Pan-TRK immunohistochemistry in gynaecological mesenchymal tumours: diagnostic implications and pitfalls.

AIMS: NTRK-rearranged sarcomas of the female genital tract mainly occur in the uterus (more commonly cervix than corpus) and are characterized by a "fibrosarcoma-like" morphology and NTRK gene rearrangements. These neoplasms may exhibit histological overlap with other entities and can present diagnostic difficulties without molecular confirmation. Pan-TRK immunohistochemistry was developed to identify tumours harbouring NTRK rearrangements. The aim of this study was to characterize pan-TRK immunohistochemical expression in a large cohort of gynaecological mesenchymal neoplasms and investigate the utility of pan-TRK immunohistochemistry to distinguish NTRK-rearranged sarcoma from its mimics. METHODS AND RESULTS: A total of 473 gynaecological mesenchymal tumours (461 without known NTRK fusions and 12 NTRK-rearranged sarcomas) were selected. Pan-TRK immunohistochemistry (EPR17341, Abcam) was performed on whole tissue sections and tissue microarrays. Molecular interrogation of pan-TRK positive tumours was performed by RNA sequencing or fluorescence in situ hybridization (FISH). Of the 12 NTRK-rearranged sarcomas, 11 (92%) exhibited diffuse (≥70%) cytoplasmic pan-TRK staining with moderate/marked intensity, while the other was negative. Eleven (2.4%) additional tumours also exhibited pan-TRK immunohistochemical expression: three low-grade endometrial stromal sarcomas, seven high-grade endometrial stromal sarcomas, and an undifferentiated uterine sarcoma. Molecular confirmation of the absence of NTRK rearrangements was possible in nine of these tumours. Of these nine neoplasms, seven exhibited focal/multifocal (<70%) pan-TRK cytoplasmic staining with weak/moderate intensity. CONCLUSION: Even though pan-TRK immunohistochemical expression is not entirely sensitive or specific for NTRK-rearranged sarcomas, these neoplasms tend to exhibit diffuse staining of moderate/strong intensity, unlike its mimics. Pan-TRK should be performed in monomorphic uterine (corpus and cervix) spindle cell neoplasms that are negative for smooth muscle markers and hormone receptors and positive for CD34 and/ or S100. Ultimately, the diagnosis requires molecular confirmation.

SMARCB1 (INI1) Deficient Tumours of the Uterine Cervix: Report of Two Cases, Including One Associated With an NTRK Fusion.

Pathogenic variants (mutations) and other molecular events involving subunits of the SWItch/Sucrose Non-Fermentable chromatin remodelling complex are common in a wide variety of malignancies. Many of these neoplasms are characterized by undifferentiated morphology. They arise at a variety of sites in the female genital tract but have rarely been reported in the uterine cervix. We report 2 primary cervical neoplasms arising in young women (ages 28 and 29 yr) exhibiting loss of nuclear immunoreactivity with SMARCB1 (INI1). In one case, which had a mixture of epithelioid and spindle cells, molecular studies revealed no SMARCB1 pathogenic variant, but showed a SPECCL1::NTRK 3 fusion, in keeping with an NTRK fusion sarcoma. The second case exhibited rhabdoid morphology and molecular testing confirmed a SMARCB1 pathogenic variant (c.425 T>G:p.(Leu142Ter) which, interpreted in conjunction with the morphology and immunohistochemistry, resulted in classification as a proximal-type epithelioid sarcoma. To our knowledge, this is the first reported cervical neoplasm exhibiting a SMARCB1 pathogenic variant and the first NTRK fusion sarcoma showing SMARCB1 protein loss. We discuss the diagnostic challenges and complexities of the molecular findings.

Epstein-Barr Virus-positive Mucocutanous Ulcer of the Uterine Cervix: Report of a Rare and Evolving Entity.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a newly described lymphoproliferative lesion characterized by the proliferation of EBV-positive atypical B cells in a variable inflammatory background associated with mucosal or cutaneous ulcers. Commonly involved sites include the oropharyngeal tract, skin, and gastrointestinal tract, with emerging reports describing EBVMCU of genitalia. To date, no lesions have been described of the uterine cervix. Herein, we report the first cervical EBVMCU incidentally discovered at large loop excision of the transformation zone performed for treating human papillomavirus induced high-grade squamous intraepithelial lesion. The patient was a 35-yr-old, human immunodeficiency virus-positive woman with a history of pulmonary tuberculosis. Histologic and immunohistochemical findings showed classic Hodgkin lymphoma-like features. Systemic lymphoproliferative disease was excluded by appropriate clinical and imaging modalities. This case report highlights the prototypical histologic features of cervical EBVMCU. We emphasize the importance of clinicopathologic correlation to avoid overtreatment of a lesion that can otherwise meet histologic criteria for a lymphoma. Clinicians and pathologists should familiarize themselves with this entity, as this indolent, pseudomaligant lesion typically occurs in immunocompromised patients and spontaneously regresses when the cause for the immunosuppression is addressed.

A Killian-Jamieson diverticulum potentially mimicking a thyroid nodule: A case report highlighting the cytology of a pharyngoesophageal diverticulum.

The authors highlight the important contribution of rapid on-site evaluation by the cytopathologist of a pharyngoesophageal diverticulum in a mass initially interpreted clinically as thyroidal in origin. They discuss pitfalls in avoiding interpretive diagnostic error and inappropriate thyroid Bethesda reporting.

Cervical Small Cell Variant of Paraganglioma With Sarcomatous Transformation: Report of a Unique Case.

We report a unique primary cervical neoplasm in a 44-yr-old woman which we believe, based on the morphology and immunophenotype, represents an extremely unusual small cell variant of paraganglioma. This represents the first report of a primary cervical paraganglioma. Following chemoradiation treatment, the tumor underwent malignant transformation into an S100 and SOX10 positive sarcoma, morphologically and immunohistochemically resembling a malignant peripheral nerve sheath tumor, which we believe represents a sarcoma derived from the sustentacular cells of the paraganglioma. Mutational analysis detected a nonsense mutation of NF1 gene in the sarcoma. This further supports the diagnosis as both somatic and germline NF1 mutations have been associated with paragangliomas and malignant peripheral nerve sheath tumors. Targeted RNA sequencing (ARCHER, expanded sarcoma panel) covering many known genes implicated in sarcoma development, did not reveal any other molecular alteration (fusion or internal tandem duplication).

Performance of Thyroid Fine-Needle Aspiration Biopsy in a Low- and Middle-Income Country.

INTRODUCTION: The 6 categories of the Bethesda System for Reporting Thyroid Cytology (TBSRTC) with associated risk of malignancy (ROM) provide evidence-based clinical management guidelines. This study aimed to determine the ROM and accuracy of FNAB in South Africa (SA). METHODS: Thyroid specimens from 3 pathology laboratories registered between January 2015 and December 2019 were considered for inclusion. ROM was obtained per TBSRTC category by cytohistological correlation and dividing the total number of specimens with malignant histology by the total number of cases operated. Accuracy was calculated based on the Bethesda category and eventual malignant histology. RESULTS: Seventeen thousand seven hundred and seventy-three histology and 4,791 cytology cases were identified. Of the 4,791 cytology cases, 931 (19%) underwent surgery. More than a third (333, 35.8%) of cases were confirmed as malignant following histological assessment, with the majority being benign (584, 62.7%). The ROM for the nondiagnostic and benign categories was 24.3% and 20.5%. The highest ROM was for category VI (91.5%), followed by categories V (69.5%), IV (51.9%), and III (38.8%). Thyroid FNAB had a sensitivity of 73%, specificity of 74%, and overall accuracy of 74%. CONCLUSION: Bethesda categories II and IV have a relatively higher ROM in SA compared to findings from other developed countries. The diagnostic accuracy of thyroid FNAB in SA and the high rate of nondiagnostic diagnoses (38%) require further investigation. A national thyroid registry could provide location-specific data to aid the implementation of appropriate local policies and national guidelines for practicing thyroid surgeons.

Immunochemistry and lung cancer: application in diagnosis, prognosis and targeted therapy.

Immunochemistry is now an established ancillary technique in lung cancer diagnosis. Not only does it help in supporting the morphological diagnosis of malignancy, but its role now extends to the determination of cell lineage, ascertaining the primary site of tumour origin and contributing to decisions on prognosis and treatment. Early detection and confirmation of lung cancer facilitate early treatment decisions. Lung cancer management now has a multidisciplinary approach which includes cytopathologists and clinicians. Some clinicians may not understand what immunochemistry is and what its role is in lung cancer diagnosis, prognosis and therapy. The purpose of this paper is to define immunochemistry, on the background of basic respiratory airway epithelial structure and cancer biology, and discuss its application in the diagnosis, treatment and determination of prognosis of lung cancer.

Classification of Male Breast Lesions According to the IAC Yokohama System for Reporting Breast Cytopathology.

OBJECTIVE: This study aims to determine the diagnostic utility of the International Academy of Cytology (IAC) Yokohama System for reporting breast cytopathology in lesions of the male breast. STUDY DESIGN: Fine-needle aspiration biopsy (FNAB) reports between 2015 and 2019 were retrospectively recategorized according to the 5-tiered IAC Yokohama Reporting System. Our database yielded a total of 1,532 FNAB reports from breast lesions, obtained from 1,350 male patients. The risk of malignancy (ROM) and diagnostic performance of FNAB were determined using follow-up histopathological diagnosis and/or clinical follow-up, where available, for each category. RESULTS: The category distribution were as follows: inadequate, 40%; benign, 57%; atypical, 0.6%; suspicious for malignancy, 0.7%; and malignant, 1.6%. The ROM in each category was nondiagnostic, 11%; benign, 3%; atypical, 28%; suspicious for malignancy, 56%; and malignant, 100%. The sensitivity, specificity, positive predictive value, and negative predictive value were recorded as 63, 100, 100, and 84.6% respectively, when only malignant cases were considered as positive tests. CONCLUSION: This study validates the IAC Yokohama System for reporting male breast cytopathology. In accordance with the aim of the Yokohama System to establish best practice guidelines for reporting breast cytopathology, this comprehensive scheme facilitates comparisons between local and international institutions. The ROM acts as an internal audit for quality assurance within one's own laboratory and provides guidance for clinical management. It highlights inefficiencies such as high inadequacy rates for category 1 and also features strengths with impressive specificity for categories 4 and 5.

Fine-needle aspiration cytology of subcutaneous fat necrosis of the newborn: the cytology spectrum with review of the literature.

Subcutaneous fat necrosis of the newborn is a rare, transient panniculitis of full-term infants. Diagnosis is usually made clinically; however, a biopsy is sometimes required. Fine-needle aspiration biopsy (FNAB) offers an alternative to biopsy. The cytology shows a spectrum of changes ranging from clumped lobules of fat with opaque cytoplasm to necrotic aspirates with dispersed fat cells with opaque cytoplasm, foamy macrophages, multinucleated giant cells, lymphocytes, and neutrophils. Radially orientated, refractile, needle-shaped crystals are visible in the cytoplasm of the fat cells and loose lying in the necrotic background. FNAB offers an alternative to biopsy with good results.

An interinstitutional review of the value of FNAB in pediatric oncology in resource-limited countries.

Fine-needle aspiration biopsy (FNAB) has been widely accepted as a reliable diagnostic modality in the general pediatric population, but its role in pediatric oncology still remains elusive. With new treatment protocols subscribing to preoperative chemotherapy, the need for a quick, minimally invasive, and accurate diagnostic procedure has arisen. This study assesses the feasibility of FNAB in childhood malignancies to render a specific diagnosis on which treatment can be initiated. An 11-year retrospective study was done on FNABs in patients 19 years and under referred for clinically malignant mass lesions. Cases were confirmed with histology, immunocytochemistry, flow cytometry, or clinical follow-up. Of the 357 patients referred for FNABs, 36 patients were lost to follow-up and 31 FNABS were inadequate. A total of 290 cases were included in the study, of which 68 (23%) cases were benign and 222 (77%) were malignant. The most frequently occurring tumors were nephroblastoma (68), non-Hodgkin's lymphoma (39), rhabdomyosarcoma (22), Hodgkin's lymphoma (22), and neuroblastoma (22). The sensitivity of the procedure for neoplasia was 96.6%, the specificity 97.0%, positive predictive value 99.0%, and negative predictive value 90.1%, with a diagnostic accuracy of 96.7%. The ability of FNAB to enable a specific diagnosis to be made, that is correct and accurate subtyping of the tumor on which chemotherapy or radiotherapy could be commenced was 75.7%. This study shows that FNAB can be used with confidence to confirm malignancy in children. With clinicoradiological correlation and the aid of ancillary techniques, FNAB allows a rapid and accurate preoperative diagnosis for definitive therapy commencement in most cases.