Proliferating inverted follicular keratosis of genital skin: Case series of a challenging variant.

BACKGROUND: Inverted follicular keratosis (IFK) is a benign cutaneous epithelial tumor typically presenting as a small papule on the head and neck. We have encountered deep endophytic tumors on genital skin with some characteristics of IFK but also atypical features, raising concern for squamous cell carcinoma (SCC). METHODS: Four such tumors were identified in our database. Histopathologic analysis and ancillary studies were performed. RESULTS: All patients were young women who presented with a solitary 0.5-1.0 cm lesion on the vulva, perineum, or inner buttock. Each showed a squamous proliferation arising from the epidermis, with endophytic growth that was deep and bulbous but not infiltrative. The tumor lobules contained eosinophilic keratinocytes, forming numerous squamous eddies. Small irregular spaces and dyskeratotic cells were frequently found. Nuclear pleomorphism was minimal to absent. All demonstrated wild-type p53 expression and lack of p16 block positivity. In situ hybridizations for human papillomavirus were negative. None of the three cases with follow-up data showed evidence of recurrence. CONCLUSIONS: The absence of infiltrative growth or significant pleomorphism, the presence of numerous squamous eddies, the reassuring immunoprofile, and the lack of evidence of recurrence support a variant of IFK and speak against SCC. We propose the term "proliferating IFK" to highlight the florid squamous proliferation. Recognition of this unusual variant would avoid overdiagnosis of SCC.

Clinical and Histopathologic Spectrum of Toxic Erythema of Chemotherapy: A Series of 56 Cases From a Single Institution.

INTRODUCTION: Although many individual cases and small series of toxic erythema of chemotherapy (TEC) have been described, the full spectrum of findings is not well understood. OBJECTIVE: To provide a comprehensive review of the clinical and histopathologic features of TEC with an emphasis on novel histopathologic findings. METHODS: We searched our electronic medical record for "toxic erythema of chemotherapy" or "neutrophilic eccrine hidradenitis." Fifty-six cases meeting clinical and histopathologic criteria were identified. The electronic medical record and accompanying hematoxylin and eosin-stained slides were retrospectively reviewed. RESULTS: The clinical findings were heterogeneous but included classic presentations such as intertriginous eruptions (34%) and acral erythema (25%). The most common histopathologic features were apoptotic keratinocytes (95%), basal vacuolar change (91%), and epithelial dysmaturation (79%). Eccrine squamous syringometaplasia was seen in over half of the cases (33/56; 59%), whereas neutrophilic eccrine hidradenitis was uncommon (16%). Interestingly, many cases showed prominent interstitial histiocytes (55%). Other novel findings included irregular orthohyperkeratosis (23%), irregular epidermal hyperplasia (14%), and acantholysis (9%). LIMITATIONS: As a retrospective study, it is subject to information bias. CONCLUSION: This is the largest reported series of TEC. In addition to confirming previously reported features, we identify novel histopathologic findings to add to the spectrum of TEC.

Characterization of T-Helper Immune Phenotype in Symmetrical Drug-Related Intertriginous and Flexural Exanthema (SDRIFE) Endorses a Delayed-Type Hypersensitivity Reaction.

ABSTRACT: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a cutaneous drug eruption with a characteristic distribution of erythema on the gluteal/inguinal region and intertriginous areas with unclear pathogenesis. In this study, we aimed to characterize the T-helper immune phenotype in SDRIFE in comparison with psoriasis and eczema to further the understanding of the pathophysiology and immune response of this rare disorder. Immunohistochemical staining was performed on 9 skin biopsies each from SDRIFE, psoriasis, and eczema using immunohistochemistry for CD3 and dual CD4/T-bet, CD4/GATA3, and CD4/RORC to quantify the percentage of Th1, Th2, and Th17 cells, respectively. A significant difference was detected in the average percentage of Th1 between all 3 groups with the highest percentage of Th1 cells seen in psoriasis, followed by SDRIFE and eczema. SDRIFE showed significantly lower Th2 expression as compared to both psoriasis and eczema. There was a trend towards a higher average percentage of Th17 in psoriasis and SDRIFE, and the ratio of Th17:Th2 was significantly higher in samples of SDRIFE compared with both eczema and psoriasis. The findings characterize SDRIFE as a Th1 and possibly Th17-driven process, which could inform future therapeutic options and substantiate the model of SDRIFE as a delayed-type hypersensitivity reaction.

Epidermal nevi and epidermolytic hyperkeratosis: A review of cases, highlighting indications for biopsy and genetics referral.

Epidermal nevi are common benign cutaneous hamartomas that may rarely demonstrate histopathologic evidence of epidermolytic hyperkeratosis (EHK), representing cutaneous mosaicism for pathogenic keratin variants. Rarely, individuals with linear epidermal nevi transmit to their children the inherited form of EHK, also known as epidermolytic ichthyosis, characterized by generalized erythema, blistering, and scaling at birth evolving to widespread hyperkeratosis. We present an updated review of reported cases of linear epidermal nevi with EHK exhibiting transmission of epidermolytic ichthyosis to guide important considerations in the care of individuals with epidermal nevi. Clinical characteristics of linear epidermal nevi do not reliably predict the presence of EHK. All reported cases of transmission to offspring have occurred in individuals with linear epidermal nevi involving more than one anatomic area suggesting increased reproductive risk with involvement of two or more anatomic sites. Therefore, genetics consultation is recommended for these individuals with biopsy-confirmed EHK. For individuals with smaller areas of epidermal nevus involvement, the implications are less well known, though genetics consultation may still be considered for those interested in further discussion of general reproductive risk.

Multiplex Immunohistochemistry and Immunofluorescence: A Practical Update for Pathologists.

Our understanding of the biology and management of human disease has undergone a remarkable evolution in recent decades. Improved understanding of the roles of complex immune populations in the tumor microenvironment has advanced our knowledge of antitumor immunity, and immunotherapy has radically improved outcomes for many advanced cancers. Digital pathology has unlocked new possibilities for the assessment and discovery of the tumor microenvironment, such as quantitative and spatial image analysis. Despite these advances, tissue-based evaluations for diagnosis and prognosis continue to rely on traditional practices, such as hematoxylin and eosin staining, supplemented by the assessment of single biomarkers largely using chromogenic immunohistochemistry (IHC). Such approaches are poorly suited to complex quantitative analyses and the simultaneous evaluation of multiple biomarkers. Thus, multiplex staining techniques have significant potential to improve diagnostic practice and immuno-oncology research. The different approaches to achieve multiplexed IHC and immunofluorescence are described in this study. Alternatives to multiplex immunofluorescence/IHC include epitope-based tissue mass spectrometry and digital spatial profiling (DSP), which require specialized platforms not available to most clinical laboratories. Virtual multiplexing, which involves digitally coregistering singleplex IHC stains performed on serial sections, is another alternative to multiplex staining. Regardless of the approach, analysis of multiplexed stains sequentially or simultaneously will benefit from standardized protocols and digital pathology workflows. Although this is a complex and rapidly advancing field, multiplex staining is now technically feasible for most clinical laboratories and may soon be leveraged for routine diagnostic use. This review provides an update on the current state of the art for tissue multiplexing, including the capabilities and limitations of different techniques, with an emphasis on potential relevance to clinical diagnostic practice.

Utility of GLI1 RNA Chromogenic in Situ Hybridization in Distinguishing Basal Cell Carcinoma From Histopathologic Mimics.

Basal cell carcinoma (BCC) is the most common human malignancy and is a leading cause of nonmelanoma skin cancer-related morbidity. BCC has several histologic mimics which may have treatment and prognostic implications. Furthermore, BCC may show alternative differentiation toward a variety of cutaneous structures. The vast majority of BCCs harbor mutations in the hedgehog signaling pathway, resulting in increased expression of the GLI family of transcription factors. GLI1 immunohistochemistry has been shown to discriminate between several tumor types but demonstrates high background signal and lack of specificity. In this study, we evaluated the utility of GLI1 RNA chromogenic in situ hybridization (CISH) as a novel method of distinguishing between BCC and other epithelial neoplasms. Expression of GLI1 by RNA CISH was retrospectively evaluated in a total of 220 cases, including 60 BCCs, 37 squamous cell carcinomas (SCCs) including conventional, basaloid, and human papillomavirus infection (HPV)-associated tumors, 16 sebaceous neoplasms, 10 Merkel cell carcinomas, 58 benign follicular tumors, and 39 ductal tumors. The threshold for positivity was determined to be greater than or equal to 3 GLI1 signals in at least 50% of tumor cells. Positive GLI1 expression was identified in 57/60 BCCs, including metastatic BCC, collision lesions with SCC, and BCCs with squamous, ductal, or clear cell differentiation or with other unusual features compared to 1/37 SCCs, 0/11 sebaceous carcinomas, 0/5 sebaceomas, 1/10 Merkel cell carcinomas, 0/39 ductal tumors, and 28/58 follicular tumors. With careful evaluation, GLI1 RNA CISH is highly sensitive (95%) and specific (98%) in distinguishing between BCC and nonfollicular epithelial neoplasms. However, GLI1 CISH is not specific for distinguishing BCC from most benign follicular tumors. Overall, detection of GLI1 RNA by CISH may be a useful tool for precise classification of histologically challenging basaloid tumors, particularly in the setting of small biopsy specimens, metaplastic differentiation, or metastatic disease.

Detection of antibody-coated Mucor in skin biopsy by direct immunofluorescence.

Cutaneous mucormycosis may be caused by direct inoculation or hematogenous spread of mucormycetes in immunocompromised patients. Skin biopsy is characterized by a deep fungal infection with frequent angioinvasion. The fungal hyphae can usually be identified on H&E stain. We report a case of cutaneous angioinvasive mucormycosis in which the fungi were also visualized on direct immunofluorescence. A 57-year-old patient with relapsed myelodysplastic syndrome status-post allogeneic hematopoietic cell transplant, diabetes mellitus, and graft-versus-host disease presented with painful, palpable, dark-red to violaceous retiform purpuric plaques. Light microscopy of punch biopsy revealed numerous broad, ribbon-like, pauci-septate hyphae in the dermis with angioinvasion, consistent with mucormycosis. Direct immunofluorescence performed on a concurrent biopsy to exclude immune complex vasculitis showed smooth IgG, IgA (weak), IgM (faint), and C3 deposition on the hyphal structures, compatible with antibody-coated fungi. Tissue culture subsequently confirmed Mucor species. Although mucormycosis was readily diagnosable on routine light microscopy in this case, recognition of the unique phenomenon of antibody-coated fungi can be crucial when the invasive fungi are sparse or only present in the direct immunofluorescence specimen.

CD30 expression in cutaneous B-cell lymphomas.

INTRODUCTION: CD30 expression has been infrequently described in cutaneous B-cell lymphomas (CBCLs). We examined CD30 expression in reactive lymphoid hyperplasia (RLH) and CBCL and correlated expression with clinicopathologic features. METHODS: CD30 was examined in 82 CBCL patients and 10 RLH patients that had been evaluated in our cutaneous lymphoma clinics. The CBCL patients included: primary cutaneous follicle center lymphoma (PCFCL), Grade 1/2 systemic/nodal follicular lymphoma (SFL); primary cutaneous marginal zone lymphoma/lymphoproliferative disorder (PCMZL/LPD); systemic marginal zone lymphoma (SMZL); primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT); and extracutaneous/systemic diffuse large B-cell lymphoma (eDLBCL). We scored CD30 expression for intensity and extent and related CD30 expression to age at first diagnosis, sex, site of biopsy, clinical appearance, extracutaneous involvement, multiple cutaneous lesions, B-symptoms, lymphadenopathy, positive positron emission tomography/computed tomography (PET/CT), elevated lactate dehydrogenase (LDH), and positive bone marrow biopsy. RESULTS: CD30 expression was identified in 35% of CBCL, ranging from few, weak, scattered cells to strong and diffuse expression. It was most common in PCFCL and was not expressed in PCDLBCL-LT. Rare PCFCL expressed strong, diffuse CD30. Some cases of PCMZL/LPD, SMZL, FL, and RLH showed scattered, strongly positive cells. CD30 expression in CBCL was associated with favorable clinical features: younger age, negative PET/CT, and an LDH within normal limits. CONCLUSIONS: CD30 may be expressed in CBCL, possibly causing diagnostic confusion. CD30 expression was most commonly identified in PCFCL and is associated with favorable clinical features. In cases with strong and diffuse expression, CD30 could be a therapeutic target.

ERG amplification is a secondary recurrent driver event in myeloid malignancy with complex karyotype and TP53 mutations.

ERG is a transcription factor encoded on chromosome 21q22.2 with important roles in hematopoiesis and oncogenesis of prostate cancer. ERG amplification has been identified as one of the most common recurrent events in acute myeloid leukemia with complex karyotype (AML-CK). In this study, we uncover three different modes of ERG amplification in AML-CK. Importantly, we present evidence to show that ERG amplification is distinct from intrachromosomal amplification of chromosome 21 (iAMP21), a hallmark segmental amplification frequently encompassing RUNX1 and ERG in a subset of high-risk B-lymphoblastic leukemia. We also characterize the association with TP53 aberrations and other chromosomal aberrations, including chromothripsis. Lastly, we show that ERG amplification can initially emerge as subclonal events in low-grade myeloid neoplasms. These findings demonstrate that ERG amplification is a recurrent secondary driver event in AML and raise the tantalizing possibility of ERG as a therapeutic target.

Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel. A subset was further characterized by transcriptional profiling and immunohistochemistry. In 6 of 7 MCC-SCCIS pairs there was highly significant mutational overlap including shared TP53 and/or RB1 mutations. In some cases, oncogenic events previously implicated in MCC (MYCL gain, MDM4 gain, HRAS mutation) were detected in both components. Although FBXW7 mutations were enriched in MCC, no gene mutation was unique to the MCC component across all cases. Transcriptome analysis identified 2736 differentially expressed genes between MCC and SCCIS. Genes upregulated in the MCC component included Polycomb repressive complex targets; downregulated transcripts included epidermal markers, and immune genes such as HLA-A. Immunohistochemical studies revealed increased expression of SOX2 in the MCC component, with diminished H3K27Me3, Rb, and HLA-A expression. In summary, MCC-SCCIS pairs demonstrate clonal relatedness. The shift to neuroendocrine phenotype is associated with loss of Rb protein expression, decrease in global H3K27Me3, and increased expression of Merkel cell genes such as SOX2. Our findings suggest an epidermal origin of MCC in this setting, and to our knowledge provide the first molecular evidence that intraepithelial squamous dysplasia may represent a direct precursor for small cell carcinoma.

Cutaneous manifestations of lupus erythematosus: a practical clinicopathological review for pathologists.

Accurate diagnosis of connective tissue diseases is often challenging, and relies upon careful correlation between clinical and histopathological features, direct immunofluorescence studies and laboratory work-up. Lupus erythematosus (LE) is a prototype of connective tissue disease with a variety of cutaneous and systemic manifestations. Microscopically, cutaneous LE is classically characterised by an interface dermatitis although other histopathological patterns also exist, depending upon the clinical presentation, location and chronicity of the skin lesions. In this article, we review the clinical, serological, histopathological and direct immunofluorescence findings in LE-specific and LE non-specific skin lesions, with an emphasis upon lesser-known variants, newly described features and helpful ancillary studies. This review will guide general pathologists and dermatopathologists in accurately diagnosing and subclassifying cutaneous LE.

PRAME expression in spindle cell melanoma, malignant peripheral nerve sheath tumour, and other cutaneous sarcomatoid neoplasms: a comparative analysis.

Diagnosis of spindle cell/sarcomatoid melanoma may be challenging due to frequent loss of expression of melanocytic marker(s) and histomorphologic resemblance to various mesenchymal tumours, particularly malignant peripheral nerve sheath tumour (MPNST). Overexpression of PReferentially expressed Antigen in MElanoma (PRAME) supports a diagnosis of melanoma when evaluating challenging melanocytic tumours. PRAME expression in MPNST and other cutaneous sarcomatoid neoplasms, however, has not been well characterised. We aimed to determine the utility of PRAME immunostain in distinguishing spindle cell melanoma from MPNST and other sarcomatoid mimics. PRAME expression was scored by extent (0 to 4+) and intensity (0 to 3) of staining. A strong positive correlation was observed between the extent and intensity scores (r = 0.84). An extent score of 4+, defined by staining in 76-100% of tumour cells, was seen in 56% (23/41) of spindle cell melanomas, 18% (7/38) of MPNSTs, 15% (4/27) of cutaneous sarcomatoid squamous cell carcinomas (SCCs), 33% (5/15) of poorly differentiated cutaneous angiosarcomas, 12% (4/33) of atypical fibroxanthomas (AFXs), 4% (1/25) of pleomorphic dermal sarcomas (PDSs), and none (0/16) of the high-grade cutaneous leiomyosarcomas. A significant difference was found between spindle cell melanoma and all other examined sarcomatoid neoplasms except angiosarcoma. While diffuse (and often strong) PRAME expression is more frequently observed in spindle cell melanoma than MPNST, sarcomatoid SCC, AFX, PDS, and high-grade leiomyosarcoma, its limited sensitivity and specificity caution against its use as a standalone diagnostic marker. PRAME may complement other epigenetic or lineage-specific markers and should only be used as part of an immunohistochemical panel when evaluating these sarcomatoid neoplasms.

p53/CK17 Dual Stain Improves Accuracy of Distinction Between Differentiated Vulvar Intraepithelial Neoplasia and Its Mimics.

Accurate diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN) is challenging, in part due to the sometimes subtle nature of its atypia. Many dVIN lesions demonstrate aberrant p53 staining; however, staining patterns overlap between dVIN and benign/reactive entities. We evaluate a p53/CK17 dual stain in an initial cohort of dVIN (n=30), benign vulvar skin (n=5), lichen sclerosus (LS, n=10), lichen simplex chronicus (LSC, n=10), and pseudoepitheliomatous hyperplasia (PEH, n=10). In the initial cohort, aberrant p53 staining was seen only in dVIN (50%, 15/30). Equivocal p53 staining patterns were seen in dVIN (37%, 11/30), LS (50%, 5/10), LSC (40%, 4/10), and PEH (40%, 4/10). All 30 dVIN cases were positive for CK17 (strong partial-thickness or full-thickness staining), but positive CK17 staining was also seen in LS (70%, 7/10), LSC (50%, 5/10), and PEH (100%, 10/10). In the initial cohort, the combination of aberrant p53 and positive CK17 was seen only for dVIN (50%, 15/30). Forty cases of LS with known follow-up (20 with progression to dVIN, 20 without) were stained to assess prognostic value. Three LS cases showed aberrant p53 staining with CK17 positivity; all progressed to dVIN. Equivocal p53 staining and CK17 positivity were seen in cases with and without progression. The p53/CK17 dual stain is more diagnostically useful than either stain alone. Negative/focal staining for CK17 argues against a diagnosis of dVIN, while aberrant p53 staining with CK17 positivity strongly supports the diagnosis.

Pigmented Purpuric Dermatosis of the Hand: Clinicopathologic Analysis of Six Cases With Review of the Literature.

ABSTRACT: Pigmented purpuric dermatosis (PPD) is a group of skin disorders characterized by red, brown, or golden macules and patches with cayenne pepper-like spots. Classic histopathologic features include a perivascular lymphocytic infiltrate with associated erythrocyte extravasation and hemosiderin deposition. Although PPD most commonly affects the lower extremities, upper extremity involvement has been infrequently reported. Cases involving the hands are particularly rare. We present 6 new cases of PPD involving the hand and review 17 previously reported cases in the literature. All cases in our series were unilateral and localized to the dorsum of the hand. PPD was considered clinically in only 2 of these cases. Histopathologic examination revealed hallmark features of PPD, namely a superficial perivascular lymphocytic infiltrate and extravasated erythrocytes. Previous reports of PPD involving the hand described concurrent involvement of other anatomic sites in most cases; only 4 cases (24%) were confined to the hands. Histopathologic descriptions of these reported cases were compatible with PPD. In sum, our series describes a unique and rare clinical presentation of PPD confined to the unilateral dorsal hand. Because of the unusual presentation, biopsy is often required for accurate diagnosis.

Microsecretory Adenocarcinoma of the Ear Canal: Novel Cutaneous Analog of a Salivary Gland Neoplasm.

ABSTRACT: Microsecretory adenocarcinoma (MSA) of the salivary gland is a new entity recently added to the World Health Organization Classification of Head and Neck Tumors. This tumor is characterized by a recurrent MEF2C-SS18 translocation. We present a nodular tumor confined to the dermis of the ear canal of a 44-year-old patient, which demonstrated classic histopathologic features and molecular alteration of MSA. Specifically, the tumor was composed of numerous tubules and microcysts filled with abundant basophilic mucinous secretion and associated with a fibromyxoid stroma. The tumor cells were diffusely positive for CK7 and SOX10 and variably positive for S100 and p63. Breakapart fluorescence in situ hybridization for SS18 confirmed rearrangement of this gene. Together, these findings support a primary cutaneous MSA, presumably arising from ceruminous glands of the ear canal. Based on current knowledge of its salivary gland counterpart, cutaneous MSA is expected to be locally invasive but unlikely to recur or metastasize on complete excision.

PRAME Expression in Junctional Melanocytic Proliferations of the Conjunctiva: A Potential Biomarker for Primary Acquired Melanosis/Conjunctival Melanocytic Intraepithelial Lesions.

ABSTRACT: Conjunctival melanocytic proliferations are diagnostically challenging, often complicated by small specimen size, and are separated into 3 broad categories. The first group includes benign nevi and primary acquired melanosis (PAM) without atypia. The second group includes junctional melanocytic proliferations with a risk of progression to invasive melanoma (PAM with atypia). The last category is conjunctival melanoma, of which 65% of tumors arise in the setting of PAM with atypia. Preferentially expressed antigen in melanoma (PRAME) immunohistochemistry has been widely adopted to differentiate cutaneous nevi and melanoma. However, there are limited studies on its utility in the evaluation of conjunctival melanocytic proliferations with little data regarding its potential utility in stratifying PAM. Twenty-eight clinically annotated cases (14 PAM without atypia and 14 PAM with atypia) were retrospectively evaluated with PRAME/MART-1 duplex immunohistochemistry and were assigned the commonly used PRAME immunoreactivity score: 0 for no staining, 1+ for 1%-25% of cells positive, 2+ for 26%-50%, 3+ for 51%-75%, and 4+ for >75%. PAM without atypia showed low (0-3+) PRAME expression in 14 of 14 cases (100%). PAM with atypia showed strong and diffuse (4+) PRAME expression in 12 of 14 cases (86.7%). Seven of eight (87.5%) PAM with severe atypia, 4 of 4 PAM (100%) with moderate atypia, and 1 of 2 PAM (50%) with mild atypia showed 4+ PRAME expression. In addition, all 5 cases that recurred or progressed (all classified as PAM with atypia) showed 4+ PRAME expression. Although additional larger studies are needed, PRAME seems to be a useful adjunct in evaluating junctional melanocytic proliferations of the conjunctiva.

PRAME Expression in Challenging Dermal Melanocytic Neoplasms and Soft Tissue Tumors With Melanocytic Differentiation.

ABSTRACT: Preferentially expressed antigen in melanoma (PRAME) is an immunohistochemical biomarker that is diffusely expressed in most cutaneous melanomas and is negative in most benign nevi. Histologically challenging dermal melanocytic neoplasms, such as cellular blue nevi (CBN) and deep penetrating nevi (DPN), and soft tissue tumors with melanocytic differentiation, such as clear cell sarcoma and perivascular epithelioid cell tumor, may resemble primary or metastatic melanoma. PRAME immunohistochemistry (IHC) was applied to archived formalin-fixed, paraffin-embedded specimens of various dermal melanocytic neoplasms and soft tissue neoplasms with melanocytic differentiation. Staining was graded based on the percentage of melanocytes labeled (0-4+ as previously reported). The gold standard was final pathologic diagnosis using histologic, immunophenotypic, and in some cases molecular findings. Fifty-four cases were evaluated. 62.5% (5/8) of blue nevus-like melanomas and 50% (1/2) of DPN-like melanomas were PRAME positive (4+). Of the other tumors, 100% (20/20) of CBN (including 1 atypical CBN with borderline features); 100% (12/12) of DPN, combined DPN, or borderline DPN; 88.9% (8/9) of perivascular epithelioid cell tumors; and 100% (3/3) of clear cell sarcoma were PRAME negative (0-2+). Within the borderline categories specifically, all 8 tumors (1 borderline CBN and 7 borderline DPN) showed low (0-2+) PRAME expression. Overall, the sensitivity for melanoma in this context was 60%, with a specificity of 97.7%. Although our sample size is limited, the results suggest that IHC staining for PRAME may be useful in supporting a diagnosis of melanoma in the setting of challenging dermal melanocytic neoplasms and other epithelioid neoplasms with melanocytic differentiation. However, PRAME IHC lacks sensitivity in this context.

Vismodegib for Preservation of Visual Function in Patients with Advanced Periocular Basal Cell Carcinoma: The VISORB Trial.

BACKGROUND: Basal cell carcinoma (BCC) is a common skin cancer often curable by excision; however, for patients with BCC around the eye, excision places visual organs and function at risk. In this article, we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision-related outcomes in patients with orbital and extensive periocular BCC (opBCC). MATERIALS AND METHODS: In this open-label, nonrandomized phase IV trial, we enrolled patients with globe- and lacrimal drainage system-threatening opBCC. To assess visual function in the context of invasive periorbital and lacrimal disease, we used a novel Visual Assessment Weighted Score (VAWS) in addition to standard ophthalmic exams. Primary endpoint was VAWS with a score of 21/50 (or greater) considered successful, signifying globe preservation. Tumor response was evaluated using RECIST v1.1. Surgical specimens were examined histologically by dermatopathologists. RESULTS: In 34 patients with opBCC, mean VAWS was 44/50 at baseline, 46/50 at 3 months, and 47/50 at 12 months or postsurgery. In total, 100% of patients maintained successful VAWS outcome at study endpoint. Compared with baseline, 3% (95% confidence interval [CI], 0.1-15.3) experienced major score decline (5+ points), 14.7% (95% CI, 5 to 31.1) experienced a minor decline (2-4 points), and 79.4% experienced a stable or improved score (95% CI, 62.1-91.3). A total of 56% (19) of patients demonstrated complete tumor regression by physical examination, and 47% (16) had complete regression by MRI/CT. A total of 79.4% (27) of patients underwent surgery, of which 67% (18) had no histologic evidence of disease, 22% (6) had residual disease with clear margins, and 11% (3) had residual disease extending to margins. CONCLUSION: Vismodegib treatment, primary or neoadjuvant, preserves globe and visual function in patients with opBCC. Clinical trail identification number.NCT02436408. IMPLICATIONS FOR PRACTICE: Use of the antihedgehog inhibitor vismodegib resulted in preservation of end-organ function, specifically with regard to preservation of the eye and lacrimal apparatus when treating extensive periocular basal cell carcinoma. Vismodegib as a neoadjuvant also maximized clinical benefit while minimizing toxic side effects. This is the first prospective clinical trial to demonstrate efficacy of neoadjuvant antihedgehog therapy for locally advanced periocular basal cell carcinoma, and the first such trial to demonstrate end-organ preservation.

Immunohistochemical expression of PAX8, PAX2, and cytokeratin in melanomas.

BACKGROUND: Deviations from the classic melanocytic immunophenotype in melanoma can present a diagnostic challenge. PAX8 and PAX2 are common markers for renal or Müllerian differentiation. While most PAX8+ or PAX2+ carcinomas are seldom confused with melanoma, some cases may show a more ambiguous immunophenotype, especially when MiTF family altered renal cell carcinoma (MiTF-RCC) is in the differential diagnosis. Neither PAX8 nor PAX2 expression has been reported in melanoma to date. We aimed to better characterize PAX8, PAX2, and cytokeratin immunoreactivity in a large series of melanomas. METHODS: Tissue microarrays consisting of 263 melanomas were immunostained for PAX8, PAX2, and cytokeratin and graded by an h-score. RESULTS: PAX8 expression was seen in 7.9% of melanomas and was significantly associated with spindle cytomorphology. PAX2 was positive in one (0.4%) melanoma. Cytokeratin positivity was seen in three (1.2%) cases and was associated with metastases. CONCLUSIONS: PAX8 is expressed in a subset of melanomas and may be strong/extensive. As PAX8 positivity does not exclude a diagnosis of melanoma, it should be used in conjunction with other immunohistochemical markers, such as cytokeratin and PAX2, when melanoma, MiTF-RCC, and other PAX8+ tumors are in the differential diagnosis.

Immunophenotypic switch in cutaneous T-cell lymphoma: A series of three cases and review of the literature.

Primary cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variable clinical behavior. Immunophenotypic switch (IS) is a phenomenon that occurs during lymphoma progression and is defined by an alteration in the immunophenotypic expression of a tumor with retention of its genotypic signature. This has been well-recognized in hematopoietic neoplasms; however, it has been rarely reported in CTCL and its clinical implications are not well understood. We present the clinical, histopathologic, immunophenotypic, and genetic findings of three cases of CTCL that demonstrated IS post treatment with variable outcomes. We add our cases to the small number previously reported to increase awareness of this phenomenon and its diagnostic challenge.