Diagnostic discordance among histopathological reviewers of melanocytic lesions.

BACKGROUND: Histopathological examination is adequate for the diagnosis of most cutaneous melanocytic neoplasms. However, there is a subset that is either difficult to definitively diagnose or would have diagnostic disagreement upon review by multiple dermatopathologists if a more exhaustive review was performed. METHODS: Melanocytic lesions underwent an independent, blinded diagnostic histopathological review of hematoxylin and eosin-stained sections. Each lesion was reviewed by three to six dermatopathologists and categorized as benign, malignant, or unknown malignant potential (UMP). Diagnoses were grouped as concordant (all the same designation); opposing (received benign and malignant designations); majority (single designation with the highest number of diagnoses, no benign/malignant opposing designations); and non-definitive (equal number of non-opposing designations [i.e., benign/UMP or malignant/UMP]). Lesions with equivocal designations (concordant or majority UMP, opposing, majority, and non-definitive) were utilized in a patient treatment model of projected surgical treatment discrepancies. RESULTS: In total, 3317 cases were reviewed, and 23.8% of lesions received equivocal diagnoses. Of these, 7.3% were majority benign, 4.8% were majority malignant, 2.7% were majority UMP, 0.5% were concordant UMP, 6.9% were opposing, and 1.6% were non-definitive. Patient treatment models of those with equivocal lesions (n = 788) revealed a potential of overall surgical treatment variations ranging from 18% to 72%, with the highest variation amongst lesions with opposing, non-definitive, or majority UMP (40%-72%) diagnoses. CONCLUSION: Histopathologic review in this large cohort demonstrated substantial diagnostic variation, with 23.8% of cases receiving equivocal diagnoses. We identified diagnostic ambiguity even in lesions where a definitive diagnosis was previously rendered by a single real-world dermatopathologist. The combined clinical impact of diagnostic discordance or a final diagnosis of UMP is highlighted by high diagnosis-dependent treatment variation in the patient treatment model, which could be underreported in a real-world setting, where review by more than one to two dermatopathologists is relatively rare.

Cutaneous Manifestations of Rheumatoid Arthritis: Diagnosis and Treatment.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by inflammatory arthritis and periarticular structural damage. Available evidence suggests that RA results from complex interactions between genetic susceptibility (e.g., HLA-DRB1), environmental factors (e.g., smoking), and immune dysregulation. Alongside joint-related symptoms, individuals with RA may also experience a wide array of skin issues, including the development of nodules, neutrophilic dermatoses, vasculitis, and vasculopathy. Treatment strategies for these manifestations vary but routinely involve corticosteroids, disease-modifying anti-rheumatic drugs, and biologics, with individualized approaches guided by disease severity. In this review, we provide comprehensive insights into the skin-related issues associated with RA, outlining their clinical characteristics and histopathological findings. Our aim is to facilitate early diagnosis and personalized treatment to improve the quality of life of affected individuals.

Spiradenoma With Adenoid Cystic Carcinoma-like Changes: A Case Series of This Rare Variant With a Potential Diagnostic Pitfall.

Spiradenomas are benign cutaneous adnexal neoplasms with sweat gland differentiation that can manifest a broad spectrum of histomorphologic appearances. While they show a characteristic histopathologic phenotype and clinical management involves surgical excision with a low risk of recurrence, there have been unusual histopathologic variants of spiradenoma reported, including cases with adenoid cystic carcinoma (ACC)-like changes. Primary cutaneous ACC is a low-grade malignancy presenting as a subcutaneous mass with the potential for local invasion, perineural invasion, and high rates of local recurrence after excision. The diagnosis of spiradenomas with ACC-like features can be challenging, especially when only the ACC-like component is present for evaluation. A retrospective analysis of 21 cases of spiradenoma with ACC-like changes were obtained from large academic institutions, was performed, and summarized below. All cases showed background of conventional spiradenoma, and the ACC-like areas represented a component in all lesions. The percentage of ACC-like component ranged from 5% to 40% in all cases. The ACC-like component was multifocal and without pleomorphism, perineural and/or vascular invasion, necrosis, or increased mitotic activity. MYB translocation and protein expression was studied in 16 cases by fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemistry. All studied cases were negative for MYB / NFIB , MYB L1, and MYB F by fluorescence in situ hybridization and polymerase chain reaction and 3 cases were positive for MYB expression by immunohistochemistry. Our study expands on spiradenomas with ACC-like features that ought to be considered in the differential diagnosis of cutaneous neoplasms such as primary cutaneous ACC. Our results indicate that a thorough histopathologic inspection and strict application of well-defined histologic criteria are necessary to support the diagnosis of this unusual histopathologic variant. These tumors can be difficult to diagnose, and awareness of their histomorphologic spectrum will facilitate definitive diagnosis and avoid misdiagnosis with other conditions.

PRAME Expression Is a Useful Tool in the Diagnosis of Primary and Metastatic Dedifferentiated and Undifferentiated Melanoma.

Although mostly recognized in the metastatic setting dedifferentiated and undifferentiated melanomas are increasingly recognized as cutaneous and, less commonly, mucosal primary tumors. Their diagnosis is challenging and dependent on sampling and recognition of a conventional melanoma precursor and/or detection of a mutation in a conventional melanoma driver gene. PRAME immunohistochemistry has recently become an important ancillary tool in the separation of melanoma from benign nevi, but no comprehensive studies exist regarding its value in the detection of dedifferentiated and undifferentiated melanomas and their separation from atypical fibroxanthoma and pleomorphic dermal sarcoma, the main differential diagnoses on sun-damaged skin. After retrieval from archival files, we performed PRAME immunohistochemistry on 11 primary and 10 metastatic dedifferentiated and undifferentiated melanomas, 11 atypical fibroxanthomas, and 10 pleomorphic dermal sarcomas. Nuclear staining was assigned extent (ranging from 0 to 4 and reflecting the percentage of PRAME-positive tumor nuclei) and intensity scores (graded as absent, weak, moderate, and strong, with assigned scores ranging from 0 to 3) with combined scores ranging from 0 to 7. Both primary and metastatic dedifferentiated and undifferentiated melanomas showed strong and diffuse nuclear PRAME staining with median combined scores of 7. Strong and diffuse staining was also seen in all conventional melanoma precursors except for desmoplastic melanoma. In contrast, PRAME staining in atypical fibroxanthoma and pleomorphic dermal sarcoma was patchy and weak with median combined scores of 2. Our data emphasize the diagnostic utility of PRAME staining as a first screening tool in the detection and workup of dedifferentiated and undifferentiated melanomas, both in the primary and metastatic settings. PRAME immunohistochemistry is particularly helpful as it is also positive in tumors without a recognizable conventional melanoma precursor and in those associated with desmoplastic melanomas, where PRAME is typically found to be negative.

A rare case of cutaneous myxoma with trichofolliculoma-like features.

Carney complex is a rare genetic disorder associated with a number of cutaneous lesions, especially cutaneous myxomas. We present a rare case of cutaneous myxoma (superficial angiomyxoma) with trichofolliculoma-like features in a patient with Carney complex, and explore how the associated histopathology provides critical context for elucidating the etiology of this benign neoplasm.

Low-grade Hidradenocarcinomas: A Clinicopathologic Study of an Unusual Carcinoma That Can Mimic its Benign Counterpart.

Hidradenocarcinomas are rare cutaneous adnexal malignancies with sweat gland differentiation that can show a broad spectrum of histomorphologic appearances, ranging from low to high grade. The diagnosis of low-grade hidradenocarcinoma can be challenging and may be mistaken for benign hidradenomas, especially on superficial and partial samples. We performed a retrospective analysis of 16 low-grade hidradenocarcinomas, obtained from 4 large academic institutions. All neoplasms presented clinically as nodular lesions that ranged in size from 1.5 to 6.0 cm. All patients were adults and their age ranged from 33 to 74 years of age. All cases shared features similar to hidradenomas in the surface and mid portion of the tumors and all tumors had 1 or more histomorphologic clues to malignancy, including the presence of an asymmetric and infiltrative growth pattern (especially at the base of the tumors), perineurial invasion, and a desmoplastic stromal reaction. In the tumors evaluated for immunohistochemistry, the tumor cells were positive for p63, EMA, AE1/AE3, MNF116, and CK7. Three patients underwent sentinel lymph node biopsy, and 2 cases showed metastatic disease to regional lymph nodes. All cases (including the 2 cases that had regional lymph node metastasis), showed no local recurrence or distant metastasis observed after a complete re-excision of the tumors (follow-up range from 6 to 72 mo). Our study highlights the salient clinical and histopathologic features of low-grade hidradenocarcinomas and emphasizes the potential diagnostic pitfalls in distinguishing this entity from other neoplasms. Our results indicate that a combination of thorough histopathologic inspection is necessary to support the diagnosis of this rare neoplasm. These tumors can be exceedingly difficult to diagnose and awareness of the subtle features of low-grade hidradenocarcinoma is of importance are as it remains a diagnostic challenge for practicing pathologists.

Pleomorphic Dermal Sarcoma With Metastasis to the Lung: A Case Report.

ABSTRACT: Atypical fibroxanthoma and pleomorphic dermal sarcoma (PDS) are dermal malignant mesenchymal tumors that lie at the ends of the same disease spectrum. Clinically indistinguishable from atypical fibroxanthoma, PDS has a more aggressive course with significantly higher rate of local recurrence and metastases. Histological findings that favor a PDS include subcutaneous invasion, tumor necrosis, lymphovascular invasion, and/or perineural infiltration. Herein, we report a case of PDS with metastasis to the lung. Our report highlights the risk of local recurrence and metastatic spread in this cutaneous tumor and the importance of distinguishing this entity from its less aggressive counterpart.

Fine needle aspiration cytopathology of pleomorphic dermal sarcoma.

INTRODUCTION: Pleomorphic dermal sarcoma (PDS) is an uncommon cutaneous mesenchymal neoplasm. It is cytomorphologically identical to atypical fibroxanthoma (AFX), but differs due to its invasion beyond the dermis. We undertook an examination of our experience with fine needle aspiration (FNA) biopsy cytology of PDS. MATERIALS AND METHODS: Our cytopathology files were searched for examples of PDS with concomitant histopathological verification. FNA biopsy smears and cell collection were performed using standard techniques. RESULTS: Seven cases of PDS were retrieved from four different patients (M:F, 1:1; age range: 63-88 years; mean age = 78 years). All patients (57%) presented with a primary tumour with one having an FNA biopsy of two local recurrences and a single distant metastasis. Five aspirates were from the extremities and two from the head/neck. Tumours ranged from 1.0 to 3.5 cm (mean, 2.2 cm). Specific cytological diagnoses were pleomorphic spindle/epithelioid sarcoma (3 cases), PDS (2), AFX (1), and atypical myofibroblastic lesion, query nodular fasciitis (1). Immunohistochemical (IHC) staining from FNA-generated cell blocks in two cases showed non-specific staining with vimentin in both cases; positive CD10, CD68, and INI-1 staining in one case; and smooth muscle actin expression in the other. Multiple negative stains were performed in both of these cases to exclude malignant melanoma, carcinoma, and specific forms of sarcoma. Cytopathology consisted of a mixture of spindle, epithelioid, and bizarre pleomorphic cells. CONCLUSION: Coupled with ancillary IHC stains, FNA biopsy can help recognise PDS as a sarcomatous cutaneous neoplasm, but is unable to distinguish PDS from AFX.

Low-Grade Hidradenocarcinoma of the Foot With Metastasis to a Lymph Node.

ABSTRACT: Hidradenocarcinoma (HAC) is a rare adnexal tumor associated with the potential for locoregional recurrence and systemic metastasis. The clinical appearance of HAC is nonspecific, frequently presenting as a solitary firm subcutaneous nodule or plaque on the head and neck region or distal extremities. These tumors show histomorphologic heterogeneity, as they can be low and high grade. Distinguishing HAC from hidradenoma, especially the low-grade variant of HAC, can be challenging as both tumors can show histologic overlapping features. In this article, we describe a case of a 33-year-old patient presenting with a low-grade HAC of the plantar foot who was subsequently found to have lymph node metastasis.

Robotic probes at the cell scale.

The miniaturization of robotic tools and probes enables the fundamental study of mechanical properties of cells and tissues.

An update on viral-induced cutaneous lymphoproliferative disorders. CME Part I.

Viral-induced cutaneous T-cell lymphomas are an uncommon group of lymphoproliferative disorders characterized by a viral infection of T and natural killer (NK) cells. This group of cutaneous T-cell lymphomas is more commonly encountered in Asians and Native Americans from Central and South America compared with Western populations. Viral-associated lymphoproliferative disorders include a spectrum of entities that range from nonneoplastic lesions, such as chronic active Epstein-Barr virus infection and infective dermatitis to malignant diseases, such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and adult T-cell leukemia/lymphoma. This review article will focus on hydroa vacciniforme-like lymphoproliferative disorder, extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid granulomatosis, and Epstein-Barr virus-positive mucocutaneous ulcers. We will review the pathogenesis of these conditions and the challenges of making a timely diagnosis in early-stage disease and discuss the common clinicopathologic manifestations, mutational landscape, and approaches to treat these highly aggressive and frequently lethal types of lymphoma.

An update on Epstein-Barr virus-and human T-lymphotropic virus type-1-induced cutaneous manifestations. CME Part II.

The Epstein-Barr virus (EBV) is a DNA virus that infects 90% of the human population, is responsible for certain cutaneous lymphomas (extranodal NK/T-cell lymhoma, hydroa vacciniforme lymphoproliferative disorder, lymphomatoid granulomatosis, others), and can be associated with a variety of cutaneous manifestations (eg, infectious mononucleosis, severe mosquito bite allergy, chronic active EBV disease, Gianotti-Crosti syndrome). EBV-related skin disorders are frequent in certain populations (South and Cental America, Africa, Asia, and Oceania) and can be diagnostically challenging. The human T-lymphotropic virus type-1 is a retrovirus, which is known to be associated with adult T-cell leukemia/lymphoma, neurologic disorders, but also cutaneous non-neoplastic manifestations (infective dermatitis, infections, and infestations). We performed an updated revision of the clinical dermatologic and histopathologic findings associated with the cutaneous non-neoplastic and preneoplastic disorders occurring in association with the EBV and human T-lymphotropic virus type-1.

Poorly differentiated cutaneous apocrine carcinomas: histopathological clues and immunohistochemical analysis for the diagnosis of this unusual neoplasm.

Primary cutaneous apocrine carcinoma (PCAC) is a rare cutaneous malignancy that is derived from apocrine glands. Histologically, these tumours can appear well-differentiated where diagnosis should be relatively straightforward. However, occasionally these tumours can exhibit high-grade features, and in such instances the diagnosis can be challenging. A retrospective analysis of 12 cases of poorly differentiated PCAC, obtained from large academic institutions, was performed, and summarised below. Immunohistochemical studies were performed in all cases with antibodies against CK7, p63, CAM 5.2, GCDFP-15, GATA3, CEA, PR, ER, HER2, calponin, SMA, androgen receptor and EMA. All 12 cases were poorly differentiated; however, there were some histopathological clues to the diagnosis of apocrine carcinoma; namely, the presence of focal glandular formation, acrosyringial involvement and the presence of single 'pagetoid' cells within epidermis. All tumours were consistently positive for CK7, GATA3 and GCDFP-15 and negative for p63. The tumours had variable expression of CAM5.2, CEA, ER, PR, HER2, androgen receptor and EMA. In three cases, there was a preservation of the myoepithelial cell layer (with calponin and SMA), which also confirmed the primary cutaneous origin. PCAC is a difficult neoplasm to diagnose, as it can appear identical to metastatic carcinomas. We describe 12 cases of poorly differentiated PCAC, highlighting their salient clinical, histopathological and immunohistochemical features, and discuss the potential diagnostic pitfalls in distinguishing this entity from other malignant neoplasms. Our results indicate that a combination of thorough histological inspection coupled with an adequate battery of immunohistochemical stains is necessary to support the diagnosis of PCAC.

Angiosarcoma-like Kaposi Sarcoma: A Distinctive Histomorphologic Variant Representing an Important Diagnostic Pitfall.

Kaposi sarcoma (KS) is a rare low-grade angioproliferative neoplasm associated with human herpesvirus 8 (HHV-8) infection with multiple clinical subtypes and varying histopathologic patterns. Histologically, many different variants of KS have been reported, yet all can be difficult to recognize and must be differentiated from other vascular tumors. In this report, we studied fourteen cases of a newly described variant of KS reminiscent of a well-differentiated angiosarcoma (angiosarcoma-like KS). All cases showed a diffuse, ill-defined infiltrative dermal-based lesion composed of numerous anastomosing vascular channels of varying caliber lined by a single layer of endothelium with minimal pleomorphism. The vascular proliferation ramified through the dermis and dissected the collagen bundles along with infiltration into the subcutaneous fat and around skin appendages. All cases showed expression of vascular markers (CD31, CD34, and ERG) and were positive for HHV-8. None showed the classic histopathology associated with KS. Without clinical guidance these tumors can be difficult to recognize as KS, creating significant diagnostic challenges. Our study expands on a rare histologic variant of KS that ought to be considered in the differential diagnosis of any cutaneous well-differentiated angiosarcoma. Awareness of this variant of KS is of important for proper diagnosis and management of these patients; thus, careful attention to the histomorphology and clinical history can help lead the pathologist to the correct diagnosis.