Purpose: Fusion-positive myoepithelial tumors (MET) are clinicopathologically heterogeneous and variably termed mixed tumors and myoepithelial carcinomas. As FET-rearranged METs lack ductal/epithelial differentiation, we test whether FET-rearranged METs are epigenetically distinct from adnexal PLAG1-rearranged METs, which we hypothesize to be analogues of salivary gland METs. Experimental Design: DNA methylation profiling from a multi-institutional cohort of 52 fusion-positive skin, soft-tissue, and bone MET cases was performed and compared with diverse tumor types, including salivary METs. The MET subgroups harbored EWSR1::KLF15, EWSR1/FUS::KLF17, EWSR1::PBX1, EWSR1::PBX3, EWSR1/FUS::POU5F1, SS18::POU5F1, EWSR1::ZNF444, and PLAG1 rearrangements. Pooled clinicopathologic and outcome analysis with new and published cases (total 185) was performed. Results: The MET subgroups showed significant heterogeneity in age, site, and histology. Specifically, EWSR1::KLF15 METs affected predominantly young children (<5 years); EWSR1::PBX1/PBX3 METs were enriched in skin/bone; and EWSR1/FUS::POU5F1, SS18::POU5F1, and EWSR1::KLF15 METs tended to display malignant histology. Conversely, PLAG1-rearranged tumors were predominantly benign, arising in older adults and located in the skin. DNA methylation profiling revealed that FET-rearranged METs were epigenetically related to SS18::POU5F1 METs and FET::NFATC2 sarcomas but entirely distinct from PLAG1-rearranged adnexal and salivary METs. Histologic features were correlated with the degree of genome-wide copy-number variation. The median disease-specific survival was shortest in SS18::POU5F1 (31 months), EWSR1::PBX3 (38 months), and EWSR1::KLF15 (45 months) METs. On multivariate analysis, age <25 years was a significant predictor of worse progression-free survival. Conclusions: FET-rearranged METs are epigenetically unrelated to cutaneous and salivary gland METs, and their malignant counterparts are best classified as sarcomas rather than carcinomas.

SS18::POU5F1-fused sarcomas are rare tumors that show an undifferentiated round cell morphology. We report for the first time a case of SS18::POU5F1-fused sarcoma occurring in the parotid gland, with a highly unusual biphasic morphology comprising of epithelioid/undifferentiated round cell component and a ganglioneuromatous component consistent with divergent differentiation. We illustrate the cytology, histomorphological, immunohistochemical profile of the tumor, and show that both components of the tumor share a common origin. We discuss the differential diagnoses of this tumor, discuss its possible histogenesis, and perform a broad review of the literature covering this uncommon tumor.

Adamantinoma-like Ewing sarcoma (ALES) is a rare malignant neoplasm currently classified as a subtype of Ewing sarcoma (ES) and is similarly molecularly defined by a FET-ETS translocation. However, ALES demonstrates some morphologic and immunohistochemical features distinct from conventional ES. In this case report, we present the clinico-pathological features of a case of ALES in the nasal septum of a 75-year-old lady, with a hitherto unreported NRAS Q61R mutation. Further studies are required to investigate the prevalence and clinical significance of the NRAS Q61R mutation in ALES.

BACKGROUND:Perivascular epithelioid cell tumours (PEComas) constitute a unique group of neoplasms with a distinctive myomelanocytic immunohistochemical phenotype and uncommonly occur in the head and neck region. We herein report the clinicopathologic features of a case of a sinonasal PEComa occurring in an 18-year-old male with a novel TRAF3::TFE3 fusion. CASE PRESENTATION:The patient presented with an infiltrative nasal cavity tumour. Histologic examination showed a tumour composed of sheets and nests of epithelioid cells with clear to eosinophilic granular cytoplasm, round to oval nuclei, inconspicuous nucleoli and no mitotic activity. The tumour cells featured strong diffuse expression of smooth muscle actin and nuclear TFE3, with patchy expression of HMB45. Neoplastic cells showed no immune-reactivity for Melan A. Molecular genetic analysis revealed a novel TRAF3(ex8)::TFE3(ex6) fusion. CONCLUSIONS:This report contributes to the expanding molecular spectrum of TFE3-altered PEComas of the head and neck region and discusses the differential diagnoses of these tumours. We further describe the evolving understanding of TFE3-altered PEComas.

Adult rhabdomyoma is an uncommon benign mesenchymal neoplasm that most often occurs in the head and neck. We present a 70 year-old male with a swelling on the floor of the mouth. Subsequent excision of the tumor revealed a hitherto undescribed morphological variant of this tumor that features a predominance of clear cells, which on light microscopy may mimic other other clear cell tumours of the head and neck region. We perform an in-depth analysis of the morphological and immunohistochemical features of this tumor, as well as discuss pitfalls in the diagnosis of this tumor and its differential diagnosis in the head and neck region.

Introduction: Angiosarcoma of the salivary gland is a rare malignant vasoformative neoplasm that shows a predilection for the parotid gland and most commonly occurs in older patients. Preoperative diagnosis may be challenging, especially on cytology, where there may be significant morphological overlap with high grade malignancies of the salivary gland.

BACKGROUND:Angiosarcoma is a sarcoma that occurs in a range of tissue types, and only rarely in the salivary glands, showing a predilection for the parotid glands of older patients. Preoperative diagnosis may be challenging, especially on cytology, with significant morphological overlap with high-grade primary salivary gland carcinomas. The molecular alterations of this rare salivary gland neoplasm are also not well-characterized. METHODS AND RESULTS:We present a case of right submandibular gland swelling in a 73-year-old male. On fine needle aspiration, including immunohistochemical stains on cell block, the tumor was initially diagnosed as poorly differentiated carcinoma. Resection of the submandibular gland revealed epithelioid angiosarcoma. We performed molecular work-up of the tumor, utilizing targeted next-generation sequencing, DNA methylation profiling and fluorescence in-situ hybridization. Histopathologic assessment revealed an infiltrative tumor comprising solid sheets of epithelioid cells. The tumor cells formed haphazardly anastomosing vascular channels with intracytoplasmic lumina containing red blood cells. On immunohistochemistry, the tumor cells were positive for CD31, CD34 and ERG. Approximately 40% of the tumor cells showed nuclear expression of GATA3. A pathogenic TP53 R267W mutation was detected on next-generation sequencing. DNA methylation analysis did not cluster the tumor with any known sarcoma type. Copy number analysis showed possible MYC amplification and CDKN2A losses, although only the latter was confirmed on fluorescence in-situ hybridization. CONCLUSION:Epithelioid angiosarcoma is an important differential diagnosis to high-grade salivary gland carcinoma. In particular, GATA3 expression may be encountered in both angiosarcoma and high-grade salivary gland carcinomas and cause diagnostic confusion. Identification of TP53 mutations and CDKN2A losses suggest shared oncogenic pathways with soft tissue angiosarcomas, and should be further investigated.

BackgroundMucoepidermoid carcinoma is a malignant salivary gland tumor which, in most cases, is composed of variable proportions of mucous, epidermoid, and intermediate cells.MethodsWe report a case of parapharyngeal mucoepidermoid carcinoma with highly unusual ("monomorphic") light microscopic features as well as atypical immunohistochemical properties. Molecular analysis was performed using the TruSight RNA fusion panel.ResultsThe tumor featured heretofore undescribed histopathological features: sheets and nests composed of monomorphic neoplastic (plump spindle to epithelioid) cells with no mucous, intermediate, glandular/columnar, or any other cell type identified. The neoplastic cells displayed variable clear cell change and only expressed cytokeratin 7. Despite this non-classical morphology, the presence of the classical CRTC1::MAML2 fusion was demonstrated.ConclusionsMucoepidermoid carcinoma featuring a uniform ("monomorphic") population of neoplastic cells is a novel observation. A confident diagnosis of mucoepidermoid carcinoma can be made upon detection of the CRTC1/3::MAML2 fusion. Our case increases the spectrum of histopathological appearances that mucoepidermoid carcinoma may display.

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.

BACKGROUND:Crystal-storing histiocytosis (CSH) is a rare disorder which most commonly occurs in the setting of concurrent lymphoproliferative disease. Morphologically, it consists of aggregates of histiocytes containing eosinophilic crystalline material, which in most cases is composed of aggregated abnormal light chains. METHODS:Using histomorphology, immunohistochemistry and in situ hybridization, the authors characterize a rare case of orbital CSH associated with extranodal marginal zone (MALT) lymphoma and report for the first time the frozen section features of CSH. RESULTS:The frozen section featured plump histiocytes with ample weakly basophilic to grayish cytoplasm with a microvacuolated appearance and focal stippling. These features stand in contrast with the formalin-fixed, paraffin embedded histomorphological appearance of aggregates of plump histiocytes with densely eosinophilic crystalline cytoplasmic material. CONCLUSION:CSH is a challenging diagnosis to make on frozen section. The artifacts that preclude its recognition, as well as differential diagnoses of this entity in the head and neck are discussed.

“Some are born great, some achieve greatness, and others have greatness thrust upon them.” ― William Shakespeare, Twelfth Night. Dr. Ondrej Hes clearly belongs to the first category (“born great”), described by William Shakespeare centuries ago. This tribute has been prepared by a group of close friends of Dr. Hes, who had the honor and privilege to know him both personally and professionally over years. On July 2, 2022, Ondrej passed away, a few days after collapsing while running from home to work (his usual routine exercise) outside the hospital in Pilsen (Plzeň) and in the nature that he loved the most. Ondrej was born in Pilsen in former Czechoslovakia on July 21, 1968, to an academic and an artistic family. He received his medical degree in 1993 at the Faculty of Medicine in Pilsen, Charles University. He subsequently completed his postgraduate training in Anatomic Pathology (1996) and went on to obtain his PhD in 2001. In a short period of time, he was promoted to Professor of Pathology at Charles University in 2009. Dr. Hes was a giant in surgical pathology, particularly genitourinary pathology, and especially so in tumors of the kidney. As a world-renowned kidney tumor pathology expert, it is hard to imagine another pathologist who has reviewed as many as renal tumors as Ondrej Hes, through his possibly largest kidney tumor registry in the world and collaborations with pathologists in all five continents. To date, he has published more than 450 peer-reviewed articles, some of which significantly impacted the practice of urologic surgical pathology in the world. His extensive work has been cited over 5300 times, with a remarkable h-index of 47, testament to his significant contribution to our profession and beyond. His curious mind along with extremely friendly and warm personality provided numerous opportunities for him to visit many pathology departments across the globe in search of “orphan renal tumors” (the term he often used for neoplasms that did not currently fit existing classification schemes). Some of the recently described eosinophilic renal tumors, such as eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), low-grade oncocytic tumor (LOT), and eosinophilic vacuolated tumor (EVT) will always remain linked to Ondrej's name, by his instrumental contributions to their first recognition. This is simply a testament to his incredible interest and true passion for patient care. Being an honorable global citizen, Ondrej made numerous and long-lasting real friendships across the world with many pathologists, residents, and fellows. One of his amazing innovative and brilliant ideas was to merge science and friendship, which led him to establish the famous “Kidney Tumor Friends (KTF)” also known as the Pilsen Urogenital Pathology Conference 15 years ago. This is a highly unique academic forum in our field, with focus on exchanging scientific ideas in genitourinary surgical pathology in an environment of rich friendship and recreation. He sometimes joked that eventually the meeting would “have more speakers than audience members,” reflecting the large group of colleagues and collaborators that was generously hosted in the Czech Republic every few years. Ondrej's two main guiding principles in this endeavor were excelling in science while maintaining friendship, which have held true to-date. Ondrej's philosophy in establishing an academic meeting in a non-competitive and relaxed environment has always been appealing to colleagues participating and friends contributing to KTF from around the world. Each KTF meeting led to many scientific collaborations and subsequent publications, including original research and review articles. Ondrej's list of professional achievements and contributions are exemplary with his articles describing new tumor pathology entities, variants/subtypes, diagnostic challenges, and more. He also served numerous international societies, organizations, committees, and working groups, such as the European Society of Pathology (ESP), International Society of Urological Pathology (ISUP), Genitourinary Pathology Society (GUPS), Arkadi M. Rywlin (AMR) International Pathology Slide Seminar Club, and WHO blue books. He was an invited speaker to numerous meetings in the four corners of the globe and had widely lectured around the world on important and challenging genitourinary pathology topics. Ondrej was always a strong believer in education and mentorship. He devoted a major part of his time to teaching medical students, residents, fellows, and junior faculty members. Every year, many pathologists (mostly junior) from all over the world came to Pilsen to train with him and to improve their diagnostic skills in the world of kidney tumors. They also often had the opportunity to collaborate with Ondrej on research projects, some of which led to individuals obtaining their PhDs. Ondrej was a multifaceted individual and a man of wide interests, including sports (he was an avid runner—national championship in the men's 800 m run), photography (some of his professional works were exhibited in Czech museums), art, music, history, politics, and most importantly, ecology. Since his youth, he was interested in nature, especially herpetofauna and entomofauna. In fact, he has authored a number of articles and five books on reptiles and amphibians (his major work and contributions to Pilsen's Zoo is well known). For more than a decade, he was actively involved in the protection and creation of wetlands in the Czech Republic. He founded Eden, an NGO (Non-governmental organization) supporting biodiversity. As he simply stated it “Each of us, even the greatest ecologist, will destroy part of nature in our lifetimes. Come with us to try and repair some of the damage. Let us together protect and recreate nature for future generation” (https://fondeden.cz/). Dr. Ondrej Hes was an incredible scientist and educator, a giant in surgical pathology, a tireless environmentalist, a passionate activist in protecting wildlife and nature, a competitive and friendly athlete, a dedicated husband and a loving father, and an amazing friend. Above all, he was an exceptional human being and an honorable global citizen, whose kindness was readily contagious. His sense of humor was enlightening and inviting; his constant smile, the most heartwarming and genuine. He was always present and ready to help anyone in need. And this reminds us of the 17th century English poet John Bunyan's famous poem: “You have not lived today until you have done something for someone who can never repay you.” And by this virtue, Ondrej Hes certainly lived many lives, and his memory and legacy will remain in our hearts and for generations to come.

This review summarizes the current state of knowledge on sclerosing polycystic adenoma, including epidemiological/clinical, histopathological/cytopathological, ultrastructural, immunohistochemical and etiopathogenetic/molecular genetic aspects. Differential diagnostic issues are briefly discussed.

Background: Oncocytic myoepithelial carcinoma ex pleomorphic adenoma neoplastic is a rare neoplastic event and may not display overt malignant radiological features.Methods: Using routine histopathology and immunohistochemistry, we characterize a case of low-grade oncocytic carcinoma ex pleomorphic adenoma.Results: The tumor arose in the left parotid gland in a 59 year old female. Computed tomography (CT) imaging demonstrated a well-defined, lobulated, enhancing lesion with relative central stellate hypoenhancement. His-tologically, the tumor displayed a multi-nodular, non-destructive, invasive pattern, low mitotic activity (one mitotic figure per 10 high power fields) and a small remnant focus of pleomorphic adenoma. The neoplastic cells showed significant expression of cytokeratin 5/6, S-100 protein, smooth muscle actin and p63.Conclusion: Low-grade oncocytic carcinoma ex pleomorphic adenoma is a challenging histopathological diagnosis which can be established with use of immunohistochemistry, generous tumor sampling and recognition of the multi-nodular, non-destructive, pattern of invasion. In the absence of clear-cut tumor encroachment into external structures, its malignant nature may not be easily identified on pre-operative imaging.

We present two patients (29 and 67 years) with histomorphologic and immunohistochemical evidence of early high-grade transformation of adenoid cystic carcinoma in the nasal cavity and floor of mouth, respectively. The component of early high-grade transformation was characterized by 1) selective expansion of the luminal (CK7+, c-kit+, p63-) cell component with severe cytologic atypia and significantly increased Ki-67 proliferation index, and 2) retained albeit attenuated abluminal (CK7-, c-kit-, p63+) cells, surrounding nests of high-grade luminal cells.

We describe a case of papillary thyroid carcinoma with fibromatosis/fasciitis-like stroma (PTC-FLS) that contained the rare BRAF c.1799_1801delTGA (p.V600_K601delinsE) mutation, which has not previously been reported in this tumour, as well as the CTNNB1 c.133T>C (p.S45P) mutation. We also report the novel observation that spindle cells of the mesenchymal component exhibit diffuse nuclear but not cytoplasmic expression of SOX11, whereas the malignant epithelial cells did not. This suggests that immunoreactivity for SOX11 can be an alternative diagnostic tool for evaluating cases of PTC-FLS where the nuclear expression of β-catenin is ambiguous.

We present a case (41 years old pregnant female) with epithelioid sarcoma arising in the left external auditory canal. On immunohistochemistry, the tumor cell diffusely expressed cytokeratins and showed patchy expression of ERG and CD34. The neoplastic cells demonstrated uniform loss of INI1-expression. Epithelioid sarcoma arising in the external auditory canal is rare. Awareness that ES may rarely arise at unusual sites is of critical importance in order to apply a broad enough panel in the immunohistochemical study, so a misdiagnosis of carcinoma can be avoided.

We present a case of a 1.0 cm primary tumor of the left parotid gland that meets the histological criteria for the recently described entity sclerosing microcystic adenocarcinoma. The patient was a 73-year-old man with a concurrent tonsillar squamous cell carcinoma, and a history of nasopharyngeal carcinoma treated with radiotherapy 23 years prior. Fine needle aspiration cytology demonstrated low-grade biphasic basaloid neoplastic cells arranged in branching sheets and clusters with minimal nuclear pleomorphism. A biphasic appearance was apparent and some of the cell clusters were bordered by a layer of flattened cells with ovoid bland nuclei. On histology, the tumor comprised small bilayered infiltrative tubules, nests, cords, and microcysts. On immunohistochemistry, EMA, SOX-10, P63, and S-100 protein highlighted a dual cell population of luminal and abluminal cells. The cells were negative for CD117, and the Ki-67 proliferation index was low (<5%).

Considering the increasing competition between brands and products, packaging has become an important framing tool to influence customers' purchasing decisions. However, given the growing environme ...

We present 783 surgical resections of typical and atypical carcinoid tumors of the lung identified in the pathology files of 20 different pathology departments. All cases were critically reviewed for clinical and pathological features and further correlated with clinical outcomes. Long-term follow-up was obtained in all the patients and statistically analyzed to determine significance of the different parameters evaluated. Of the histopathological features analyzed, the presence of mitotic activity of 4 mitoses or more per 2 mm2, necrosis, lymphatic invasion, and lymph node metastasis were identified as statistically significant. Tumors measuring 3 cm or more were also identified as statistically significant and correlated with clinical outcomes. Based on our analysis, we consider that the separation of low- and intermediate-grade neuroendocrine neoplasms of the lung needs to be readjusted in terms of mitotic count as the risk of overgrading these neoplasms exceeds 10% under the current criteria. We also consider that tumor size is an important feature to be considered in the assessment of these neoplasms and together with the histological grade of the tumor offers important features that can be correlated with clinical outcomes.