Jason R. Pettus

Objective: Pleomorphic adenomas classically arise from salivary gland epithelial tissue and may occur after trauma. Criteria for establishing trauma-tumor causation are outdated. This case presents a patient with two separate post-traumatic pleomorphic adenomas and proposes updated criteria for evaluating trauma-related tumor causation. Methods: A 59-year-old presented with a frontotemporal scalp lesion one year after workplace head trauma. Nine years earlier she underwent parotidectomy of a pleomorphic adenoma following jaw trauma. Results: The excised scalp lesion was a benign mixed tumor of skin. Histopathologic differences between the scalp and parotid lesions established them as separate primary tumors. The case was evaluated for causation during a workers’ compensation claim. Discussion: The case demonstrates a rare occurrence of multiple post-traumatic benign mixed tumors. We propose an updated and comprehensive set of criteria for objectively assessing trauma-tumor causation.

Purpose: To evaluate whether comprehensive sampling of cervical lymphadenectomy tissue increases lymph node yield (LNY) and improves staging adequacy beyond standard grossing practice. Methods: At a single academic center, a comprehensive grossing protocol was introduced in which entire cervical lymphadenectomy specimens (levels I–V) were submitted for histologic evaluation rather than only grossly identified lymph nodes. Ninety‐one cervical lymphadenectomy specimens from 22 HNSCC patients were analyzed. For each case, standard‐protocol LNY was recorded; additional lymph nodes (positive and negative) recovered by the comprehensive protocol were counted, and changes in pathologic stage and adequacy relative to the 18‐node benchmark were assessed. Additional prosection time, tissue block usage, and the correlation between standard and added nodes were also evaluated. Results: The comprehensive protocol increased LNY by a mean of 15.9 ± 12.9 nodes per patient (median 13; 50.1% overall increase), and by 3.8 ± 5.2 nodes per specimen. Only two additional positive nodes (< 0.6%), measuring 1.4 and 4.1 mm, were identified and did not change staging. Two patients with LNY < 18 under the standard protocol exceeded 18 nodes with the comprehensive protocol. Implementation added a mean of 18.5 prosection minutes and 23 extra blocks per case, with poor correlation between standard and added nodes ( r ² = 0.15). Conclusion: Comprehensive submission markedly increases lymph node counts and can convert some dissections from inadequate to adequate by numeric criteria. However, in this cohort it produced no staging changes and required substantial laboratory resources. These findings support selective rather than universal use of comprehensive sampling in neck dissection evaluation.

Purpose: Salivary duct carcinoma (SDC) is the most common malignancy to arise in a pleomorphic adenoma (PA). Intracapsular or non-invasive carcinoma ex PA (CXPA) is defined by the presence of malignant-appearing tumor cells within the PA that do not violate the tumor border. Knowledge regarding the possible morphologic spectrum and prognosis of intratumoral CXPA is scarce. This study aims to evaluate the morphologic, immunohistochemical, and clinical features of PAs with apocrine / salivary-duct-like intratumoral atypia. Methods: Surgical pathology databases were queried for in situ or intracapsular/intratumoral SDC ex PAs and PAs with atypical epithelial cells (AEC). Exclusion criteria included recurrent lesions, invasion, positive margins, atypia only in myoepithelial cells, or other morphologic variants. Chromogenic multiplex (androgen receptor (AR) and HER2) and monoplex (p40) assays were performed on all available cases, as well as on a control group of non-atypical benign PAs and overtly invasive SDCs. Clinical outcomes were recorded. Results: 96 cases were identified: 23 AEC, 6 apocrine metaplasia, 41 benign PA, 8 SDC ex PA. All AEC, apocrine metaplasia, and benign cases were treated with surgery alone, with 3 AEC cases also receiving a neck dissection. No case recurred. Five of 8 SDC ex PA recurred; 3 died of disease. AR and HER2 were respectively expressed in 96% and 22–48% of AEC; 83% and 0% of apocrine metaplasia; 51% and 0% of benign PA; and 86–100% and 38–57% of SDC ex PA. Patients had increasing average age from benign (~ 50 years) to atypical/in situ (60 years) to invasive carcinoma (~ 70 years). Conclusion: The presence of epithelial atypia within a PA (ranging from isolated AR expression to apocrine metaplasia to overtly dysplastic/malignant epithelial cells) does not portend recurrence or metastasis if the atypia is confined within the borders of the adenoma and negative margins are achieved. Therefore, use of the term “in situ/intracapsular/intratumoral salivary duct carcinoma ex pleomorphic adenoma” is discouraged in light of good prognosis and potential for overtreatment by clinical teams. Nomenclature such as pleomorphic adenoma with epithelial “atypia” or “dysplasia” is recommended, followed by a comment regarding the morphologic features and likely indolent behavior.

Purpose Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored. Methods We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing. Results Fifteen lesions (3–42 mm) were identified, predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88–12.4). Morphologically, 11 AML contained 30–80% smooth muscle, 10–25% vasculature, and 2–60% adipose tissue, while four AL contained 70–80% smooth muscle and 20–30% vasculature. Other histologic observations included ulceration, thrombosis, inflammation, myxoid change, senescent nuclei, and extramedullary hematopoiesis; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin, desmin, and/or caldesmon) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2. Conclusion Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AML. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests “sinonasal angioleiomyoma with adipocytic differentiation” may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.

Clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC) are the two most frequently encountered subtypes of renal cell carcinoma (RCC). Rarely, these two entities are identified intermingled within the same mass and have been labeled either collision tumors juxtaposed by random chance or composite tumors that have arisen from a common tumorigenic precursor cell. Regarding this distinction, authors have commonly relied upon macroscopic, histologic, and clinicopathologic findings, which may be prone to subjectivity. Objective molecular evidence has been lacking. We present a renal tumor showing a mixed CCRCC and PRCC with corroborating histologic, immunophenotypic, chromosomal microarray analysis (CMA), and next-generation sequencing (NGS) analysis for the respective tumor components, including classic findings of chromosome 3p loss and VHL mutation within the CCRCC component and gain of chromosomes 7 and 17 within the PRCC component. Of novel interest, CMA revealed a shared loss of chromosome 21q in both components with no other identifiable shared or overlapping mutations. This report adds unique evidence supporting the possibility of a true composite renal cell carcinoma composed of two commonly recognized subtypes. This finding may help to inform early molecular pathogenetic mechanism of RCC tumorigenesis.

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. 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. 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. 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.

A 67-year-old woman with transverse myelitis and seizure disorder secondary to suspected central nervous system (CNS) systemic lupus erythematosus (SLE) and seropositive rheumatoid arthritis had two episodes of severe nephrotic syndrome 15 years apart. She underwent a renal biopsy in both episodes, showing tip lesion variant focal segmental glomerulosclerosis (FSGS). The patient responded both times to prednisone treatment, achieving a complete remission within 2 months in the first episode and remission 4 months in the second episode. A year after her second episode, the patient had a third episode of severe nephrotic syndrome. She achieved an equally rapid complete remission in 3 months without steroid treatment, as she was concomitantly treated with the Janus Kinase (JAK) inhibitor tofacitinib for a flare of rheumatoid arthritis. This case report suggests that JAK inhibitors may have therapeutic use in FSGS, which is supported by experimental data in the medical literature.

To our knowledge, we describe the first mesenchymal tumor with a novel GLI1‐FOXO4 fusion gene. This well‐circumscribed kidney tumor displayed variably myxoid and epithelioid histologic features with a focally nodular growth pattern. The tumor cells showed bland, round to ovoid nuclei, with no overt high‐grade features. The tumor showed focal immunopositivity for smooth muscle actin and Melan‐A, which raised the possibility of a relationship with a perivascular epithelioid cell tumor. The clinical and morphologic features appear distinct from other reported neoplasms harboring GLI1 or FOXO4 gene rearrangements. The patient underwent radical nephrectomy and is without evidence of disease during a relatively short clinical follow‐up period. However, the features of this tumor likely warrant long‐term follow‐up to monitor for the possibility of a late recurrence or metastasis. In addition to reporting this novel fusion‐positive tumor, we also provide a brief review of GLI1 and FOXO4 gene functions in both normal and neoplastic contexts.