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Context.--Detecting copy number variations (CNVs) at certain loci can aid in the diagnosis of histologically ambiguous melanocytic neoplasms. Droplet digital polymerase chain reaction (ddPCR) is a rapid, automated, and inexpensive method for CNV detection in other cancers, but not yet melanoma. Objective.--To evaluate the performance of a 4-gene ddPCR panel that simultaneously tests for ras responsive binding element protein 1 (RREB1) gain; cyclin-dependent kinase inhibitor 2A (CDKN2A) loss; MYC proto-oncogene, bHLH transcription factor (MYC) gain; and MYB protooncogene, transcription factor (MYB) loss in melanocytic neoplasms. Design.--One hundred sixty-four formalin-fixed, paraffin-embedded skin samples were used to develop the assay, of which 65 were used to evaluate its performance. Chromosomal microarray analysis (CMA) data were used as the gold standard. Results.--ddPCR demonstrated high concordance with CMA in detecting RREB1 gain (sensitivity, 86.7%; specificity, 88.9%), CDKN2A loss (sensitivity, 80%; specificity, 100%), MYC gain (sensitivity, 70%; specificity, 100%), and MYB loss (sensitivity, 71.4%; specificity, 100%). When one CNV was required to designate the test as positive, the 4-gene ddPCR panel distinguished nevi from melanomas with a sensitivity of 78.4% and a specificity of 71.4%. For reference, CMA had a sensitivity of 86.2% and a specificity of 78.6%. Our data also revealed interesting relationships with histology, namely (1) a positive correlation between RREB1 ddPCR copy number and degree of tumor progression; (2) a statistically significant correlation between MYC gain and nodular growth; and (3) a statistically significant correlation between MYB loss and a sheetlike pattern of growth. Conclusions.--With further validation, ddPCR may aid both in our understanding of melanomagenesis and in the diagnosis of challenging melanocytic neoplasms. doi: 10.5858/arpa.2024-0027OA, Melanoma is an aggressive malignancy with a high rate of metastasis. It is the most common cause of death from skin cancer. (1,2) Early diagnosis and resection is often associated [...]

Context.--Pseudocarcinomatous urothelial hyperplasia (PCUH) architecturally and cytologically mimics cancer. The urine cytology features of PCUH have not been described. Objective.--To describe PCUH features in urine cytology. Design.--We reviewed urine cytology cases with concurrent PCUH tissue specimens from 5 academic institutions and classified them by using The Paris System criteria. Results.--Thirty-nine patients included 31 men and 8 women with a mean age of 67 years (range, 39-87 years). All patients had prior pelvic irradiation, and most presented with hematuria (n = 27). The specimens included voided urine (n = 16); bladder washing (n = 11); and urine, not otherwise specified (n = 12). The specimen preparation included cytospin (n = 29) and ThinPrep (n = 10). Original interpretations were negative for high-grade urothelial carcinoma (n = 28), atypical urothelial cells (AUCs; n = 10), and high-grade urothelial carcinoma (HGUC; n = 1). Twenty-five urine specimens (64%) had findings of PCUH. These specimens were moderately cellular and composed of sheets, cohesive groups, or isolated urothelial cells. Nucleoli were present in 23 cases. The nuclear membrane was smooth to irregular (n = 9), smooth (n = 8), and irregular (n = 8). The chromatin was glassy (n = 8), vesicular (n = 7), hyperchromatic (n = 7), and vesicular to finely granular (n = 3). The cytoplasm varied from dense squamoid, to finely vacuolated, to vacuolated. Nucleomegaly was observed in all 25 specimens, and nuclearcytoplasmic ratio greater than 0.5 was seen in 11 of 25 cases (44%). The background contained acute inflammation (n = 14), was clean (n = 9), and contained red blood cells (n = 2). All cases originally interpreted as AUCs and HGUC had PCUH features. Conclusions.--PCUH urine features can overlap with AUCs, HGUC, and other nonurothelial malignancies. In our cohort, 44% (11 of 25) of urine specimens with PCUH changes were initially misclassified. Recognition of cytologic features of PCUH is important to avoid overcalling reactive changes. (Arch Pathol Lab Med. 2023;147:716-721; doi: 10.5858/arpa.2022-0125-OA), Pseudocarcinomatous urothelial hyperplasia (PCUH) was first described by Baker and Young in 2000. (1) In 4 cases following radiation therapy, the authors described an inverted proliferation of urothelial nests within [...]

Pharyngocutaneous fistula after laryngectomy is common and significantly increases the morbidity of the procedure. Intraoperative, objective variables that can reliably predict fistula formation would be useful to surgeons deciding how to reconstruct the laryngectomy defect. Retrospective chart review of 50 radiated patients and 10 non-radiated patients who underwent total laryngectomy at a single tertiary care institution. Patients with pharyngocutaneous fistula were selected to ensure a representative sample were available for comparison. All patients had pathology slides available for re-review by a single, blinded pathologist. Margins of both radiated (n = 50) and non-radiated (n = 10) larynges were examined for 7 histologic features, and odds ratios were calculated to assess whether these features were associated with fistula. When evaluating all 60 patients, both telangiectatic capillaries and hyalinized arterioles were associated with fistula (OR 3.72 and 9.21, respectively). Collinearity between the variables was evaluated; findings indicated a high likelihood of having hyalinized arterioles if telangiectatic capillaries were also present (OR 31.67 [3.13, 320.06]). Microvascular changes in radiated tissue have previously been described in other anatomic subsites, but the larynx and pharynx have not been specifically evaluated. Laryngectomy mucosal margins appear to display similar changes, and evidence of this damage may be associated with fistula formation. These features could potentially guide the surgeon to alter the reconstructive technique.

Carcinosarcomas are rare malignant tumors derived of both epithelial and mesenchymal elements. Herein, we report an elderly man originally diagnosed with a squamous cell carcinoma of the hand. Upon excision, the tumor was found to be a more aggressive carcinosarcoma. Immunohistochemical stains revealed that the sarcoma component of the lesion was vimentin positive, whereas the primary carcinoma tumor cells were positive for p63 and CK903. Both components were negative for CD34 and D2-40. This tumor was found to have angiolymphatic invasion and eventually metastasized to the axillary lymph nodes and lungs.

Background: Differentiated high‐grade thyroid carcinoma (DHGTC) is recently recognized by the World Health Organization (WHO) as a subgroup of thyroid carcinomas with high‐grade features while retaining the architectural and/or cytologic features of well‐differentiated follicular–cell‐derived tumors. The cytomorphology of DHGTC is not well documented despite potential implications for patient triage and management. Methods: The pathology archives of six institutions were searched for cases diagnosed on resection as "high‐grade thyroid carcinoma" using WHO criteria. The fine‐needle aspiration (FNA) cohort represents a 10‐year period (2013–2023); all were reviewed to confirm DHGTC classification. The corresponding FNAs were assessed for 32 cytomorphologic features. Results: Forty cases of DHGTC with prior FNA were identified. The mean patient age was 64.2 years. The average lesion size was 4.9 cm, and the majority demonstrated a TI‐RADS score of 4 or 5 (95.2%). Three main high‐grade subsets of DHGTC based on corresponding histology included papillary thyroid carcinoma (65%), follicular carcinoma (22.5%), and oncocytic carcinoma (12.5%). Over 97% of FNA cases were classified as Bethesda category IV or above. Approximately 25% of DHGTC showed cytologic features that included marked cytologic atypia, increased anisonucleosis, large oval nuclei, mitotic activity, or necrosis (p <.05); 68% of DHGTC cases were associated with high‐risk molecular alterations. TERT mutations occurred in 41%, of which 89% of these were associated with a second mutation, usually RAS or BRAF p.V600E. Conclusions: Cytology has a low sensitivity for DHGTC, although a subset of DHGTCs have cytologic features raising the possibility of a high‐grade thyroid carcinoma. Other findings include high‐risk molecular changes and clinicopathologic features such as older patient age and larger lesion size. A subset of thyroid FNAs of differentiated high‐grade thyroid carcinomas show marked nuclear atypia, mitotic activity, or necrosis together with high‐risk molecular alterations. [ABSTRACT FROM AUTHOR]

Introduction : Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and highly aggressive malignant neoplasm characterized by high-grade undifferentiated morphologic features and recurrent inactivating mutations of SMARCA4. These tumors consistently exhibit loss of SMARCA4 (BRG1) while displaying variable expression of other nonspecific markers. Recently, we encountered a SMARCA4-UT demonstrating immunoreactivity for GATA3, and we sought to characterize this phenomenon in a larger series. Methods : A total of nine SMARCA4-UTs were examined from 3 large academic institutions. The clinicopathologic and molecular characteristics were studied and GATA3 immunohistochemistry was performed. Results : The cohort included 5 male and 4 female patients, with a median age of 54 years and a median smoking history of 37 pack-years. At initial diagnosis, mediastinal lymph node involvement was observed in 5 patients (56%) while distant metastases were present in 7 patients (78%). The median survival was 6 months. Histologically, the tumors were characterized by sheets of undifferentiated epithelioid and/or rhabdoid cells, accompanied by frequent mitotic figures and necrosis. Immunohistochemically, all tumors displayed a complete loss of BRG1 expression. Notably, 4 of 9 tumors (44%) were positive for GATA3 expression, including one tumor that exhibited strong and diffuse immunoreactivity. Conclusions : GATA3 expression in SMARCA4-UT may pose diagnostic challenges, requiring differentiation from other GATA3-positive tumors. This distinction is crucial for accurate prognostication and treatment decisions. [ABSTRACT FROM AUTHOR]

Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.

Neuroendocrine tumor metastases to the pancreas are rare, and they share substantial overlap with the significantly more common primary pancreatic neuroendocrine neoplasms, representing a potential diagnostic pitfall. Elucidating whether a neuroendocrine tumor within the pancreas is a primary neoplasm versus a metastasis has significant prognostic and treatment implications. Correlation with clinical history and imaging as well as incorporating an appropriate immunohistochemical panel are essential to establish the correct diagnosis. Herein, we present 2 rare neuroendocrine tumors that metastasized to the pancreas: a medullary thyroid carcinoma and an atypical carcinoid tumor of lung origin. We also provide a brief review of the literature. [ABSTRACT FROM AUTHOR]

The goal of surgical treatment for oropharynx squamous cell carcinoma (SCCa) is resection to negative margins. Current methods of orienting resection specimens often do not give a comprehensive view, especially in oropharynx SCCa where specimens can lack anatomic landmarks. We created standardized two‐dimensional maps of oropharynx anatomy drawn to scale to improve communication between surgeons and pathologists. Notes regarding surgery including anatomic landmarks, areas of concern, additional margins, and relevant clinical information were added to the map. The maps guided pathology work‐up, and the pathologist could communicate details back to the surgeon on how the specimen was sectioned or locations of microscopic foci to direct future treatment and clinical monitoring. The use of two‐dimensional maps for oropharynx SCCa specimens offers a standardized solution to address the challenges of anatomic orientation. These maps summarized key pathological information, preserved clinical details from the specimens, and guided multidisciplinary conferences when planning adjuvant treatment. [ABSTRACT FROM AUTHOR]