Development of the alopecia areata scale for clinical use: Results of an academic-industry collaborative effort.

BACKGROUND: The current classification for alopecia areata (AA) does not provide a consistent assessment of disease severity. OBJECTIVE: To develop an AA severity scale based on expert experience. METHODS: A modified Delphi process was utilized. An advisory group of 22 AA clinical experts from the United States was formed to develop this AA scale. Representatives from the pharmaceutical industry provided feedback during its development. RESULTS: Survey responses were used to draft severity criteria, aspiring to develop a simple scale that may be easily applied in clinical practice. A consensus vote was held to determine the final AA severity statement, with all AA experts agreeing to adopt the proposed scale. LIMITATIONS: The scale is a static assessment intended to be used in clinical practice and not clinical trials. CONCLUSION: The final AA disease severity scale, anchored in the extent of hair loss, captures key features commonly used by AA experts in clinical practice. This scale will better aid clinicians in appropriately assessing severity in patients with this common disease.

Parakeratosis and pagetoid melanocytosis in the evaluation of dysplastic nevi and melanoma.

BACKGROUND: It is our experience that parakeratosis with pagetosis is common in early melanoma when there is no history of trauma in the anatomical site. In lesions where the differential diagnosis includes dysplastic nevus (DN) and melanoma, we hypothesize that parakeratosis may be a marker for cases in which immunohistochemistry (IHC) may identify occult pagetosis. METHODS: We performed a retrospective case-control study on cases with a histologic differential diagnosis of DN versus melanoma, including 423 cases with parakeratosis and 125 cases without parakeratosis. IHC staining (Mart-1 and/or Sox-10) was performed in all cases. The frequency of pagetosis and diagnostic upgrades in the cases versus the controls was calculated. RESULTS: The presence of parakeratosis was significantly associated with pagetosis (p < 0.0001). Diagnostic upgrades were more frequent in the cases with parakeratosis versus controls without parakeratosis (p = 0.0029). In the favored moderate DN group, 56% of cases were upgraded compared to 30% of the controls (p = 0.0017). In the favored mild DN and severe DN groups, there were more case upgrades compared to the controls (p = 0.1386, p = 0.2738). CONCLUSIONS: Parakeratosis may be a useful marker to identify lesions with occult pagetosis for which IHC would be appropriate and may result in a diagnostic upgrade.

Drug-induced psoriasiform alopecia associated with interleukin-17 inhibitor therapy.

Drug-induced psoriasiform alopecia is an increasingly recognized form of alopecia mostly reported in association with TNF-alpha inhibitors. However, drug-induced psoriasiform alopecia in association with IL-17A inhibitors has not been described. We present a 62-year-old woman with severe psoriasis who developed new psoriatic plaques on the scalp with alopecia after initiating ixekizumab (anti-IL-17A). Scalp biopsy specimens revealed a non-cicatricial alopecia with increased telogen/catagen follicles, atrophy of the sebaceous glands, peribulbar and perifollicular inflammation with frequent lymphocytes, plasma cells, eosinophils, psoriasiform dermatitis, and lack of intra-corneal or intra-epidermal neutrophils. Overall, the clinical and histopathologic findings were most compatible with a drug-induced psoriasiform alopecia in association with IL-17A inhibitor therapy. Our case shows that drug-induced psoriasiform alopecia can paradoxically occur in patients on IL-17A inhibitor therapy and contributes to the growing list of cutaneous eruptions associated with biologic agents.

Incorporation of dermoscopy improves inter-observer agreement among dermatopathologists in histologic assessment of melanocytic neoplasms.

Histopathologic assessment of melanocytic neoplasms is the current gold standard of diagnosis. However, there are well recognized limitations including inter-observer diagnostic discordance. This study aimed to determine if integrating dermoscopy with histopathology of melanocytic neoplasms impacts diagnosis and improves inter-observer agreement. We conducted a prospective cohort study in a pigmented lesion clinic. Consecutive melanocytic lesions were identified for biopsy based on atypical gross or dermoscopic features. Standardized immunohistochemistry and levels were ordered on each specimen. The cases were randomized. Three dermatopathologists blinded to the clinical impression assessed each lesion. The cases were then re-randomized and re-assessed with addition of gross clinical and dermoscopic images. Inter-rater reliability (IRR) using Fleiss' kappa statistic revealed an increase from 0.447 without to 0.496 with dermoscopy amongst all dermatopathologists. The kappa increased from 0.495 before to 0.511 with dermoscopy in separating high-grade atypia or melanoma from moderate atypia or less. In 16 of 136 cases, at least 2 of 3 dermatopathologists favored a diagnosis of melanoma only after dermoscopy. In total, the consensus grade of atypia changed in 24.3% (33/ 136) of cases thereby representing changes to excisional margins and patient follow up. This study is limited by the cohort size. Dermoscopy significantly impacts diagnosis and improves identification of early melanomas in high risk populations and improves inter-observer agreement.

Vulvar Elastosis: A Novel Diagnostic Entity.

ABSTRACT: In vulvar biopsies, we have observed histopathologic abnormalities of elastic fibers identical to solar elastosis, with thick, curled, and irregular pale grey fibers in the dermis. In severe cases, changes resemble nodular solar elastosis. We retrospectively evaluated 238 vulvar biopsies with the goal of defining and characterizing changes of vulvar elastosis. Of 238 vulvar biopsies reviewed, 107 (45%) exhibited vulvar elastosis. Patients with vulvar elastosis were older (mean = 65 years old) compared to those without (mean = 44 years old). Sixty-six (62%) were graded as mild, 27 (25%) moderate, and 14 (13%) severe. Vulvar elastosis was significantly more common in women ≥45 years old (P-value < 0.001). There was moderate correlation between age and severity (correlation coefficient = 0.55, P-value < 0.001). Vulvar elastosis was observed in a variety of inflammatory and non-inflammatory pathologies. In 5 cases, the sole pathology was vulvar elastosis presenting clinically as either a pruritic or painful white to white-yellow papule or plaque, or vulvar pain or burning without a clinical lesion. Vulvar elastosis is a novel diagnostic entity occurring in a sun-protected site and its pathogenesis may be a degenerative phenomenon possibly related to advancing age and/or hormonal changes.

Desmoplastic Melanomas Mimicking Neurofibromas.

Desmoplastic melanoma can be difficult to diagnose and on average have a significantly higher T stage at the time of diagnosis compared with conventional melanomas. Histologically, these tumors typically consist of spindle cells in a fibrous matrix. The spindle cells may display fibroblast and/or Schwann cell-like features. In this study, we describe the features of 12 cases of desmoplastic melanoma closely simulating neurofibroma. Although the spindle cells in these tumors may be indistinguishable from those of neurofibroma, features such as prominent fibroplasia (12/12), poor lateral circumscription (8/9), diffuse infiltration of subcutaneous tissue (7/9), and lymphoid aggregates (10/12) may be helpful clues to the diagnosis. No immunohistochemical markers were reliable in distinguishing neurofibroma-like desmoplastic melanomas from neurofibroma. Clinical follow-up was available in 8 cases, of which 4 were initially misdiagnosed as benign neoplasms and given no further re-excision. All 4 of these cases recurred; 2 of which showed transformation to a more aggressive phenotype.

Retrospective Cohort: Genomic Differences Between Pigmented Spindle Cell Nevi of Reed and Reed-Like Melanomas.

BACKGROUND: Some melanomas closely resemble pigmented spindle cell nevi (PSCN) of Reed histologically. The distinction of these entities is important for clinical management. A recent study showed most PSCN (78%) are fusion-driven, commonly involving NTRK3 (57%). Conversely, BRAF V600E mutations are not characteristic of PSCN but are frequent in melanoma. OBJECTIVE: In this study, we assessed clinical, histologic and genomic differences between PSCN of Reed and Reed-like melanomas (RLMs). METHODS: We performed BRAF V600E immunohistochemistry (IHC) for 18 PSCN and 20 RLM cases. All 23 benign PSCN cases previously underwent whole transcriptome and targeted DNA sequencing with a 1711 gene panel. RESULTS: We previously demonstrated the majority of PSCN (18 of 23) has chimeric fusions. Among PSCN without a chimeric fusion, BRAF mutations were common. Noncanonical BRAF mutations were identified in 2 of 5 nonfusion cases, and 1 case had a canonical BRAF mutation. Alternatively, 70% of RLM demonstrated a BRAF V600E mutation. RLM also occurred more frequently in older patients. LIMITATIONS: The overall sample size was small. CONCLUSIONS: In diagnostically challenging cases, ancillary IHC studies can assist in distinguishing PSCN from RLM. Our study suggests positive staining by IHC for BRAF V600E and older age strongly favors a diagnosis of RLM.

Dilation of Multiple Eccrine Ducts as a Highly Specific Marker for Cicatricial Alopecia.

BACKGROUND: Eccrine duct dilation (EDD) was recently described to occur more frequently in cicatricial alopecias than noncicatricial alopecias. Because single EDD can be useful in the evaluation of alopecias, we aimed to determine whether dilation of multiple eccrine duct units, or "multiple eccrine duct dilation (MEDD)," could more specifically discriminate between cicatricial and noncicatricial alopecias. METHODS: We retrospectively evaluated 611 scalp biopsies (342 cicatricial alopecias and 269 noncicatricial alopecias). RESULTS: Among cicatricial alopecias, MEDD was found in 21% (25/118) of central centrifugal cicatricial alopecia, 26% (29/109) of lichen planopilaris, 13% (10/73) of discoid lupus erythematosus, 31% (5/16) of acne keloidalis nuchae, and 26% (7/26) of folliculitis decalvans. In noncicatricial alopecias, MEDD was found in 1% (1/102) of androgenetic alopecia, 0.7% (1/150) of alopecia areata, and 0% (0/17) of telogen effluvium. In cicatricial alopecias, MEDD occurred in a significantly higher frequency (22%; 76/342) compared with noncicatricial alopecias (0.7%; 2/269) (P-value <0.0001). The presence of MEDD correlated with a diagnosis of cicatricial alopecia with 22% sensitivity and 99% specificity. MEDD also occurred more frequently in cases with moderate to severe inflammation and fibroplasia, suggesting that EDD is a reactive change secondary to the scarring processes. CONCLUSION: The presence of MEDD on scalp biopsies may be a highly specific marker of cicatricial alopecia and can aid in rendering a more accurate diagnosis. MEDD without other definitive histopathologic features of cicatricial alopecia may compel pathologists to pursue additional workup and/or raise the possibility that a cicatricial alopecia cannot be entirely excluded.

Premature Desquamation of the Inner Root Sheath in Noninflamed Hair Follicles as a Specific Marker for Central Centrifugal Cicatricial Alopecia.

BACKGROUND: Premature desquamation of the inner root sheath (PDIRS) is considered one of the distinctive features in central centrifugal cicatricial alopecia (CCCA). However, PDIRS can be seen in other alopecia subtypes, and its utility in the diagnosis of CCCA has been debated. We aimed to examine a large cohort of alopecia cases for the presence of PDIRS in association with and without inflammation to determine whether PDIRS in noninflamed follicles can be used as a specific marker of CCCA. METHODS: Retrospective analysis was performed on 501 histologically unambiguous cases of alopecia (111 of CCCA, 102 of lichen planopilaris, 62 of discoid lupus erythematosus, 16 of acne keloidalis nuchae, 27 of folliculitis decalvans, 80 of androgenetic alopecia, 97 of alopecia areata, and 6 of psoriatic alopecia). The frequency of PDIRS, including cases with and without inflammation, was determined. RESULTS: PDIRS was identified in all alopecia subtypes evaluated. When PDIRS was identified in lichen planopilaris, discoid lupus erythematosus, acne keloidalis nuchae, and alopecia areata, 100% of cases were in inflamed follicles. PDIRS in noninflamed follicles occurred in 73% (81/111) of CCCA, 33% (2/6) of psoriatic alopecia, 11% (3/27) of folliculitis decalvans, and 1% (1/97) of androgenetic alopecia. The presence of PDIRS in at least one noninflamed hair follicle correlated with a diagnosis of CCCA with a sensitivity of 73% and a specificity of 98% (P-value <0.0001). CONCLUSION: Identifying PDIRS in noninflamed hair follicles is a useful histologic feature in the evaluation of scalp biopsies and seems to be relatively specific for CCCA.

Distinct Genomic Patterns in Pigmented Epithelioid Melanocytoma: A Molecular and Histologic Analysis of 16 Cases.

Pigmented epithelioid melanocytoma (PEM) is considered an intermediate grade melanocytic lesion that is histologically indistinguishable from epithelioid blue nevi associated with Carney complex. PEM are characterized by an intradermal population of heavily pigmented epithelioid-shaped melanocytes along with some spindled and dendritic melanocytes with frequent melanophages. These melanocytic tumors occasionally involve regional lymph nodes but only rarely result in distant metastases. Recent studies have demonstrated a variable but limited number of specific genomic aberrations including protein kinase A regulatory subunit alpha (PRKAR1A), BRAF, GNAQ, and MAP2K1 mutations as well as protein kinase C alpha isoform (PRKCA) fusions. We performed an 8-year retrospective review of our database and identified 16 cases of PEM. Using targeted DNA sequencing and RNA-seq to assess 1714 cancer-related genes, we detected gene fusions involving PRKCA in 31% of cases (5/16) with 5' partners SCARB1(12q24) in 2 cases, CD63 (12q13) in 1 case, ATP2B4 (1q32) in 1 case, and MAP3K3 (17q23) in 1 case. Additional fusions were identified in TPR-NTRK1 (1/16), ALK (1/16), and MYO5A-NTRK3 (1/16). PRKCA fusion lesions tended to occur in younger-aged patients and histologic examination demonstrated sheets of monomorphic epithelioid-shaped melanocytes, moderate to high-grade nuclear atypia, and higher mitotic activity (P=0.037). Our gene panel also identified previously described mutations in PRKAR1A, GNAQ, MAP2K1, BRAF, NF1. To our knowledge, this is the largest and most comprehensive study of PEM integrating molecular data with histologic features that can be utilized in future studies for improved subclassification and prognostication of heavily pigmented melanocytic neoplasms.

The role of TERT promoter mutations in differentiating recurrent nevi from recurrent melanomas: A retrospective, case-control study.

BACKGROUND: Repigmentation at previous biopsy sites pose a significant diagnostic dilemma given clinical and histologic similarities between recurrent nevi and locally recurrent melanoma. Though common in melanoma, the role of TERT promoter mutations (TPMs) in recurrent nevi is unknown. OBJECTIVE: We investigated the role of TPMs in recurrent nevi and whether the presence of hotspot TPM distinguishes recurrent nevi from locally recurrent melanoma. We also characterized clinical and histologic features differentiating these lesions. METHODS: We analyzed 11 locally recurrent melanomas, 17 recurrent nevi, and melanoma and nevus controls to determine TPM status. We also assessed clinical and histologic features of the recurrent groups. RESULTS: Hotspot TPMs were more common in recurrent melanomas than recurrent nevi (P = .008). Recurrent melanomas were more likely to have solar elastosis (P = .0047), multilayering of melanocytes in the epidermis (P = .0221), adnexal involvement (P = .0069), and epidermal consumption (P = .0204). Recurrent nevi had intra-epidermal atypia limited to the area above the scar (P < .0001) and occurred earlier after the original biopsy (P < .0008). Solar elastosis, months to recurrence, and hotspot TPMs were independently associated with recurrent melanoma in multivariate analysis. LIMITATIONS: This was a retrospective study. CONCLUSION: Hotspot TPMs are significantly more frequent in recurrent melanomas and could serve as a diagnostic clue in histologically ambiguous cases.

Micropapular Cutaneous Sarcoidosis Reviewed.

BACKGROUND: Micropapular cutaneous sarcoidosis (MPCS) is a rare variant of sarcoidosis. Herein we review the literature and include a recent case of MPCS discussing pathogenesis, diagnosis, treatment, and prognosis. METHOD: A review was conducted using the terms "micropapular sarcoidosis" and "micropapular sarcoid." A recent case of a 50-year-old male patient with biopsy-identified MPCS was also included in the review. RESULTS: In total, 12 cases with an aggregate of 18 patients were included in the review. Presentation among all patients was consistent, with scattered, occasionally pruritic, faintly erythematous shiny white papules. Skin biopsy demonstrated noncaseating granulomas. Systemic prednisone, oxytetracycline, and hydroxychloroquine, as well as topical betamethasone, were used for therapy. CONCLUSION: In our review there does not seem to be a clear link as to the definite cause of the MPCS. While the relationships to tuberculosis and autoimmunity seem to be often emphasized, there was no clear association with either etiology.

Ewing-Like Sarcoma: A Case of a Primary Cutaneous Primitive Neuroectodermal Tumor With Atypical Immunohistochemistry and Lack of Fusion Oncogene Detection.

We present a 25-year-old male patient with a primary cutaneous primitive neuroectodermal tumor (cPNET) with unusual immunohistochemistry and lack of fusion oncogene generation. The lesion expressed CD99 and WT-1, and the histological features were consistent with cPNET. Differential diagnoses such as rhabdomyosarcoma, desmoplastic small round blue cell tumor, hematolymphoid neoplasm, neuroblastoma, and CIC-DUX round cell sarcoma were ruled out based on immunohistochemistry, genetic studies, and histology. Previous cPNET cases have been published detailing abnormal immunochemistry and genetic expression. However, to our knowledge, fusion oncogene negativity in cPNET tumors has only been reported in one other published case series. These reports, including this study, reinforce the fact that a high index of suspicion should be used when diagnosing these tumors, regardless of immunohistochemical and genetic variability. This case highlights that the typical genetic and immunohistochemical features of cPNET may be more variable than previously thought. Future studies are needed to better understand these variations of cPNET.

Immune privilege disruption in folliculotropic mycosis fungoides: investigation of major histocompatibility complex antigen expression.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is a cutaneous T-cell lymphoma mainly affecting the hair follicle, which seems to represent a place of immune privilege phenomenon. OBJECTIVES: To explore a possible role of immune privilege (IP) in FMF analyzing the major histocompatibility complex (MHC) expression. METHODS: Immunohistochemistry for HLA-G and MHC-II was performed to formalin-fixed paraffin-embedded cutaneous skin biopsies of FMF patients (n = 43), conventional mycosis fungoides (CMF; n = 13), alopecia areata (AA; n = 13), and normal scalp skin (NS; n = 12). RESULTS: HLA-G expression was lower in FMF (34%: 14/41) and CMF (18%: 2/11) groups compared to alopecia areata (92%:11/12) and normal scalp skin group (100%: 12/12). MHC-II expression in hair follicle was greater in the FMF group (18/42: 43%) compared to AA (0%) and NS (0%). HLA-G and MHC-II expression in cellular infiltrate had no difference among FMF and CMF groups and was different compared to the AA group. CONCLUSIONS: Our data support the hypothesis of disruption of immune privilege based on the lower expression of HLA-G and higher expression of MHC-II in the follicular epithelium in mycosis fungoides compared to alopecia areata and normal scalp skin. The lack of difference between FMF and CMF groups did not support the role of these molecules as a driver of folliculotropism. The expression of MHC molecules seems to be different between neoplastic and inflammatory infiltrates. The definitive significance of expression of the MHC molecules remains unclear, and more studies are necessary to fully understand the role of these molecules in cutaneous lymphomas.

Naked Hair Shafts as a Marker of Cicatricial Alopecia.

Naked hair shafts (NHS) are free-floating hair shafts devoid of surrounding epithelium, supporting structures, and/or embedded in inflammation that may result from destruction of hair follicles by scarring processes such as inflammation and fibroplasia. Extensive examination of NHS has not been performed in scalp biopsies of alopecia. We retrospectively evaluated 622 scalp biopsies of alopecia [345 cicatricial alopecias (central centrifugal cicatricial alopecia, lichen planopilaris, discoid lupus erythematosus, acne keloidalis nuchae, and folliculitis decalvans] and 277 non-cicatricial alopecias [alopecia areata, androgenic alopecia, telogen effluvium, and psoriatic alopecia)] for the presence of NHS. NHS occurred in 0.72% (2/277) of non-cicatricial alopecias (1/102 of alopecia areata, 1/150 of androgenic alopecia, 0/17 of telogen effluvium, and 0/8 of psoriatic alopecia) and 20% (72/345) of cicatricial alopecias (27/118 of central centrifugal cicatricial alopecia, 29/109 of lichen planopilaris, 2/75 of discoid lupus erythematosus, 11/16 of acne keloidalis nuchae, and 3/27 of folliculitis decalvans). The presence of NHS was significantly increased in cicatricial alopecias in comparison with non-cicatricial alopecias; P value <0.0001. Among the cicatricial alopecias, 26% (92/345) had mild inflammation and/or fibrosis, of which 9% (9/92) had NHS. There were 73% (253/345) that had moderate to severe inflammation and/or fibrosis, of which 24% (63/253) had NHS, indicating that as the severity of inflammation and fibrosis increases, so does the presence of NHS. NHS rarely occurs in non-cicatricial alopecias. This variation may result from destruction of hair follicles by the inflammatory and scarring processes. The presence of NHS may be a useful adjunctive histopathologic feature in the diagnosis of cicatricial alopecia.

Genomic Assessment of Blitz Nevi Suggests Classification as a Subset of Blue Nevus Rather Than Spitz Nevus: Clinical, Histopathologic, and Molecular Analysis of 18 Cases.

Blitz nevi/tumors are a distinct subset of melanocytic neoplasia which show mixed morphologic features of Spitz and blue nevus. Genomically, most blue nevi have GNAQ or GNA11 mutations while most Spitzoid neoplasms have either an HRAS mutation or translocations involving MET, ROS, BRAF, ALK1, NTRK1, and RET. The criteria used for the assessment of malignancy in blue and Spitzoid lesions are different, and these lesions have different prognostic markers. In this study, we assess the clinical, morphological, and genomic changes in 18 cases of Blitz nevi/tumors to better characterize this subset of neoplasms and determine their optimal genomic classification. Most lesions occurred on the extremities followed by the head and neck region typical of blue nevi. Histology showed most cases having a prominent plexiform growth pattern with cells aggregating around the adnexal structures and neurovascular bundles also typical of blue nevi. Using next generation sequencing, we detected the presence of somatic mutations in GNAQ or GNA11 in 4 of 7 cases (57%) of Blitz nevi with sufficient DNA available for sequencing. Normal skin samples in these 4 cases were sequenced to confirm that the GNAQ or GNA11 mutations were somatic mutations. All 4 cases were negative for immunohistochemical assessment for wild-type BRAF, RET, ALK, and NTRK1 and mutational analysis of HRAS was also negative in all cases. Hence, our study suggests that Blitz nevi/tumors are a distinct subset which genomically are best classified as a subset of blue nevi.

Metastatic calcinosis cutis in a patient with Hodgkin's lymphoma.

Calcinosis cutis results from the deposition of insoluble calcium salts in the skin and subcutaneous tissue. Herein, we report a case of extensive metastatic calcinosis cutis in an 18-year-old woman with stage IV Hodgkin lymphoma with skeletal involvement. With combination therapy including radiation directed at her lymphoma and diltiazem, her lesions improved dramatically. This case demonstrates the previously unreported association between calcinosis cutis and Hodgkin lymphoma.