Dermatopathology

The Diagnosis: Persistent Still Disease

At the time of presentation, the patient had not taken systemic medications for a year. Laboratory studies revealed leukocytosis with neutrophilia and a serum ferritin level of 5493 ng/mL (reference range, 15-200 ng/mL). Rheumatoid factor and antinuclear antibody serologies were within reference range. Microbiologic workup was negative. Lymph node and bone marrow biopsies were negative for a lymphoproliferative disorder. Skin biopsies were performed on the back and forearm. Histologic evaluation revealed orthokeratosis, slight acanthosis, and dyskeratosis confined to the upper layers of the epidermis without evidence of interface dermatitis. There was a mixed perivascular infiltrate composed of lymphocytes and neutrophils with no attendant vasculitic change (Figure).

The patient was discharged on prednisone and seen for outpatient follow-up weeks later. Six weeks later, the cutaneous eruption remained unchanged. The patient was unable to start other systemic medications due to lack of insurance and ineligibility for the local patient-assistance program; he was subsequently lost to follow-up. 

Adult-onset Still disease is a rare, systemic, inflammatory condition with a broad spectrum of clinical presentations.^1-3 Still disease affects all age groups, and children with Still disease (<16 years) usually have a concurrent diagnosis of juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis).^1,2,4 Still disease preferentially affects adolescents and adults aged 16 to 35 years, with more than 75% of new cases occurring in this age range.¹ Worldwide, the incidence and prevalence of Still disease is disputed with no conclusive rates established.^1,3

Still disease is characterized by 4 cardinal signs: high spiking fevers (temperature, ≥39°C); leukocytosis with a predominance of neutrophils (≥10,000 cells/mm³ with ≥80% neutrophils); arthralgia or arthritis; and an evanescent, nonpruritic, salmon-colored morbilliform eruption of the skin, typically on the trunk or extremities.² Histologic evaluation of the classic Still disease eruption displays perivascular inflammation of the superficial dermis with infiltration by lymphocytes and histiocytes.³

In 1992, major and minor diagnostic criteria were established for adult-onset Still disease. For diagnosis, patients must meet 5 criteria, including 2 major criteria.⁵ Major criteria include arthralgia or arthritis present for more than 2 weeks, fever (temperature, >39°C) for at least 1 week, the classic Still disease morbilliform eruption (ie, salmon colored, evanescent, morbilliform), and leukocytosis with more than 80% neutrophils. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, negative rheumatoid factor and antinuclear antibody serologies, and abnormal liver function (defined as elevated transaminases).⁵ Although not included in the diagnostic criteria, there have been reports of elevated serum ferritin levels in patients with Still disease, a finding that potentially is useful in distinguishing between active and inactive rheumatic conditions.^6,7

Several case reports have described persistent Still disease, a subtype of Still disease in which patients present with brown-red, persistent, pruritic macules, papules, and plaques that are widespread and oddly shaped.^8,9 Histologically, this subtype is characterized by necrotic keratinocytes in the epidermis and dermal perivascular inflammation composed of neutrophils and lymphocytes.¹⁰ This histology differs from classic Still disease in that the latter typically does not have superficial epidermal dyskeratosis. Our case is consistent with reports of persistent Still disease.

Although the etiology of Still disease remains to be elucidated, HLA-B17, -B18, -B35, and -DR2 have been associated with the disease.³ Furthermore, helper T cell T_H1, IL-2, IFN-γ, and tumor necrosis factor α have been implicated in disease pathology, enabling the use of newer targeted pharmacologic therapies. Canakinumab, an IL-1β inhibitor, has been found to improve arthritis, fever, and rash in patients with Still disease.¹¹ These findings are particularly encouraging for patients who have not experienced improvement with traditional antirheumatic drugs, such as our patient who was not steroid responsive.³

Although a salmon-colored, evanescent, morbilliform eruption in the context of other systemic signs and symptoms readily evokes consideration of Still disease, the less common fixed cutaneous eruption seen in our case may evade accurate diagnosis. Our case aims to increase awareness of this unusual and rare subtype of the cutaneous eruption of Still disease, as a timely diagnosis may prevent potentially life-threatening sequelae including cardiopulmonary disease and respiratory failure.^3,5,9

The Diagnosis: Persistent Still Disease

At the time of presentation, the patient had not taken systemic medications for a year. Laboratory studies revealed leukocytosis with neutrophilia and a serum ferritin level of 5493 ng/mL (reference range, 15-200 ng/mL). Rheumatoid factor and antinuclear antibody serologies were within reference range. Microbiologic workup was negative. Lymph node and bone marrow biopsies were negative for a lymphoproliferative disorder. Skin biopsies were performed on the back and forearm. Histologic evaluation revealed orthokeratosis, slight acanthosis, and dyskeratosis confined to the upper layers of the epidermis without evidence of interface dermatitis. There was a mixed perivascular infiltrate composed of lymphocytes and neutrophils with no attendant vasculitic change (Figure).

The patient was discharged on prednisone and seen for outpatient follow-up weeks later. Six weeks later, the cutaneous eruption remained unchanged. The patient was unable to start other systemic medications due to lack of insurance and ineligibility for the local patient-assistance program; he was subsequently lost to follow-up. 

Adult-onset Still disease is a rare, systemic, inflammatory condition with a broad spectrum of clinical presentations.^1-3 Still disease affects all age groups, and children with Still disease (<16 years) usually have a concurrent diagnosis of juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis).^1,2,4 Still disease preferentially affects adolescents and adults aged 16 to 35 years, with more than 75% of new cases occurring in this age range.¹ Worldwide, the incidence and prevalence of Still disease is disputed with no conclusive rates established.^1,3

Still disease is characterized by 4 cardinal signs: high spiking fevers (temperature, ≥39°C); leukocytosis with a predominance of neutrophils (≥10,000 cells/mm³ with ≥80% neutrophils); arthralgia or arthritis; and an evanescent, nonpruritic, salmon-colored morbilliform eruption of the skin, typically on the trunk or extremities.² Histologic evaluation of the classic Still disease eruption displays perivascular inflammation of the superficial dermis with infiltration by lymphocytes and histiocytes.³

In 1992, major and minor diagnostic criteria were established for adult-onset Still disease. For diagnosis, patients must meet 5 criteria, including 2 major criteria.⁵ Major criteria include arthralgia or arthritis present for more than 2 weeks, fever (temperature, >39°C) for at least 1 week, the classic Still disease morbilliform eruption (ie, salmon colored, evanescent, morbilliform), and leukocytosis with more than 80% neutrophils. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, negative rheumatoid factor and antinuclear antibody serologies, and abnormal liver function (defined as elevated transaminases).⁵ Although not included in the diagnostic criteria, there have been reports of elevated serum ferritin levels in patients with Still disease, a finding that potentially is useful in distinguishing between active and inactive rheumatic conditions.^6,7

Several case reports have described persistent Still disease, a subtype of Still disease in which patients present with brown-red, persistent, pruritic macules, papules, and plaques that are widespread and oddly shaped.^8,9 Histologically, this subtype is characterized by necrotic keratinocytes in the epidermis and dermal perivascular inflammation composed of neutrophils and lymphocytes.¹⁰ This histology differs from classic Still disease in that the latter typically does not have superficial epidermal dyskeratosis. Our case is consistent with reports of persistent Still disease.

Although the etiology of Still disease remains to be elucidated, HLA-B17, -B18, -B35, and -DR2 have been associated with the disease.³ Furthermore, helper T cell T_H1, IL-2, IFN-γ, and tumor necrosis factor α have been implicated in disease pathology, enabling the use of newer targeted pharmacologic therapies. Canakinumab, an IL-1β inhibitor, has been found to improve arthritis, fever, and rash in patients with Still disease.¹¹ These findings are particularly encouraging for patients who have not experienced improvement with traditional antirheumatic drugs, such as our patient who was not steroid responsive.³

Although a salmon-colored, evanescent, morbilliform eruption in the context of other systemic signs and symptoms readily evokes consideration of Still disease, the less common fixed cutaneous eruption seen in our case may evade accurate diagnosis. Our case aims to increase awareness of this unusual and rare subtype of the cutaneous eruption of Still disease, as a timely diagnosis may prevent potentially life-threatening sequelae including cardiopulmonary disease and respiratory failure.^3,5,9

The Diagnosis: Persistent Still Disease

At the time of presentation, the patient had not taken systemic medications for a year. Laboratory studies revealed leukocytosis with neutrophilia and a serum ferritin level of 5493 ng/mL (reference range, 15-200 ng/mL). Rheumatoid factor and antinuclear antibody serologies were within reference range. Microbiologic workup was negative. Lymph node and bone marrow biopsies were negative for a lymphoproliferative disorder. Skin biopsies were performed on the back and forearm. Histologic evaluation revealed orthokeratosis, slight acanthosis, and dyskeratosis confined to the upper layers of the epidermis without evidence of interface dermatitis. There was a mixed perivascular infiltrate composed of lymphocytes and neutrophils with no attendant vasculitic change (Figure).

The patient was discharged on prednisone and seen for outpatient follow-up weeks later. Six weeks later, the cutaneous eruption remained unchanged. The patient was unable to start other systemic medications due to lack of insurance and ineligibility for the local patient-assistance program; he was subsequently lost to follow-up. 

Adult-onset Still disease is a rare, systemic, inflammatory condition with a broad spectrum of clinical presentations.^1-3 Still disease affects all age groups, and children with Still disease (<16 years) usually have a concurrent diagnosis of juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis).^1,2,4 Still disease preferentially affects adolescents and adults aged 16 to 35 years, with more than 75% of new cases occurring in this age range.¹ Worldwide, the incidence and prevalence of Still disease is disputed with no conclusive rates established.^1,3

Still disease is characterized by 4 cardinal signs: high spiking fevers (temperature, ≥39°C); leukocytosis with a predominance of neutrophils (≥10,000 cells/mm³ with ≥80% neutrophils); arthralgia or arthritis; and an evanescent, nonpruritic, salmon-colored morbilliform eruption of the skin, typically on the trunk or extremities.² Histologic evaluation of the classic Still disease eruption displays perivascular inflammation of the superficial dermis with infiltration by lymphocytes and histiocytes.³

In 1992, major and minor diagnostic criteria were established for adult-onset Still disease. For diagnosis, patients must meet 5 criteria, including 2 major criteria.⁵ Major criteria include arthralgia or arthritis present for more than 2 weeks, fever (temperature, >39°C) for at least 1 week, the classic Still disease morbilliform eruption (ie, salmon colored, evanescent, morbilliform), and leukocytosis with more than 80% neutrophils. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, negative rheumatoid factor and antinuclear antibody serologies, and abnormal liver function (defined as elevated transaminases).⁵ Although not included in the diagnostic criteria, there have been reports of elevated serum ferritin levels in patients with Still disease, a finding that potentially is useful in distinguishing between active and inactive rheumatic conditions.^6,7

Several case reports have described persistent Still disease, a subtype of Still disease in which patients present with brown-red, persistent, pruritic macules, papules, and plaques that are widespread and oddly shaped.^8,9 Histologically, this subtype is characterized by necrotic keratinocytes in the epidermis and dermal perivascular inflammation composed of neutrophils and lymphocytes.¹⁰ This histology differs from classic Still disease in that the latter typically does not have superficial epidermal dyskeratosis. Our case is consistent with reports of persistent Still disease.

Although the etiology of Still disease remains to be elucidated, HLA-B17, -B18, -B35, and -DR2 have been associated with the disease.³ Furthermore, helper T cell T_H1, IL-2, IFN-γ, and tumor necrosis factor α have been implicated in disease pathology, enabling the use of newer targeted pharmacologic therapies. Canakinumab, an IL-1β inhibitor, has been found to improve arthritis, fever, and rash in patients with Still disease.¹¹ These findings are particularly encouraging for patients who have not experienced improvement with traditional antirheumatic drugs, such as our patient who was not steroid responsive.³

Although a salmon-colored, evanescent, morbilliform eruption in the context of other systemic signs and symptoms readily evokes consideration of Still disease, the less common fixed cutaneous eruption seen in our case may evade accurate diagnosis. Our case aims to increase awareness of this unusual and rare subtype of the cutaneous eruption of Still disease, as a timely diagnosis may prevent potentially life-threatening sequelae including cardiopulmonary disease and respiratory failure.^3,5,9

All physicians will see changes in reimbursement in 2017. A new president with a new agenda makes for an interesting time ahead for health care in the United States. However, in this time of flux, there is one constant: the Final Rule, an informal term for the annual update on how the Medicare system will function and how much you will get paid for what you do.¹ The document is 393 pages and outlines what is new in the Medicare system, with lots of supplements giving granular details about physician work, overhead, and supply and labor costs. In this column, I have taken the liberty of dissecting the Final Rule for you and to bring attention to its high and low points for dermatologists.

Changes in Relative Value Units

The conversion factor has gone up, meaning you will be paid a bit more this year for what you do; it is not enough to account for inflation or the increasing cost of unfunded mandates, but it is better than nothing. Although the conversion factor was $35.8043 in 2016, it increased by more than 0.2% on January 1, 2017, to $35.8887.¹ How is this conversion factor calculated? We go up 0.5% due to MACRA (Medicare Access and CHIP Reauthorization Act), down 0.013% due to budget neutrality, down 0.07% due to multiple procedure payment reduction changes, and down another 0.18% due to the misvalued code target.¹ The misvalued code target is related to targets established by statute for 2016 to 2018 and payment rates are reduced across the board if they are not met.

If payments suffer from reductions in work value, they may not happen all at once. If the Centers for Medicare & Medicaid Services (CMS) reduce total relative value units (RVUs) by more than 20%, reductions will take place over at least 2 years with a single year drop maximum of 19%.¹ Unfortunately, such limits do not apply to revised codes, which can take as big a hit as the CMS cares to make.

Changes to Global Periods

In 2015, we learned that 10- and 90-day global periods would be eliminated in 2017 and 2018, respectively, with great concern on the part of the government about the number and level of evaluation and management services embedded in these codes. The implementation of global policy elimination was prohibited by MACRA and the CMS was required to develop and implement a process to gather data on services furnished in the global period from a representative sample of physicians, which they will use to value surgical services beginningin 2019.¹ The CMS decided to capture this data with a new set of time-based G codes (which would be onerous for all practicing physicians), not just the unlucky folks who were to be the sample mandated under MACRA.² During the comment period, it became obvious to the CMS that this concept was flawed for many reasons and it decided to hold a town hall meeting at the CMS headquarters on August 25, 2016, on data collection on resources used in furnishing global services in which 90 minutes of live testimony in the morning was followed by another 90 minutes by telephone in the afternoon.³ This meeting, which I attended, resulted in the CMS changing the all-practitioner reporting program to a specified sample with others allowed to opt in. Practitioners in groups of less than 10 are exempt, and only physicians in Florida, Kentucky, Louisiana, Nevada, New Jersey, North Dakota, Ohio, Oregon, and Rhode Island must capture data beginning in July 2017.¹ These data only have to be captured on codes that are used by more than 100 practitioners and are furnished at least 10,000 times or have allowed charges of greater than $10,000,000 annually. If you are lucky enough to live in one of the testing states, you must start on July 1 but can start before July 1 if you wish. Practitioners in smaller practices or in other geographic areas are encouraged to report data if feasible but are not required to do so. Current Procedural Terminology (CPT) code 99024 will be used for reporting postoperative services rather than the proposed onerous set of G codes, and reporting will not be required for preoperative visits included in the global package or for services not related to the patient’s visit.

Changes to Chronic Care Management

There are new and modified chronic care management codes that are not of use to you unless you are the primary provider for the patient and you and the patient meet multiple stringent requirements.⁴ The patient must have multiple illnesses, use multiple medications, be unable to perform activities of daily living, require a caregiver, and/or have repeat admissions or emergency department visits. Typical adult patients who receive complex chronic care management services are treated with 3 or more prescription medications and may be receiving other types of therapeutic interventions (eg, physical therapy, occupational therapy). Typical pediatric patients receive 3 or more therapeutic interventions (eg, medications, nutritional support, respiratory therapy). All patients have 2 or more chronic continuous or episodic health conditions that are expected to last at least 12 months or until the death of the patient and place the patient at serious risk for death, acute exacerbation/decompensation, or functional decline.⁴

Changes to Moderate Sedation Codes

The economic value of providing moderate sedation (eg, drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation) used to be embedded in a variety of CPT codes, which is no longer the case in 2017. Diazepam or similar drugs swallowed or dissolved under the tongue are not included. The new CPT codes 99151, 99152, 99153, 99155, 99156, and 99157 are not to be used to report administration of medications for pain control or minimal sedation (anxiolysis). An independent trained observer, an individual who is qualified to monitor the patient during the procedure and who has no other duties (eg, assisting at surgery) during the procedure, must be present. If you are thinking of using these codes, read the entire section in the CPT manual,⁴ check your state laws, and consult your malpractice carrier and perhaps even your health care attorney.

Changes to Nail Procedure Codes

Current Procedural Terminology code 11752 (excision of nail and nail matrix, partial or complete [eg, ingrown or deformed nail], for permanent removal; with amputation of tuft of distal phalanx) is now gone, while base code 11750 remains. If you are doing nail surgery and removing underlying bone, instead use code 26236 (partial excision [craterization, saucerization, or diaphysectomy] bone [eg, osteomyelitis]; distal phalanx of finger), 28124 (partial excision [craterization, saucerization, sequestrectomy, or diaphysectomy] bone [eg, osteomyelitis or bossing]; phalanx of toe), or other codes in the same section of the CPT manual if they more precisely describe the procedure performed.

Changes to Slide Consultation Codes

The slide consultation codes 88321 (consultation and report on referred slides prepared elsewhere), 88323 (consultation and report on referred material requiring preparation of slides), and 88325 (consultation, comprehensive, with review of records and specimens, with report on referred material) were revalued this year, with the first 2 showing no change but the latter showing an increase in value from 2.50 to 2.85 RVUs.¹ None are meant to be routine. If you have every slide looked at by someone else for “quality assurance reasons,” the consultation is not reportable. If you use these consultation codes too often, the CMS might have concerns about fraud and abuse. Visit http://data.cms.gov to see how you compare to your peers.

Changes to Reflectance Confocal Microscopy Codes

Reflectance confocal microscopy had new codes for 2016, which were carrier priced, and in 2017 they have real RVUs per the CMS. The payments for these codes have a national average reimbursement of $161.85 for 96931 (reflectance confocal microscopy for cellular and subcellular imaging of skin; image acquisition and interpretation and report, first lesion), $104.80 for 96932 (image acquisition only, first lesion), and $45.94 for 96933 (interpretation and report only, first lesion).⁵ The respective add-on codes have values of $83.26 for 96934 (image acquisition and interpretation and report, each additional lesion [list separately in addition to code for primary procedure]), $35.17 for 96935 (image acquisition only, each additional lesion [list separately in addition to code for primary procedure]), and $43.78 for 96936 (interpretation and report only, each additional lesion [list separately in addition to code for primary procedure]).

Other Coding Changes

There are a whole bunch of new codes in the “Genomic Sequencing Procedures and Other Molecular Multianalyte Assays” (MMAAs) section of CPT. The important thing for you to remember is these codes are for the laboratory performing the assay to report, not the physician ordering it. There is a new Appendix O for proprietary laboratory analysis MMAAs, including those that do not have a Category I code. These MMAAs are identified in Appendix O by a 4-digit number followed by the letter M.⁴

There are some revisions to psychotherapy codes 90832 to 90847. These codes are outside our scope of practice and should only be used by psychiatrists, social workers, psychologists, or other appropriate mental health workers.

Final Thoughts

It has not been a breakout year for telehealth and we still do not have payment for store-and-forward teledermatology, except in a few designated rural areas. With the advent of the rhetoric we have heard after the presidential election, any speculation on what will happen to the brave new world of the merit-based incentive payment system, alternative payment models, and other regulations are anyone’s guess.

All physicians will see changes in reimbursement in 2017. A new president with a new agenda makes for an interesting time ahead for health care in the United States. However, in this time of flux, there is one constant: the Final Rule, an informal term for the annual update on how the Medicare system will function and how much you will get paid for what you do.¹ The document is 393 pages and outlines what is new in the Medicare system, with lots of supplements giving granular details about physician work, overhead, and supply and labor costs. In this column, I have taken the liberty of dissecting the Final Rule for you and to bring attention to its high and low points for dermatologists.

Changes in Relative Value Units

The conversion factor has gone up, meaning you will be paid a bit more this year for what you do; it is not enough to account for inflation or the increasing cost of unfunded mandates, but it is better than nothing. Although the conversion factor was $35.8043 in 2016, it increased by more than 0.2% on January 1, 2017, to $35.8887.¹ How is this conversion factor calculated? We go up 0.5% due to MACRA (Medicare Access and CHIP Reauthorization Act), down 0.013% due to budget neutrality, down 0.07% due to multiple procedure payment reduction changes, and down another 0.18% due to the misvalued code target.¹ The misvalued code target is related to targets established by statute for 2016 to 2018 and payment rates are reduced across the board if they are not met.

If payments suffer from reductions in work value, they may not happen all at once. If the Centers for Medicare & Medicaid Services (CMS) reduce total relative value units (RVUs) by more than 20%, reductions will take place over at least 2 years with a single year drop maximum of 19%.¹ Unfortunately, such limits do not apply to revised codes, which can take as big a hit as the CMS cares to make.

Changes to Global Periods

In 2015, we learned that 10- and 90-day global periods would be eliminated in 2017 and 2018, respectively, with great concern on the part of the government about the number and level of evaluation and management services embedded in these codes. The implementation of global policy elimination was prohibited by MACRA and the CMS was required to develop and implement a process to gather data on services furnished in the global period from a representative sample of physicians, which they will use to value surgical services beginningin 2019.¹ The CMS decided to capture this data with a new set of time-based G codes (which would be onerous for all practicing physicians), not just the unlucky folks who were to be the sample mandated under MACRA.² During the comment period, it became obvious to the CMS that this concept was flawed for many reasons and it decided to hold a town hall meeting at the CMS headquarters on August 25, 2016, on data collection on resources used in furnishing global services in which 90 minutes of live testimony in the morning was followed by another 90 minutes by telephone in the afternoon.³ This meeting, which I attended, resulted in the CMS changing the all-practitioner reporting program to a specified sample with others allowed to opt in. Practitioners in groups of less than 10 are exempt, and only physicians in Florida, Kentucky, Louisiana, Nevada, New Jersey, North Dakota, Ohio, Oregon, and Rhode Island must capture data beginning in July 2017.¹ These data only have to be captured on codes that are used by more than 100 practitioners and are furnished at least 10,000 times or have allowed charges of greater than $10,000,000 annually. If you are lucky enough to live in one of the testing states, you must start on July 1 but can start before July 1 if you wish. Practitioners in smaller practices or in other geographic areas are encouraged to report data if feasible but are not required to do so. Current Procedural Terminology (CPT) code 99024 will be used for reporting postoperative services rather than the proposed onerous set of G codes, and reporting will not be required for preoperative visits included in the global package or for services not related to the patient’s visit.

Changes to Chronic Care Management

There are new and modified chronic care management codes that are not of use to you unless you are the primary provider for the patient and you and the patient meet multiple stringent requirements.⁴ The patient must have multiple illnesses, use multiple medications, be unable to perform activities of daily living, require a caregiver, and/or have repeat admissions or emergency department visits. Typical adult patients who receive complex chronic care management services are treated with 3 or more prescription medications and may be receiving other types of therapeutic interventions (eg, physical therapy, occupational therapy). Typical pediatric patients receive 3 or more therapeutic interventions (eg, medications, nutritional support, respiratory therapy). All patients have 2 or more chronic continuous or episodic health conditions that are expected to last at least 12 months or until the death of the patient and place the patient at serious risk for death, acute exacerbation/decompensation, or functional decline.⁴

Changes to Moderate Sedation Codes

The economic value of providing moderate sedation (eg, drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation) used to be embedded in a variety of CPT codes, which is no longer the case in 2017. Diazepam or similar drugs swallowed or dissolved under the tongue are not included. The new CPT codes 99151, 99152, 99153, 99155, 99156, and 99157 are not to be used to report administration of medications for pain control or minimal sedation (anxiolysis). An independent trained observer, an individual who is qualified to monitor the patient during the procedure and who has no other duties (eg, assisting at surgery) during the procedure, must be present. If you are thinking of using these codes, read the entire section in the CPT manual,⁴ check your state laws, and consult your malpractice carrier and perhaps even your health care attorney.

Changes to Nail Procedure Codes

Current Procedural Terminology code 11752 (excision of nail and nail matrix, partial or complete [eg, ingrown or deformed nail], for permanent removal; with amputation of tuft of distal phalanx) is now gone, while base code 11750 remains. If you are doing nail surgery and removing underlying bone, instead use code 26236 (partial excision [craterization, saucerization, or diaphysectomy] bone [eg, osteomyelitis]; distal phalanx of finger), 28124 (partial excision [craterization, saucerization, sequestrectomy, or diaphysectomy] bone [eg, osteomyelitis or bossing]; phalanx of toe), or other codes in the same section of the CPT manual if they more precisely describe the procedure performed.

Changes to Slide Consultation Codes

The slide consultation codes 88321 (consultation and report on referred slides prepared elsewhere), 88323 (consultation and report on referred material requiring preparation of slides), and 88325 (consultation, comprehensive, with review of records and specimens, with report on referred material) were revalued this year, with the first 2 showing no change but the latter showing an increase in value from 2.50 to 2.85 RVUs.¹ None are meant to be routine. If you have every slide looked at by someone else for “quality assurance reasons,” the consultation is not reportable. If you use these consultation codes too often, the CMS might have concerns about fraud and abuse. Visit http://data.cms.gov to see how you compare to your peers.

Changes to Reflectance Confocal Microscopy Codes

Reflectance confocal microscopy had new codes for 2016, which were carrier priced, and in 2017 they have real RVUs per the CMS. The payments for these codes have a national average reimbursement of $161.85 for 96931 (reflectance confocal microscopy for cellular and subcellular imaging of skin; image acquisition and interpretation and report, first lesion), $104.80 for 96932 (image acquisition only, first lesion), and $45.94 for 96933 (interpretation and report only, first lesion).⁵ The respective add-on codes have values of $83.26 for 96934 (image acquisition and interpretation and report, each additional lesion [list separately in addition to code for primary procedure]), $35.17 for 96935 (image acquisition only, each additional lesion [list separately in addition to code for primary procedure]), and $43.78 for 96936 (interpretation and report only, each additional lesion [list separately in addition to code for primary procedure]).

Other Coding Changes

There are a whole bunch of new codes in the “Genomic Sequencing Procedures and Other Molecular Multianalyte Assays” (MMAAs) section of CPT. The important thing for you to remember is these codes are for the laboratory performing the assay to report, not the physician ordering it. There is a new Appendix O for proprietary laboratory analysis MMAAs, including those that do not have a Category I code. These MMAAs are identified in Appendix O by a 4-digit number followed by the letter M.⁴

There are some revisions to psychotherapy codes 90832 to 90847. These codes are outside our scope of practice and should only be used by psychiatrists, social workers, psychologists, or other appropriate mental health workers.

Final Thoughts

It has not been a breakout year for telehealth and we still do not have payment for store-and-forward teledermatology, except in a few designated rural areas. With the advent of the rhetoric we have heard after the presidential election, any speculation on what will happen to the brave new world of the merit-based incentive payment system, alternative payment models, and other regulations are anyone’s guess.

All physicians will see changes in reimbursement in 2017. A new president with a new agenda makes for an interesting time ahead for health care in the United States. However, in this time of flux, there is one constant: the Final Rule, an informal term for the annual update on how the Medicare system will function and how much you will get paid for what you do.¹ The document is 393 pages and outlines what is new in the Medicare system, with lots of supplements giving granular details about physician work, overhead, and supply and labor costs. In this column, I have taken the liberty of dissecting the Final Rule for you and to bring attention to its high and low points for dermatologists.

Changes in Relative Value Units

The conversion factor has gone up, meaning you will be paid a bit more this year for what you do; it is not enough to account for inflation or the increasing cost of unfunded mandates, but it is better than nothing. Although the conversion factor was $35.8043 in 2016, it increased by more than 0.2% on January 1, 2017, to $35.8887.¹ How is this conversion factor calculated? We go up 0.5% due to MACRA (Medicare Access and CHIP Reauthorization Act), down 0.013% due to budget neutrality, down 0.07% due to multiple procedure payment reduction changes, and down another 0.18% due to the misvalued code target.¹ The misvalued code target is related to targets established by statute for 2016 to 2018 and payment rates are reduced across the board if they are not met.

If payments suffer from reductions in work value, they may not happen all at once. If the Centers for Medicare & Medicaid Services (CMS) reduce total relative value units (RVUs) by more than 20%, reductions will take place over at least 2 years with a single year drop maximum of 19%.¹ Unfortunately, such limits do not apply to revised codes, which can take as big a hit as the CMS cares to make.

Changes to Global Periods

In 2015, we learned that 10- and 90-day global periods would be eliminated in 2017 and 2018, respectively, with great concern on the part of the government about the number and level of evaluation and management services embedded in these codes. The implementation of global policy elimination was prohibited by MACRA and the CMS was required to develop and implement a process to gather data on services furnished in the global period from a representative sample of physicians, which they will use to value surgical services beginningin 2019.¹ The CMS decided to capture this data with a new set of time-based G codes (which would be onerous for all practicing physicians), not just the unlucky folks who were to be the sample mandated under MACRA.² During the comment period, it became obvious to the CMS that this concept was flawed for many reasons and it decided to hold a town hall meeting at the CMS headquarters on August 25, 2016, on data collection on resources used in furnishing global services in which 90 minutes of live testimony in the morning was followed by another 90 minutes by telephone in the afternoon.³ This meeting, which I attended, resulted in the CMS changing the all-practitioner reporting program to a specified sample with others allowed to opt in. Practitioners in groups of less than 10 are exempt, and only physicians in Florida, Kentucky, Louisiana, Nevada, New Jersey, North Dakota, Ohio, Oregon, and Rhode Island must capture data beginning in July 2017.¹ These data only have to be captured on codes that are used by more than 100 practitioners and are furnished at least 10,000 times or have allowed charges of greater than $10,000,000 annually. If you are lucky enough to live in one of the testing states, you must start on July 1 but can start before July 1 if you wish. Practitioners in smaller practices or in other geographic areas are encouraged to report data if feasible but are not required to do so. Current Procedural Terminology (CPT) code 99024 will be used for reporting postoperative services rather than the proposed onerous set of G codes, and reporting will not be required for preoperative visits included in the global package or for services not related to the patient’s visit.

Changes to Chronic Care Management

There are new and modified chronic care management codes that are not of use to you unless you are the primary provider for the patient and you and the patient meet multiple stringent requirements.⁴ The patient must have multiple illnesses, use multiple medications, be unable to perform activities of daily living, require a caregiver, and/or have repeat admissions or emergency department visits. Typical adult patients who receive complex chronic care management services are treated with 3 or more prescription medications and may be receiving other types of therapeutic interventions (eg, physical therapy, occupational therapy). Typical pediatric patients receive 3 or more therapeutic interventions (eg, medications, nutritional support, respiratory therapy). All patients have 2 or more chronic continuous or episodic health conditions that are expected to last at least 12 months or until the death of the patient and place the patient at serious risk for death, acute exacerbation/decompensation, or functional decline.⁴

Changes to Moderate Sedation Codes

The economic value of providing moderate sedation (eg, drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation) used to be embedded in a variety of CPT codes, which is no longer the case in 2017. Diazepam or similar drugs swallowed or dissolved under the tongue are not included. The new CPT codes 99151, 99152, 99153, 99155, 99156, and 99157 are not to be used to report administration of medications for pain control or minimal sedation (anxiolysis). An independent trained observer, an individual who is qualified to monitor the patient during the procedure and who has no other duties (eg, assisting at surgery) during the procedure, must be present. If you are thinking of using these codes, read the entire section in the CPT manual,⁴ check your state laws, and consult your malpractice carrier and perhaps even your health care attorney.

Changes to Nail Procedure Codes

Current Procedural Terminology code 11752 (excision of nail and nail matrix, partial or complete [eg, ingrown or deformed nail], for permanent removal; with amputation of tuft of distal phalanx) is now gone, while base code 11750 remains. If you are doing nail surgery and removing underlying bone, instead use code 26236 (partial excision [craterization, saucerization, or diaphysectomy] bone [eg, osteomyelitis]; distal phalanx of finger), 28124 (partial excision [craterization, saucerization, sequestrectomy, or diaphysectomy] bone [eg, osteomyelitis or bossing]; phalanx of toe), or other codes in the same section of the CPT manual if they more precisely describe the procedure performed.

Changes to Slide Consultation Codes

The slide consultation codes 88321 (consultation and report on referred slides prepared elsewhere), 88323 (consultation and report on referred material requiring preparation of slides), and 88325 (consultation, comprehensive, with review of records and specimens, with report on referred material) were revalued this year, with the first 2 showing no change but the latter showing an increase in value from 2.50 to 2.85 RVUs.¹ None are meant to be routine. If you have every slide looked at by someone else for “quality assurance reasons,” the consultation is not reportable. If you use these consultation codes too often, the CMS might have concerns about fraud and abuse. Visit http://data.cms.gov to see how you compare to your peers.

Changes to Reflectance Confocal Microscopy Codes

Reflectance confocal microscopy had new codes for 2016, which were carrier priced, and in 2017 they have real RVUs per the CMS. The payments for these codes have a national average reimbursement of $161.85 for 96931 (reflectance confocal microscopy for cellular and subcellular imaging of skin; image acquisition and interpretation and report, first lesion), $104.80 for 96932 (image acquisition only, first lesion), and $45.94 for 96933 (interpretation and report only, first lesion).⁵ The respective add-on codes have values of $83.26 for 96934 (image acquisition and interpretation and report, each additional lesion [list separately in addition to code for primary procedure]), $35.17 for 96935 (image acquisition only, each additional lesion [list separately in addition to code for primary procedure]), and $43.78 for 96936 (interpretation and report only, each additional lesion [list separately in addition to code for primary procedure]).

Other Coding Changes

There are a whole bunch of new codes in the “Genomic Sequencing Procedures and Other Molecular Multianalyte Assays” (MMAAs) section of CPT. The important thing for you to remember is these codes are for the laboratory performing the assay to report, not the physician ordering it. There is a new Appendix O for proprietary laboratory analysis MMAAs, including those that do not have a Category I code. These MMAAs are identified in Appendix O by a 4-digit number followed by the letter M.⁴

There are some revisions to psychotherapy codes 90832 to 90847. These codes are outside our scope of practice and should only be used by psychiatrists, social workers, psychologists, or other appropriate mental health workers.

Final Thoughts

It has not been a breakout year for telehealth and we still do not have payment for store-and-forward teledermatology, except in a few designated rural areas. With the advent of the rhetoric we have heard after the presidential election, any speculation on what will happen to the brave new world of the merit-based incentive payment system, alternative payment models, and other regulations are anyone’s guess.

To the Editor:

Pemphigus foliaceus is a rare autoimmune blistering disorder that typically presents with crusted scaly erosions in a seborrheic distribution. We describe a case of pemphigus foliaceus localized to the right cheek of 10 years’ duration that spread to other areas. With a PubMed search of articles indexed for MEDLINE yielding only 14 cases of localized pemphigus foliaceus (Table), it represents an extremely rare entity that often is a diagnostic challenge and may be a harbinger for disseminated disease months to years after the inciting lesion appears.

A 51-year-old woman presented with an asymptomatic cutaneous eruption that had remained localized to the right cheek for 10 years before it increased in size and new lesions developed on the left cheek, chest, and upper back. No inciting factors, such as contactants, insect bites, infections, medications, or recent travel were identified. On physical examination a well-demarcated, hypertrophic, verrucouslike plaque with central pink atrophy and exfoliative scale involved the right malar and submalar regions but spared the mucocutaneous junctions of the face (Figure 1). Subtle dark brown papules, some with overlying scale, speckled the left cheek, right jawline, chest, and upper back. The oral cavity was clear.

Leading differentials included hypertrophic discoid lupus erythematosus and pemphigus vegetans. Other considerations included sarcoidosis, granuloma faciale, lupus vulgaris, disseminated coccidioidomycosis or blastomycosis, and squamous cell carcinoma.

An initial biopsy revealed a lymphocytic lichenoid dermatitis with epidermal hyperplasia and scattered eosinophils for which the following differentials were provided: insect bite, hypertrophic lichen planus, prurigo nodularis superimposed on rosacea, and allergic contact dermatitis. Under these histologic diagnoses, tacrolimus ointment 0.03%, topical mid-potency corticosteroid, and a combination of oral doxycycline and metronidazole gel 1% were prescribed but failed to ameliorate her condition.

Because the clinical differentials were vast and noncorrelative with the original pathology, additional biopsies were performed: one from the edge of the large malar plaque, which was transected for hematoxylin and eosin (H&E) and tissue cultures; one perilesional to the large malar plaque for direct immunofluorescence (DIF); and one from the papule on the right jawline for H&E. Tissue cultures were negative for fungal and mycobacterial organisms. Both specimens submitted for H&E showed the prominent epidermal hyperplasia and lymphocytic dermal infiltrate noted on the original H&E but also demonstrated intragranular acantholysis (Figure 2). The DIF revealed intercellular IgG and C3 deposition throughout the epidermis (Figure 3). Indirect immunofluorescence was negative, but enzyme-linked immunosorbent assay detected circulating antidesmoglein-1 but not antidesmoglein-3 autoantibodies. Other serologies including antinuclear antibody, anti–double-stranded DNA, antihistone, anti–Sjögren syndrome A, and anti–Sjögren syndrome B antibodies were negative.

The diagnosis of localized pemphigus foliaceus was made and management with oral prednisone and mycophenolate mofetil resulted in improvement within weeks.

Localized pemphigus foliaceus is extremely rare with only 14 cases reported in the literature (Table).^1-10 Its diagnosis is challenging, as the clinical presentation simulates various entities and the histological features and serological markers are difficult to capture.

Localized pemphigus foliaceus typically presents as an isolated, erythematous, scaly, crusted plaque involving the nose, cheek, or scalp and may mimic several conditions including contact dermatitis, seborrheic dermatitis, rosacea, cutaneous sarcoidosis, discoid lupus erythematosus, lupus vulgaris, impetigo contagiosa, solar keratosis, and nonmelanoma skin cancer.^1-10

The predilection for sun-exposed areas suggests UV radiation may induce binding of antidesmoglein-1 autoantibodies with subsequent cytokine-mediated inflammation and acantholysis at these sites.^11-13 Similarly, the immunomodulatory agent imiquimod has been reported to induce pemphigus foliaceus at its application sites.⁶

When pemphigus foliaceus is clinically discernible, the histology and DIF are in accordance with the clinical diagnosis 53.8% of the time.¹³ In cases of localized pemphigus foliaceus in which the diagnosis is more elusive, many biopsies often are needed to capture the characteristic intragranular acantholysis; this feature often is so subtle that unless the diagnosis is suspected, it is underappreciated or undetectable. In chronic lesions, it may be masked by secondary changes such as acanthosis, hyperkeratosis, and parakeratosis.¹⁴

In pemphigus foliaceus, detection of circulating antidesmoglein-1 autoantibodies by enzyme-linked immunosorbent assay is slightly more sensitive and specific compared to indirect immunofluorescence, but both correlate with disease activity.^15,16 The low or absent autoantibody titers in localized pemphigus foliaceus may reflect its limited involvement, but dissemination of the disease with subsequent elevation of autoantibody titers may occur months to years after initial presentation,^1,2,9 as was the case with our patient.

The majority of localized pemphigus foliaceus cases require systemic prednisone, sometimes in conjunction with nonsteroidal immunosuppressants or topical high-potency corticosteroids.^1-3,5,6,8-10 One case was efficaciously managed with tacrolimus ointment 0.1%.⁷

Localized pemphigus foliaceus is a rare and challenging entity that must be a diagnostic consideration for any chronic focal plaque on the face or scalp, as it may herald disseminated disease.

To the Editor:

Pemphigus foliaceus is a rare autoimmune blistering disorder that typically presents with crusted scaly erosions in a seborrheic distribution. We describe a case of pemphigus foliaceus localized to the right cheek of 10 years’ duration that spread to other areas. With a PubMed search of articles indexed for MEDLINE yielding only 14 cases of localized pemphigus foliaceus (Table), it represents an extremely rare entity that often is a diagnostic challenge and may be a harbinger for disseminated disease months to years after the inciting lesion appears.

A 51-year-old woman presented with an asymptomatic cutaneous eruption that had remained localized to the right cheek for 10 years before it increased in size and new lesions developed on the left cheek, chest, and upper back. No inciting factors, such as contactants, insect bites, infections, medications, or recent travel were identified. On physical examination a well-demarcated, hypertrophic, verrucouslike plaque with central pink atrophy and exfoliative scale involved the right malar and submalar regions but spared the mucocutaneous junctions of the face (Figure 1). Subtle dark brown papules, some with overlying scale, speckled the left cheek, right jawline, chest, and upper back. The oral cavity was clear.

Leading differentials included hypertrophic discoid lupus erythematosus and pemphigus vegetans. Other considerations included sarcoidosis, granuloma faciale, lupus vulgaris, disseminated coccidioidomycosis or blastomycosis, and squamous cell carcinoma.

An initial biopsy revealed a lymphocytic lichenoid dermatitis with epidermal hyperplasia and scattered eosinophils for which the following differentials were provided: insect bite, hypertrophic lichen planus, prurigo nodularis superimposed on rosacea, and allergic contact dermatitis. Under these histologic diagnoses, tacrolimus ointment 0.03%, topical mid-potency corticosteroid, and a combination of oral doxycycline and metronidazole gel 1% were prescribed but failed to ameliorate her condition.

Because the clinical differentials were vast and noncorrelative with the original pathology, additional biopsies were performed: one from the edge of the large malar plaque, which was transected for hematoxylin and eosin (H&E) and tissue cultures; one perilesional to the large malar plaque for direct immunofluorescence (DIF); and one from the papule on the right jawline for H&E. Tissue cultures were negative for fungal and mycobacterial organisms. Both specimens submitted for H&E showed the prominent epidermal hyperplasia and lymphocytic dermal infiltrate noted on the original H&E but also demonstrated intragranular acantholysis (Figure 2). The DIF revealed intercellular IgG and C3 deposition throughout the epidermis (Figure 3). Indirect immunofluorescence was negative, but enzyme-linked immunosorbent assay detected circulating antidesmoglein-1 but not antidesmoglein-3 autoantibodies. Other serologies including antinuclear antibody, anti–double-stranded DNA, antihistone, anti–Sjögren syndrome A, and anti–Sjögren syndrome B antibodies were negative.

The diagnosis of localized pemphigus foliaceus was made and management with oral prednisone and mycophenolate mofetil resulted in improvement within weeks.

Localized pemphigus foliaceus is extremely rare with only 14 cases reported in the literature (Table).^1-10 Its diagnosis is challenging, as the clinical presentation simulates various entities and the histological features and serological markers are difficult to capture.

Localized pemphigus foliaceus typically presents as an isolated, erythematous, scaly, crusted plaque involving the nose, cheek, or scalp and may mimic several conditions including contact dermatitis, seborrheic dermatitis, rosacea, cutaneous sarcoidosis, discoid lupus erythematosus, lupus vulgaris, impetigo contagiosa, solar keratosis, and nonmelanoma skin cancer.^1-10

The predilection for sun-exposed areas suggests UV radiation may induce binding of antidesmoglein-1 autoantibodies with subsequent cytokine-mediated inflammation and acantholysis at these sites.^11-13 Similarly, the immunomodulatory agent imiquimod has been reported to induce pemphigus foliaceus at its application sites.⁶

When pemphigus foliaceus is clinically discernible, the histology and DIF are in accordance with the clinical diagnosis 53.8% of the time.¹³ In cases of localized pemphigus foliaceus in which the diagnosis is more elusive, many biopsies often are needed to capture the characteristic intragranular acantholysis; this feature often is so subtle that unless the diagnosis is suspected, it is underappreciated or undetectable. In chronic lesions, it may be masked by secondary changes such as acanthosis, hyperkeratosis, and parakeratosis.¹⁴

In pemphigus foliaceus, detection of circulating antidesmoglein-1 autoantibodies by enzyme-linked immunosorbent assay is slightly more sensitive and specific compared to indirect immunofluorescence, but both correlate with disease activity.^15,16 The low or absent autoantibody titers in localized pemphigus foliaceus may reflect its limited involvement, but dissemination of the disease with subsequent elevation of autoantibody titers may occur months to years after initial presentation,^1,2,9 as was the case with our patient.

The majority of localized pemphigus foliaceus cases require systemic prednisone, sometimes in conjunction with nonsteroidal immunosuppressants or topical high-potency corticosteroids.^1-3,5,6,8-10 One case was efficaciously managed with tacrolimus ointment 0.1%.⁷

Localized pemphigus foliaceus is a rare and challenging entity that must be a diagnostic consideration for any chronic focal plaque on the face or scalp, as it may herald disseminated disease.

To the Editor:

Pemphigus foliaceus is a rare autoimmune blistering disorder that typically presents with crusted scaly erosions in a seborrheic distribution. We describe a case of pemphigus foliaceus localized to the right cheek of 10 years’ duration that spread to other areas. With a PubMed search of articles indexed for MEDLINE yielding only 14 cases of localized pemphigus foliaceus (Table), it represents an extremely rare entity that often is a diagnostic challenge and may be a harbinger for disseminated disease months to years after the inciting lesion appears.

A 51-year-old woman presented with an asymptomatic cutaneous eruption that had remained localized to the right cheek for 10 years before it increased in size and new lesions developed on the left cheek, chest, and upper back. No inciting factors, such as contactants, insect bites, infections, medications, or recent travel were identified. On physical examination a well-demarcated, hypertrophic, verrucouslike plaque with central pink atrophy and exfoliative scale involved the right malar and submalar regions but spared the mucocutaneous junctions of the face (Figure 1). Subtle dark brown papules, some with overlying scale, speckled the left cheek, right jawline, chest, and upper back. The oral cavity was clear.

Leading differentials included hypertrophic discoid lupus erythematosus and pemphigus vegetans. Other considerations included sarcoidosis, granuloma faciale, lupus vulgaris, disseminated coccidioidomycosis or blastomycosis, and squamous cell carcinoma.

An initial biopsy revealed a lymphocytic lichenoid dermatitis with epidermal hyperplasia and scattered eosinophils for which the following differentials were provided: insect bite, hypertrophic lichen planus, prurigo nodularis superimposed on rosacea, and allergic contact dermatitis. Under these histologic diagnoses, tacrolimus ointment 0.03%, topical mid-potency corticosteroid, and a combination of oral doxycycline and metronidazole gel 1% were prescribed but failed to ameliorate her condition.

Because the clinical differentials were vast and noncorrelative with the original pathology, additional biopsies were performed: one from the edge of the large malar plaque, which was transected for hematoxylin and eosin (H&E) and tissue cultures; one perilesional to the large malar plaque for direct immunofluorescence (DIF); and one from the papule on the right jawline for H&E. Tissue cultures were negative for fungal and mycobacterial organisms. Both specimens submitted for H&E showed the prominent epidermal hyperplasia and lymphocytic dermal infiltrate noted on the original H&E but also demonstrated intragranular acantholysis (Figure 2). The DIF revealed intercellular IgG and C3 deposition throughout the epidermis (Figure 3). Indirect immunofluorescence was negative, but enzyme-linked immunosorbent assay detected circulating antidesmoglein-1 but not antidesmoglein-3 autoantibodies. Other serologies including antinuclear antibody, anti–double-stranded DNA, antihistone, anti–Sjögren syndrome A, and anti–Sjögren syndrome B antibodies were negative.

The diagnosis of localized pemphigus foliaceus was made and management with oral prednisone and mycophenolate mofetil resulted in improvement within weeks.

Localized pemphigus foliaceus is extremely rare with only 14 cases reported in the literature (Table).^1-10 Its diagnosis is challenging, as the clinical presentation simulates various entities and the histological features and serological markers are difficult to capture.

Localized pemphigus foliaceus typically presents as an isolated, erythematous, scaly, crusted plaque involving the nose, cheek, or scalp and may mimic several conditions including contact dermatitis, seborrheic dermatitis, rosacea, cutaneous sarcoidosis, discoid lupus erythematosus, lupus vulgaris, impetigo contagiosa, solar keratosis, and nonmelanoma skin cancer.^1-10

The predilection for sun-exposed areas suggests UV radiation may induce binding of antidesmoglein-1 autoantibodies with subsequent cytokine-mediated inflammation and acantholysis at these sites.^11-13 Similarly, the immunomodulatory agent imiquimod has been reported to induce pemphigus foliaceus at its application sites.⁶

When pemphigus foliaceus is clinically discernible, the histology and DIF are in accordance with the clinical diagnosis 53.8% of the time.¹³ In cases of localized pemphigus foliaceus in which the diagnosis is more elusive, many biopsies often are needed to capture the characteristic intragranular acantholysis; this feature often is so subtle that unless the diagnosis is suspected, it is underappreciated or undetectable. In chronic lesions, it may be masked by secondary changes such as acanthosis, hyperkeratosis, and parakeratosis.¹⁴

In pemphigus foliaceus, detection of circulating antidesmoglein-1 autoantibodies by enzyme-linked immunosorbent assay is slightly more sensitive and specific compared to indirect immunofluorescence, but both correlate with disease activity.^15,16 The low or absent autoantibody titers in localized pemphigus foliaceus may reflect its limited involvement, but dissemination of the disease with subsequent elevation of autoantibody titers may occur months to years after initial presentation,^1,2,9 as was the case with our patient.

The majority of localized pemphigus foliaceus cases require systemic prednisone, sometimes in conjunction with nonsteroidal immunosuppressants or topical high-potency corticosteroids.^1-3,5,6,8-10 One case was efficaciously managed with tacrolimus ointment 0.1%.⁷

Localized pemphigus foliaceus is a rare and challenging entity that must be a diagnostic consideration for any chronic focal plaque on the face or scalp, as it may herald disseminated disease.

Metastatic Clear Cell Renal Cell Carcinoma

The differential diagnosis of cutaneous neoplasms with clear cells is broad. Clear cell features can be seen in primary tumors arising from the epidermis and cutaneous adnexa as well as in mesenchymal and melanocytic neoplasms. Furthermore, metastatic disease should be considered in the histologic differential diagnosis, as many visceral malignancies have clear cell features. This patient was subsequently found to have a large renal mass with metastasis to the lungs, spleen, and bone. The histologic findings support the diagnosis of metastatic clear cell renal cell carcinoma (RCC) to the skin.

Approximately 30% of patients with clear cell RCC present with metastatic disease with approximately 8% of those involving the skin.^1,2 Cutaneous RCC metastases show a predilection for the head, especially the scalp. The clinical presentation is variable, but there often is a history of a rapidly growing brown, black, or purple nodule or plaque. A thorough review of the patient's history should be conducted if metastatic RCC is in the differential diagnosis, as it has been reported to occur up to 20 years after initial diagnosis.³

Histologically, clear cell RCC (quiz image) is composed of nests of tumor cells with clear cytoplasm and centrally located nuclei with prominent nucleoli. The clear cell features result from abundant cytoplasmic glycogen and lipid but may not be present in every case. One of the most important histologic features is the presence of delicate branching blood vessels (Figure 1). Numerous extravasated red blood cells also may be present. Positive immunohistochemical staining for PAX8, CD10, and RCC antigens support the diagnosis.⁴

Balloon cell nevi (Figure 2) most commonly occur on the head and neck in adolescents and young adults but clinically are indistinguishable from other banal nevi. The nevus cells are large with foamy to finely vacuolated cytoplasm and lack atypia. The clear cell change is the result of melanosome degeneration and may be extensive. The presence of melanin pigment, nests of typical nevus cells, and positive staining with MART-1 can help distinguish the tumor from xanthomas and RCC.⁵

Clear cell hidradenoma (Figure 3) is a well-circumscribed tumor of sweat gland origin that arises in the dermis. The architecture usually is solid, cystic, or a combination of both. The cytology is classically bland with poroid, squamoid, or clear cell morphology. Clear cells that are positive on periodic acid-Schiff staining predominate in up to one-third of cases. Carcinoembryonic antigen and epithelial membrane antigen can be used to highlight the eosinophilic cuticles of ducts within solid areas.⁶

Sebaceous carcinoma (Figure 4) most frequently arises in a periorbital distribution, although extraocular lesions are known to occur. Histologically, there is a proliferation of both mature sebocytes and basaloid cells in the dermis, occasionally involving the epidermis. The mature sebocytes demonstrate clear cell features with foamy to vacuolated cytoplasm and large nuclei with scalloped borders. The clear cells may vary greatly in number and often are sparse in poorly differentiated tumors in which pleomorphic basaloid cells may predominate. The basaloid cells may resemble those of squamous or basal cell carcinoma, leading to a diagnostic dilemma in some cases. Special staining with Sudan black B and oil red O highlights the cytoplasmic lipid but must be performed on frozen section specimens. Although not entirely specific, immunohistochemical expression of epithelial membrane antigen, androgen receptor, and membranous vesicular adipophilin staining in sebaceous carcinoma can assist in the diagnosis.⁷

Cutaneous xanthomas (Figure 5) may arise in patients of any age and represent deposition of lipid-laden macrophages. Classification often is dependent on the clinical presentation; however, some subtypes demonstrate unique morphologic features (eg, verruciform xanthomas). Xanthomas classically arise in association with elevated serum lipids, but they also may occur in normolipemic patients. Individuals with Erdheim-Chester disease have an increased propensity to develop xanthelasma. Similarly, plane xanthomas have been associated with monoclonal gammopathy. Histologically, xanthomas are characterized by sheets of foamy macrophages within the dermis and subcutis. Positive immunohistochemical staining for CD68 highlighting the histiocytic nature of the cells and the absence of a delicate vascular network aid in the differentiation from RCC.

Metastatic Clear Cell Renal Cell Carcinoma

The differential diagnosis of cutaneous neoplasms with clear cells is broad. Clear cell features can be seen in primary tumors arising from the epidermis and cutaneous adnexa as well as in mesenchymal and melanocytic neoplasms. Furthermore, metastatic disease should be considered in the histologic differential diagnosis, as many visceral malignancies have clear cell features. This patient was subsequently found to have a large renal mass with metastasis to the lungs, spleen, and bone. The histologic findings support the diagnosis of metastatic clear cell renal cell carcinoma (RCC) to the skin.

Approximately 30% of patients with clear cell RCC present with metastatic disease with approximately 8% of those involving the skin.^1,2 Cutaneous RCC metastases show a predilection for the head, especially the scalp. The clinical presentation is variable, but there often is a history of a rapidly growing brown, black, or purple nodule or plaque. A thorough review of the patient's history should be conducted if metastatic RCC is in the differential diagnosis, as it has been reported to occur up to 20 years after initial diagnosis.³

Histologically, clear cell RCC (quiz image) is composed of nests of tumor cells with clear cytoplasm and centrally located nuclei with prominent nucleoli. The clear cell features result from abundant cytoplasmic glycogen and lipid but may not be present in every case. One of the most important histologic features is the presence of delicate branching blood vessels (Figure 1). Numerous extravasated red blood cells also may be present. Positive immunohistochemical staining for PAX8, CD10, and RCC antigens support the diagnosis.⁴

Balloon cell nevi (Figure 2) most commonly occur on the head and neck in adolescents and young adults but clinically are indistinguishable from other banal nevi. The nevus cells are large with foamy to finely vacuolated cytoplasm and lack atypia. The clear cell change is the result of melanosome degeneration and may be extensive. The presence of melanin pigment, nests of typical nevus cells, and positive staining with MART-1 can help distinguish the tumor from xanthomas and RCC.⁵

Clear cell hidradenoma (Figure 3) is a well-circumscribed tumor of sweat gland origin that arises in the dermis. The architecture usually is solid, cystic, or a combination of both. The cytology is classically bland with poroid, squamoid, or clear cell morphology. Clear cells that are positive on periodic acid-Schiff staining predominate in up to one-third of cases. Carcinoembryonic antigen and epithelial membrane antigen can be used to highlight the eosinophilic cuticles of ducts within solid areas.⁶

Sebaceous carcinoma (Figure 4) most frequently arises in a periorbital distribution, although extraocular lesions are known to occur. Histologically, there is a proliferation of both mature sebocytes and basaloid cells in the dermis, occasionally involving the epidermis. The mature sebocytes demonstrate clear cell features with foamy to vacuolated cytoplasm and large nuclei with scalloped borders. The clear cells may vary greatly in number and often are sparse in poorly differentiated tumors in which pleomorphic basaloid cells may predominate. The basaloid cells may resemble those of squamous or basal cell carcinoma, leading to a diagnostic dilemma in some cases. Special staining with Sudan black B and oil red O highlights the cytoplasmic lipid but must be performed on frozen section specimens. Although not entirely specific, immunohistochemical expression of epithelial membrane antigen, androgen receptor, and membranous vesicular adipophilin staining in sebaceous carcinoma can assist in the diagnosis.⁷

Cutaneous xanthomas (Figure 5) may arise in patients of any age and represent deposition of lipid-laden macrophages. Classification often is dependent on the clinical presentation; however, some subtypes demonstrate unique morphologic features (eg, verruciform xanthomas). Xanthomas classically arise in association with elevated serum lipids, but they also may occur in normolipemic patients. Individuals with Erdheim-Chester disease have an increased propensity to develop xanthelasma. Similarly, plane xanthomas have been associated with monoclonal gammopathy. Histologically, xanthomas are characterized by sheets of foamy macrophages within the dermis and subcutis. Positive immunohistochemical staining for CD68 highlighting the histiocytic nature of the cells and the absence of a delicate vascular network aid in the differentiation from RCC.

Metastatic Clear Cell Renal Cell Carcinoma

The differential diagnosis of cutaneous neoplasms with clear cells is broad. Clear cell features can be seen in primary tumors arising from the epidermis and cutaneous adnexa as well as in mesenchymal and melanocytic neoplasms. Furthermore, metastatic disease should be considered in the histologic differential diagnosis, as many visceral malignancies have clear cell features. This patient was subsequently found to have a large renal mass with metastasis to the lungs, spleen, and bone. The histologic findings support the diagnosis of metastatic clear cell renal cell carcinoma (RCC) to the skin.

Approximately 30% of patients with clear cell RCC present with metastatic disease with approximately 8% of those involving the skin.^1,2 Cutaneous RCC metastases show a predilection for the head, especially the scalp. The clinical presentation is variable, but there often is a history of a rapidly growing brown, black, or purple nodule or plaque. A thorough review of the patient's history should be conducted if metastatic RCC is in the differential diagnosis, as it has been reported to occur up to 20 years after initial diagnosis.³

Histologically, clear cell RCC (quiz image) is composed of nests of tumor cells with clear cytoplasm and centrally located nuclei with prominent nucleoli. The clear cell features result from abundant cytoplasmic glycogen and lipid but may not be present in every case. One of the most important histologic features is the presence of delicate branching blood vessels (Figure 1). Numerous extravasated red blood cells also may be present. Positive immunohistochemical staining for PAX8, CD10, and RCC antigens support the diagnosis.⁴

Balloon cell nevi (Figure 2) most commonly occur on the head and neck in adolescents and young adults but clinically are indistinguishable from other banal nevi. The nevus cells are large with foamy to finely vacuolated cytoplasm and lack atypia. The clear cell change is the result of melanosome degeneration and may be extensive. The presence of melanin pigment, nests of typical nevus cells, and positive staining with MART-1 can help distinguish the tumor from xanthomas and RCC.⁵

Clear cell hidradenoma (Figure 3) is a well-circumscribed tumor of sweat gland origin that arises in the dermis. The architecture usually is solid, cystic, or a combination of both. The cytology is classically bland with poroid, squamoid, or clear cell morphology. Clear cells that are positive on periodic acid-Schiff staining predominate in up to one-third of cases. Carcinoembryonic antigen and epithelial membrane antigen can be used to highlight the eosinophilic cuticles of ducts within solid areas.⁶

Sebaceous carcinoma (Figure 4) most frequently arises in a periorbital distribution, although extraocular lesions are known to occur. Histologically, there is a proliferation of both mature sebocytes and basaloid cells in the dermis, occasionally involving the epidermis. The mature sebocytes demonstrate clear cell features with foamy to vacuolated cytoplasm and large nuclei with scalloped borders. The clear cells may vary greatly in number and often are sparse in poorly differentiated tumors in which pleomorphic basaloid cells may predominate. The basaloid cells may resemble those of squamous or basal cell carcinoma, leading to a diagnostic dilemma in some cases. Special staining with Sudan black B and oil red O highlights the cytoplasmic lipid but must be performed on frozen section specimens. Although not entirely specific, immunohistochemical expression of epithelial membrane antigen, androgen receptor, and membranous vesicular adipophilin staining in sebaceous carcinoma can assist in the diagnosis.⁷

Cutaneous xanthomas (Figure 5) may arise in patients of any age and represent deposition of lipid-laden macrophages. Classification often is dependent on the clinical presentation; however, some subtypes demonstrate unique morphologic features (eg, verruciform xanthomas). Xanthomas classically arise in association with elevated serum lipids, but they also may occur in normolipemic patients. Individuals with Erdheim-Chester disease have an increased propensity to develop xanthelasma. Similarly, plane xanthomas have been associated with monoclonal gammopathy. Histologically, xanthomas are characterized by sheets of foamy macrophages within the dermis and subcutis. Positive immunohistochemical staining for CD68 highlighting the histiocytic nature of the cells and the absence of a delicate vascular network aid in the differentiation from RCC.

As employers search for ways to reduce the cost of providing health care to their employees, there is a growing trend toward narrowed provider networks and exclusive laboratory contracts. In the case of clinical pathology, some of these choices make sense from the employer’s perspective. A complete blood cell count or comprehensive metabolic panel is done on a machine and the result is much the same regardless of the laboratory. So why not have all laboratory tests performed by the lowest bidder?

Laboratories vary in quality and anatomic pathology services are different from blood tests. Each slide must be interpreted by a physician and skill in the interpretation of skin specimens varies widely. Dermatopathology was one of the first subspecialties to be recognized within pathology, as it requires a high level of expertise. Clinicopathological correlation often is key to the accurate interpretation of a specimen. The stakes are high, and a delay in diagnosis of melanoma remains one of the most serious errors in medicine and one of the most common causes for litigation in dermatology.

The accurate interpretation of skin biopsy specimens becomes especially difficult when inadequate or misleading clinical information accompanies the specimen. A study of 589 biopsies submitted by primary care physicians and reported by general pathologists demonstrated a 6.5% error rate. False-negative errors were the most common, but false-positives also were observed.¹ A study of pigmented lesions referred to the University of California, San Francisco, demonstrated a discordance rate of 14.3%.² The degree of discordance would be expected to vary based on the range of diagnoses included in each study.

Board-certified dermatopathologists have varying areas of expertise and there is notable subjectivity in the interpretation of biopsy specimens. In the case of problematic pigmented lesions such as atypical Spitz nevi, there can be low interobserver agreement even among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30).³ The low concordance among expert dermatopathologists demonstrates that light microscopic features alone often are inadequate for diagnosis. Advanced studies, including immunohistochemical stains, can help to clarify the diagnosis. In the case of atypical Spitz tumors, the contribution of special stains to the final diagnosis is statistically similar to that of hematoxylin and eosin sections and age, suggesting that nothing alone is sufficiently reliable to establish a definitive diagnosis in every case.⁴ Although helpful, these studies are costly, and savings obtained by sending cases to the lowest bidder can evaporate quickly. Costs are higher when factoring in molecular studies, which can run upwards of $3000 per slide; the cost of litigation related to incorrect diagnoses; or the human costs of an incorrect diagnosis.

As a group, dermatopathologists are highly skilled in the interpretation of skin specimens, but challenging lesions are common in the routine practice of dermatopathology. A study of 1249 pigmented melanocytic lesions demonstrated substantial agreement among expert dermatopathologists for less problematic lesions, though agreement was greater for patients 40 years and older (κ=0.67) than for younger patients (κ=0.49). Agreement was lower for patients with atypical mole syndrome (κ=0.31).⁵ These discrepancies occur despite the fact that there is good interobserver reproducibility for grading of individual histological features such as asymmetry, circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, symmetrical melanin, deep melanin, cytological atypia, mitoses, dermal lymphocytic infiltrate, and necrosis.⁶ These results indicate that accurate diagnoses cannot be reliably established simply by grading a list of histological features. Accurate diagnosis requires complex pattern recognition and integration of findings. Conflicting criteria often are present and an accurate interpretation requires considerable judgment as to which features are significant and which are not.

Separation of sebaceous adenoma, sebaceoma, and well-differentiated sebaceous carcinoma is another challenging area, and interobserver consensus can be as low as 11%,⁷ which suggests notable subjectivity in the criteria for diagnosis of nonmelanocytic tumors and emphasizes the importance of communication between the dermatopathologist and clinician when determining how to manage an ambiguous lesion. The interpretation of inflammatory skin diseases, alopecia, and lymphoid proliferations also can be problematic, and expert consultation often is required.

All dermatologists receive substantial training in dermatopathology, which puts them in an excellent position to interpret ambiguous findings in the context of the clinical presentation. Sometimes the dermatologist who has seen the clinical presentation can be in the best position to make the diagnosis. All clinicians must be wary of bias and an objective set of eyes often can be helpful. Communication is crucial to ensure appropriate care for each patient, and policies that restrict the choice of pathologist can be damaging.

As employers search for ways to reduce the cost of providing health care to their employees, there is a growing trend toward narrowed provider networks and exclusive laboratory contracts. In the case of clinical pathology, some of these choices make sense from the employer’s perspective. A complete blood cell count or comprehensive metabolic panel is done on a machine and the result is much the same regardless of the laboratory. So why not have all laboratory tests performed by the lowest bidder?

Laboratories vary in quality and anatomic pathology services are different from blood tests. Each slide must be interpreted by a physician and skill in the interpretation of skin specimens varies widely. Dermatopathology was one of the first subspecialties to be recognized within pathology, as it requires a high level of expertise. Clinicopathological correlation often is key to the accurate interpretation of a specimen. The stakes are high, and a delay in diagnosis of melanoma remains one of the most serious errors in medicine and one of the most common causes for litigation in dermatology.

The accurate interpretation of skin biopsy specimens becomes especially difficult when inadequate or misleading clinical information accompanies the specimen. A study of 589 biopsies submitted by primary care physicians and reported by general pathologists demonstrated a 6.5% error rate. False-negative errors were the most common, but false-positives also were observed.¹ A study of pigmented lesions referred to the University of California, San Francisco, demonstrated a discordance rate of 14.3%.² The degree of discordance would be expected to vary based on the range of diagnoses included in each study.

Board-certified dermatopathologists have varying areas of expertise and there is notable subjectivity in the interpretation of biopsy specimens. In the case of problematic pigmented lesions such as atypical Spitz nevi, there can be low interobserver agreement even among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30).³ The low concordance among expert dermatopathologists demonstrates that light microscopic features alone often are inadequate for diagnosis. Advanced studies, including immunohistochemical stains, can help to clarify the diagnosis. In the case of atypical Spitz tumors, the contribution of special stains to the final diagnosis is statistically similar to that of hematoxylin and eosin sections and age, suggesting that nothing alone is sufficiently reliable to establish a definitive diagnosis in every case.⁴ Although helpful, these studies are costly, and savings obtained by sending cases to the lowest bidder can evaporate quickly. Costs are higher when factoring in molecular studies, which can run upwards of $3000 per slide; the cost of litigation related to incorrect diagnoses; or the human costs of an incorrect diagnosis.

As a group, dermatopathologists are highly skilled in the interpretation of skin specimens, but challenging lesions are common in the routine practice of dermatopathology. A study of 1249 pigmented melanocytic lesions demonstrated substantial agreement among expert dermatopathologists for less problematic lesions, though agreement was greater for patients 40 years and older (κ=0.67) than for younger patients (κ=0.49). Agreement was lower for patients with atypical mole syndrome (κ=0.31).⁵ These discrepancies occur despite the fact that there is good interobserver reproducibility for grading of individual histological features such as asymmetry, circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, symmetrical melanin, deep melanin, cytological atypia, mitoses, dermal lymphocytic infiltrate, and necrosis.⁶ These results indicate that accurate diagnoses cannot be reliably established simply by grading a list of histological features. Accurate diagnosis requires complex pattern recognition and integration of findings. Conflicting criteria often are present and an accurate interpretation requires considerable judgment as to which features are significant and which are not.

Separation of sebaceous adenoma, sebaceoma, and well-differentiated sebaceous carcinoma is another challenging area, and interobserver consensus can be as low as 11%,⁷ which suggests notable subjectivity in the criteria for diagnosis of nonmelanocytic tumors and emphasizes the importance of communication between the dermatopathologist and clinician when determining how to manage an ambiguous lesion. The interpretation of inflammatory skin diseases, alopecia, and lymphoid proliferations also can be problematic, and expert consultation often is required.

All dermatologists receive substantial training in dermatopathology, which puts them in an excellent position to interpret ambiguous findings in the context of the clinical presentation. Sometimes the dermatologist who has seen the clinical presentation can be in the best position to make the diagnosis. All clinicians must be wary of bias and an objective set of eyes often can be helpful. Communication is crucial to ensure appropriate care for each patient, and policies that restrict the choice of pathologist can be damaging.

As employers search for ways to reduce the cost of providing health care to their employees, there is a growing trend toward narrowed provider networks and exclusive laboratory contracts. In the case of clinical pathology, some of these choices make sense from the employer’s perspective. A complete blood cell count or comprehensive metabolic panel is done on a machine and the result is much the same regardless of the laboratory. So why not have all laboratory tests performed by the lowest bidder?

Laboratories vary in quality and anatomic pathology services are different from blood tests. Each slide must be interpreted by a physician and skill in the interpretation of skin specimens varies widely. Dermatopathology was one of the first subspecialties to be recognized within pathology, as it requires a high level of expertise. Clinicopathological correlation often is key to the accurate interpretation of a specimen. The stakes are high, and a delay in diagnosis of melanoma remains one of the most serious errors in medicine and one of the most common causes for litigation in dermatology.

The accurate interpretation of skin biopsy specimens becomes especially difficult when inadequate or misleading clinical information accompanies the specimen. A study of 589 biopsies submitted by primary care physicians and reported by general pathologists demonstrated a 6.5% error rate. False-negative errors were the most common, but false-positives also were observed.¹ A study of pigmented lesions referred to the University of California, San Francisco, demonstrated a discordance rate of 14.3%.² The degree of discordance would be expected to vary based on the range of diagnoses included in each study.

Board-certified dermatopathologists have varying areas of expertise and there is notable subjectivity in the interpretation of biopsy specimens. In the case of problematic pigmented lesions such as atypical Spitz nevi, there can be low interobserver agreement even among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30).³ The low concordance among expert dermatopathologists demonstrates that light microscopic features alone often are inadequate for diagnosis. Advanced studies, including immunohistochemical stains, can help to clarify the diagnosis. In the case of atypical Spitz tumors, the contribution of special stains to the final diagnosis is statistically similar to that of hematoxylin and eosin sections and age, suggesting that nothing alone is sufficiently reliable to establish a definitive diagnosis in every case.⁴ Although helpful, these studies are costly, and savings obtained by sending cases to the lowest bidder can evaporate quickly. Costs are higher when factoring in molecular studies, which can run upwards of $3000 per slide; the cost of litigation related to incorrect diagnoses; or the human costs of an incorrect diagnosis.

As a group, dermatopathologists are highly skilled in the interpretation of skin specimens, but challenging lesions are common in the routine practice of dermatopathology. A study of 1249 pigmented melanocytic lesions demonstrated substantial agreement among expert dermatopathologists for less problematic lesions, though agreement was greater for patients 40 years and older (κ=0.67) than for younger patients (κ=0.49). Agreement was lower for patients with atypical mole syndrome (κ=0.31).⁵ These discrepancies occur despite the fact that there is good interobserver reproducibility for grading of individual histological features such as asymmetry, circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, symmetrical melanin, deep melanin, cytological atypia, mitoses, dermal lymphocytic infiltrate, and necrosis.⁶ These results indicate that accurate diagnoses cannot be reliably established simply by grading a list of histological features. Accurate diagnosis requires complex pattern recognition and integration of findings. Conflicting criteria often are present and an accurate interpretation requires considerable judgment as to which features are significant and which are not.

Separation of sebaceous adenoma, sebaceoma, and well-differentiated sebaceous carcinoma is another challenging area, and interobserver consensus can be as low as 11%,⁷ which suggests notable subjectivity in the criteria for diagnosis of nonmelanocytic tumors and emphasizes the importance of communication between the dermatopathologist and clinician when determining how to manage an ambiguous lesion. The interpretation of inflammatory skin diseases, alopecia, and lymphoid proliferations also can be problematic, and expert consultation often is required.

All dermatologists receive substantial training in dermatopathology, which puts them in an excellent position to interpret ambiguous findings in the context of the clinical presentation. Sometimes the dermatologist who has seen the clinical presentation can be in the best position to make the diagnosis. All clinicians must be wary of bias and an objective set of eyes often can be helpful. Communication is crucial to ensure appropriate care for each patient, and policies that restrict the choice of pathologist can be damaging.

The Diagnosis: Blaschkoid Graft-vs-host Disease

The patient had a history of myelodysplastic syndrome and underwent a bone marrow transplant 1 year prior to presentation. She had acute graft-vs-host disease (GVHD) 6 weeks following the transplant, which resolved with high-dose prednisone followed by UVB phototherapy. Skin biopsy demonstrated lichenoid dermatitis with vacuolar degeneration, dyskeratosis, and prominent pigment incontinence (Figure). Based on these findings and her clinical presentation, a diagnosis of blaschkoid GVHD was made.

Although acute GVHD is the result of immunocompetent donor T cells recognizing host tissues as foreign and initiating an immune response, the pathophysiology of chronic GVHD is not well understood.^1,2 Theories for disease pathogenesis in chronic GVHD suggest an underlying autoimmune and/or alloreactive process.^2-5 The skin often is the first organ affected in acute GVHD, and patients generally present with a pruritic morbilliform eruption that begins on the trunk and spreads to the rest of the body.^1,2 Cutaneous manifestations of chronic GVHD may be protean. Lesions can resemble systemic sclerosis or morphea, lichen planus, psoriasis, ichthyosis, and many other conditions.²

The differential diagnosis of linear dermatoses includes herpes zoster, contact dermatitis, lichen striatus (blaschkitis), nevus unius lateris, inflammatory linear verrucous epidermal nevus, and incontinentia pigmenti.^6,7 Lichen planus-like chronic GVHD occurring in a linear distribution has been described.^6-14 Distinction between dermatomal and blaschkoid processes is diagnostically important. In the case of GVHD, dermatomal distribution may suggest an association between GVHD and prior herpes simplex virus or varicella-zoster virus infection.^6,8 Herpesvirus may alter surface antigens of keratinocytes, rendering them targets of donor lymphocytes, and antibodies to viral particles may cross-react with host keratinocyte HLA antigens. It also is possible that dermatomal GVHD may simply be a type of isomorphic response (Köbner phenomenon).⁸

When cutaneous GVHD follows Blaschko lines, other mechanisms appear to be at play.^9-14 It is plausible that these patients have an underlying genetic mosaicism, perhaps the result of a postzygotic mutation, that results in a daughter cell population that expresses surface antigens different from those of the primary cell population found elsewhere in the skin. Donor lymphocytes may selectively react to this mosaic population, leading to the clinical picture of chronic GVHD oriented along Blaschko lines.^10,11,13,14 

In conclusion, lichenoid linear GVHD following Blaschko lines is an uncommon presentation of chronic GVHD that highlights the heterogeneity of this disease and should be considered in the appropriate clinical setting.

The Diagnosis: Blaschkoid Graft-vs-host Disease

The patient had a history of myelodysplastic syndrome and underwent a bone marrow transplant 1 year prior to presentation. She had acute graft-vs-host disease (GVHD) 6 weeks following the transplant, which resolved with high-dose prednisone followed by UVB phototherapy. Skin biopsy demonstrated lichenoid dermatitis with vacuolar degeneration, dyskeratosis, and prominent pigment incontinence (Figure). Based on these findings and her clinical presentation, a diagnosis of blaschkoid GVHD was made.

Although acute GVHD is the result of immunocompetent donor T cells recognizing host tissues as foreign and initiating an immune response, the pathophysiology of chronic GVHD is not well understood.^1,2 Theories for disease pathogenesis in chronic GVHD suggest an underlying autoimmune and/or alloreactive process.^2-5 The skin often is the first organ affected in acute GVHD, and patients generally present with a pruritic morbilliform eruption that begins on the trunk and spreads to the rest of the body.^1,2 Cutaneous manifestations of chronic GVHD may be protean. Lesions can resemble systemic sclerosis or morphea, lichen planus, psoriasis, ichthyosis, and many other conditions.²

The differential diagnosis of linear dermatoses includes herpes zoster, contact dermatitis, lichen striatus (blaschkitis), nevus unius lateris, inflammatory linear verrucous epidermal nevus, and incontinentia pigmenti.^6,7 Lichen planus-like chronic GVHD occurring in a linear distribution has been described.^6-14 Distinction between dermatomal and blaschkoid processes is diagnostically important. In the case of GVHD, dermatomal distribution may suggest an association between GVHD and prior herpes simplex virus or varicella-zoster virus infection.^6,8 Herpesvirus may alter surface antigens of keratinocytes, rendering them targets of donor lymphocytes, and antibodies to viral particles may cross-react with host keratinocyte HLA antigens. It also is possible that dermatomal GVHD may simply be a type of isomorphic response (Köbner phenomenon).⁸

When cutaneous GVHD follows Blaschko lines, other mechanisms appear to be at play.^9-14 It is plausible that these patients have an underlying genetic mosaicism, perhaps the result of a postzygotic mutation, that results in a daughter cell population that expresses surface antigens different from those of the primary cell population found elsewhere in the skin. Donor lymphocytes may selectively react to this mosaic population, leading to the clinical picture of chronic GVHD oriented along Blaschko lines.^10,11,13,14 

In conclusion, lichenoid linear GVHD following Blaschko lines is an uncommon presentation of chronic GVHD that highlights the heterogeneity of this disease and should be considered in the appropriate clinical setting.

The Diagnosis: Blaschkoid Graft-vs-host Disease

The patient had a history of myelodysplastic syndrome and underwent a bone marrow transplant 1 year prior to presentation. She had acute graft-vs-host disease (GVHD) 6 weeks following the transplant, which resolved with high-dose prednisone followed by UVB phototherapy. Skin biopsy demonstrated lichenoid dermatitis with vacuolar degeneration, dyskeratosis, and prominent pigment incontinence (Figure). Based on these findings and her clinical presentation, a diagnosis of blaschkoid GVHD was made.

Although acute GVHD is the result of immunocompetent donor T cells recognizing host tissues as foreign and initiating an immune response, the pathophysiology of chronic GVHD is not well understood.^1,2 Theories for disease pathogenesis in chronic GVHD suggest an underlying autoimmune and/or alloreactive process.^2-5 The skin often is the first organ affected in acute GVHD, and patients generally present with a pruritic morbilliform eruption that begins on the trunk and spreads to the rest of the body.^1,2 Cutaneous manifestations of chronic GVHD may be protean. Lesions can resemble systemic sclerosis or morphea, lichen planus, psoriasis, ichthyosis, and many other conditions.²

The differential diagnosis of linear dermatoses includes herpes zoster, contact dermatitis, lichen striatus (blaschkitis), nevus unius lateris, inflammatory linear verrucous epidermal nevus, and incontinentia pigmenti.^6,7 Lichen planus-like chronic GVHD occurring in a linear distribution has been described.^6-14 Distinction between dermatomal and blaschkoid processes is diagnostically important. In the case of GVHD, dermatomal distribution may suggest an association between GVHD and prior herpes simplex virus or varicella-zoster virus infection.^6,8 Herpesvirus may alter surface antigens of keratinocytes, rendering them targets of donor lymphocytes, and antibodies to viral particles may cross-react with host keratinocyte HLA antigens. It also is possible that dermatomal GVHD may simply be a type of isomorphic response (Köbner phenomenon).⁸

When cutaneous GVHD follows Blaschko lines, other mechanisms appear to be at play.^9-14 It is plausible that these patients have an underlying genetic mosaicism, perhaps the result of a postzygotic mutation, that results in a daughter cell population that expresses surface antigens different from those of the primary cell population found elsewhere in the skin. Donor lymphocytes may selectively react to this mosaic population, leading to the clinical picture of chronic GVHD oriented along Blaschko lines.^10,11,13,14 

In conclusion, lichenoid linear GVHD following Blaschko lines is an uncommon presentation of chronic GVHD that highlights the heterogeneity of this disease and should be considered in the appropriate clinical setting.

Papular Mucinosis/Scleromyxedema

Papular mucinosis/scleromyxedema, also known as generalized lichen myxedematosus, is a rare dermal mucinosis characterized by a papular eruption that can have an associated IgG λ paraproteinemia. The clinical presentation is gradual with the development of firm, flesh-colored, 2- to 3-mm papules often involving the hands, face, and neck that can progress to plaques that cover the entire body. Skin stiffening also can be seen.¹ Extracutaneous symptoms are common and include dysphagia, arthralgia, myopathy, and cardiac dysfunction.² Occasionally, central nervous system involvement can lead to the often fatal dermato-neuro syndrome.^3,4

Histologically, papular mucinosis/scleromyxedema demonstrates increased, irregularly arranged fibroblasts in the reticular dermis with increased dermal mucin deposition (quiz image and Figure 1). The epidermis is normal or slightly thinned due to pressure from dermal changes. There may be a mild superficial perivascular lymphocytic infiltrate and atrophy of hair follicles.5 In this case, the clinical and histologic findings best supported a diagnosis of papular mucinosis/scleromyxedema.

Infundibulofolliculitis is a pruritic follicular papular eruption typically involving the neck, trunk, and proximal upper arms and shoulders. It is most common in black men who reside in hot and humid climates. Although infundibulofolliculitis would be included in the clinical differential diagnosis for the current patient, the histopathologic findings were quite distinct for the correct diagnosis of papular mucinosis/scleromyxedema. Infundibulofolliculitis shows widening of the upper part of the hair follicle (infundibulum) and infundibular inflammatory infiltrate with follicular spongiosis (Figure 2). Neither mucin deposition nor fibroblast proliferation is appreciated in infundibulofolliculitis.^6,7 

Granuloma annulare (GA) often can be distinguished clinically from papular mucinosis/scleromyxedema due to the annular appearance of papules and plaques in GA and the lack of stiffness of underlying skin. Interstitial granuloma annulare is a histologic variant of GA that can be included in the histologic differential diagnosis of papular mucinosis/scleromyxedema. Histologically, there is an interstitial infiltrate of cytologically bland histiocytes dissecting between collagen bundles in interstitial GA (Figure 3). Necrobiosis and collections of mucin often are inconspicuous. Occasionally, the presence of eosinophils can be a helpful clue.⁸ A fibroblast proliferation is not a feature of GA.

Reticular erythematous mucinosis also is a type of cutaneous mucinosis but with a classic clinical appearance of a reticulated erythematous plaque on the chest or back, making it clinically distinct from papular mucinosis/scleromyxedema and the presentation described in the current patient. Reticular erythematous mucinosis can be histologically distinguished from papular mucinosis/scleromyxedema by the presence of a superficial and deep perivascular lymphocytic infiltrate with increased dermal mucin deposition (Figure 4). It often shows a positive IgM deposition on the basement membrane on direct immunofluorescence.⁹

Similar to papular mucinosis/scleromyxedema, scleredema shows thickening of the skin with decreased movement of involved areas. Scleredema often involves the upper back, shoulders, and neck where affected areas often have a peau d'orange appearance. Scleredema is classified into 3 clinical forms based on clinical associations. Type 1 often is preceded by an infection, classically Streptococcus pyogenes. Type 2 is associated with a hematologic dyscrasia such as multiple myeloma, or it can have an associated paraproteinemia that is typically of the IgA κ type, which is distinct from papular mucinosis/scleromyxedema where IgG λ paraproteinemia typically is seen. Type 3 is associated with diabetes mellitus. Histologically, scleredema also is distinct from papular mucinosis/scleromyxedema. Although increased mucin is seen in the dermis, the mucin is classically more prominent in the deep reticular dermis as compared with papular mucinosis/scleromyxedema (Figure 5). Additionally, collagen bundles are thickened with clear separation between them. Hyperplasia of fibroblasts in the dermis that is a characteristic feature of papular mucinosis/scleromyxedema is not observed in scleredema.¹⁰

Papular Mucinosis/Scleromyxedema

Papular mucinosis/scleromyxedema, also known as generalized lichen myxedematosus, is a rare dermal mucinosis characterized by a papular eruption that can have an associated IgG λ paraproteinemia. The clinical presentation is gradual with the development of firm, flesh-colored, 2- to 3-mm papules often involving the hands, face, and neck that can progress to plaques that cover the entire body. Skin stiffening also can be seen.¹ Extracutaneous symptoms are common and include dysphagia, arthralgia, myopathy, and cardiac dysfunction.² Occasionally, central nervous system involvement can lead to the often fatal dermato-neuro syndrome.^3,4

Histologically, papular mucinosis/scleromyxedema demonstrates increased, irregularly arranged fibroblasts in the reticular dermis with increased dermal mucin deposition (quiz image and Figure 1). The epidermis is normal or slightly thinned due to pressure from dermal changes. There may be a mild superficial perivascular lymphocytic infiltrate and atrophy of hair follicles.5 In this case, the clinical and histologic findings best supported a diagnosis of papular mucinosis/scleromyxedema.

Infundibulofolliculitis is a pruritic follicular papular eruption typically involving the neck, trunk, and proximal upper arms and shoulders. It is most common in black men who reside in hot and humid climates. Although infundibulofolliculitis would be included in the clinical differential diagnosis for the current patient, the histopathologic findings were quite distinct for the correct diagnosis of papular mucinosis/scleromyxedema. Infundibulofolliculitis shows widening of the upper part of the hair follicle (infundibulum) and infundibular inflammatory infiltrate with follicular spongiosis (Figure 2). Neither mucin deposition nor fibroblast proliferation is appreciated in infundibulofolliculitis.^6,7 

Granuloma annulare (GA) often can be distinguished clinically from papular mucinosis/scleromyxedema due to the annular appearance of papules and plaques in GA and the lack of stiffness of underlying skin. Interstitial granuloma annulare is a histologic variant of GA that can be included in the histologic differential diagnosis of papular mucinosis/scleromyxedema. Histologically, there is an interstitial infiltrate of cytologically bland histiocytes dissecting between collagen bundles in interstitial GA (Figure 3). Necrobiosis and collections of mucin often are inconspicuous. Occasionally, the presence of eosinophils can be a helpful clue.⁸ A fibroblast proliferation is not a feature of GA.

Reticular erythematous mucinosis also is a type of cutaneous mucinosis but with a classic clinical appearance of a reticulated erythematous plaque on the chest or back, making it clinically distinct from papular mucinosis/scleromyxedema and the presentation described in the current patient. Reticular erythematous mucinosis can be histologically distinguished from papular mucinosis/scleromyxedema by the presence of a superficial and deep perivascular lymphocytic infiltrate with increased dermal mucin deposition (Figure 4). It often shows a positive IgM deposition on the basement membrane on direct immunofluorescence.⁹

Similar to papular mucinosis/scleromyxedema, scleredema shows thickening of the skin with decreased movement of involved areas. Scleredema often involves the upper back, shoulders, and neck where affected areas often have a peau d'orange appearance. Scleredema is classified into 3 clinical forms based on clinical associations. Type 1 often is preceded by an infection, classically Streptococcus pyogenes. Type 2 is associated with a hematologic dyscrasia such as multiple myeloma, or it can have an associated paraproteinemia that is typically of the IgA κ type, which is distinct from papular mucinosis/scleromyxedema where IgG λ paraproteinemia typically is seen. Type 3 is associated with diabetes mellitus. Histologically, scleredema also is distinct from papular mucinosis/scleromyxedema. Although increased mucin is seen in the dermis, the mucin is classically more prominent in the deep reticular dermis as compared with papular mucinosis/scleromyxedema (Figure 5). Additionally, collagen bundles are thickened with clear separation between them. Hyperplasia of fibroblasts in the dermis that is a characteristic feature of papular mucinosis/scleromyxedema is not observed in scleredema.¹⁰

Papular Mucinosis/Scleromyxedema

Papular mucinosis/scleromyxedema, also known as generalized lichen myxedematosus, is a rare dermal mucinosis characterized by a papular eruption that can have an associated IgG λ paraproteinemia. The clinical presentation is gradual with the development of firm, flesh-colored, 2- to 3-mm papules often involving the hands, face, and neck that can progress to plaques that cover the entire body. Skin stiffening also can be seen.¹ Extracutaneous symptoms are common and include dysphagia, arthralgia, myopathy, and cardiac dysfunction.² Occasionally, central nervous system involvement can lead to the often fatal dermato-neuro syndrome.^3,4

Histologically, papular mucinosis/scleromyxedema demonstrates increased, irregularly arranged fibroblasts in the reticular dermis with increased dermal mucin deposition (quiz image and Figure 1). The epidermis is normal or slightly thinned due to pressure from dermal changes. There may be a mild superficial perivascular lymphocytic infiltrate and atrophy of hair follicles.5 In this case, the clinical and histologic findings best supported a diagnosis of papular mucinosis/scleromyxedema.

Infundibulofolliculitis is a pruritic follicular papular eruption typically involving the neck, trunk, and proximal upper arms and shoulders. It is most common in black men who reside in hot and humid climates. Although infundibulofolliculitis would be included in the clinical differential diagnosis for the current patient, the histopathologic findings were quite distinct for the correct diagnosis of papular mucinosis/scleromyxedema. Infundibulofolliculitis shows widening of the upper part of the hair follicle (infundibulum) and infundibular inflammatory infiltrate with follicular spongiosis (Figure 2). Neither mucin deposition nor fibroblast proliferation is appreciated in infundibulofolliculitis.^6,7 

Granuloma annulare (GA) often can be distinguished clinically from papular mucinosis/scleromyxedema due to the annular appearance of papules and plaques in GA and the lack of stiffness of underlying skin. Interstitial granuloma annulare is a histologic variant of GA that can be included in the histologic differential diagnosis of papular mucinosis/scleromyxedema. Histologically, there is an interstitial infiltrate of cytologically bland histiocytes dissecting between collagen bundles in interstitial GA (Figure 3). Necrobiosis and collections of mucin often are inconspicuous. Occasionally, the presence of eosinophils can be a helpful clue.⁸ A fibroblast proliferation is not a feature of GA.

Reticular erythematous mucinosis also is a type of cutaneous mucinosis but with a classic clinical appearance of a reticulated erythematous plaque on the chest or back, making it clinically distinct from papular mucinosis/scleromyxedema and the presentation described in the current patient. Reticular erythematous mucinosis can be histologically distinguished from papular mucinosis/scleromyxedema by the presence of a superficial and deep perivascular lymphocytic infiltrate with increased dermal mucin deposition (Figure 4). It often shows a positive IgM deposition on the basement membrane on direct immunofluorescence.⁹

Similar to papular mucinosis/scleromyxedema, scleredema shows thickening of the skin with decreased movement of involved areas. Scleredema often involves the upper back, shoulders, and neck where affected areas often have a peau d'orange appearance. Scleredema is classified into 3 clinical forms based on clinical associations. Type 1 often is preceded by an infection, classically Streptococcus pyogenes. Type 2 is associated with a hematologic dyscrasia such as multiple myeloma, or it can have an associated paraproteinemia that is typically of the IgA κ type, which is distinct from papular mucinosis/scleromyxedema where IgG λ paraproteinemia typically is seen. Type 3 is associated with diabetes mellitus. Histologically, scleredema also is distinct from papular mucinosis/scleromyxedema. Although increased mucin is seen in the dermis, the mucin is classically more prominent in the deep reticular dermis as compared with papular mucinosis/scleromyxedema (Figure 5). Additionally, collagen bundles are thickened with clear separation between them. Hyperplasia of fibroblasts in the dermis that is a characteristic feature of papular mucinosis/scleromyxedema is not observed in scleredema.¹⁰

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs, eyes, and skin. Cutaneous involvement is reported in 25% to 35% of patients with sarcoidosis and may occur in a variety of forms including macules, papules, plaques, and lupus pernio.^1,2 Dermatologists commonly are confronted with the diagnosis and management of sarcoidosis because of its high incidence of cutaneous involvement. Due to the protean nature of the disease, skin biopsy plays a key role in confirming the diagnosis. Histological evidence of noncaseating granulomas in combination with an appropriate clinical and radiographic picture is necessary for the diagnosis of sarcoidosis.^1,2 Brincker and Wilbek³ first described the link between pulmonary sarcoidosis and an increased incidence of malignancy in 1974. Since then, a number of studies have suggested that sarcoidosis may be associated with an increased risk for hematologic malignancy as well as an increased risk for cancers of the lungs, stomach, colon, liver, and skin.^4,5 To date, few studies exist that examine the relationship between cutaneous sarcoidosis and malignancy.⁶

We describe 3 patients with sarcoidosis who developed squamous cell carcinoma (SCC) of the skin, including 2 black patients, which highlights the potential for SCC development.

Case Reports

Patient 1

A black woman in her 60s with a history of sarcoidosis affecting the lungs and skin that was well controlled with biweekly adalimumab 40 mg subcutaneous injections presented with a new dark painful lesion on the right third finger. She reported the lesion had been present for 1 to 2 years prior to the current presentation and was increasing in size. She had no history of prior skin cancers.

Physical examination revealed a waxy, brown-pigmented papule with overlying scale on the ulnar aspect of the right third digit near the web space (Figure 1A). A shave biopsy revealed atypical keratinocytes involving all layers of the epidermis along with associated parakeratotic scale consistent with a diagnosis of SCC in situ (Figure 1B). Human papillomavirus staining was negative. Due to the location of the lesion, the patient underwent Mohs micrographic surgery and the lesion was completely excised.

Patient 2

A black woman in her 60s with a history of cutaneous sarcoidosis that was maintained on minocycline 100 mg twice daily, chloroquine 250 mg daily, tacrolimus ointment 0.1%, tretinoin cream 0.025%, and intermittent intralesional triamcinolone acetonide injections to the nose, as well as quiescent pulmonary sarcoidosis, developed a new, growing, asymptomatic, hyperpigmented lesion on the left side of the submandibular neck over a period of a few months. A biopsy was performed and the lesion was found to be an SCC, which subsequently was completely excised.

Patient 3

A white man in his 60s with a history of prior quiescent pulmonary sarcoidosis, remote melanoma, and multiple nonmelanoma skin cancers developed scaly papules on the scalp for months, one that was interpreted by an outside pathologist as an invasive SCC (Figure 2A). He was referred to our institution for Mohs micrographic surgery. On presentation when his scalp was shaved for surgery, he was noted to have several violaceous, annular, thin plaques on the scalp (Figure 2B). A biopsy of an annular plaque demonstrated several areas of granulomatous dermatitis consistent with a diagnosis of cutaneous sarcoidosis (Figure 2C). The patient had clinical lymphadenopathy of the neck and supraclavicular region. Given the patient’s history, the differential diagnosis for these lesions included metastatic SCC, lymphoma, and sarcoidosis. The patient underwent a positron emission tomography scan, which demonstrated fluorodeoxyglucose-positive regions in both lungs and the right side of the neck. After evaluation by the pulmonary and otorhinolaryngology departments, including a lymph node biopsy, the positron emission tomography–enhancing lesions were ultimately determined to be consistent with sarcoidosis.

The patient underwent Mohs micrographic surgery for treatment of the scalp SCC and was started on triamcinolone cream 0.1% for the body, clobetasol propionate foam 0.05% for the scalp, and hydroxychloroquine sulfate 400 mg daily for the cutaneous sarcoidosis. His annular scalp lesions resolved, but over the following 12 months the patient had numerous clinically suspicious skin lesions that were biopsied and were consistent with multiple basal cell carcinomas, actinic keratoses, and SCC in situ. They were treated with surgery, cryosurgical destruction with liquid nitrogen, and 5-fluorouracil cream.

Comment

The potential increased risk for malignancy in patients with sarcoidosis has been well documented.^3-6 Brincker and Wilbek³ first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.³ In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al⁵ noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.⁵ In a retrospective cohort study examining more than 9000 patients, Askling et al⁴ also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.⁴ Reich et al⁷ cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.⁷

Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.⁸ Alexandrescu et al⁶ evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.⁶

We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.

Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.

The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.^1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4⁺ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.^1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.^1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.^6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.⁶

Conclusion

An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs, eyes, and skin. Cutaneous involvement is reported in 25% to 35% of patients with sarcoidosis and may occur in a variety of forms including macules, papules, plaques, and lupus pernio.^1,2 Dermatologists commonly are confronted with the diagnosis and management of sarcoidosis because of its high incidence of cutaneous involvement. Due to the protean nature of the disease, skin biopsy plays a key role in confirming the diagnosis. Histological evidence of noncaseating granulomas in combination with an appropriate clinical and radiographic picture is necessary for the diagnosis of sarcoidosis.^1,2 Brincker and Wilbek³ first described the link between pulmonary sarcoidosis and an increased incidence of malignancy in 1974. Since then, a number of studies have suggested that sarcoidosis may be associated with an increased risk for hematologic malignancy as well as an increased risk for cancers of the lungs, stomach, colon, liver, and skin.^4,5 To date, few studies exist that examine the relationship between cutaneous sarcoidosis and malignancy.⁶

We describe 3 patients with sarcoidosis who developed squamous cell carcinoma (SCC) of the skin, including 2 black patients, which highlights the potential for SCC development.

Case Reports

Patient 1

A black woman in her 60s with a history of sarcoidosis affecting the lungs and skin that was well controlled with biweekly adalimumab 40 mg subcutaneous injections presented with a new dark painful lesion on the right third finger. She reported the lesion had been present for 1 to 2 years prior to the current presentation and was increasing in size. She had no history of prior skin cancers.

Physical examination revealed a waxy, brown-pigmented papule with overlying scale on the ulnar aspect of the right third digit near the web space (Figure 1A). A shave biopsy revealed atypical keratinocytes involving all layers of the epidermis along with associated parakeratotic scale consistent with a diagnosis of SCC in situ (Figure 1B). Human papillomavirus staining was negative. Due to the location of the lesion, the patient underwent Mohs micrographic surgery and the lesion was completely excised.

Patient 2

A black woman in her 60s with a history of cutaneous sarcoidosis that was maintained on minocycline 100 mg twice daily, chloroquine 250 mg daily, tacrolimus ointment 0.1%, tretinoin cream 0.025%, and intermittent intralesional triamcinolone acetonide injections to the nose, as well as quiescent pulmonary sarcoidosis, developed a new, growing, asymptomatic, hyperpigmented lesion on the left side of the submandibular neck over a period of a few months. A biopsy was performed and the lesion was found to be an SCC, which subsequently was completely excised.

Patient 3

A white man in his 60s with a history of prior quiescent pulmonary sarcoidosis, remote melanoma, and multiple nonmelanoma skin cancers developed scaly papules on the scalp for months, one that was interpreted by an outside pathologist as an invasive SCC (Figure 2A). He was referred to our institution for Mohs micrographic surgery. On presentation when his scalp was shaved for surgery, he was noted to have several violaceous, annular, thin plaques on the scalp (Figure 2B). A biopsy of an annular plaque demonstrated several areas of granulomatous dermatitis consistent with a diagnosis of cutaneous sarcoidosis (Figure 2C). The patient had clinical lymphadenopathy of the neck and supraclavicular region. Given the patient’s history, the differential diagnosis for these lesions included metastatic SCC, lymphoma, and sarcoidosis. The patient underwent a positron emission tomography scan, which demonstrated fluorodeoxyglucose-positive regions in both lungs and the right side of the neck. After evaluation by the pulmonary and otorhinolaryngology departments, including a lymph node biopsy, the positron emission tomography–enhancing lesions were ultimately determined to be consistent with sarcoidosis.

The patient underwent Mohs micrographic surgery for treatment of the scalp SCC and was started on triamcinolone cream 0.1% for the body, clobetasol propionate foam 0.05% for the scalp, and hydroxychloroquine sulfate 400 mg daily for the cutaneous sarcoidosis. His annular scalp lesions resolved, but over the following 12 months the patient had numerous clinically suspicious skin lesions that were biopsied and were consistent with multiple basal cell carcinomas, actinic keratoses, and SCC in situ. They were treated with surgery, cryosurgical destruction with liquid nitrogen, and 5-fluorouracil cream.

Comment

The potential increased risk for malignancy in patients with sarcoidosis has been well documented.^3-6 Brincker and Wilbek³ first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.³ In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al⁵ noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.⁵ In a retrospective cohort study examining more than 9000 patients, Askling et al⁴ also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.⁴ Reich et al⁷ cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.⁷

Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.⁸ Alexandrescu et al⁶ evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.⁶

We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.

Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.

The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.^1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4⁺ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.^1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.^1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.^6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.⁶

Conclusion

An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs, eyes, and skin. Cutaneous involvement is reported in 25% to 35% of patients with sarcoidosis and may occur in a variety of forms including macules, papules, plaques, and lupus pernio.^1,2 Dermatologists commonly are confronted with the diagnosis and management of sarcoidosis because of its high incidence of cutaneous involvement. Due to the protean nature of the disease, skin biopsy plays a key role in confirming the diagnosis. Histological evidence of noncaseating granulomas in combination with an appropriate clinical and radiographic picture is necessary for the diagnosis of sarcoidosis.^1,2 Brincker and Wilbek³ first described the link between pulmonary sarcoidosis and an increased incidence of malignancy in 1974. Since then, a number of studies have suggested that sarcoidosis may be associated with an increased risk for hematologic malignancy as well as an increased risk for cancers of the lungs, stomach, colon, liver, and skin.^4,5 To date, few studies exist that examine the relationship between cutaneous sarcoidosis and malignancy.⁶

We describe 3 patients with sarcoidosis who developed squamous cell carcinoma (SCC) of the skin, including 2 black patients, which highlights the potential for SCC development.

Case Reports

Patient 1

A black woman in her 60s with a history of sarcoidosis affecting the lungs and skin that was well controlled with biweekly adalimumab 40 mg subcutaneous injections presented with a new dark painful lesion on the right third finger. She reported the lesion had been present for 1 to 2 years prior to the current presentation and was increasing in size. She had no history of prior skin cancers.

Physical examination revealed a waxy, brown-pigmented papule with overlying scale on the ulnar aspect of the right third digit near the web space (Figure 1A). A shave biopsy revealed atypical keratinocytes involving all layers of the epidermis along with associated parakeratotic scale consistent with a diagnosis of SCC in situ (Figure 1B). Human papillomavirus staining was negative. Due to the location of the lesion, the patient underwent Mohs micrographic surgery and the lesion was completely excised.

Patient 2

A black woman in her 60s with a history of cutaneous sarcoidosis that was maintained on minocycline 100 mg twice daily, chloroquine 250 mg daily, tacrolimus ointment 0.1%, tretinoin cream 0.025%, and intermittent intralesional triamcinolone acetonide injections to the nose, as well as quiescent pulmonary sarcoidosis, developed a new, growing, asymptomatic, hyperpigmented lesion on the left side of the submandibular neck over a period of a few months. A biopsy was performed and the lesion was found to be an SCC, which subsequently was completely excised.

Patient 3

A white man in his 60s with a history of prior quiescent pulmonary sarcoidosis, remote melanoma, and multiple nonmelanoma skin cancers developed scaly papules on the scalp for months, one that was interpreted by an outside pathologist as an invasive SCC (Figure 2A). He was referred to our institution for Mohs micrographic surgery. On presentation when his scalp was shaved for surgery, he was noted to have several violaceous, annular, thin plaques on the scalp (Figure 2B). A biopsy of an annular plaque demonstrated several areas of granulomatous dermatitis consistent with a diagnosis of cutaneous sarcoidosis (Figure 2C). The patient had clinical lymphadenopathy of the neck and supraclavicular region. Given the patient’s history, the differential diagnosis for these lesions included metastatic SCC, lymphoma, and sarcoidosis. The patient underwent a positron emission tomography scan, which demonstrated fluorodeoxyglucose-positive regions in both lungs and the right side of the neck. After evaluation by the pulmonary and otorhinolaryngology departments, including a lymph node biopsy, the positron emission tomography–enhancing lesions were ultimately determined to be consistent with sarcoidosis.

The patient underwent Mohs micrographic surgery for treatment of the scalp SCC and was started on triamcinolone cream 0.1% for the body, clobetasol propionate foam 0.05% for the scalp, and hydroxychloroquine sulfate 400 mg daily for the cutaneous sarcoidosis. His annular scalp lesions resolved, but over the following 12 months the patient had numerous clinically suspicious skin lesions that were biopsied and were consistent with multiple basal cell carcinomas, actinic keratoses, and SCC in situ. They were treated with surgery, cryosurgical destruction with liquid nitrogen, and 5-fluorouracil cream.

Comment

The potential increased risk for malignancy in patients with sarcoidosis has been well documented.^3-6 Brincker and Wilbek³ first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.³ In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al⁵ noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.⁵ In a retrospective cohort study examining more than 9000 patients, Askling et al⁴ also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.⁴ Reich et al⁷ cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.⁷

Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.⁸ Alexandrescu et al⁶ evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.⁶

We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.

Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.

The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.^1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4⁺ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.^1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.^1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.^6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.⁶

Conclusion

An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.

WASHINGTON – A novel biologic treatment strategy involving subcutaneous low-dose interleukin-2 therapy for refractory systemic lupus erythematosus (SLE) showed promise in a single-center, combined phase I/IIa trial.

In 12 patients with active and refractory SLE – that is, patients with SLE disease activity index (SLEDAI) score of at least 6 who were on at least two different immunosuppressive therapies – low-dose IL-2 treatment led to an effective and cycle-dependent increase in the percentage of CD25hi cells among regulatory T cells (Treg). The increase was statistically significant (P less than .001), Jens Humrich, MD, and his colleagues reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

wildpixel/Thinkstock

sworcester@frontlinemedcom.com

WASHINGTON – A novel biologic treatment strategy involving subcutaneous low-dose interleukin-2 therapy for refractory systemic lupus erythematosus (SLE) showed promise in a single-center, combined phase I/IIa trial.

In 12 patients with active and refractory SLE – that is, patients with SLE disease activity index (SLEDAI) score of at least 6 who were on at least two different immunosuppressive therapies – low-dose IL-2 treatment led to an effective and cycle-dependent increase in the percentage of CD25hi cells among regulatory T cells (Treg). The increase was statistically significant (P less than .001), Jens Humrich, MD, and his colleagues reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

wildpixel/Thinkstock

sworcester@frontlinemedcom.com

WASHINGTON – A novel biologic treatment strategy involving subcutaneous low-dose interleukin-2 therapy for refractory systemic lupus erythematosus (SLE) showed promise in a single-center, combined phase I/IIa trial.

In 12 patients with active and refractory SLE – that is, patients with SLE disease activity index (SLEDAI) score of at least 6 who were on at least two different immunosuppressive therapies – low-dose IL-2 treatment led to an effective and cycle-dependent increase in the percentage of CD25hi cells among regulatory T cells (Treg). The increase was statistically significant (P less than .001), Jens Humrich, MD, and his colleagues reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

wildpixel/Thinkstock

sworcester@frontlinemedcom.com

Blastomycosis
Blastomycosis is caused by Blastomyces dermatitidis, which is endemic in the Midwestern and southeastern United States where it occurs environmentally in wood and soil. Unlike many fungal infections, blastomycosis most often develops in immunocompetent hosts. Infection is usually acquired via inhalation,¹ and cutaneous disease typically is secondary to pulmonary infection. Although not common, traumatic inoculation also can cause cutaneous blastomycosis. Skin lesions include crusted verrucous nodules and plaques with elevated borders.^1,2 Histologic features include pseudoepitheliomatous hyperplasia with intraepidermal neutrophilic microabscesses (Figure 1), and a neutrophilic and granulomatous dermal infiltrate. Organisms often are found within histiocytes (quiz image) or small abscesses. The yeasts usually are 8 to 15 µm in diameter with a thick cell wall and occasionally display broad-based budding.

Chromoblastomycosis is caused by dematiaceous (pigmented) fungi, including Fonsecaea, Phialophora, Cladophialophora, and Rhinocladiella species,³ which are present in soil and vegetable debris in tropical and subtropical regions. Infection typically occurs in the foot or lower leg from traumatic inoculation, such as a thorn or splinter injury.² Histologically, chromoblastomycosis is characterized by pseudoepitheliomatous hyperplasia; suppurative and granulomatous dermatitis; and sclerotic (Medlar) bodies, which are 5 to 12 µm in diameter, round, brown, sometimes septate cells resembling copper pennies (Figure 2).²

Coccidioidomycosis is caused by Coccidioides immitis, which is found in soil in the southwestern United States. Infection most often occurs via inhalation of airborne arthrospores.² Cutaneous lesions occasionally are observed following dissemination or rarely following primary inoculation injury. They may present as papules, nodules, pustules, plaques, and ulcers, with the face being the most commonly affected site.¹ Histologically, coccidioidomycosis is characterized by pseudoepitheliomatous hyperplasia, suppurative and granulomatous dermatitis, and large spherules (up to 100 µm in diameter) containing numerous small endospores (Figure 3).

Cryptococcosis is caused by Cryptococcus neoformans, a fungus found in soil, fruit, and pigeon droppings throughout the world.^2,3 The most common route of infection is via the respiratory tract. Systemic spread and central nervous system involvement may occur in immunocompromised hosts.² Skin involvement is uncommon and may present on the head and neck with umbilicated papules, pustules, nodules, plaques, or ulcers. Histologically, Cryptococcus is a spherical yeast, often 4 to 20 µm in diameter. Replication is by narrow-based budding. A characteristic feature is a mucoid capsule, which retracts during processing, leaving a clear space around the yeast (Figure 4). When present, the mucoid capsule can be highlighted on mucicarmine or Alcian blue staining. Histologic variants of cryptococcosis include granulomatous (high host immune response), gelatinous (low host immune response), and suppurative types.³  

Blastomycosis
Blastomycosis is caused by Blastomyces dermatitidis, which is endemic in the Midwestern and southeastern United States where it occurs environmentally in wood and soil. Unlike many fungal infections, blastomycosis most often develops in immunocompetent hosts. Infection is usually acquired via inhalation,¹ and cutaneous disease typically is secondary to pulmonary infection. Although not common, traumatic inoculation also can cause cutaneous blastomycosis. Skin lesions include crusted verrucous nodules and plaques with elevated borders.^1,2 Histologic features include pseudoepitheliomatous hyperplasia with intraepidermal neutrophilic microabscesses (Figure 1), and a neutrophilic and granulomatous dermal infiltrate. Organisms often are found within histiocytes (quiz image) or small abscesses. The yeasts usually are 8 to 15 µm in diameter with a thick cell wall and occasionally display broad-based budding.

Chromoblastomycosis is caused by dematiaceous (pigmented) fungi, including Fonsecaea, Phialophora, Cladophialophora, and Rhinocladiella species,³ which are present in soil and vegetable debris in tropical and subtropical regions. Infection typically occurs in the foot or lower leg from traumatic inoculation, such as a thorn or splinter injury.² Histologically, chromoblastomycosis is characterized by pseudoepitheliomatous hyperplasia; suppurative and granulomatous dermatitis; and sclerotic (Medlar) bodies, which are 5 to 12 µm in diameter, round, brown, sometimes septate cells resembling copper pennies (Figure 2).²

Coccidioidomycosis is caused by Coccidioides immitis, which is found in soil in the southwestern United States. Infection most often occurs via inhalation of airborne arthrospores.² Cutaneous lesions occasionally are observed following dissemination or rarely following primary inoculation injury. They may present as papules, nodules, pustules, plaques, and ulcers, with the face being the most commonly affected site.¹ Histologically, coccidioidomycosis is characterized by pseudoepitheliomatous hyperplasia, suppurative and granulomatous dermatitis, and large spherules (up to 100 µm in diameter) containing numerous small endospores (Figure 3).

Cryptococcosis is caused by Cryptococcus neoformans, a fungus found in soil, fruit, and pigeon droppings throughout the world.^2,3 The most common route of infection is via the respiratory tract. Systemic spread and central nervous system involvement may occur in immunocompromised hosts.² Skin involvement is uncommon and may present on the head and neck with umbilicated papules, pustules, nodules, plaques, or ulcers. Histologically, Cryptococcus is a spherical yeast, often 4 to 20 µm in diameter. Replication is by narrow-based budding. A characteristic feature is a mucoid capsule, which retracts during processing, leaving a clear space around the yeast (Figure 4). When present, the mucoid capsule can be highlighted on mucicarmine or Alcian blue staining. Histologic variants of cryptococcosis include granulomatous (high host immune response), gelatinous (low host immune response), and suppurative types.³  

Blastomycosis
Blastomycosis is caused by Blastomyces dermatitidis, which is endemic in the Midwestern and southeastern United States where it occurs environmentally in wood and soil. Unlike many fungal infections, blastomycosis most often develops in immunocompetent hosts. Infection is usually acquired via inhalation,¹ and cutaneous disease typically is secondary to pulmonary infection. Although not common, traumatic inoculation also can cause cutaneous blastomycosis. Skin lesions include crusted verrucous nodules and plaques with elevated borders.^1,2 Histologic features include pseudoepitheliomatous hyperplasia with intraepidermal neutrophilic microabscesses (Figure 1), and a neutrophilic and granulomatous dermal infiltrate. Organisms often are found within histiocytes (quiz image) or small abscesses. The yeasts usually are 8 to 15 µm in diameter with a thick cell wall and occasionally display broad-based budding.

Chromoblastomycosis is caused by dematiaceous (pigmented) fungi, including Fonsecaea, Phialophora, Cladophialophora, and Rhinocladiella species,³ which are present in soil and vegetable debris in tropical and subtropical regions. Infection typically occurs in the foot or lower leg from traumatic inoculation, such as a thorn or splinter injury.² Histologically, chromoblastomycosis is characterized by pseudoepitheliomatous hyperplasia; suppurative and granulomatous dermatitis; and sclerotic (Medlar) bodies, which are 5 to 12 µm in diameter, round, brown, sometimes septate cells resembling copper pennies (Figure 2).²

Coccidioidomycosis is caused by Coccidioides immitis, which is found in soil in the southwestern United States. Infection most often occurs via inhalation of airborne arthrospores.² Cutaneous lesions occasionally are observed following dissemination or rarely following primary inoculation injury. They may present as papules, nodules, pustules, plaques, and ulcers, with the face being the most commonly affected site.¹ Histologically, coccidioidomycosis is characterized by pseudoepitheliomatous hyperplasia, suppurative and granulomatous dermatitis, and large spherules (up to 100 µm in diameter) containing numerous small endospores (Figure 3).

Cryptococcosis is caused by Cryptococcus neoformans, a fungus found in soil, fruit, and pigeon droppings throughout the world.^2,3 The most common route of infection is via the respiratory tract. Systemic spread and central nervous system involvement may occur in immunocompromised hosts.² Skin involvement is uncommon and may present on the head and neck with umbilicated papules, pustules, nodules, plaques, or ulcers. Histologically, Cryptococcus is a spherical yeast, often 4 to 20 µm in diameter. Replication is by narrow-based budding. A characteristic feature is a mucoid capsule, which retracts during processing, leaving a clear space around the yeast (Figure 4). When present, the mucoid capsule can be highlighted on mucicarmine or Alcian blue staining. Histologic variants of cryptococcosis include granulomatous (high host immune response), gelatinous (low host immune response), and suppurative types.³