Squamoid Eccrine Ductal Carcinoma Displays Ultraviolet Mutations and Intermediate Gene Expression Relative to Squamous Cell Carcinoma, Microcystic Adnexal Carcinoma, and Porocarcinoma.

Squamoid eccrine ductal carcinoma is a rare infiltrative tumor with morphologic features intermediate between squamous cell carcinoma (SCC) and sweat gland carcinomas such as microcystic adnexal carcinoma. Although currently classified as a sweat gland carcinoma, it has been debated whether squamoid eccrine ductal carcinoma is better classified as a variant of SCC. Furthermore, therapeutic options for patients with advanced disease are lacking. Here, we describe clinicopathologic features of a cohort of 15 squamoid eccrine ductal carcinomas from 14 unique patients, with next-generation sequencing DNA profiling for 12 cases. UV signature mutations were the dominant signature in the majority of cases. TP53 mutations were the most highly recurrent specific gene alteration, followed by mutations in NOTCH genes. Recurrent mutations in driver oncogenes were not identified. By unsupervised comparison of global transcriptome profiles in squamoid eccrine ductal carcinoma (n = 7) to SCC (n = 10), porocarcinoma (n = 4), and microcystic adnexal carcinoma (n = 4), squamoid eccrine ductal carcinomas displayed an intermediate phenotype between SCC and sweat gland tumors. Squamoid eccrine ductal carcinoma displayed significantly higher expression of 364 genes (including certain eccrine markers) and significantly lower expression of 525 genes compared with other groups. Our findings support the classification of squamoid eccrine ductal carcinoma as a carcinoma with intermediate features between SCC and sweat gland carcinoma.

Acantholytic Dyskeratoses of the Vulva: Clinicopathologic Characterization of 16 Cases and Review of the Literature.

The vulva and perineum are rarely involved by acantholytic dyskeratoses, including Hailey-Hailey disease, Darier disease, papular acantholytic dyskeratosis of the genitocrural area, acantholytic dyskeratotic acanthoma, and warty dyskeratoma. These entities show broad histomorphologic overlap, generally requiring clinical correlation for definitive classification. This institutional series aims to better characterize vulvar acantholytic dyskeratoses and provide a practical literature review and diagnostic aid for gynecologic pathologists. Our institutional archives contained 16 vulvar acantholytic dyskeratoses diagnosed between 1990 and 2023. Affected patients were 36 to 79 (mean, 58) years old and presented with one or more asymptomatic (n = 9) or pruritic (n = 6) lesions involving the vulva (predominantly the labia majora), with additional perineal involvement in 2. Four patients have known Hailey-Hailey disease. Eleven cases comprised singular, raised, erythematous, or skin-colored papules, measuring 0.2 to 0.6 (mean, 0.3) cm. Two patients had oligofocal (both with known Hailey-Hailey disease) vulvar lesions, and 2 had multifocal vulvar lesions (one with known Hailey-Hailey disease). Histologically, all showed acantholysis and dyskeratoses (abundant in 8, focal in 8, with corps ronds generally more conspicuous than corps grains). Additional features included suprabasal clefting (n = 14), dermal papillomatosis (n = 12), and acanthosis (n = 8). Adnexal involvement was rare (n = 1). No histologic features reliably distinguished sporadic versus syndromic acantholytic dyskeratoses. Sporadic lesions were cured by local excision. Patients with Hailey-Hailey disease were variably responsive to corticosteroids. Neither our series nor the literature indicate a significant correlation between sporadic or syndromic acantholytic dyskeratosis and squamous cell carcinoma. Important differential diagnoses include pemphigus vulgaris and pemphigus vegetans, for which direct immunofluorescence may be performed, when indicated.

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.

Cutaneous sarcoidosis mimicking pigmented purpuric dermatosis.

Sarcoidosis is a systemic inflammatory disorder characterized by the formation of non-caseating granulomas. Cutaneous involvement of sarcoidosis is common and has a wide variety of clinical presentations. Herein, we present a case of cutaneous sarcoidosis mimicking pigmented purpuric dermatosis (PPD) in a 26-year-old female treated with topical tofacitinib cream and a literature review of all other reported cases of cutaneous sarcoidosis with PPD-like features.

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.

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.

Spindle Cell/Pleomorphic Lipoma With Trichodiscoma-like Epithelial Hyperplasia Mimicking Atypical Fibroxanthoma/Pleomorphic Dermal Sarcoma.

ABSTRACT: A 58-year-old man presented with a lesion on the nose suspicious for basal cell carcinoma. An initial biopsy specimen reviewed at an outside institution showed a cytologically atypical spindle cell proliferation that lacked expression of cytokeratins or melanocytic markers. The resulting differential diagnosis included atypical fibroxanthoma and pleomorphic dermal sarcoma. Histopathologic examination of the excision specimen at our institution revealed an intradermal pleomorphic and spindle cell tumor which extended into underlying skeletal muscle. The tumor was associated with a fibromyxoid stroma, scattered adipocytes, and hyperplastic folliculosebaceous epithelium at the periphery. The pleomorphic tumor cells showed hyperchromatic nuclei with smudgy chromatin, and no mitotic activity was detected. Overall, the cellularity was less than would be expected for atypical fibroxanthoma/pleomorphic dermal sarcoma. Furthermore, the tumor cells were strongly positive for CD34 and showed diffuse loss of retinoblastoma protein by immunohistochemistry. Consequently, a diagnosis of benign CD34-positive pleomorphic spindle cell tumor was rendered, with features overlapping between spindle cell/pleomorphic lipoma and trichodiscoma. Subsequent single-nucleotide pleomorphism array testing revealed heterozygous loss of chromosome 13q in a region that spanned the RB1 locus and copy number loss at 16q, favoring that the proliferation in fact represents a spindle cell/pleomorphic lipoma with trichodiscoma-like epithelial induction. This case highlights an important diagnostic pitfall that may be avoided by recognizing characteristic architectural and cytologic features of this spectrum of lesions.

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.

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.

MYC gene amplification by fluorescence in situ hybridization and MYC protein expression by immunohistochemistry in the diagnosis of cutaneous angiosarcoma: Systematic review and appropriate use criteria.

BACKGROUND: Secondary angiosarcoma (AS) most commonly follows breast cancer and includes postirradiation AS (PRAS) and lymphedema-associated AS. The frequent amplification of MYC (8q24.21) in secondary AS and the rising incidence of PRAS and atypical vascular lesions (AVLs) have prompted interest in the diagnostic and prognostic utility of MYC in AS. METHODS: Retrospective series with ≥2 cases of cutaneous AS and describing the use of fluorescence in situ hybridization (FISH) for MYC amplification or immunohistochemistry (IHC) for MYC overexpression were included. RESULTS: Sixteen studies met inclusion criteria. Overall, 93% of cases evaluated by FISH and IHC were concordant. The sensitivity of FISH in primary AS was only 6.8%, and protein overexpression occurred without amplification in sun-damaged skin. FISH and IHC were over 78% sensitive in secondary AS but negative in over 98% of AVLs. MYC amplification and FLT4 coamplification were associated with shorter overall survival in secondary AS. CONCLUSION: FISH for MYC amplification and IHC for MYC overexpression are useful in distinguishing PRAS from AVLs and may also have prognostic value in secondary AS. In contrast, these methods have little diagnostic or prognostic value in primary AS and should not be used to distinguish primary AS from benign vascular neoplasms.

Primary cutaneous malignant perivascular epithelioid cell tumor: Case of a rare tumor with review of the literature.

Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with characteristic epithelioid or spindled cytomorphology that typically grow around blood vessels. These tumors are phenotypically and immunohistochemically distinct, expressing markers of both melanocytic and smooth muscle differentiation. Herein, we describe a case of histopathologically malignant cutaneous PEComa without metastatic spread, with review of the pertinent literature. Telescoping punch biopsy demonstrated an epithelioid neoplasm with marked atypia, hypercellularity, and increased mitotic activity. Immunohistochemical stains for HMB-45, NK1-C3, PGP9.5, MiTF, CD10, and CD68 were positive within tumor cells. In addition, there was diffuse expression of caldesmon and focal cytoplasmic staining for smooth muscle actin on the excision specimen. The patient underwent treatment with surgical excision with adjuvant radiation and surveillance computed tomography (CT). The patient remains free of recurrence or metastatic disease after 10 months of follow-up. To our knowledge, this is only the third reported case of a malignant cutaneous PEComa reported in the literature to date.

Cutaneous soft tissue tumors: diagnostically disorienting epithelioid tumors that are not epithelial, and other perplexing mesenchymal lesions.

Cutaneous soft tissue tumors with epithelioid features present a diagnostic challenge given that many entities in this category are rare, and they show morphologic overlap with significantly more common cutaneous epithelial and melanocytic neoplasms. The challenge is compounded by overlapping expression of epithelial or melanocytic markers in some of these entities. A broad spectrum of primary cutaneous epithelioid soft tissue tumors exists, including benign and malignant counterparts of tumors with various differentiation including melanocytic, peripheral nerve sheath, angiomatous, fibrohistiocytic, and myoid or myoepithelial, in addition to translocation-associated tumors lacking a derivative tissue type. Given this spectrum, an initial targeted immunohistochemical panel for epithelioid dermal and subcutaneous neoplasms is recommended, covering a broad spectrum of differentiation. In diagnostically challenging cases, select molecular studies can be employed to make critical distinctions between entities sharing morphologic and immunohistochemical properties. Due to sometimes marked differences in prognosis and treatment, knowledge and familiarity with epithelioid soft tissue tumors is key for any surgical pathologist who evaluates skin and subcutaneous biopsies and excision specimens. This concise review provides brief descriptions, key diagnostic features, and important modern ancillary studies for the diagnosis of non-epithelial, non-melanocytic cutaneous tumors that can exhibit a prominent degree of epithelioid morphology.

Next-generation sequencing implicates oncogenic roles for p53 and JAK/STAT signaling in microcystic adnexal carcinomas.

Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (<8) prioritized somatic mutations, and lacked an ultraviolet (UV) signature. The most recurrent mutation was TP53 inactivation in four (22%) tumors. Frame-preserving insertions affecting the kinase domain of JAK1 were detected in three (17%) cases, and were nonoverlapping with TP53 mutations. Seven (39%) cases demonstrated copy number gain of at least one oncogene. By immunohistochemistry, p53 expression was significantly higher in microcystic adnexal carcinomas with TP53 mutations compared with those without such mutations and syringomas. Similarly, phospho-STAT3 expression was significantly higher in microcystic adnexal carcinomas harboring JAK1 kinase insertions compared with those with wild-type JAK1 and syringomas. In conclusion, microcystic adnexal carcinomas are molecularly heterogeneous tumors, with inactivated p53 or activated JAK/STAT signaling in a subset. Unlike most other nonmelanoma skin cancers involving sun-exposed areas, most microcystic adnexal carcinomas lack evidence of UV damage, and hence likely originate from a relatively photo-protected progenitor population in the dermis. These findings have implications for the biology, diagnosis, and treatment of microcystic adnexal carcinomas, including potential for therapeutic targeting of p53 or the JAK/STAT pathway in advanced tumors.

DNA copy number changes correlate with clinical behavior in melanocytic neoplasms: proposal of an algorithmic approach.

Increasingly, molecular methods are being utilized in the workup of melanocytic neoplasms. To this end, we sought to correlate data from a single nucleotide polymorphism (SNP) array platform based on molecular inversion probes with clinical data. Copy number variation (CNV) data were obtained on 95 melanocytic tumors (6 ordinary nevi, 15 atypical nevi, 34 ambiguous neoplasms, and 40 melanomas) from 92 patients. The average number of significant CNVs was 0 for nevi, 0.6 for atypical nevi (range 0-3), 2.8 for ambiguous neoplasms (range 0-17), and 18.1 for melanomas (range 0-69). Clinical follow-up data were available in 57 of 95 lesions (56 of 92 patients). Tumors from patients with adverse events demonstrated an average number of CNVs of 24.5 (range 6-69) as compared with 7.9 (range 0-35) among tumors without an associated adverse event (p ≤ 0.001). No adverse events were observed in nevi including atypical nevi. Adverse events were found in 2 of 19 ambiguous neoplasms and 10 of 32 melanomas with follow up. In these two latter groups of neoplasms, the correlation between adverse events and the average number of CNVs remained statistically significant even when controlled for Breslow depth (21.5 versus 8.7, p value = 0.036). No neoplasm with adverse events had ≤3 CNVs. These results provide further evidence that SNP array testing for CNVs may be helpful in the classification and prognostication of ambiguous neoplasms. Based on these results, an algorithmic approach to challenging melanocytic neoplasms using CNV data is suggested, using as cutoff of >3 CNVs with some caveats, as the threshold for a positive result. Future clinical validation, using a larger cohort of relevant tumors, will be necessary.

Genital verruciform xanthoma: lessons from a contemporary multi-institutional series.

AIMS: Verruciform xanthoma (VX) is an uncommon lesion, seen in the oral mucosa and rarely occurring at cutaneous genital sites. Reports of exceptional VX presentations dominate the literature; herein, we assess the clinical and histological features of a cohort of routine, consecutive cases. METHODS AND RESULTS: Clinicopathological features of genital VXs from four academic centres were reviewed. A cohort of 25 lesions from 24 patients (22 male, two female; median age = 62 years), occurred on the scrotum (84%), penis (8%) and perineum/vulva (8%). VX was never suspected clinically; considerations ranged from fibroepithelial polyps to squamous cell carcinoma. Classic diagnostic criteria were present at least focally in each lesion, including verrucous architecture, prominent wedge-shaped parakeratosis extending between exophytic epidermal projections and neutrophils in the stratum corneum. Xanthomatous cells were present in all cases, but scattered to rare in 24%. CONCLUSIONS: Consecutive genital VXs reliably exhibited classic histopathological features, although the essential finding of xanthomatous cells may be scarce. Our comparison to meta-analyses of published cases found relatively fewer penile and vulvar examples. Additionally, the median age was older than in published series, which have emphasised syndromic associations.

Fat necrosis with an associated lymphocytic infiltrate represents a histopathologic clue that distinguishes cellular dermatofibroma from dermatofibrosarcoma protuberans.

BACKGROUND: Cellular dermatofibromas (CDFs) and dermatofibrosarcoma protuberans (DFSP) can be challenging to differentiate from one another. Morphologically, both entities commonly extend into the subcutis, exhibit high cellularity with limited cytologic atypia and have a mixed fascicular-to-storiform growth pattern. We sought to evaluate the significance of fat necrosis with an associated lymphocytic infiltrate as a histopathologic clue for distinguishing CDFs from DFSP. METHODS: We identified cases in our pathology database with a primary diagnosis of CDF or DFSP. Punch or excisional biopsy specimens with extension into the subcutis were selected. Previously biopsied lesions and specimens that did not interact with the subcutis were excluded. Histopathologic features were evaluated in hematoxylin and eosin stained sections. RESULTS: Fat necrosis with lymphocytic infiltrate was present in 20/20 cases of CDF. None of the 20 DFSP cases had fat necrosis with lymphocytic infiltrate although 4/20 had fat necrosis alone. CONCLUSIONS: Fat necrosis with associated lymphocytic response can aid in the distinction between CDF and DFSP.

Superficial sarcomas with CIC rearrangement are aggressive neoplasms: A series of eight cases.

CIC rearranged sarcomas have significant overlap with Ewing sarcoma, are aggressive, and typically present in deep soft tissue. They most commonly have a t(4;19)(q35;q13) with CIC-DUX4 fusion. Superficial presentation is rare. We report eight (6F, 2M; median 45-years-old, range 14-65) superficial CIC-rearranged sarcomas, involving the extremities (n = 4), vulva (n = 2), and trunk (n = 2). The tumors were composed of nodules/sheets of round cells with necrosis and hemorrhage separated by dense hyaline bands. Tumor cells had vesicular chromatin, prominent nucleoli and frequent mitotic figures. One showed pagetoid spread. Targeted next-generation sequencing was positive for CIC-DUX4 fusion (6/6); fluorescence in situ hybridization (FISH) was positive for CIC rearrangement (2/3). Eight of eight had evidence of CIC-DUX4 fusion/rearrangement by molecular techniques. Immunohistochemistry was positive for CD99+ (8/8) and DUX4+ (4/4). FISH for EWSR1 rearrangement was negative (5/5). Of five patients with at least 6 months follow-up, three of five died of disease, all within 2 years of presentation. One is alive with disease at 48 months. One is disease free at 3 months. Superficial CIC-rearranged sarcomas should be considered in cases exhibiting features reminiscent of Ewing sarcoma, but with increased pleomorphism and/or geographic necrosis. In contrast to superficial Ewing sarcomas, superficial CIC-rearranged sarcomas are aggressive.

Neurofilament is superior to cytokeratin 20 in supporting cutaneous origin for neuroendocrine carcinoma.

AIM: Primary cutaneous neuroendocrine carcinoma, or Merkel cell carcinoma (MCC), cannot be distinguished morphologically from small-cell neuroendocrine carcinomas (SmCC) from other sites. Immunohistochemistry is required to confirm cutaneous origin, and is also used for detection of sentinel lymph node (SLN) metastases of MCC. Cytokeratin 20 (CK20) expression is commonly used for these purposes, but is negative in some MCC cases, and has unclear specificity. We evaluated immunohistochemistry for neurofilament and CK20 in MCC compared with SmCC from other sites. METHODS AND RESULTS: We evaluated neurofilament expression in 55 MCC specimens from 39 unique patients, including nine CK20-negative MCC tumours. Neurofilament expression was observed in 42 of 55 (76.4%) MCC cases, including seven of nine (77.8%) CK20-negative MCC cases. Neurofilament was expressed in nine of 12 (75%) Merkel cell polyomavirus-positive tumours and five of 10 (50%) virus-negative tumours. Compared to a standard immunohistochemical panel (cytokeratin cocktail and CK20), neurofilament was 87.5% sensitive for detecting SLN metastases. Neurofilament and CK20 expression was also assessed in 61 extracutaneous SmCC from 60 unique patients, with primary sites including lung (27), bladder (18), cervix (3), gastrointestinal tract (3), sinonasal tract (2) and other sites (7). The specificity of neurofilament and CK20 for MCC versus non-cutaneous SmCC was 96.7% and 59.0%, respectively. CONCLUSIONS: Neurofilament has superior specificity to CK20 in distinguishing MCC from non-cutaneous SmCC. Neurofilament is frequently expressed in CK20- and virus-negative MCC tumours. Limitations of neurofilament immunohistochemistry include lower sensitivity than CK20 and subtle staining in some tumours. However, our findings indicate that neurofilament is useful for excluding non-cutaneous SmCC.

Altered Rb, p16, and p53 expression is specific for porocarcinoma relative to poroma.

BACKGROUND: Porocarcinomas are rare aggressive carcinomas that harbor tumor suppressor mutations and must be distinguished from benign entities such as poromas. METHODS: To determine whether altered expression of these genes was diagnostically informative, we examined p53, Rb, and p16 staining patterns in 15 poromas and 16 porocarcinomas. RESULTS: Poromas consistently displayed diffuse strong expression of Rb in all but one case that displayed focal loss (1/15, 7%), and no evidence of aberrancy in p53 or p16. Porocarcinomas displayed diffuse or focal loss of Rb expression in 9/16 (56%) cases, diffuse loss or overexpression of p53 in 8/15 (53%), and diffuse loss or overexpression of p16 in 6/14 (43%). Diffuse aberrancy in p53 and Rb expression correlated with tumor mutations in TP53 and RB1, respectively, whereas focal Rb loss was associated with wild type RB1. Diffuse p16 overexpression correlated with Rb loss rather than CDKN2A mutation. For porocarcinomas with all three stains evaluable, 10/13 (77%) displayed aberrancy in at least one marker. CONCLUSIONS: Our findings suggest that altered p53, p16, and/or Rb expression is relatively specific to porocarcinoma in comparison with poroma. Technical limitations of this panel, including possible focal Rb loss, must be kept in mind, especially in limited samples.