Pleomorphic Dermal Sarcoma.

Pleomorphic dermal sarcoma (PDS) is a rare cutaneous/subcutaneous neoplasm of purported mesenchymal differentiation that exists along a clinicopathologic spectrum with atypical fibroxanthoma (AFX). While PDS and AFX share histopathologic and immunohistochemical features, PDS exhibits deeper tissue invasion and has a higher rate of metastasis and local recurrence than AFX. Given its aggressive clinical course, early recognition and clinical management of PDS are essential for optimizing patient outcomes. This review aims to provide a brief overview of the clinicopathologic and molecular features, prognosis, and treatment of PDS.

Subcutaneous Leiomyosarcoma: An Aggressive Malignancy Portending a Significant Risk of Metastasis and Death.

Subcutaneous leiomyosarcoma (LMS) is a rare, poorly understood variant. The current literature on the subject is sparse, consisting of isolated case reports and small clinicopathologic studies compromised by the inclusion of both its more common and indolent counterpart, cutaneous LMS (atypical intradermal smooth muscle neoplasm), as well as highly aggressive deep-seated tumors. Thus, precise clinicopathologic characterization is limited. Cases of subcutaneous LMS reviewed at the University of Michigan and Cleveland Clinic from 1994 to 2022 were included in this retrospective study. A total of 39 cases were identified. The mean age was 61 years, and the cohort was predominantly male (23/39; 59%). Tumors averaged 4.2 cm and most commonly arose on the extremities (32/39; 82%). The majority (38/39; 97%) were diagnosed at an early pathologic stage (pT1 or pT2). Histopathologically, most tumors were well-circumscribed and were assigned a Fédération Nationale des Centers de Lutte Contre le Cancer grade of either 1 or 2 (24/39; 62%). The majority (22/39; 56%) appeared to arise in association with a blood vessel. Of the 36 cases with accessible clinical data and follow-up (mean 34 mo, range 0 to 94 mo), 12 (33%) were noted to have metastasized, with the lung representing the most common anatomic location. One case recurred locally. Six of 36 patients (17%) died from the disease at an average of 47 months after diagnosis (range 16 to 94 mo). Metastasis or death from disease was significantly associated with the Fédération Nationale des Centers de Lutte Contre le Cancer grade ( P =0.0015), the presence of necrosis ( P =0.032), tumor size ( P =0.049), and AJCC tumor stage ( P =0.036). These data demonstrate that subcutaneous LMS are more aggressive than dermal-based tumors and have a prognosis akin to that of deep-seated LMS.

Hypertrophic Lichen Planus: An Up-to-Date Review and Differential Diagnosis.

CONTEXT.­: Hypertrophic lichen planus (HLP) is a variant of lichen planus that can be difficult to diagnose based on histopathologic features alone. Thus, patient clinical history and clinicopathologic correlation are essential considerations to make the correct diagnosis. OBJECTIVE.­: To discuss the clinical and histologic presentation of HLP and provide a thorough review of commonly encountered mimickers in the differential diagnosis. DATA SOURCES.­: Data were derived from a literature review, personal clinical and research experiences, and a review of cases in the archives of a tertiary care referral center. CONCLUSIONS.­: In general, HLP involves the lower extremities and is characterized by thickened, scaly nodules and plaques that are often pruritic and chronic in nature. HLP affects both males and females and is most common in adults 50 to 75 years of age. Unlike conventional lichen planus, HLP tends to have eosinophils and classically displays a lymphocytic infiltrate most concentrated around the tips of rete ridges. The differential diagnosis for HLP is broad and encompasses numerous entities in many different categories, including premalignant and malignant neoplasms, reactive squamoproliferative tumors, benign epidermal neoplasms, connective tissue disease, autoimmune bullous disease, infection, and drug-related reactions. Therefore, a high index of suspicion must be maintained to avoid a misdiagnosis and potential inappropriate treatments.

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 vascular tumors: an updated review.

Cutaneous vascular tumors constitute a heterogeneous group of entities that share overlapping morphologic and immunohistochemical features, which can be diagnostically challenging for pathologists and dermatopathologists. Our understanding and knowledge of vascular neoplasms have improved over time, resulting in both a refinement of their classification by the International Society for the Study of Vascular Anomalies (ISSVA) and an improvement in the accurate diagnosis and clinical management of vascular neoplasms. This review article aims to summarize the updated clinical, histopathological, and immunohistochemical characteristics of cutaneous vascular tumors, as well as to highlight their associated genetic mutations. Such entities include infantile hemangioma, congenital hemangioma, tufted angioma, spindle cell hemangioma, epithelioid hemangioma, pyogenic granuloma, Kaposiform hemangioendothelioma, retiform hemangioendothelioma, pseudomyogenic hemangioendothelioma, Kaposi sarcoma, angiosarcoma, and epithelioid hemangioendothelioma.

Expression of SATB2 in primary cutaneous sarcomatoid neoplasms: a potential diagnostic pitfall.

SATB2 can be used as an immunohistochemical marker for osteoblastic differentiation. The differential diagnosis of a cutaneous sarcomatoid neoplasm sometimes includes osteosarcoma when the tumour concomitantly involves the skin, soft tissue, and bone, or when there is a past medical history of osteosarcoma. As the utility of SATB2 immunohistochemistry in these scenarios was unclear, we aimed to determine the frequency and the pattern of SATB2 expression in a variety of cutaneous sarcomatoid neoplasms. SATB2 expression by immunohistochemistry was evaluated by intensity (0-3) and extent (0-100%) of staining to generate an h-score for each case. Expression levels were classified into high-positive (h-score ≥100), low-positive (20-99), and negative (<20) groups. Positive SATB2 expression was observed in 18/23 (78%) atypical fibroxanthomas (AFX), 10/19 (53%) pleomorphic dermal sarcomas, 9/20 (45%) cutaneous sarcomatoid squamous cell carcinomas, 14/39 (36%) sarcomatoid melanomas, 2/13 (15%) poorly differentiated cutaneous angiosarcomas, 10/17 (59%) high-grade cutaneous leiomyosarcomas, and 7/8 (88%) osteosarcoma controls. With the exception of AFX, all cutaneous neoplasms showed significantly lower average h-scores than osteosarcoma. AFX gave the highest average h-score (71) and percentage of high-positive cases (48%) among all examined cutaneous neoplasms. Only two (1.5%) of all cutaneous cases showed strong intensity of staining. Common SATB2 expression in various cutaneous sarcomatoid neoplasms poses a potential diagnostic pitfall when the differential diagnosis includes osteosarcoma. Requirement of strong staining and a high-positive h-score improves the specificity of SATB2 in differentiating these tumours from osteosarcoma.

Mesenchymal tumours with melanocytic expression: a potential pitfall in the differential diagnosis of malignant melanoma.

Mesenchymal tumours with melanocytic expression can pose a diagnostic challenge because they frequently demonstrate both morphological and immunohistochemical overlap with other cutaneous melanocytic neoplasms. Therefore, they present potential pathological pitfalls that may lead to a misdiagnosis of malignant melanoma. Mesenchymal neoplasms that closely mimic melanoma include malignant melanotic nerve sheath tumour (melanotic schwannoma), epithelioid schwannoma, malignant peripheral nerve sheath, cutaneous syncytial myoepithelioma, clear cell sarcoma of soft tissue, and perivascular epithelioid cell tumour. Awareness of these melanoma mimics is necessary for establishing the correct diagnosis so that the appropriate clinical management can be rendered to the patient. This in-depth review highlights key diagnostic features and molecular genetics and also discusses the differential diagnosis and treatment of mesenchymal tumours that exhibit melanocytic expression.

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.

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 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.

Cytologic features of small cell melanoma.

Small cell melanoma (SCM) is an aggressive variant of malignant melanoma (MM), which has been rarely described in the cytology literature. The aim of this study was to describe the clinical and cytologic features of a series of cases of metastatic SCM with discussion of the differential diagnosis of metastatic SCM diagnosed by fine-needle aspiration (FNA). A retrospective review of cases was performed, identifying two FNA cases and one core biopsy with touch preparation of metastatic SCM. Clinical presentation, cytomorphology features, ancillary tests, and final diagnoses were documented and analyzed. Patients ranged in age from 69 to 85 years-old. Cytomorphologic features included the presence of a monomorphic population of dispersed small round blue cells, with scant cytoplasm, high nuclear to cytoplasmic ratios, dense nuclear chromatin, and inconspicuous nucleoli. Acinar like arrangement (n = 2) and nuclear molding (n = 1) were also present. All cases showed diffuse positivity for the melanocytic markers SOX10 and Melan A by immunohistochemistry (IHC). Expression of neuroendocrine markers was variable. Diagnosing metastatic SCM at unusual anatomic sites by FNA cytology is a challenging task, especially in patients without known prior history of melanoma. Cytomorphology of SCM is unique, differing from conventional MM in many aspects, including the presence of acinar formations and a lack of typical melanoma features, such as large cells, intracytoplasmic melanin, and macronucleoli. IHC is critical for establishing the diagnosis of SCM.

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.