Defining the first bona fide cell model for SMARCA4-deficient, undifferentiated tumor.

The World Health Organization's tumor classification guidelines are frequently updated and renewed as knowledge of cancer biology advances. For instance, in 2021, a novel lung tumor subtype named SMARCA4-deficient, undifferentiated tumor (SMARCA4-dUT, code 8044/3) was included. To date, there is no defined cell model for SMARCA4-dUT that could be used to help thoracic clinicians and researchers in the study of this newly defined tumor type. As this tumor type was recently described, it is feasible that some cell models formerly classified as lung adenocarcinoma (LUAD) could now be better classified as SMARCA4-dUT. Thus, in this work, we aimed to identify a bona fide cell model for the experimental study of SMARCA4-dUT. We compared the differential expression profiles of 36 LUAD-annotated cell lines and 38 cell lines defined as rhabdoid in repositories. These comparative results were integrated with the mutation and expression profiles of the SWI/SNF complex members, and they were surveyed for the presence of the SMARCA4-dUT markers SOX2, SALL4, and CD34, measured by RT-qPCR and western blotting. Finally, the cell line with the paradigmatic SMARCA4-dUT markers was engrafted into immunocompromised mice to assess the histological morphology of the formed tumors and compare them with those formed by a bona fide LUAD cancer cell line. NCI-H522, formerly classified as LUAD, displayed expression profiles nearer to rhabdoid tumors than LUAD tumors. Furthermore, NCI-H522 has most of the paradigmatic features of SMARCA4-dUT: hemizygous inactivating mutation of SMARCA4, severe SMARCA2 downregulation, and high-level expression of stem cell markers SOX2 and SALL4. In addition, the engrafted tumors of NCI-H522 did not display a typical differentiated glandular structure as other bona fide LUAD cell lines (A549) do but had rather a largely undifferentiated morphology, characteristic of SMARCA4-dUT. Thus, we propose the NCI-H522 as the first bona fide cell line model of SMARCA4-dUT. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Histogenetic insights and genetic landscape of fibromatosis-like undifferentiated gastric carcinoma: a focused study.

BACKGROUND: The aim of this study was to elucidate the histogenesis and genetic underpinnings of fibromatosis-like undifferentiated gastric carcinoma (FLUGC), a rare pathological entity. METHOD: Through a detailed analysis of seven cases, including histopathological evaluation, CTNNB1 gene mutation screening, human epidermal growth factor receptor 2 (HER2) protein level quantification, and HER2 gene amplification assessment to identify the pathological and molecular characteristics of FLUGC. RESULTS: Of the seven patients in this study, five were male and two were female (age: 39-73 years). Four patients presented with lesions in the gastric antrum and three had lesions in the lateral curvature of the stomach. Histopathologically, over 90% of the tumor consisted of aggressive fibromatosis-like tissue, including proliferating spindle fibroblasts and myofibroblasts and varying amounts of collagenous fibrous tissues. Undifferentiated cancer cells, accounting for less than 10%, were dispersed among the aggressive fibromatosis-like tissues. These cells were characterized by their small size and were relatively sparse without glandular ducts or nested mass-like structures. Immunophenotyping results showed positive expression of CKpan, CDX2, villin, and p53 in undifferentiated cancer cells; positive expression of vimentin in aggressive fibromatosis-like tissue; positive cytoplasmic expression of ß-catenin; and focal cytoplasmic positive expression of smooth muscle actin (SMA). Genetic analysis did not reveal any mutations in the CTNNB1 gene test, nor was there amplification in the HER2 gene fluorescence in situ hybridization (FISH) test. Additionally, the Epstein-Barr encoding region (EBER) of in situ hybridization was negative; and the mismatch repair (MMR) protein was positive. Programmed cell death-1 (PD-1) was < 1-5%; programmed cell death ligand 1 (PD-L1): TPS = 1-4%, CPS = 3-8. CONCLUSION: The study highlights the significance of CTNNB1, HER2, EBER, and MMR as pivotal genetic markers in FLUGC, underscoring their relevance for diagnosis and clinical management. The rarity and distinct pathological features of FLUGC emphasize the importance of accurate diagnosis to prevent underdiagnosis or misdiagnosis and to raise awareness within the medical community.

Case report metastatic SMARCB1 (INI1)-deficient gastric undifferentiated carcinoma in pleural effusion: A case report and literature review.

INI1-deficient gastric undifferentiated carcinoma is a rare tumour that may present as high-grade epithelioid morphology without apparent rhabdoid tumour cells. Syncytial tumour cells may be a crucial clue in such cases, especially in cytological specimens. Cell block and immunocytochemical staining can be valuable tools in achieving an accurate diagnosis.

Undifferentiated Carcinoma with Osteoclast-like Giant Cells of the Pancreas: Molecular Genetic Analysis of 13 Cases.

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas is a rare malignancy regarded as a subvariant of pancreatic ductal carcinoma (PDAC) characterized by variable prognosis. UCOGC shows a strikingly similar spectrum of oncogenic DNA mutations to PDAC. In the current work, we analyzed the landscape of somatic mutations in a set of 13 UCOGC cases via next-generation sequencing (NGS). We detected a spectrum of pathogenic or likely pathogenic mutations similar to those observed in PDAC following previously published results (10 KRAS, 9 TP53, 4 CDKN2A, and 1 SMAD4, CIC, GNAS, APC, ATM, NF1, FBXW7, ATR, and FGFR3). Our results support the theory that UCOGC is a variant of PDAC, despite its unique morphology; however, a UCOGC-specific genomic signature as well as predictive markers remain mainly unknown. Programmed death ligand 1 (PD-L1) status remains an important predictive marker based on previous studies.

Meta-analysis of multi-modality therapies in sinonasal undifferentiated carcinoma-A timely update.

OBJECTIVES: Sinonasal undifferentiated carcinoma (SNUC) is a rare but aggressive tumour with very poor prognosis. There are currently no well-established clinical trials to guide therapy and the impact of various treatment modalities on survival is not well defined. We aim to provide an updated systematic review on current treatment modalities on survival outcomes. DESIGN AND SETTING: Individual patient data were extracted, and survival data pooled in a one-stage meta-analysis. Descriptive statistics were analysed using the Kaplan-Meier method. Patient-level comparisons stratified by treatment modalities, adjusted for demographics, were conducted using shared-frailty Cox regression. PARTICIPANTS AND MAIN OUTCOME MEASURES: Participants include all patients diagnosed with SNUC based on histological evidence. We looked at the overall cumulative survival outcome for different treatment modalities and overall survival by treatment modality in low versus high stage SNUC patients. RESULTS AND CONCLUSION: Seventeen studies were identified, comprising 208 patients from 1993 to 2020. There was no significant difference in cumulative overall survival in low versus high stage patients, and no significant difference in outcomes by treatment modality. The overall cumulative survival of SNUC is 30% at 95 months. Among patients treated with various combinations of treatment modalities, patients with chemoradiotherapy had the highest cumulative survival of 42% at 40 months. Definitive chemoradiotherapy was associated with improved disease survival rate. Regardless of tumour stage, patients should be treated early and aggressively, with no superiority of one treatment regimen over another. Trimodality treatment does not confer survival advantage over bimodality treatment.

Common clinicopathological and immunological features of sarcomatoid carcinoma across organs: A histomorphology-based cross-organ study.

Sarcomatoid carcinoma (SC), which can occur in any organ, is a rare disease. To elucidate common characteristics of SC beyond organs, we evaluated clinicopathological and immunological features of SC defined by the single histological criterion beyond organs compared to randomly matched conventional carcinoma (non-SC) adjusted for the disease stage. Immunological features were assessed by multiplex immunohistochemistry, comparing immune cell density in tumor tissues and tumor programmed death-ligand 1 (PD-L1) expression. A total of 101 patients with SC or non-SC (31 lung, 19 esophagus, 22 pancreas, 15 liver, 4 bile duct, 6 kidney, 2 uterus and 2 ovary) were identified among 7197 patients who underwent surgery at our institute (1997-2020). SC was significantly associated with worse survival (HR: 1.571; 95% CI: 1.084-2.277; P = .017). The frequency of postoperative progression within 6 months was significantly higher for SC patients (54% vs 28%; P = .002). The immune profiling revealed the densities of CD8+ T cells (130 vs 72 cells/mm2 ; P = .004) and tumor-associated macrophages (566 vs 413 cells/mm2 ; P < .0001) and the tumor PD-L1 expression score (40% vs 5%; P < .0001) were significantly higher in SCs than in non-SCs. Among 73 SC patients with postoperative progression, multivariate Cox regression analysis showed that immunotherapy tended to be associated with favorable survival (HR: 0.256; 95% CI: 0.062-1.057; P = .060). Collectively, SCs shared clinicopathological and immunological features across organs. Our study can initiate to standardize the pathological definition of SC and provide a rationale for the investigation and development for this rare disease in a cross-organ manner.

Mesonephric-like adenocarcinoma of the female genital tract: novel observations and detailed molecular characterisation of mixed tumours and mesonephric-like carcinosarcomas.

AIMS: To report novel observations in five mesonephric-like adenocarcinomas (MLAs) of the female genital tract. METHODS AND RESULTS: We report two endometrial MLAs in association with endometrioid carcinoma and atypical hyperplasia and three (one endometrial, two ovarian) cases with a sarcomatoid component (mesonephric-like carcinosarcoma). Pathogenic KRAS mutations, which are characteristic of MLA, were identified in all cases although interestingly, in one of the mixed carcinomas, this was confined to the endometrioid component. The concurrent MLA, endometrioid carcinoma and atypical hyperplasia components in one case harboured identical EGFR, PTEN and CCNE1 mutations, suggesting that the atypical hyperplasia gave rise to a Müllerian carcinoma with both endometrioid and mesonephric-like components. The carcinosarcomas all contained a component of MLA and a sarcomatous component with chondroid elements. In the ovarian carcinosarcomas, the coexisting epithelial and sarcomatous components shared some mutations including KRAS and CREBBP, suggesting that they are clonally related. Furthermore, in one case CREBBP and KRAS mutations detected in the MLA and sarcomatous components were also detected in an associated undifferentiated carcinoma component, suggesting that it was clonally related to the MLA and sarcomatous components. CONCLUSIONS: Our observations provide additional evidence that MLAs have a Müllerian origin and characterise mesonephric-like carcinosarcomas in which chondroid elements appear to be characteristic. In reporting these findings, we provide recommendations for distinction between a mesonephric-like carcinosarcoma and a MLA with a spindle cell component.

The Role of Induction Therapy for Sinonasal Cancers.

OPINION STATEMENT: The role of induction chemotherapy in sinonasal cancers is promising; however, prospective studies with higher grades of evidence are needed. With the currently available literature, the authors would advocate for the use of induction chemotherapy (IC) in locally advanced sinonasal squamous cell carcinoma (T3-T4) for organ preservation and potentially for improved survival outcomes. In sinonasal undifferentiated carcinoma (SNUC), IC should be considered in all patients given its tendency for aggressive invasion and poor outcomes. In SNUC, response to IC may direct the modality of definitive treatment to follow. In responders (partial or complete), chemoradiation therapy should be strongly considered. In non-responders or in those with progression of disease, surgical therapy is favored. For esthesioneuroblastoma, surgical resection with negative margins and adjuvant radiation therapy remains the gold standard. However, IC may be considered for locally advanced disease especially with orbital invasion or in recurrent/distant disease. There is no definite indication for IC in sinonasal adenoid cystic carcinoma or sinonasal adenocarcinoma. Recommendations are summarized in Table 1.

Comprehensive review of undifferentiated carcinoma of the pancreas: from epidemiology to treatment.

Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments.

Sinonasal undifferentiated carcinoma with metastasis to the extradural spine.

Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer of the sinonasal tract and is often characterized by intracranial invasion. However, SNUC rarely metastasizes to the spine. In this paper, we present a case of extradural metastasis and invasion of the adjacent spine by SNUC. A 42-year-old man presented to our hospital with two-month history of anosmia and nosebleeds. Imaging studies showed a neoplasm of the ethmoid sinus with extension into the anterior cranial fossa. The patient underwent resection of the carcinoma and began chemoradiotherapy. After completing chemoradiotherapy the patient complained of neck pain radiating down the right arm, and imaging showed an extradural mass at the C5 vertebral level. The patient underwent laminectomy for debulking of this tumor. One month later, the patient complained of recurrent weakness and pain in the right shoulder and arm. Imaging showed an extradural tumor wrapping around the C7 and C8 nerve roots, as well as a separate tumor at C2 adherent to the dura. The extradural tumor at C2 was surgically resected. Further imaging showed multiple new soft tissue masses at the thoracic level. We present a case of SNUC metastasis to the extradural spine representing the second case reported in the literature. Peri-dural metastasis and resulting symptoms should be included in the differential diagnosis and assessment of patients with SNUC.

Application Of New WHO Classification On Malignancies Of Sinonasal Tract: Correlation With Epidemiology And Survival In Pakistani Population.

Objectives: To analyse the clinicopathological characteristics of sinonasal malignancies in the light of the updates regarding head and neck tumours. METHODS: The retrospective study was conducted at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised data of patients diagnosed with primary malignant tumours of the sinonasal tract between 2015 and 2020. Slides related to biopsies and resection specimens were retrieved from the institutional database and reviewed by two pathologists. Follow-up data was also obtained. Data was analysed using SPSS 20. RESULTS: Of the 245 samples, 144(58.7%) were epithelial tumours, 46(18.7%) neuroectodermal tumours, 41(16.7%) haematolymphoid tumours and 14(5.7%) were malignant soft tissue tumours. A heavy reliance was placed on immunohistochemical stains to diagnose poorly-differentiated tumours. Survival was dismal, especially with early and frequent spread to the brain (33.3% in cases of Sinonasal Undifferentiated Carcinoma). CONCLUSIONS: A wide array of sinonasal malignancies was seen. Updated knowledge of the malignancies prevalent in the region is imperative for timely diagnosis and treatment.

[Undifferentiated pancreatic carcinoma with osteoclast-like giant cells]. / Nedifferentsirovannaya kartsinoma podzheludochnoi zhelezy s osteoklastopodobnymi gigantskimi kletkami.

In the structure of malignant oncological diseases of the Russian population, pancreatic cancer (PCa) occupies the 10th place with a high mortality rate in case of late diagnosis, which is primarily due to the minimal clinical manifestations of this pathology and the absence of precancer as a potential substrate for screening. Undifferentiated pancreatic carcinoma with osteoclast-like giant cell (UC-OGC) is a rare histological variant of PCa with discussed bidirectional histogenesis (epithelial and mesenchymal), epithelial-mesenchymal transition in the tumor and variable prognosis depending on the predominant cellular component. A review of the literature reflecting debatable issues of origin, clinical and pathological characteristics and prognosis of UC-OGC, as well as a description of a clinical case is relevant due to the rare occurrence of this tumor in the routine work of pathologists and oncologists.

ZEB1 expression is frequently detected in undifferentiated and de-differentiated carcinomas, but is not specific among endometrial carcinomas.

AIMS: The pathological diagnosis of undifferentiated and de-differentiated endometrial carcinomas (UC/DCs) is prognostically important. However, undifferentiated components may be confused with other subtypes, particularly grade 3 endometrioid carcinomas (G3ECs). Zinc finger E-box binding homeobox 1 (ZEB1) has recently been identified as a promising marker because it is frequently expressed in the undifferentiated components of UC/DCs, but not in other carcinomas. Therefore, we herein evaluated the diagnostic utility of ZEB1 with an emphasis on distinguishing between UC/DCs and G3ECs using an expanded cohort of endometrial carcinomas and carcinosarcomas. METHODS AND RESULTS: Immunostaining for ZEB1 was performed on whole-tissue sections of 19 UC/DCs, 194 non-UC/DC endometrial carcinomas and 29 carcinosarcomas. Staining was defined as negative (< 5%), focal (5-50%) and diffuse expression (> 50%). ZEB1 was expressed in 84% of the undifferentiated components of UC/DCs (diffuse in 14, focal in two). Focal expression was observed in eight non-UC/DC endometrial carcinomas and diffuse expression in seven, with the latter comprising G3ECs (four of 76), serous carcinoma (one of 37), clear cell carcinoma (one of 21) and neuroendocrine carcinoma (one of three). Epithelial differentiation was morphologically and immunohistochemically less evident in G3ECs and neuroendocrine carcinoma with diffuse ZEB1 expression. All carcinosarcomas showed diffuse ZEB1 expression in their sarcomatous components. CONCLUSION: Immunostaining for ZEB1 was sufficiently sensitive to detect undifferentiated components. Diffuse ZEB1 expression showed high specificity for distinguishing between undifferentiated components and G3ECs; however, ZEB1 expression was not entirely specific to UC/DCs. The integration of ZEB1 into the diagnosis of UC/DCs requires careful examination to exclude other tumours, such as less differentiated G3ECs, neuroendocrine carcinomas and carcinosarcomas.

Effect of Helicobacter pylori infection on malignancy of undifferentiated-type gastric cancer.

BACKGROUND: Although almost all cases of gastric cancer are caused by Helicobacter pylori (HP) infection, there are some rare exceptions. Furthermore, the clinicopathological characteristics of gastric cancer may differ depending on HP infection status. This study aimed to determine the clinicopathological characteristics of undifferentiated-type gastric cancer (UD-GC) according to HP status. METHODS: The study involved 83 patients with UD-GC who were selected from 1559 patients with gastric cancer who underwent endoscopic resection at our hospital and whose HP infection status was confirmed. Clinicopathological characteristics were evaluated according to HP status (eradicated, n = 28; infected, n = 32; not infected, n = 23). RESULTS: In patients without HP infection, UD-GCs were < 20 mm and intramucosal with no vascular invasion. In patients with eradicated HP, there was no correlation between development of UD-GC and time since eradication. Nine of twelve patients with a tumor detected ≥ 5 years after eradication had undergone yearly endoscopy. Submucosal invasion was observed in two of four patients and lymphovascular invasion in three of four patients whose UD-GC was detected ≥ 10 years after eradication. There was no significant between-group difference in the frequency of lesions with invasion into the submucosal layer or deeper (14.3%, 10.5%, and 0% in the UD-E, UD-I, and UD-U groups, respectively). CONCLUSION: The clinicopathological characteristics of UD-GC were similar between HP-infected patients and HP-eradicated patients. Three of four patients with eradicated HP whose UD-GC developed ≥ 10 years after eradication were not eligible for endoscopic treatment and required additional surgery resection. In contrast, UD-GC was curable by endoscopic resection in all patients without HP infection.

Molecular Biomarkers in Sinonasal Cancers: New Frontiers in Diagnosis and Treatment.

PURPOSE OF REVIEW: Sinonasal tumors are rare and heterogeneous diseases which pose challenges in diagnosis and treatment. Despite significant progress made in surgical, oncological, and radiotherapy fields, their prognosis still remains poor. Therefore, alternative strategies should be studied in order to refine diagnosis and improve patient care. RECENT FINDINGS: In recent years, in-depth molecular studies have identified new biological markers, such as genetic abnormalities and epigenetic variations, which have allowed to refine diagnosis and predict prognosis. As a consequence, new histological entities have been described and specific subgroup stratifications within the well-known histotypes have been made possible. These discoveries have expanded indications for immunotherapy and targeted therapies in order to reduce tumor spread, thus representing a valuable implementation of standard treatments. Recent findings in molecular biology have paved the way for better understanding and managing such rare and aggressive tumors. Although further efforts need to be made in this direction, expectations are promising.

Undifferentiated carcinoma with osteoclast-like giant cells: A pathologic-radiologic correlation of a rare histologic subtype of pancreatic ductal adenocarcinoma.

Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) is an exceedingly rare subtype of pancreatic ductal adenocarcinoma. Histologically, UC-OGC is characterized by three cell types namely, a neoplastic mononuclear cell component, non-neoplastic osteoclast-like giant cells, and a non-neoplastic mononuclear histiocytic component. The behavior of this tumor is unpredictable; but many patients survive many years after diagnosis. UC-OGC may have a better prognosis compared to conventional pancreatic adenocarcinoma due to its slower local spread, less aggressive nature, better response to surgical resection and/or chemotherapy, and fewer metastases. Due to likely differences in prognosis and significant impact on patient management, it is important to distinguish this subtype from other types of pancreatic adenocarcinoma. We report a case of a small (<1 cm) undifferentiated carcinoma with osteoclast-like giant cells of the posterior pancreatic body discovered incidentally on magnetic resonance image (MRI) scan of a middle-aged man. The radiologic and pathologic findings are presented along with a discussion of the differential diagnosis of this exceedingly rare entity.

Risk stratification and prognostic factors in patients with unresectable undifferentiated carcinoma of the pancreas.

BACKGROUND: Undifferentiated carcinoma (UC) of the pancreas has been considered a highly aggressive malignancy. However, only a few studies have systematically described the clinical course of UC patients. The aim of this study was to clarify the prognosis and construct a prognostic model for patients with unresectable UC. METHODS: This study was conducted at 17 institutions in Japan, and a total of 55 patients were analyzed. RESULTS: The median overall survival (OS) of patients with unresectable UC was 3.95 months. In the multivariate Cox proportional hazards (CPH) model, age ≥65 years, Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, and C-reactive protein (CRP) >10 mg/L were independent prognostic factors for OS (age ≥65 years: hazard ratio [HR], 2.732; 95% confidence interval [CI], 1.353-5.515; ECOG PS ≥ 2: HR, 7.866; 95% CI, 1.981-31.241; CRP >10 mg/L: HR, 1.956; 95% CI, 1.013-3.775). Based on the ß coefficients from the CPH model, the prognostic scores were defined as follows: age ≥65 years (3 points), ECOG PS ≥ 2 (6 points), and CRP >10 ml/L (2 points). The final prognostic model was the sum of the points. The derived prognostic model stratified patients into high-risk (score ≥4) and low-risk (score 0-3) groups, with significant differences in OS (1.45 vs. 8.19 months, respectively; p < 0.001). CONCLUSIONS: The prognostic model stratified patients into high-risk and low-risk groups. These findings suggest that this model can serve as a tool for patient information and decision-making with regard to the therapeutic strategy for UC.

Dedifferentiated and undifferentiated neoplasms: A conceptual approach.

This review provides a conceptual approach to dedifferentiation across a variety of tumor types, with particular attention to genetic events that tie together morphologically disparate areas of these neoplasms. First, working definitions of the terms differentiated, undifferentiated, and dedifferentiated are developed. Then, specific examples of tumors with a particular propensity for undergoing dedifferentiation are highlighted, with emphasis on both immunohistochemical studies and molecular lesions that enable surgical pathologists to establish diagnostic clarity in morphologically vexing situations. Throughout this review, the historical arc of the literature is followed, and therefore the discussion of specific tumor types begins with dedifferentiated chondrosarcoma, the neoplasm that inspired the terminology regarding dedifferentiation that remains in use today. Selected other sarcomas with well-established pathways of dedifferentiation are subsequently discussed, followed by descriptions of this process in subtypes of carcinoma and melanoma.

Undifferentiated and dedifferentiated neoplasms of the female genital tract.

Undifferentiated neoplasms in the female gynecologic tract comprise two main groups-undifferentiated carcinoma, most common in the endometrium and ovary, and undifferentiated uterine sarcoma, although tumors with an undifferentiated appearance may occur in all gynecologic organs. Their differential diagnosis is broad and generous sampling, careful morphological evaluation, judicious use of immunohistochemistry, and in many cases, molecular testing is often essential in the diagnostic work-up. As some of these neoplasms fail to respond to conventional chemotherapy regimens and/or radiation therapy, targeted therapy may be valuable in treating these highly aggressive tumors, thus the importance of precise diagnosis. In this review we discuss the clinicopathological features of undifferentiated carcinoma, dedifferentiated carcinoma, and undifferentiated uterine sarcoma, followed by a comprehensive analysis of morphological mimickers. Finally, we briefly review ovarian and lower genital tract tumors with an undifferentiated histological appearance.

Undifferentiated and dedifferentiated head and neck carcinomas.

Undifferentiated carcinomas arising at salivary gland and head and neck mucosal sites may originate either de novo or through a process of dedifferentiation of a differentiated carcinoma. While in the latter group the diagnosis is largely dependent on the identification of the differentiated component or recognition of a specific genotype, the classification of undifferentiated carcinomas that lack a differentiated component is mainly based on the identification of specific genetic drivers, like for example the NUTM1 fusions in NUT carcinoma. A further category is represented by virus associated carcinomas (mainly HPV and EBV), that frequently displays an undifferentiated morphology. Overall, these tumors often represent a diagnostic challenge, especially in small biopsies. This review summarizes and discuss the diagnostic approach to the main head and neck carcinoma types that frequently or occasionally display an undifferentiated appearance, with a focus on salivary gland, oropharyngeal, nasopharyngeal and sinonasal subsites.