on the penis is rare.⁵ We report a case of multiple eruptive syringomas located exclusively on the penis mimicking a sexually transmitted condition.

A 53-year-old man who was otherwise healthy presented with multiple flesh-colored papules on the penis that initially began to develop 30 years prior, but increased crops of lesions appeared 4 to 6 weeks prior to presentation. The patient described the lesions as rashlike, nonpruritic, and sensitive to the touch. He denied any discharge, oozing, crusting, or bleeding from the lesions. He did not report any high-risk sexual behaviors and stated that he was in a monogamous relationship with his wife. He had a medical history of molluscum contagiosum that was diagnosed and treated with cryotherapy 30 years prior; however, he did not have a history of any other sexually transmitted diseases. He also did not have a history of diabetes mellitus or thyroid disease.

Physical examination revealed multiple pink papules on the dorsal and ventral shaft of the penis, measuring 2 to 4 mm in diameter, with koebnerization (Figure 1). Based on clinical examination, the differential included condyloma, inflamed seborrheic keratosis, bowenoid papulosis, atypical molluscum contagiosum, or lichen planus. Consequently, a punch biopsy of the penile shaft was performed and histopathologic examination revealed proliferation of ducts focally that were tadpole shaped and embedded in a sclerotic stroma. The lining of the ducts was composed of cuboidal cells, some with clear cell change. The microscopic findings were consistent with penile syringomas (Figure 2). Laboratory results revealed the patient was negative for human immunodeficiency virus, hepatitis B, hepatitis C, and syphilis. The patient was given topical hydrocortisone butyrate and tacrolimus for symptomatic treatment. He declined further aggressive treatment.

To prevent misdiagnosis and unnecessary treatment, it is important to have syringomas as part of the differential diagnosis when patients present with multiple small flesh-colored papules on the penis. The lesions should be biopsied for accurate diagnosis and to provide reassurance to patients who usually come in for evaluation for fear of having acquired a sexually transmitted disease.

To the Editor:

Syringomas are small, benign, asymptomatic eccrine or apocrine tumors that present as multiple discrete flesh-colored papules. They are more common in females than males.¹ The etiology of eruptive syringomas is unclear, though an inflammatory process has been implicated in the abnormal proliferation of sweat glands.² However, a minority of tumors have been known to have an autosomal-dominant mode of transmission. Multiple or eruptive syringomas are associated with Down syndrome, Marfan syndrome, Ehlers-Danlos syndrome, and Blau syndrome.³ The clear cell variant has been found to be associated with diabetes mellitus.⁴ Syringomas most commonly appear on the lower eyelids, upper cheeks, neck, and upper chest; presentation on the penis is rare.⁵ We report a case of multiple eruptive syringomas located exclusively on the penis mimicking a sexually transmitted condition.

A 53-year-old man who was otherwise healthy presented with multiple flesh-colored papules on the penis that initially began to develop 30 years prior, but increased crops of lesions appeared 4 to 6 weeks prior to presentation. The patient described the lesions as rashlike, nonpruritic, and sensitive to the touch. He denied any discharge, oozing, crusting, or bleeding from the lesions. He did not report any high-risk sexual behaviors and stated that he was in a monogamous relationship with his wife. He had a medical history of molluscum contagiosum that was diagnosed and treated with cryotherapy 30 years prior; however, he did not have a history of any other sexually transmitted diseases. He also did not have a history of diabetes mellitus or thyroid disease.

Physical examination revealed multiple pink papules on the dorsal and ventral shaft of the penis, measuring 2 to 4 mm in diameter, with koebnerization (Figure 1). Based on clinical examination, the differential included condyloma, inflamed seborrheic keratosis, bowenoid papulosis, atypical molluscum contagiosum, or lichen planus. Consequently, a punch biopsy of the penile shaft was performed and histopathologic examination revealed proliferation of ducts focally that were tadpole shaped and embedded in a sclerotic stroma. The lining of the ducts was composed of cuboidal cells, some with clear cell change. The microscopic findings were consistent with penile syringomas (Figure 2). Laboratory results revealed the patient was negative for human immunodeficiency virus, hepatitis B, hepatitis C, and syphilis. The patient was given topical hydrocortisone butyrate and tacrolimus for symptomatic treatment. He declined further aggressive treatment.

To prevent misdiagnosis and unnecessary treatment, it is important to have syringomas as part of the differential diagnosis when patients present with multiple small flesh-colored papules on the penis. The lesions should be biopsied for accurate diagnosis and to provide reassurance to patients who usually come in for evaluation for fear of having acquired a sexually transmitted disease.

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

The Diagnosis: Merkel Cell Carcinoma 

An excisional biopsy revealed that the dermis was mostly replaced by a malignant neoplastic infiltrate morphologically resembling small cell carcinoma (Figure 1). The cells had uniform hyperchromatic nuclei with fairly even chromatin and generally inconspicuous nucleoli. There was a tendency for smudgy artifacts at the periphery of the infiltrate, and the cells had relatively scant cytoplasm with slight streaming. Occasional apoptotic forms were present. Immunohistochemistry showed strong dotlike staining with cytokeratin 20 and moderate positivity with synaptophysin and chromogranin A (Figure 2). Unusually, there also was weak staining in a few tumor cells with thyroid transcription factor 1, a marker usually indicative of small cell carcinoma of the lungs that typically is negative in Merkel cell carcinoma (MCC). A second thyroid transcription factor 1 monoclonal antibody used in a double immunostain for lung adenocarcinomas was completely negative. This second antibody is more specific but less sensitive than the stand-alone version. The skin biopsy results confirmed the diagnosis of MCC. Given the patient's frailty and comorbidities, wide local excision was not performed and the patient was referred to radiation oncology. He died several months later from metastatic MCC. 

Merkel cell carcinoma is an uncommon skin malignancy that can be easily mistaken for other conditions if the clinician is not familiar with its typical presentation. It most commonly is found on the head and neck in elderly individuals, most often aged 60 to 80 years,¹ with a notable history of sun exposure and/or immunosuppression. It is an aggressive skin cancer that originally was thought to be due to pathogenic changes of Merkel cells,² which are specialized touch receptors located at the dermoepidermal junction of the skin; however, newer evidence has suggested that MCC arises from malignant changes to skin stem cells.³ It shares more characteristics with extracutaneous neuroendocrine tumors and is more aptly labeled by pathologists as a primary neuroendocrine carcinoma of the skin.⁴  

The frequency of MCC is highest in Australia, likely due to intense sun exposure, where the age-adjusted incidence rate reported in Queensland was 1.6 per 100,000 individuals from 2006 to 2010.⁵ The lowest incidence rates were reported in Finland (0.11 and 0.12 per 100,000 males and females, respectively)⁶ and Denmark (2.2 cases per million person-years).⁷ The clinical features of MCC are summarized by the mnemonic AEIOU: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin.⁸ In a 2008 study of 195 patients, 89% of primary MCC lesions met 3 or more criteria, 32% met 4 or more criteria, and 7% met all 5 criteria.⁸  

The classic presentation of MCC is a pink-red to violaceous nodule on the head or neck in an elderly patient, but there is a need to maintain suspicion of malignancy when examining a presumed infected cystic lesion, especially when a round of antibiotics has not ameliorated the symptoms. According to Heath et al,⁸ of 106 patients treated for MCC, 56% of first clinical impressions were benign. A PubMed and Scopus search was performed with the MeSH headings Merkel cell carcinoma +/- presentation to uncover similar unusual presentations between 1970 and the present day. Merkel cell carcinoma has been misdiagnosed as seemingly benign lesions including lipoma,⁹ allergic contact dermatitis,¹⁰ and atheroma.¹¹ The differential diagnosis of MCC also includes cysts, amelanotic melanoma, basal cell carcinoma, dermatofibrosarcoma protuberans, squamous cell carcinoma, fungal kerion, leiomyosarcoma, neurothekeoma, abscesses, and cutaneous lymphoma.  

Merkel cell polyomavirus has been implicated in the malignant transformation of MCC. It is a small, human, nonenveloped, double-stranded DNA virus1 and is found in approximately 70% to 80% of MCC cases.¹² Merkel cell polyomavirus is a respiratory tract pathogen that is acquired by immunocompetent infants; it integrates itself into the host's genome and then enters a long latency period to later reactivate in immunocompromised adults.¹³ 

Wide local excision down to fascia is the mainstay of treatment of MCC, with recommended margins of 1 to 2 cm.¹⁴ Mohs micrographic surgery also can be considered.¹⁵ Similar to other neuroendocrine tumors, MCC is considered a radiosensitive tumor; radiation likely improves local control and is recommended in early-stage disease.^16,17 It also has been described as the sole treatment modality in patients who are not candidates for surgery. The role of chemotherapy is more controversial, as responses do not appear to be long-lasting but should be considered in patients with advanced disease.^14,18 There have been major advances in immunotherapy with the recent approvals of avelumab, an anti-PD-L1 inhibitor,¹⁹ and pembrolizumab,²⁰ an anti-PD-1 inhibitor, for metastatic MCC. Clinical trials for MCC using kinase inhibitors and somatostatin analogues currently are ongoing.²¹  

Several studies have demonstrated high rates of occult nodal disease in clinically node-negative patients, which has led to widespread use of sentinel lymph node biopsies^.22,23 A sentinel lymph node biopsy is recommended at the time of surgery to aid with treatment decisions and prognosis.²⁴  

Merkel cell carcinoma is highly aggressive, and more than one-third of patients die from their disease, making it twice as lethal as melanoma. Overall survival rates remain low (5-year overall survival, 0%-18%) for advanced disease.⁵ Unfortunately, progression to metastasis is common and most often occurs within 2 years of diagnosis.^17,25 Follow-up after treatment of MCC is crucial, with the 2019 National Comprehensive Cancer Network (NCCN) guidelines suggesting a physical examination with complete skin and complete lymph node examination every 3 to 6 months for 3 years and every 6 to 12 months thereafter.¹⁵ 

This case is an important reminder to include MCC in the differential diagnosis of presumed infected cysts, particularly on sun-exposed sites in elderly patients, as our patient was treated with antibiotics twice without improvement. An infected cyst with a lack of response to antibiotics should alert clinicians to the potential of malignancy.  

The Diagnosis: Merkel Cell Carcinoma 

An excisional biopsy revealed that the dermis was mostly replaced by a malignant neoplastic infiltrate morphologically resembling small cell carcinoma (Figure 1). The cells had uniform hyperchromatic nuclei with fairly even chromatin and generally inconspicuous nucleoli. There was a tendency for smudgy artifacts at the periphery of the infiltrate, and the cells had relatively scant cytoplasm with slight streaming. Occasional apoptotic forms were present. Immunohistochemistry showed strong dotlike staining with cytokeratin 20 and moderate positivity with synaptophysin and chromogranin A (Figure 2). Unusually, there also was weak staining in a few tumor cells with thyroid transcription factor 1, a marker usually indicative of small cell carcinoma of the lungs that typically is negative in Merkel cell carcinoma (MCC). A second thyroid transcription factor 1 monoclonal antibody used in a double immunostain for lung adenocarcinomas was completely negative. This second antibody is more specific but less sensitive than the stand-alone version. The skin biopsy results confirmed the diagnosis of MCC. Given the patient's frailty and comorbidities, wide local excision was not performed and the patient was referred to radiation oncology. He died several months later from metastatic MCC. 

Merkel cell carcinoma is an uncommon skin malignancy that can be easily mistaken for other conditions if the clinician is not familiar with its typical presentation. It most commonly is found on the head and neck in elderly individuals, most often aged 60 to 80 years,¹ with a notable history of sun exposure and/or immunosuppression. It is an aggressive skin cancer that originally was thought to be due to pathogenic changes of Merkel cells,² which are specialized touch receptors located at the dermoepidermal junction of the skin; however, newer evidence has suggested that MCC arises from malignant changes to skin stem cells.³ It shares more characteristics with extracutaneous neuroendocrine tumors and is more aptly labeled by pathologists as a primary neuroendocrine carcinoma of the skin.⁴  

The frequency of MCC is highest in Australia, likely due to intense sun exposure, where the age-adjusted incidence rate reported in Queensland was 1.6 per 100,000 individuals from 2006 to 2010.⁵ The lowest incidence rates were reported in Finland (0.11 and 0.12 per 100,000 males and females, respectively)⁶ and Denmark (2.2 cases per million person-years).⁷ The clinical features of MCC are summarized by the mnemonic AEIOU: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin.⁸ In a 2008 study of 195 patients, 89% of primary MCC lesions met 3 or more criteria, 32% met 4 or more criteria, and 7% met all 5 criteria.⁸  

The classic presentation of MCC is a pink-red to violaceous nodule on the head or neck in an elderly patient, but there is a need to maintain suspicion of malignancy when examining a presumed infected cystic lesion, especially when a round of antibiotics has not ameliorated the symptoms. According to Heath et al,⁸ of 106 patients treated for MCC, 56% of first clinical impressions were benign. A PubMed and Scopus search was performed with the MeSH headings Merkel cell carcinoma +/- presentation to uncover similar unusual presentations between 1970 and the present day. Merkel cell carcinoma has been misdiagnosed as seemingly benign lesions including lipoma,⁹ allergic contact dermatitis,¹⁰ and atheroma.¹¹ The differential diagnosis of MCC also includes cysts, amelanotic melanoma, basal cell carcinoma, dermatofibrosarcoma protuberans, squamous cell carcinoma, fungal kerion, leiomyosarcoma, neurothekeoma, abscesses, and cutaneous lymphoma.  

Merkel cell polyomavirus has been implicated in the malignant transformation of MCC. It is a small, human, nonenveloped, double-stranded DNA virus1 and is found in approximately 70% to 80% of MCC cases.¹² Merkel cell polyomavirus is a respiratory tract pathogen that is acquired by immunocompetent infants; it integrates itself into the host's genome and then enters a long latency period to later reactivate in immunocompromised adults.¹³ 

Wide local excision down to fascia is the mainstay of treatment of MCC, with recommended margins of 1 to 2 cm.¹⁴ Mohs micrographic surgery also can be considered.¹⁵ Similar to other neuroendocrine tumors, MCC is considered a radiosensitive tumor; radiation likely improves local control and is recommended in early-stage disease.^16,17 It also has been described as the sole treatment modality in patients who are not candidates for surgery. The role of chemotherapy is more controversial, as responses do not appear to be long-lasting but should be considered in patients with advanced disease.^14,18 There have been major advances in immunotherapy with the recent approvals of avelumab, an anti-PD-L1 inhibitor,¹⁹ and pembrolizumab,²⁰ an anti-PD-1 inhibitor, for metastatic MCC. Clinical trials for MCC using kinase inhibitors and somatostatin analogues currently are ongoing.²¹  

Several studies have demonstrated high rates of occult nodal disease in clinically node-negative patients, which has led to widespread use of sentinel lymph node biopsies^.22,23 A sentinel lymph node biopsy is recommended at the time of surgery to aid with treatment decisions and prognosis.²⁴  

Merkel cell carcinoma is highly aggressive, and more than one-third of patients die from their disease, making it twice as lethal as melanoma. Overall survival rates remain low (5-year overall survival, 0%-18%) for advanced disease.⁵ Unfortunately, progression to metastasis is common and most often occurs within 2 years of diagnosis.^17,25 Follow-up after treatment of MCC is crucial, with the 2019 National Comprehensive Cancer Network (NCCN) guidelines suggesting a physical examination with complete skin and complete lymph node examination every 3 to 6 months for 3 years and every 6 to 12 months thereafter.¹⁵ 

This case is an important reminder to include MCC in the differential diagnosis of presumed infected cysts, particularly on sun-exposed sites in elderly patients, as our patient was treated with antibiotics twice without improvement. An infected cyst with a lack of response to antibiotics should alert clinicians to the potential of malignancy.  

The Diagnosis: Merkel Cell Carcinoma 

An excisional biopsy revealed that the dermis was mostly replaced by a malignant neoplastic infiltrate morphologically resembling small cell carcinoma (Figure 1). The cells had uniform hyperchromatic nuclei with fairly even chromatin and generally inconspicuous nucleoli. There was a tendency for smudgy artifacts at the periphery of the infiltrate, and the cells had relatively scant cytoplasm with slight streaming. Occasional apoptotic forms were present. Immunohistochemistry showed strong dotlike staining with cytokeratin 20 and moderate positivity with synaptophysin and chromogranin A (Figure 2). Unusually, there also was weak staining in a few tumor cells with thyroid transcription factor 1, a marker usually indicative of small cell carcinoma of the lungs that typically is negative in Merkel cell carcinoma (MCC). A second thyroid transcription factor 1 monoclonal antibody used in a double immunostain for lung adenocarcinomas was completely negative. This second antibody is more specific but less sensitive than the stand-alone version. The skin biopsy results confirmed the diagnosis of MCC. Given the patient's frailty and comorbidities, wide local excision was not performed and the patient was referred to radiation oncology. He died several months later from metastatic MCC. 

Merkel cell carcinoma is an uncommon skin malignancy that can be easily mistaken for other conditions if the clinician is not familiar with its typical presentation. It most commonly is found on the head and neck in elderly individuals, most often aged 60 to 80 years,¹ with a notable history of sun exposure and/or immunosuppression. It is an aggressive skin cancer that originally was thought to be due to pathogenic changes of Merkel cells,² which are specialized touch receptors located at the dermoepidermal junction of the skin; however, newer evidence has suggested that MCC arises from malignant changes to skin stem cells.³ It shares more characteristics with extracutaneous neuroendocrine tumors and is more aptly labeled by pathologists as a primary neuroendocrine carcinoma of the skin.⁴  

The frequency of MCC is highest in Australia, likely due to intense sun exposure, where the age-adjusted incidence rate reported in Queensland was 1.6 per 100,000 individuals from 2006 to 2010.⁵ The lowest incidence rates were reported in Finland (0.11 and 0.12 per 100,000 males and females, respectively)⁶ and Denmark (2.2 cases per million person-years).⁷ The clinical features of MCC are summarized by the mnemonic AEIOU: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin.⁸ In a 2008 study of 195 patients, 89% of primary MCC lesions met 3 or more criteria, 32% met 4 or more criteria, and 7% met all 5 criteria.⁸  

The classic presentation of MCC is a pink-red to violaceous nodule on the head or neck in an elderly patient, but there is a need to maintain suspicion of malignancy when examining a presumed infected cystic lesion, especially when a round of antibiotics has not ameliorated the symptoms. According to Heath et al,⁸ of 106 patients treated for MCC, 56% of first clinical impressions were benign. A PubMed and Scopus search was performed with the MeSH headings Merkel cell carcinoma +/- presentation to uncover similar unusual presentations between 1970 and the present day. Merkel cell carcinoma has been misdiagnosed as seemingly benign lesions including lipoma,⁹ allergic contact dermatitis,¹⁰ and atheroma.¹¹ The differential diagnosis of MCC also includes cysts, amelanotic melanoma, basal cell carcinoma, dermatofibrosarcoma protuberans, squamous cell carcinoma, fungal kerion, leiomyosarcoma, neurothekeoma, abscesses, and cutaneous lymphoma.  

Merkel cell polyomavirus has been implicated in the malignant transformation of MCC. It is a small, human, nonenveloped, double-stranded DNA virus1 and is found in approximately 70% to 80% of MCC cases.¹² Merkel cell polyomavirus is a respiratory tract pathogen that is acquired by immunocompetent infants; it integrates itself into the host's genome and then enters a long latency period to later reactivate in immunocompromised adults.¹³ 

Wide local excision down to fascia is the mainstay of treatment of MCC, with recommended margins of 1 to 2 cm.¹⁴ Mohs micrographic surgery also can be considered.¹⁵ Similar to other neuroendocrine tumors, MCC is considered a radiosensitive tumor; radiation likely improves local control and is recommended in early-stage disease.^16,17 It also has been described as the sole treatment modality in patients who are not candidates for surgery. The role of chemotherapy is more controversial, as responses do not appear to be long-lasting but should be considered in patients with advanced disease.^14,18 There have been major advances in immunotherapy with the recent approvals of avelumab, an anti-PD-L1 inhibitor,¹⁹ and pembrolizumab,²⁰ an anti-PD-1 inhibitor, for metastatic MCC. Clinical trials for MCC using kinase inhibitors and somatostatin analogues currently are ongoing.²¹  

Several studies have demonstrated high rates of occult nodal disease in clinically node-negative patients, which has led to widespread use of sentinel lymph node biopsies^.22,23 A sentinel lymph node biopsy is recommended at the time of surgery to aid with treatment decisions and prognosis.²⁴  

Merkel cell carcinoma is highly aggressive, and more than one-third of patients die from their disease, making it twice as lethal as melanoma. Overall survival rates remain low (5-year overall survival, 0%-18%) for advanced disease.⁵ Unfortunately, progression to metastasis is common and most often occurs within 2 years of diagnosis.^17,25 Follow-up after treatment of MCC is crucial, with the 2019 National Comprehensive Cancer Network (NCCN) guidelines suggesting a physical examination with complete skin and complete lymph node examination every 3 to 6 months for 3 years and every 6 to 12 months thereafter.¹⁵ 

This case is an important reminder to include MCC in the differential diagnosis of presumed infected cysts, particularly on sun-exposed sites in elderly patients, as our patient was treated with antibiotics twice without improvement. An infected cyst with a lack of response to antibiotics should alert clinicians to the potential of malignancy.  

To the Editor:

A 50-year old man with Fitzpatrick skin type IV, human immunodeficiency virus (HIV), fatty liver disease, and moderate psoriasis (10% body surface area [BSA] affected) currently treated with clobetasol spray and calcitriol ointment presented with persistent psoriatic lesions on the trunk, arms, legs, and buttocks. His CD4 count was 460 and his HIV RNA count was 48 copies/mL on polymerase chain reaction 2 months prior to the current presentation. He had been undergoing phototherapy 3 times weekly for the last 5 months for treatment of psoriasis.

At the current presentation, he was started on an apremilast starter pack with the dosage titrated from 10 mg to 30 mg over the course of 1 week. He was maintained on a dose of 30 mg twice daily after 1 week and continued clobetasol spray, calcitriol ointment, and phototherapy 3 times weekly with the intent to reduce the frequency after adequate control of psoriasis was achieved. After 3 months of treatment, the affected BSA was 0%. He continued apremilast, and phototherapy was reduced to once weekly. Phototherapy was discontinued after 7 months of concomitant treatment with apremilast after clearance was maintained. It was reinitiated twice weekly after a mild flare (3% BSA affected). After 20 total months of treatment, the patient was no longer able to afford apremilast treatment and presented with a severe psoriasis flare (40% BSA affected). He was switched to acitretin with a plan to apply for apremilast financial assistance programs.

Psoriasis treatment in the HIV population poses a challenge given the immunosuppressed state of these patients, the risk of reactivation of latent infections, and the refractory nature of psoriasis in the setting of HIV. Two of the authors (S.P.R. and J.J.W.) previously reported a case of moderate to severe psoriasis in a patient with HIV and hepatitis C who demonstrated treatment success with apremilast until it was discontinued due to financial implications.¹ Currently, apremilast is not widely used to treat psoriasis in the HIV population. The National Psoriasis Foundation 2010 guidelines recommended UV light therapy for treatment of moderate to severe psoriasis in HIV-positive patients, with oral retinoids as the second-line treatment.² There remains a need for updated guidelines on the use of systemic agents for psoriasis treatment in the HIV population.

Apremilast, a phosphodiesterase 4 inhibitor, is an oral therapy that restores the balance of proinflammatory and anti-inflammatory cytokines by inhibiting inflammatory cytokine (eg, tumor necrosis factor α, IFN-γ, IL-2, IL-12, IL-23) secretion and stimulating anti-inflammatory cytokine (eg, IL-6, IL-10) production. In 2015, the phase 3 ESTEEM 1³ and ESTEEM 2⁴ trials demonstrated the efficacy of apremilast 30 mg twice daily for treatment of psoriasis. In both trials, the psoriasis area and severity index 75 response rate at week 16 was significantly higher with apremilast compared to placebo alone (33.1% and 28.8% vs 5.2% and 5.8%, respectively; P<.001 for both trials). Apremilast also was noted to improve difficult-to-treat nail, scalp, and palmoplantar psoriasis.^3,4

Use of other systemic agents such as tumor necrosis factor α inhibitors and ustekinumab has been reported in HIV-positive patients.^5-7 There is no current data on IL-17 and IL-23 inhibitors. Acitretin generally is recommended as a second-line agent in HIV patients given its lack of immunosuppression²; however, methotrexate and cyclosporine should be avoided given the risk of opportunistic infections.⁸

Apremilast is a promising therapy with a favorable safety profile that should be considered as an adjuvant treatment to first-line agents such as phototherapy in HIV-positive patients. Apremilast has been successfully used in an HIV patient with a concomitant chronic hepatitis C infection.¹ Systemic medications such as apremilast should be managed in coordination with infectious disease specialists with close monitoring of CD4 levels and viral loads as well as prophylactic agents.

To the Editor:

A 50-year old man with Fitzpatrick skin type IV, human immunodeficiency virus (HIV), fatty liver disease, and moderate psoriasis (10% body surface area [BSA] affected) currently treated with clobetasol spray and calcitriol ointment presented with persistent psoriatic lesions on the trunk, arms, legs, and buttocks. His CD4 count was 460 and his HIV RNA count was 48 copies/mL on polymerase chain reaction 2 months prior to the current presentation. He had been undergoing phototherapy 3 times weekly for the last 5 months for treatment of psoriasis.

At the current presentation, he was started on an apremilast starter pack with the dosage titrated from 10 mg to 30 mg over the course of 1 week. He was maintained on a dose of 30 mg twice daily after 1 week and continued clobetasol spray, calcitriol ointment, and phototherapy 3 times weekly with the intent to reduce the frequency after adequate control of psoriasis was achieved. After 3 months of treatment, the affected BSA was 0%. He continued apremilast, and phototherapy was reduced to once weekly. Phototherapy was discontinued after 7 months of concomitant treatment with apremilast after clearance was maintained. It was reinitiated twice weekly after a mild flare (3% BSA affected). After 20 total months of treatment, the patient was no longer able to afford apremilast treatment and presented with a severe psoriasis flare (40% BSA affected). He was switched to acitretin with a plan to apply for apremilast financial assistance programs.

Psoriasis treatment in the HIV population poses a challenge given the immunosuppressed state of these patients, the risk of reactivation of latent infections, and the refractory nature of psoriasis in the setting of HIV. Two of the authors (S.P.R. and J.J.W.) previously reported a case of moderate to severe psoriasis in a patient with HIV and hepatitis C who demonstrated treatment success with apremilast until it was discontinued due to financial implications.¹ Currently, apremilast is not widely used to treat psoriasis in the HIV population. The National Psoriasis Foundation 2010 guidelines recommended UV light therapy for treatment of moderate to severe psoriasis in HIV-positive patients, with oral retinoids as the second-line treatment.² There remains a need for updated guidelines on the use of systemic agents for psoriasis treatment in the HIV population.

Apremilast, a phosphodiesterase 4 inhibitor, is an oral therapy that restores the balance of proinflammatory and anti-inflammatory cytokines by inhibiting inflammatory cytokine (eg, tumor necrosis factor α, IFN-γ, IL-2, IL-12, IL-23) secretion and stimulating anti-inflammatory cytokine (eg, IL-6, IL-10) production. In 2015, the phase 3 ESTEEM 1³ and ESTEEM 2⁴ trials demonstrated the efficacy of apremilast 30 mg twice daily for treatment of psoriasis. In both trials, the psoriasis area and severity index 75 response rate at week 16 was significantly higher with apremilast compared to placebo alone (33.1% and 28.8% vs 5.2% and 5.8%, respectively; P<.001 for both trials). Apremilast also was noted to improve difficult-to-treat nail, scalp, and palmoplantar psoriasis.^3,4

Use of other systemic agents such as tumor necrosis factor α inhibitors and ustekinumab has been reported in HIV-positive patients.^5-7 There is no current data on IL-17 and IL-23 inhibitors. Acitretin generally is recommended as a second-line agent in HIV patients given its lack of immunosuppression²; however, methotrexate and cyclosporine should be avoided given the risk of opportunistic infections.⁸

Apremilast is a promising therapy with a favorable safety profile that should be considered as an adjuvant treatment to first-line agents such as phototherapy in HIV-positive patients. Apremilast has been successfully used in an HIV patient with a concomitant chronic hepatitis C infection.¹ Systemic medications such as apremilast should be managed in coordination with infectious disease specialists with close monitoring of CD4 levels and viral loads as well as prophylactic agents.

To the Editor:

A 50-year old man with Fitzpatrick skin type IV, human immunodeficiency virus (HIV), fatty liver disease, and moderate psoriasis (10% body surface area [BSA] affected) currently treated with clobetasol spray and calcitriol ointment presented with persistent psoriatic lesions on the trunk, arms, legs, and buttocks. His CD4 count was 460 and his HIV RNA count was 48 copies/mL on polymerase chain reaction 2 months prior to the current presentation. He had been undergoing phototherapy 3 times weekly for the last 5 months for treatment of psoriasis.

At the current presentation, he was started on an apremilast starter pack with the dosage titrated from 10 mg to 30 mg over the course of 1 week. He was maintained on a dose of 30 mg twice daily after 1 week and continued clobetasol spray, calcitriol ointment, and phototherapy 3 times weekly with the intent to reduce the frequency after adequate control of psoriasis was achieved. After 3 months of treatment, the affected BSA was 0%. He continued apremilast, and phototherapy was reduced to once weekly. Phototherapy was discontinued after 7 months of concomitant treatment with apremilast after clearance was maintained. It was reinitiated twice weekly after a mild flare (3% BSA affected). After 20 total months of treatment, the patient was no longer able to afford apremilast treatment and presented with a severe psoriasis flare (40% BSA affected). He was switched to acitretin with a plan to apply for apremilast financial assistance programs.

Psoriasis treatment in the HIV population poses a challenge given the immunosuppressed state of these patients, the risk of reactivation of latent infections, and the refractory nature of psoriasis in the setting of HIV. Two of the authors (S.P.R. and J.J.W.) previously reported a case of moderate to severe psoriasis in a patient with HIV and hepatitis C who demonstrated treatment success with apremilast until it was discontinued due to financial implications.¹ Currently, apremilast is not widely used to treat psoriasis in the HIV population. The National Psoriasis Foundation 2010 guidelines recommended UV light therapy for treatment of moderate to severe psoriasis in HIV-positive patients, with oral retinoids as the second-line treatment.² There remains a need for updated guidelines on the use of systemic agents for psoriasis treatment in the HIV population.

Apremilast, a phosphodiesterase 4 inhibitor, is an oral therapy that restores the balance of proinflammatory and anti-inflammatory cytokines by inhibiting inflammatory cytokine (eg, tumor necrosis factor α, IFN-γ, IL-2, IL-12, IL-23) secretion and stimulating anti-inflammatory cytokine (eg, IL-6, IL-10) production. In 2015, the phase 3 ESTEEM 1³ and ESTEEM 2⁴ trials demonstrated the efficacy of apremilast 30 mg twice daily for treatment of psoriasis. In both trials, the psoriasis area and severity index 75 response rate at week 16 was significantly higher with apremilast compared to placebo alone (33.1% and 28.8% vs 5.2% and 5.8%, respectively; P<.001 for both trials). Apremilast also was noted to improve difficult-to-treat nail, scalp, and palmoplantar psoriasis.^3,4

Use of other systemic agents such as tumor necrosis factor α inhibitors and ustekinumab has been reported in HIV-positive patients.^5-7 There is no current data on IL-17 and IL-23 inhibitors. Acitretin generally is recommended as a second-line agent in HIV patients given its lack of immunosuppression²; however, methotrexate and cyclosporine should be avoided given the risk of opportunistic infections.⁸

Apremilast is a promising therapy with a favorable safety profile that should be considered as an adjuvant treatment to first-line agents such as phototherapy in HIV-positive patients. Apremilast has been successfully used in an HIV patient with a concomitant chronic hepatitis C infection.¹ Systemic medications such as apremilast should be managed in coordination with infectious disease specialists with close monitoring of CD4 levels and viral loads as well as prophylactic agents.

To the Editor:

Netherton syndrome (NS) is a rare autosomal-recessive ichthyosiform disease.¹ The incidence is estimated to be 1 in 200,000 individuals.² Netherton syndrome presents with generalized erythroderma and scaling, characteristic hair shaft abnormalities, and dysregulation of the immune system. Treatment is largely symptomatic and includes fragrance-free emollients, keratolytics, tretinoin, and corticosteroids, either alone or in combination. We report a case of NS in a man with congenital erythroderma, pili torti, and elevated IgE levels.

A 23-year-old man presented with generalized scaly skin that was present since birth. He was the first child born of nonconsanguineous parents. His medical history was suggestive of atopic diatheses such as allergic rhinitis and recurrent urticaria. The patient was of thin build and had widespread erythematous, annular, and polycyclic scaly lesions (Figure 1A), some with characteristic double-edged scale (Figure 1B). The skin was dry due to anhidrosis that was present since birth. Flexural lichenification was present at the cubital fossa of both arms. Scalp hairs were easily pluckable and had generalized thinning of hair density. Hair mount examination showed characteristic features of both trichorrhexis invaginata (Figure 2A) and pili torti (Figure 2B).

Netherton syndrome is caused by mutation of the SPINK5 gene, serine protease inhibitor Kazal type 5; the corresponding gene is located on the long arm of chromosome 5.³ The gene encodes a serine protease inhibitor proprotein LEKTI (lymphoepithelial Kazal type inhibitor).⁴ The product of the gene is thought to be necessary for epidermal cell growth and differentiation. The classic clinical triad of NS includes ichthyosiform dermatosis with double-edged scale, hair shaft abnormalities, and atopy or elevated IgE levels.⁵ Generalized (congenital) erythroderma usually becomes evident at birth or shortly thereafter. Half of patients develop lesions of ILC on the trunk and limbs during childhood.⁶ A typical ILC lesion is characterized by an erythematous scaly patch that may be annular or polycyclic with double-edged scale at the advancing border. The ability to sweat is impaired, which may cause episodes of hyperpyrexia, especially during humid weather. Patients with hyperpyrexia may be incorrectly diagnosed with bacterial infection and treated with antipyretic drugs or a prolonged course of antibiotics. Trichorrhexis invaginata, also referred to as bamboo hair or ball-and-socket defect, is the pathognomonic hair shaft abnormality seen in NS.⁷ Other hair shaft abnormalities in this syndrome include trichorrhexis nodosa and pili torti.⁸ Our patient had hair shaft abnormalities of trichorrhexis invaginata and pili torti, which are rare findings. The third component of this syndrome is atopy, which generally manifests as angioedema, urticaria, allergic rhinitis, peripheral eosinophilia, atopic dermatitis–like skin lesions, asthma, and elevated IgE levels.⁹

Treatment with emollients, topical steroids, tacrolimus, and psoralen plus UVA does not elicit a satisfactory response. The Table highlights the clinical features and management of NS.

To the Editor:

Netherton syndrome (NS) is a rare autosomal-recessive ichthyosiform disease.¹ The incidence is estimated to be 1 in 200,000 individuals.² Netherton syndrome presents with generalized erythroderma and scaling, characteristic hair shaft abnormalities, and dysregulation of the immune system. Treatment is largely symptomatic and includes fragrance-free emollients, keratolytics, tretinoin, and corticosteroids, either alone or in combination. We report a case of NS in a man with congenital erythroderma, pili torti, and elevated IgE levels.

A 23-year-old man presented with generalized scaly skin that was present since birth. He was the first child born of nonconsanguineous parents. His medical history was suggestive of atopic diatheses such as allergic rhinitis and recurrent urticaria. The patient was of thin build and had widespread erythematous, annular, and polycyclic scaly lesions (Figure 1A), some with characteristic double-edged scale (Figure 1B). The skin was dry due to anhidrosis that was present since birth. Flexural lichenification was present at the cubital fossa of both arms. Scalp hairs were easily pluckable and had generalized thinning of hair density. Hair mount examination showed characteristic features of both trichorrhexis invaginata (Figure 2A) and pili torti (Figure 2B).

Netherton syndrome is caused by mutation of the SPINK5 gene, serine protease inhibitor Kazal type 5; the corresponding gene is located on the long arm of chromosome 5.³ The gene encodes a serine protease inhibitor proprotein LEKTI (lymphoepithelial Kazal type inhibitor).⁴ The product of the gene is thought to be necessary for epidermal cell growth and differentiation. The classic clinical triad of NS includes ichthyosiform dermatosis with double-edged scale, hair shaft abnormalities, and atopy or elevated IgE levels.⁵ Generalized (congenital) erythroderma usually becomes evident at birth or shortly thereafter. Half of patients develop lesions of ILC on the trunk and limbs during childhood.⁶ A typical ILC lesion is characterized by an erythematous scaly patch that may be annular or polycyclic with double-edged scale at the advancing border. The ability to sweat is impaired, which may cause episodes of hyperpyrexia, especially during humid weather. Patients with hyperpyrexia may be incorrectly diagnosed with bacterial infection and treated with antipyretic drugs or a prolonged course of antibiotics. Trichorrhexis invaginata, also referred to as bamboo hair or ball-and-socket defect, is the pathognomonic hair shaft abnormality seen in NS.⁷ Other hair shaft abnormalities in this syndrome include trichorrhexis nodosa and pili torti.⁸ Our patient had hair shaft abnormalities of trichorrhexis invaginata and pili torti, which are rare findings. The third component of this syndrome is atopy, which generally manifests as angioedema, urticaria, allergic rhinitis, peripheral eosinophilia, atopic dermatitis–like skin lesions, asthma, and elevated IgE levels.⁹

Treatment with emollients, topical steroids, tacrolimus, and psoralen plus UVA does not elicit a satisfactory response. The Table highlights the clinical features and management of NS.

To the Editor:

Netherton syndrome (NS) is a rare autosomal-recessive ichthyosiform disease.¹ The incidence is estimated to be 1 in 200,000 individuals.² Netherton syndrome presents with generalized erythroderma and scaling, characteristic hair shaft abnormalities, and dysregulation of the immune system. Treatment is largely symptomatic and includes fragrance-free emollients, keratolytics, tretinoin, and corticosteroids, either alone or in combination. We report a case of NS in a man with congenital erythroderma, pili torti, and elevated IgE levels.

A 23-year-old man presented with generalized scaly skin that was present since birth. He was the first child born of nonconsanguineous parents. His medical history was suggestive of atopic diatheses such as allergic rhinitis and recurrent urticaria. The patient was of thin build and had widespread erythematous, annular, and polycyclic scaly lesions (Figure 1A), some with characteristic double-edged scale (Figure 1B). The skin was dry due to anhidrosis that was present since birth. Flexural lichenification was present at the cubital fossa of both arms. Scalp hairs were easily pluckable and had generalized thinning of hair density. Hair mount examination showed characteristic features of both trichorrhexis invaginata (Figure 2A) and pili torti (Figure 2B).

Netherton syndrome is caused by mutation of the SPINK5 gene, serine protease inhibitor Kazal type 5; the corresponding gene is located on the long arm of chromosome 5.³ The gene encodes a serine protease inhibitor proprotein LEKTI (lymphoepithelial Kazal type inhibitor).⁴ The product of the gene is thought to be necessary for epidermal cell growth and differentiation. The classic clinical triad of NS includes ichthyosiform dermatosis with double-edged scale, hair shaft abnormalities, and atopy or elevated IgE levels.⁵ Generalized (congenital) erythroderma usually becomes evident at birth or shortly thereafter. Half of patients develop lesions of ILC on the trunk and limbs during childhood.⁶ A typical ILC lesion is characterized by an erythematous scaly patch that may be annular or polycyclic with double-edged scale at the advancing border. The ability to sweat is impaired, which may cause episodes of hyperpyrexia, especially during humid weather. Patients with hyperpyrexia may be incorrectly diagnosed with bacterial infection and treated with antipyretic drugs or a prolonged course of antibiotics. Trichorrhexis invaginata, also referred to as bamboo hair or ball-and-socket defect, is the pathognomonic hair shaft abnormality seen in NS.⁷ Other hair shaft abnormalities in this syndrome include trichorrhexis nodosa and pili torti.⁸ Our patient had hair shaft abnormalities of trichorrhexis invaginata and pili torti, which are rare findings. The third component of this syndrome is atopy, which generally manifests as angioedema, urticaria, allergic rhinitis, peripheral eosinophilia, atopic dermatitis–like skin lesions, asthma, and elevated IgE levels.⁹

Treatment with emollients, topical steroids, tacrolimus, and psoralen plus UVA does not elicit a satisfactory response. The Table highlights the clinical features and management of NS.