Myoepithelial Tumors of Bone With EWSR1::PBX3 Fusion: A Spectrum From Benign to Malignant.

The EWSR1::PBX3 fusion gene, commonly associated with cutaneous syncytial myoepitheliomas, is also found in myoepithelial tumors (METs) of bone and soft tissue. These tumors typically demonstrate benign histology and favorable outcomes. This study examines 6 previously unreported intraosseous METs harboring the EWSR1::PBX3 fusion, focusing on their histopathologic characteristics, immunophenotype, clinical and radiographic profiles, and patient outcomes. The cohort comprised 5 men and 1 woman, aged 25 to 65 years (median age: 31 years), with tumors located in the proximal tibia (3 cases), distal radius (2 cases), and ilium (1 case) and sizes between 3.2 and 12.2 cm (median size: 3.9 cm). Imaging showed osteolytic lesions with varying degrees of cortical involvement and soft tissue extension in 3 cases. Histologically, 4 tumors showed mainly uniform oval-to-spindled cells in syncytial or fascicular arrangements within a collagenous matrix, displaying either bland nuclear features or mild atypia, and low to slightly elevated mitotic activity (≤1 per 10 high-power fields in 3 cases and 6 per 10 high-power fields in 1), classifying them as benign or atypical METs. In contrast, 2 tumors exhibited pronounced nuclear atypia with ovoid, spindled, epithelioid and round cells, hyperchromatic nuclei, inconspicuous nucleoli, increased N/C ratios, high mitotic rates (17 and 19 per 10 high-power fields), and extensive necrosis. Both tumors behaved aggressively-one patient underwent amputation after neoadjuvant chemotherapy and radiation, and the other died within 7 months with the disease still present. Immunohistochemically, the tumors consistently expressed epithelial membrane antigen and S100 but lacked keratin (AE1/AE3) expression. Our study demonstrated that bone METs with EWSR1::PBX3 fusions encompass a histologic continuum from benign to malignant, with benign/atypical METs mirroring their cutaneous analogs in morphology, and malignant variants distinguished by heterogeneous cytologic and architectural features, pronounced nuclear atypia, and high mitotic rates.

Cutaneous Syncytial Myoepithelioma: An Uncommon and Distinct Variant of Cutaneous Epithelioid Neoplasm.

BACKGROUND: Cutaneous syncytial myoepithelioma (CSM) is an uncommon and distinct variant of cutaneous myoepithelioma. We aim to present a case of CSM to enhance the recognition of this unique variant, encompassing its clinical characteristics, histopathological features, immunohistochemical staining, and therapeutic approaches. CASE PRESENTATION: A 10-year-old girl presented with a dome-shaped nodule located on the skin of her left medial distal arm. Microscopic examination of the skin biopsy revealed a well-defined dermal nodular lesion, surrounded by an epidermal collarette. Tumor cells were composed of epithelioid to spindle-shaped cells with round-to-oval nuclei, small nucleoli, and abundant eosinophilic cytoplasm with a syncytial-like growth pattern. A moderate degree of nuclear pleomorphism was noted. Mitotic activity was not prominent. Immunohistochemical staining revealed positive staining for epithelial membrane antigen, GLUT1, collagen IV, and S100. Smooth muscle actin, CD10, and CD68 showed patchy positivity. CD31, CD34, p63, SOX10, anaplastic lymphoma kinase (ALK), glial fibrillary acidic protein, pankeratin (AE1/AE3/PCK26), Melan-A, and CD1a were negative. Fluorescence in situ hybridization targeting TFE3 and ALK genes was negative. The differential diagnosis included ALK-negative epithelioid cell histiocytoma, epithelioid perineurioma, and CSM. Based on the above findings, a diagnosis of CSM was rendered. DISCUSSION: CSM is a benign cutaneous neoplasm composed of sheets of histiocytoid or short spindle cells with pale eosinophilic cytoplasm with a syncytial-like growth pattern. Clinically, CSM often presents as a painless, slow-growing nodule or plaque in a broad anatomical distribution with a preference for the distal extremities. CSM is characteristically positive for epithelial membrane antigen (EMA) and S100 protein and negative for keratins. In challenging cases, molecular testing for EWSR1 gene rearrangement and EWSR1-PBX3 gene fusion aid in confirming the diagnosis. CONCLUSIONS: The histologic features of CSM present a unique set of challenges posing a diagnostic dilemma, as they can bear resemblance to a range of benign and malignant cutaneous neoplasms including ALK-negative epithelioid cell histiocytoma, epithelioid perineurioma, malignant or nevoid melanoma, and epithelioid sarcoma. An accurate diagnosis is crucial for guiding proper clinical management considering that this entity typically demonstrates an excellent prognosis following a complete surgical excision.

Thoracic SMARCA4-Deficient Undifferentiated Tumors With Unusual Presentations: A Case Series.

CONTEXT: Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently described aggressive neoplasm of young smokers defined by SMARCA4 inactivating mutations and characterized by cells with rhabdoid morphology, high mitotic activity, and abundant necrosis. OBJECTIVE: Describe and compare 3 unusual presentations of SMARCA4-UT in older adults, including one presenting as a metastatic lesion mimicking a primary bone sarcoma. Discuss the molecular characteristics of SMARCA4-UT and their relationship to nonsmall-cell lung carcinomas with SMARCA4. DESIGN: Three patients with SMARCA4-UTs were identified utilizing a natural language search in CoPath. hematoxylin and eosin sections from all patients as well as Papanicolaou-stained slides and Diff-Quik-stained slides for the first patient were examined. A broad range of immunostains, including BRG1/SMARCA4, were evaluated. Molecular testing was performed via next-generation sequencing. RESULTS: The 3 patients were aged 58, 70, and 70 years. All had a significant smoking history. The first patient presented with an iliac bone mass and mediastinal lymphadenopathy, the second with mediastinal adenopathy, and the third with a paratracheal mass. All 3 tumors showed a diffuse proliferation of pleomorphic, rhabdoid cells with high mitotic activity and tumor necrosis. SMARCA4 was lost in all 3 tumors by immunohistochemistry. Molecular testing revealed SMARCA4 alterations in the first 2. CONCLUSIONS: Thoracic SMARCA4-UT should be considered in the differential diagnosis of pleomorphic rhabdoid tumors in older adults with a smoking history. Although most present as lung and/or mediastinal masses, they may occasionally present as a metastasis and mimic an undifferentiated sarcoma, representing a potential diagnostic pitfall.

Recurrence Status, Perineural Invasion, and Hypothyroidism Are Associated With Lymph Node Metastasis in Cutaneous Squamous Cell Carcinoma: A Case-Control Study.

BACKGROUND: Lymph node metastasis is a critical prognostic indicator for mortality in patients with cutaneous squamous cell carcinoma (SCC). OBJECTIVE: To identify and characterize key risk factors for SCC lymph node metastasis. METHODS: This was a multi-institutional, case-control study of 65 cutaneous SCCs with known lymph node metastasis matched with 195 cutaneous SCCs without lymph node metastasis (3:1 matching). The cases and controls were matched by anatomic location, age, and sex. Odds ratios (ORs) and their 95% confidence intervals (CIs) were generated to determine the association between specific risk factors and lymph node metastasis in a multivariate analysis. RESULTS: Recurrent tumors (p < .001), perineural invasion (p < .001), lymphovascular invasion (p = .002), size of 2 cm or greater (p = .008), and hypothyroidism (p = .03) were significantly more common in the lymph node metastasis cohort. Recurrence (OR 6.3, 95% CI 2.6-15.3), perineural invasion (OR 4.5, 95% CI 1.7-11.8), and hypothyroidism (OR 2.7, 95% CI 1.04-7.0) remained significant on performing a multivariate analysis. CONCLUSION: Lymph node metastasis in SCC is associated with recurrence, perineural invasion, lymphovascular invasion, size of 2 cm or greater, and hypothyroidism. Clinical consideration of these findings within the context of current staging systems may help improve patient outcomes.

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

BACKGROUND: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests. METHODS: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2. RESULTS: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain." LIMITATIONS: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded. CONCLUSIONS: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

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.

Locally Advanced Gastrointestinal Stromal Tumor in a 33-Year-Old Woman Seeking to Conceive.

Gastrointestinal stromal tumors (GISTs) are rare neoplasms of the gastrointestinal tract. They commonly present with nonspecific symptoms and thus are often discovered incidentally. They are best identified by CT scan, and most stain positive for CD117 (C-Kit), CD34, and/or DOG-1. Several risk stratification classification systems have been developed based on tumor size, mitotic rate, location, and perforation. Traditional chemotherapy and radiation therapy have been very ineffective, making surgery the mainstay of treatment. The discovery of mutations associated with these tumors has revolutionized the treatment approach. Imatinib mesylate, a selective tyrosine kinase receptor inhibitor, used as adjuvant or neoadjuvant therapy, has greatly improved the morbidity and mortality associated with GISTs. As the survival of patients has increased with the long-term use of targeted therapies, quality-of-life issues now have become much more relevant and have come to the forefront of care. We present a young woman who was successfully treated for GIST but now faces associated long-term adverse effects of imatinib, including the challenge of preserving fertility and the potential for childbearing.

Clinical, Dermatoscopic, and Histological Findings in a Diagnosis of Pityriasis Lichenoides.

Pityriasis lichenoides et varioliformis acuta (PLEVA) is a rare cutaneous eruption of erythematous macules and papules distributed over the flexural surfaces and the trunk. Histopathologic analysis is useful in diagnosis, and dermoscopic findings have been described in several small case series. We present a case of a mid-20s female who was diagnosed with PLEVA based on clinical and histopathological findings, and we also demonstrate a unique dermoscopic finding. Additionally, we review the current literature detailing dermoscopy findings with associated histopathology in PLEVA and pityriasis lichenoides chronica (PLC).

Disseminated Histoplasmosis Diagnosed by "Touch Prep".

Disseminated histoplasmosis is a rare but serious complication of infection with the dimorphic fungus Histoplasma capsulatum. We report a case of disseminated histoplasmosis with cutaneous involvement diagnosed by touch wet preparation and confirmed with histopathology and culture. "Touch prep" performed from a lesional punch biopsy, prepared with Wright-Giemsa followed by chlorazol black containing KOH, revealed abundant yeast organisms localized within multinucleated giant cells, and a rapid diagnosis of disseminated histoplasmosis with cutaneous involvement was achieved. This report demonstrates the utility of wet prep techniques as an invaluable and rapid beside diagnostic tool in the setting of cutaneous histoplasmosis. In addition, we compare the distinguishing histopathologic features of the infectious organisms within the differential diagnosis of parasitized histiocytes.

Nanoparticle Formulation of Indocyanine Green Improves Image-Guided Surgery in a Murine Model of Breast Cancer.

PURPOSE: Negative surgical margins (NSMs) have favorable prognostic implications in breast tumor resection surgery. Fluorescence image-guided surgery (FIGS) has the ability to delineate surgical margins in real time, potentially improving the completeness of tumor resection. We have recently developed indocyanine green (ICG)-loaded self-assembled hyaluronic acid (HA) nanoparticles (NanoICG) for solid tumor imaging, which were shown to enhance intraoperative contrast. PROCEDURES: This study sought to assess the efficacy of NanoICG on completeness of breast tumor resection and post-surgical survival. BALB/c mice bearing iRFP+/luciferase+ 4T1 syngeneic breast tumors were administered NanoICG or ICG, underwent FIGS, and were compared to bright light surgery (BLS) and sham controls. RESULTS: NanoICG increased the number of complete resections and improved tumor-free survival. This was a product of improved intraoperative contrast enhancement and the identification of a greater number of small, occult lesions than ICG and BLS. Additionally, NanoICG identified chest wall invasion and predicted recurrence in a model of late-stage breast cancer. CONCLUSIONS: NanoICG is an efficacious intraoperative contrast agent and could potentially improve surgical outcomes in breast cancer.

Erythroderma: A Rare Complication of Dyshidrotic Eczema.

A 47-year-old man with a history of dyshidrotic eczema presented to the emergency department with diffuse erythema, chills and pruritus of three weeks' duration. The patient had received two injections of methotrexate in the preceding two weeks, both of which had failed to improve his whole-body erythema and pruritus. In the emergency department, the patient was evaluated for infection and admitted for the dermatology consultation. After being seen on the general medical floor by the dermatology service the diagnosis of erythroderma was made and the patient was treated with intravenous (IV) cyclosporine therapy, with which his rash dramatically improved over three days. This case report summarizes the presentation and differential of erythroderma, and highlights the importance of having a high index of suspicion for this potentially fatal disease.

Disseminated Acanthamoeba Infection Presenting With Cutaneous Lesions in an Immunocompromised Patient: A Case Report, Review of Histomorphologic Findings, and Potential Diagnostic Pitfalls.

OBJECTIVES: Free-living amoebas are exceedingly rare causes of cutaneous infections and present unique diagnostic and therapeutic challenges. We describe a case of disseminated acanthamoebiasis with cutaneous manifestations and summarize additional diagnostic, prognostic, and therapeutic highlights. METHODS: A 58-year-old man with relapsed chronic lymphocytic leukemia had several weeks of progressive, painful ulcerations on the forehead, arms, abdomen, and thighs. A biopsy was performed for histopathologic evaluation. RESULTS: The biopsy specimen showed inflammatory infiltrate with abscess formation involving the epidermis, dermis, and subcutis. Scattered cells showed nuclei with a prominent central karyosome, dispersed chromatin, and either abundant foamy basophilic cytoplasm or two well-demarcated cytoplasmic walls. Acanthamoeba species was confirmed by polymerase chain reaction from the formalin-fixed, paraffin-embedded tissue. CONCLUSIONS: Cutaneous lesions from acanthamoebiasis are exceptionally rare but should be included in the differential diagnosis of necrotic cutaneous lesions in immunocompromised patients. Although infrequently encountered, pathologists need to be aware of the morphologic features of free-living amoebas. Immunohistochemical and molecular studies can confirm the diagnosis. Multiagent treatment regimens, when initiated empirically, have been more successful than single-agent regimens, but infections involving the central nervous system are almost universally fatal.

Napsin A expression in small cell carcinoma of the lung: a cytologic study with review of differentials.

INTRODUCTION: Napsin A is a diagnostic marker for pulmonary adenocarcinoma and a useful alternative to thyroid transcription factor 1 (TTF-1). TTF-1 also stains pulmonary small cell carcinoma (SCCA). Napsin A expression in SCCAs is not as established as it is in non-SCCAs. We analyzed napsin A and TTF-1 expression in 36 previously confirmed cytologic cases of pulmonary SCCA. Ours is currently the largest cytologic series of such cases examined for napsin A expression. MATERIALS AND METHODS: Thirty-six patients, (20 men, 16 women), age 43-87 years, mean 57 years, had primary or metastatic pulmonary SCCA diagnosed by fine-needle aspiration biopsies of mediastinum (n = 5); liver (n = 3); subcutaneous nodule (n = 1); lung (n = 6); and axillary, cervical, and mediastinal lymph nodes (n = 20), as well as a pleural effusion (n = 1). Napsin A and TTF-1 expression was tested. Also, previous expression (or lack thereof) with immunocytochemical stains pancytokeratin and neuroendocrine markers (synaptophysin, chromogranin, and cluster of differentiation marker CD56) were noted. RESULTS: All cases of pulmonary SCCA were positive for pancytokeratin. TTF-1 was positive in 35 of 36 cases (97%), and napsin A was negative in all 36 cases (100%). All 36 cases expressed ≥ 1 neuroendocrine marker, including the TTF-1 negative case. CONCLUSIONS: This study showed napsin A was negative in all pulmonary SCCAs. This stain may prove to be a useful exclusionary marker in distinguishing pulmonary SCCA from other poorly differentiated lung carcinomas with similar morphologic features, especially those with concomitant TTF-1 expression.

Epithelioid sarcoma-like (pseudomyogenic) hemangioendothelioma, clinically mimicking dermatofibroma, diagnosed by skin biopsy in a 30-year-old man.

Epithelioid sarcoma-like (pseudomyogenic) hemangioendothelioma (ESHE) represents a rare soft tissue and bone tumor that typically presents as nodule(s) in the distal extremities of young adults. The nodules traverse several tissue planes simultaneously and can involve the dermis, subcutis, skeletal muscle and bone. ESHE shares clinical and microscopic features with epithelioid sarcoma (ES), and, accordingly, is commonly misdiagnosed as ES. However, unlike ES, which has a poor prognosis, ESHE commonly follows an indolent course. Herein, we report a case of ESHE diagnosed by skin biopsy that clinically mimicked a dermatofibroma. We also provide clinical photographs of the lesions in various stages of development, representing information that has not been previously published, to our knowledge.

Soft tissue sarcomas--new approaches to diagnosis and classification.

The study of sarcoma pathology is a rapidly evolving field. The continued refinement of classic diagnostic techniques in conjunction with the molecular diagnostics has resulted in an abundance of data regarding this diverse and rare group of tumors. We anticipate that cutting edge technology including next generation sequencing will continue to further our understanding of saromagenesis and enable more precise classification and diagnosis of sarcomas in the future.

Chromophobe renal cell carcinoma with sarcomatoid differentiation: a clinicopathologic study of 14 cases.

OBJECTIVE: To investigate the clinicopathologic features of chromophobe renal cell carcinoma with sarcomatoid differentiation. STUDY DESIGN: A search was made through the surgical pathology and expert consult files of two major academic institutions from 2003 to 2011 for cases of chromophobe renal cell carcinoma with sarcomatoid differentiation. RESULTS: Fourteen patients were identified. The patients included 9 males (64%) and 5 females (36%). The mean patient age was 60.4 years (range, 40-82 years). There was a left-sided predominance: left (9 patients) and right (5 patients). The mean tumor size was 14.6 cm (range, 9.5-28.0 cm), and the mean percentage sarcomatoid differentiation was 67% (range, 30-99%). All tumors exhibited moderate to extensive areas of necrosis. The nonsarcomatoid component in all cases demonstrated classic features of chromophobe renal cell carcinoma. Nine patients (64%) had pT3 disease and 5 patients (36%) had pT4 disease. Five patients (36%) had positive surgical margins. Three patients (21%) had tissue diagnosis of metastatic disease at the time of initial surgery. Six patients (43%) had subsequent pathologic and/or radiologic evidence of multiple or isolated metastatic disease. Follow-up information was available in all 14 patients. Mean follow-up time was 16 weeks (range, 2-84 weeks). Ten of 14 patients (71%) died of disease, 9 of those within 6 months (mean survival time of 10 weeks), 3 patients (21%) were alive with disease, and only 1 patient (7%) was alive with no evidence of disease. CONCLUSION: This study is one of the largest series to date specifically examining the clinicopathologic features of sarcomatoid chromophobe renal cell carcinoma in radical nephrectomy specimens and confirms the observation that these tumors behave more aggressively than conventional clear cell renal cell carcinoma or papillary renal cell carcinoma.