RESUMEN
Mechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly described due to its rare nature. A subset of SNSCC are associated with the human papillomavirus (HPV); however, it is unknown whether HPV is a driver of HPV-associated SNSCC tumorigenesis or merely a neutral bystander. We hypothesized that performing the first large high-throughput sequencing study of SNSCC would reveal molecular mechanisms of tumorigenesis driving HPV-associated and HPV-independent SNSCC and identify targetable pathways. High-throughput sequencing was performed on 64 patients with HPV-associated and HPV-independent sinonasal carcinomas. Mutation annotation, viral integration, copy number, and pathway-based analyses were performed. Analysis of HPV-associated SNSCC revealed similar mutational patterns observed in HPV-associated cervical and head and neck squamous cell carcinoma, including lack of TP53 mutations and the presence of known hotspot mutations in PI3K and FGFR3. Further similarities included enrichment of APOBEC mutational signature, viral integration at known hotspot locations, and frequent mutations in epigenetic regulators. HPV-associated SNSCC-specific recurrent mutations were also identified including KMT2C , UBXN11 , AP3S1 , MT-ND4 , and MT-ND5 . Mutations in KMT2D and FGFR3 were associated with decreased overall survival. We developed the first known HPV-associated SNSCC cell line and combinatorial small molecule inhibition of YAP/TAZ and PI3K pathways synergistically inhibited tumor cell clonogenicity. In conclusion, HPV-associated SNSCC and HPV-independent SNSCC are driven by molecularly distinct mechanisms of tumorigenesis. Combinatorial blockade of YAP/TAZ and vertical inhibition of the PI3K pathway may be useful in targeting HPV-associated SNSCC whereas targeting MYC and horizontal inhibition of RAS/PI3K pathways for HPV-independent SNSCC. One Sentence Summary: This study solidifies HPV as a driver of HPV-associated SNSCC tumorigenesis, identifies molecular mechanisms distinguishing HPV-associated and HPV-independent SNSCC, and elucidates YAP/TAZ and PI3K blockade as key targets for HPV-associated SNSCC.
RESUMEN
Since their original description as a distinctive neoplastic entity, ~50 TFE3 -rearranged perivascular epithelioid cell tumors (PEComas) have been reported. We herein report 25 new TFE3 -rearranged PEComas and review the published literature to further investigate their clinicopathologic spectrum. Notably, 5 of the 25 cases were associated with a prior history of chemotherapy treatment for cancer. This is in keeping with prior reports, based mainly on small case series, with overall 11% of TFE3 -rearranged PEComas being diagnosed postchemotherapy. The median age of our cohort was 38 years. Most neoplasms demonstrated characteristic features such as nested architecture, epithelioid cytology, HMB45 positive, and muscle marker negative immunophenotype. SFPQ was the most common TFE3 fusion partner present in half of the cases, followed by ASPSCR1 and NONO genes. Four of 7 cases in our cohort with meaningful follow-up presented with or developed systemic metastasis, while over half of the reported cases either recurred locally, metastasized, or caused patient death. Follow-up for the remaining cases was limited (median 18.5 months), suggesting that the prognosis may be worse. Size, mitotic activity, and necrosis were correlated with aggressive behavior. There is little evidence that treatment with MTOR inhibitors, which are beneficial against TSC -mutated PEComas, is effective against TFE3 -rearranged PEComas: only one of 6 reported cases demonstrated disease stabilization. As co-expression of melanocytic and muscle markers, a hallmark of conventional TSC -mutated PEComa is uncommon in the spectrum of TFE3 -rearranged PEComa, an alternative terminology may be more appropriate, such as " TFE3 -rearranged PEComa-like neoplasms," highlighting their distinctive morphologic features and therapeutic implications.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Biomarcadores de Tumor , Reordenamiento Génico , Neoplasias de Células Epitelioides Perivasculares , Humanos , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patología , Neoplasias de Células Epitelioides Perivasculares/tratamiento farmacológico , Femenino , Masculino , Adulto , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Adulto Joven , Anciano , Adolescente , Predisposición Genética a la Enfermedad , Inmunohistoquímica , Resultado del Tratamiento , Fenotipo , Antineoplásicos/uso terapéuticoRESUMEN
Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term "olfactory carcinoma" to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.
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Biomarcadores de Tumor , Proteínas de Unión al ADN , Estesioneuroblastoma Olfatorio , Neoplasias de los Senos Paranasales , Factores de Transcripción , Vía de Señalización Wnt , Humanos , Anciano , Persona de Mediana Edad , Masculino , Factores de Transcripción/genética , Femenino , Vía de Señalización Wnt/genética , Proteínas de Unión al ADN/genética , Estesioneuroblastoma Olfatorio/patología , Estesioneuroblastoma Olfatorio/genética , Estesioneuroblastoma Olfatorio/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Neoplasias de los Senos Paranasales/patología , Neoplasias de los Senos Paranasales/genética , Neoplasias de los Senos Paranasales/metabolismo , Adulto , Proteínas Nucleares/genética , Mutación , Anciano de 80 o más Años , Neoplasias Nasales/patología , Neoplasias Nasales/genética , Neoplasias Nasales/metabolismo , InmunohistoquímicaRESUMEN
Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.
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Adenocarcinoma , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Mutación/genética , GenómicaRESUMEN
Adenoid cystic carcinoma (AdCC) metastasis to kidney is rare. We identified 10 patients with metastatic AdCC in multi-institutional collaboration. Core needle biopsy was the most common specimen (n = 6). Patients were predominately female (n = 7) with a median age of 48 years (35-62 years). The most common primary location of the AdCC was head and neck (n = 6, among them parotid gland = 4), followed by lung (n = 2), breast (n = 1), and vulva (n = 1). Median lapse between primary AdCC and renal metastasis was almost 13 years (154 months, range 1-336 months). Moreover, all but one patient had unilateral kidney metastasis. The majority of metastatic AdCC within the kidney demonstrated mixed growth patterns, frequently cribriform, and tubular morphology. Follow-up available for 8 patients showed 6 alive with disease and 2 died of disease (the longest survival was 4 years past the diagnosis of renal metastasis). A systematic literature review including 29 patients revealed that kidney metastasis by AdCC is usually a late event, is typically unilateral, and is usually composed of one to three foci, and thus has clinical features which mimic a primary renal tumor.
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Carcinoma Adenoide Quístico , Neoplasias Renales , Femenino , Humanos , Persona de Mediana Edad , Carcinoma Adenoide Quístico/patología , Riñón/patología , Neoplasias Renales/diagnóstico , Neoplasias Renales/secundario , Recurrencia Local de Neoplasia/patología , Glándula Parótida/patologíaRESUMEN
Keratocystoma is a rare salivary gland lesion that has been reported primarily in children and young adults. Because of a scarcity of reported cases, very little is known about it, including its molecular underpinnings, biological potential, and histologic spectrum. Purported to be a benign neoplasm, keratocystoma bears a striking histologic resemblance to benign lesions like metaplastic Warthin tumor on one end of the spectrum and squamous cell carcinoma on the other end. This overlap can cause diagnostic confusion, and it raises questions about the boundaries and definition of keratocystoma as an entity. This study seeks to utilize molecular tools to evaluate the pathogenesis of keratocystoma as well as its relationship with its histologic mimics. On the basis of targeted RNA sequencing (RNA-seq) results on a sentinel case, RUNX2 break-apart fluorescence in situ hybridization (FISH) was successfully performed on 4 cases diagnosed as keratocystoma, as well as 13 cases originally diagnosed as tumors that morphologically resemble keratocystoma: 6 primary squamous cell carcinomas, 3 metaplastic/dysplastic Warthin tumors, 2 atypical squamous cysts, 1 proliferating trichilemmal tumor, and 1 cystadenoma. RNA-seq and/or reverse transcriptase-PCR were attempted on all FISH-positive cases. Seven cases were positive for RUNX2 rearrangement, including 3 of 4 tumors originally called keratocystoma, 2 of 2 called atypical squamous cyst, 1 of 1 called proliferating trichilemmal tumor, and 1 of 6 called squamous cell carcinoma. RNA-seq and/or reverse transcriptase-PCR identified IRF2BP2::RUNX2 in 6 of 7 cases; for the remaining case, the partner remains unknown. The cases positive for RUNX2 rearrangement arose in the parotid glands of 4 females and 3 males, ranging from 8 to 63 years old (mean, 25.4 years; median, 15 years). The RUNX2 -rearranged cases had a consistent histologic appearance: variably sized cysts lined by keratinizing squamous epithelium, plus scattered irregular squamous nests, with essentially no cellular atypia or mitotic activity. The background was fibrotic, often with patchy chronic inflammation and/or giant cell reaction. One case originally called squamous cell carcinoma was virtually identical to the other cases, except for a single focus of small nerve invasion. The FISH-negative case that was originally called keratocystoma had focal cuboidal and mucinous epithelium, which was not found in any FISH-positive cases. The tumors with RUNX2 rearrangement were all treated with surgery only, and for the 5 patients with follow-up, there were no recurrences or metastases (1 to 120 months), even for the case with perineural invasion. Our findings solidify that keratocystoma is a cystic neoplastic entity, one which appears to consistently harbor RUNX2 rearrangements, particularly IRF2BP2::RUNX2 . Having a diagnostic genetic marker now allows for a complete understanding of this rare tumor. They arise in the parotid gland and affect a wide age range. Keratocystoma has a consistent morphologic appearance, which includes large squamous-lined cysts that mimic benign processes like metaplastic Warthin tumor and also small, irregular nests that mimic squamous cell carcinoma. Indeed, RUNX2 analysis has considerable promise for resolving these differential diagnoses. Given that one RUNX2 -rearranged tumor had focal perineural invasion, it is unclear whether that finding is within the spectrum of keratocystoma or whether it could represent malignant transformation. Most important, all RUNX2 -rearranged cases behaved in a benign manner.
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Adenolinfoma , Carcinoma de Células Escamosas , Quistes , Neoplasias de las Glándulas Salivales , Masculino , Femenino , Adulto Joven , Niño , Humanos , Adolescente , Adulto , Persona de Mediana Edad , Adenolinfoma/patología , Hibridación Fluorescente in Situ , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Neoplasias de las Glándulas Salivales/patología , Carcinoma de Células Escamosas/patología , ADN Polimerasa Dirigida por ARN/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisisRESUMEN
Adamantinoma-like Ewing sarcoma (ALES) is a rare malignancy currently considered a variant of Ewing sarcoma with most known cases harboring EWSR1 rearrangements. Herein we present a series of 6 cases of EWSR1 -negative ALES. The tumors arose in the sinonasal tract (n=3), major salivary glands (submandibular gland=1; parotid=1), and anterior mediastinum (n=1) in patients ranging from 25 to 79 years of age. Most tumors were basaloid in appearance, growing in large nests separated by interlobular fibrosis without overt squamous pearls. However, 1 case closely resembled a well-differentiated neuroendocrine tumor with uniformly round nuclei, eosinophilic cytoplasm, and trabecular architecture. All cases were diffusely positive for pan-cytokeratin, p40 or p63, and CD99. A subset of cases showed diffuse reactivity for synaptophysin, including 1 sinonasal tumor which also demonstrated sustentacular S100 protein expression. Molecular testing showed FUS rearrangements in all cases. Gene partners included known ETS family members FEV (n=2) and FLI1 (n=1). Our results expand the molecular diagnostic considerations for ALES to include FUS rearrangements. We also show that ALES may harbor FUS :: FLI1 fusion, which has not been previously reported in the Ewing family of tumors. Furthermore, ALES may show unusual histologic and immunophenotypic features that can overlap with olfactory carcinoma including S100-positive sustentacular cells. ALES should be considered in the diagnostic differential of small round cell tumors and tumors with neuroendocrine differentiation with immunohistochemical workup to include p40 and CD99/NKX2.2.
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Adamantinoma , Tumores Neuroectodérmicos Periféricos Primitivos , Sarcoma de Ewing , Sarcoma , Humanos , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Adamantinoma/genética , Adamantinoma/patología , Proteína EWS de Unión a ARN/genética , Sarcoma/genética , Biomarcadores de Tumor/genética , Proteínas de Fusión Oncogénica/genética , Proteína FUS de Unión a ARNRESUMEN
Although the definitions of sinonasal neuroendocrine and neuroectodermal neoplasms did not change substantially in the 5th edition WHO Classification of Head and Neck Tumours, the diagnosis of olfactory neuroblastoma (ONB), small cell neuroendocrine carcinoma, and large cell neuroendocrine carcinoma remains quite challenging in practice. Ambiguities surrounding the amount of keratin expression allowable in ONB and the amount of neuroendocrine differentiation seen in sinonasal undifferentiated carcinoma (SNUC) lead to significant diagnostic discrepancies at the high grade end of this tumor spectrum. Furthermore, a group of problematic neuroepithelial tumors that show overlapping features of ONB and neuroendocrine carcinoma have never been recognized in formal classification schemes. Since publication of the 5th edition WHO, two new tumor entities have been proposed that help resolve these problems. Olfactory carcinoma is defined by high grade keratin-positive neuroectodermal cells with frequent intermixed glands and shows recurrent Wnt pathway, ARID1A, and RUNX1 alterations. IDH2-mutant sinonasal carcinoma is a molecularly-defined category that encompasses tumors with undifferentiated (SNUC), large cell neuroendocrine, and neuroepithelial phenotypes. This review will provide a practical overview of these emerging entities and their application to diagnostic challenges in the post-WHO sinonasal neuroendocrine and neuroectodermal tumor classification.
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Carcinoma Neuroendocrino , Estesioneuroblastoma Olfatorio , Neoplasias del Seno Maxilar , Neoplasias Nasales , Neoplasias de los Senos Paranasales , Humanos , Nueva Orleans , Carcinoma Neuroendocrino/patología , Neoplasias de los Senos Paranasales/patología , Neoplasias del Seno Maxilar/patología , Estesioneuroblastoma Olfatorio/diagnóstico , Estesioneuroblastoma Olfatorio/patología , Queratinas , Neoplasias Nasales/patología , Cavidad Nasal/patologíaRESUMEN
INTRODUCTION: Benign (B) follicular lesions of the thyroid are among the most encountered specimens on fine needle aspiration (FNA). Although FNA and The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) remain highly accurate, minimally invasive and robust tools in triaging thyroid nodules, false positive (FP) diagnoses may still occur. Endocrine-type degenerative atypia can cause diagnoses of suspicious for malignancy (SFM) or malignant (M), resulting in overtreatment and exposure to undue surgical risk in patients. MATERIALS AND METHODS: We performed a multi-institutional retrospective clinicopathologic correlation of benign thyroid nodules with degenerative atypia on FNA. Review of cytologic material was conducted to identify potential cytomorphologic features which may have prompted these diagnoses. RESULTS: Among 342 patients with benign thyroid nodules harboring degenerative atypia, 123 had available preceding FNA cytopathology. TBSRTC nondiagnostic, B, atypia of undetermined significance, follicular neoplasm, SFM, and M, comprised 3.3%, 49.6%, 30.1%, 13.0%, 2.4%, and 1.6% of cases. Among patients with FP diagnoses (SFM and M), 100% underwent total thyroidectomy, and 40.0% underwent additional neck lymph node dissections. Among remaining patients, 61.0%, 39.0%, and 0% underwent lobectomy, thyroidectomy, and lymph node dissection. The number of patients who underwent total thyroidectomy was significantly different (P = 0.03) between those with FP nodules and those without. CONCLUSIONS: We demonstrate that 4.1% of nodules harboring endocrine-type degenerative atypia may be given FP diagnoses on initial FNA. Such atypia may be indistinguishable from that of Graves' Disease, dyshormonogenic goiter, and radiation therapy. FP diagnoses of degenerative atypia can expose patients to undue surgical procedures and risks.
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Adenocarcinoma Folicular , Neoplasias de la Tiroides , Nódulo Tiroideo , Humanos , Nódulo Tiroideo/diagnóstico , Nódulo Tiroideo/patología , Biopsia con Aguja Fina/métodos , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patología , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/patología , Estudios RetrospectivosRESUMEN
Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed to stem from chromosome instability in neoplastic cells. We tested this hypothesis in a large cohort assembled over the last 20 years. We found that the only solid cancers to which patients with STS are predisposed are squamous cell carcinomas of the head and neck, anus, or skin, a spectrum reminiscent of cancers seen in patients with immunodeficiency. Whole-genome sequencing showed no increase in chromosome instability, such as translocations or chromothripsis. Moreover, STS-associated cancers acquired telomere maintenance mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the immune status of patients with STS revealed a striking T cell immunodeficiency at the time of cancer diagnosis. A similar immunodeficiency that impaired tumor surveillance was documented in mice with short telomeres. We conclude that STS patients' predisposition to solid cancers is due to T cell exhaustion rather than autonomous defects in the neoplastic cells themselves.
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Carcinoma de Células Escamosas , Telomerasa , Animales , Ratones , Telómero/genética , Telómero/metabolismo , Carcinoma de Células Escamosas/genética , Inestabilidad Cromosómica , Mutación , Telomerasa/genética , Telomerasa/metabolismo , Linfocitos T/metabolismoRESUMEN
The classification of salivary gland tumors is ever-evolving with new variants of tumors being described every year. Next-generation sequencing panels have helped to prove and disprove prior assumptions about tumors' relationships to one another, and have helped refine this classification. Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs at all major and minor salivary gland and seromucous gland sites. Most AdCC are predominantly myoepithelial and basaloid with variable cribriform, tubular, and solid growth. The luminal tubular elements are often less conspicuous. AdCC has largely been characterized by canonical MYB fusions, with MYB::NFIB and rarer MYBL1::NFIB. Anecdotal cases of AdCC, mostly in nonmajor salivary gland sites, have been noted to have unusual patterns, including squamous differentiation and macrocystic growth. Recently, this has led to the recognition of a subtype termed "metatypical adenoid cystic carcinoma." Another unusual histology that we have seen with a wide range of architecture, is striking tubular hypereosinophilia. The hypereosinophilia and luminal cell prominence is in stark contrast to the vast majority of AdCC that are basaloid and myoepithelial predominant. A total of 16 cases with tubular hypereosinophilia were collected, forming morular, solid, micropapillary, and glomeruloid growth, and occasionally having rhabdoid or Paneth-like cells. They were subjected to molecular profiling demonstrating canonical MYB::NFIB (5 cases) and MYBL1::NFIB (2 cases), as well as noncanonical EWSR1::MYB (2 cases) and FUS::MYB (1 case). The remaining 6 cases had either no fusion (3 cases) or failed sequencing (3 cases). All cases were present in nonmajor salivary gland sites, with seromucous glands being the most common. These include sinonasal tract (7 cases), laryngotracheal (2 cases), external auditory canal (2 cases), nasopharynx (1 case), base of tongue (2 cases), palate (1 case), and floor of mouth (1 case). A tissue microarray of 102 conventional AdCC, including many in major salivary gland sites was examined for EWSR1 and FUS by fluorescence in situ hybridization and showed that these novel fusions were isolated to this histology and nonmajor salivary gland location. In summary, complex and striking tubular hypereosinophilia and diverse architectures are present within the spectrum of AdCC, particularly in seromucous gland sites, and may show variant EWSR1/FUS::MYB fusions.
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Carcinoma Adenoide Quístico , Eosinofilia , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Hibridación Fluorescente in Situ , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN/genética , Proteína FUS de Unión a ARNRESUMEN
This case series assesses the incidence of human papillomavirus (HPV)-associated sinonasal squamous cell carcinoma (SNSCC) and the prevalence of HPV-positive SNSCC among US adults.
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Carcinoma de Células Escamosas , Senos Paranasales , Humanos , Adulto , Virus del Papiloma Humano , Incidencia , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/patologíaRESUMEN
BACKGROUND: Intercalated duct lesions (IDLs) are benign salivary gland proliferations that resemble normal intercalated ducts and are subdivided into hyperplastic, adenoma or hybrid types depending on circumscription. While IDLs were historically regarded as non-neoplastic, frequent association with basal cell adenoma (BCA) and epithelial-myoepithelial carcinoma (EMC) has raised the possibility that they are neoplastic precursors. METHODS: In this study, we performed ß-catenin immunohistochemistry and targeted molecular analysis on IDLs to clarify their pathogenesis. RESULTS: We identified 15 IDLs from the parotid glands of eight men and six women with a median age of 65 years (range 42-85 years). These lesions included nine hyperplastic, three adenoma, and three hybrid types. Nuclear ß-catenin localization was present in 7 of 13 lesions tested (54%). Next generation sequencing was successfully completed in 12 IDLs, of which seven (58%) had likely oncogenic mutations. These included three recurrent CTNNB1 mutations in hyperplastic (n = 2) and hybrid (n = 1) lesions and two recurrent HRAS hotspot mutations in adenomas. CONCLUSION: Despite substantial heterogeneity, these findings confirm that a majority of IDLs are genuinely neoplastic, and some demonstrate molecular overlap with both BCA and EMC, supporting their theorized role as precursors to these tumors. Nevertheless, no oncogenic drivers were present in a significant subset of cases, suggesting that some IDLs may be truly reactive and hyperplastic. As such, IDL appear to represent a diverse morphologic and molecular spectrum that include both neoplastic and hyperplastic lesions. Reconsideration of the boundary between IDL and BCA in the future may be necessary to simplify classification.
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Adenoma , Carcinoma , Neoplasias de las Glándulas Salivales , Masculino , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Neoplasias de las Glándulas Salivales/patología , beta Catenina/análisis , Biomarcadores de Tumor/análisis , Carcinoma/patología , Adenoma/genética , Adenoma/patología , Conductos Salivales/patología , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Striated duct adenoma (SDA) is a rare salivary gland neoplasm defined by histologic similarity to normal striated ducts. However, doubt persists about whether SDA represents a genuine entity distinct from canalicular adenoma and if a malignant counterpart exists. This study aims to evaluate the molecular underpinnings of SDA to clarify its pathogenesis and classification. We identified 10 SDA and 2 tumors called low-grade adenocarcinoma not otherwise specified that were retrospectively recognized to resemble SDA. All cases showed recurrent histologic features including (1) discrete monophasic tubules, (2) tall columnar eosinophilic cells, (3) monotonous oval nuclei, and (4) scant fibrous stroma, and most were positive for S100 protein (91%), SOX10 (80%), and CK7 (80%). Although 1 case was previously called adenocarcinoma based on interdigitation with normal acini, this pattern was also seen in some SDA, and likely does not indicate malignancy; the significance of growth surrounding nerve in 1 other case is less clear. Targeted sequencing identified IDH2 R172X mutations in all 8 cases with sufficient tissue, with positivity for IDH1/2 mutation-specific immunohistochemistry in 9 cases stained. In contrast, 5 canalicular adenomas lacked IDH2 mutations or other oncogenic alterations. Overall, IDH2 R172X mutations are a defining feature of SDA that, in combination with its recognizable pathologic profile, confirm it is a unique entity separate from canalicular adenoma. IDH1/2 mutation-specific immunohistochemistry may provide a convenient tool to facilitate diagnosis. Both morphology and IDH2 mutations raise parallels between SDA and breast tall cell carcinoma with reverse polarity.
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Adenoma , Isocitrato Deshidrogenasa , Neoplasias de las Glándulas Salivales , Humanos , Adenocarcinoma/patología , Adenoma/patología , Biomarcadores de Tumor/genética , Mutación , Estudios Retrospectivos , Neoplasias de las Glándulas Salivales/genética , Glándulas Salivales/metabolismo , Glándulas Salivales/patología , Isocitrato Deshidrogenasa/genéticaRESUMEN
BACKGROUND: Microsecretory adenocarcinoma (MSA) is a newly described salivary gland neoplasm characterized by MEF2C::SS18 fusions. MSA was previously thought to occur exclusively in salivary glands. Here, we expand the spectrum of known primary sites of this tumor by describing a series of cutaneous tumors with analogous findings. METHODS: We identified four cutaneous primary tumors with histopathologic features identical to MSA of the salivary glands. These cases were evaluated by immunohistochemistry, fluorescence in situ hybridization (FISH) for SS18 rearrangement and targeted RNA-sequencing. We also queried a pan-tumor database of advanced carcinomas for MEF2C::SS18. RESULTS: The cases occurred in men ranging from 61 to 74 years (mean, 68). They arose from the skin of the nose, chin, scalp, and external auditory canal. All included cords/microcysts of eosinophilic cells with bland oval nuclei and bluish mucin within fibromyxoid stroma. The scalp tumor also exhibited high-grade transformation (marked atypia, elevated mitotic rate, and necrosis), a feature unreported in salivary MSA. By immunohistochemistry, all cases were positive for S100. Two showed a myoepithelial component positive for p40 and smooth muscle actin or calponin. Three cases harbored MEF2C::SS18 by RNA sequencing, while one with limited tissue had SS18 rearrangement via FISH. Two patients had no evidence of recurrence or metastasis in limited follow-up (3 and 6 months). The pan-tumor database query also did not identify MEF2C::SS18 in any advanced cutaneous carcinomas. CONCLUSION: This report expands the sites that can be involved by MSA. Similar to salivary cases, MEF2C::SS18 represents a recurrent fusion in MSA of the skin. Unusual features in cutaneous cases not seen in salivary MSA include one case with high-grade transformation and two cases with a myoepithelial cell component. Identification of this fusion expands the spectrum of salivary-analog cutaneous tumors and aids in precise tumor classification.
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Adenocarcinoma , Carcinoma , Neoplasias de las Glándulas Salivales , Neoplasias Cutáneas , Humanos , Hibridación Fluorescente in Situ , Biomarcadores de Tumor/genética , Adenocarcinoma/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Carcinoma/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
Thyroblastoma is a novel thyroid malignancy included in the 5th Edition WHO Classification of Endocrine and Neuroendocrine Tumours. The majority of tumors now classified as thyroblastoma were originally regarded to be malignant thyroid teratomas. However, these neoplasms were recently recognized as a separate entity based on a distinctive constellation of primitive multilineage elements, including immature thyroid epithelium, undifferentiated or rhabdomyoblastic spindle cell proliferations, and neuroepithelial blastema, as well as recurrent DICER1 hotspot mutations. Thyroblastoma is an aggressive tumor that leads to death from disease in ~50% of patients, making it essential to differentiate this entity from a wide range of other thyroid tumors that show overlapping histologic features or DICER1 mutations. This review aims to provide a practical overview of the background, clinicopathologic features, molecular underpinnings, and differential diagnosis of this recently-described and molecularly-defined entity.
Asunto(s)
Tumores Neuroendocrinos , Teratoma , Neoplasias de la Tiroides , Humanos , Teratoma/genética , Teratoma/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Mutación , Ribonucleasa III/genética , ARN Helicasas DEAD-box/genéticaRESUMEN
The landscape of salivary gland carcinomas is ever-changing, with a growing list of new tumors and newly elucidated variants of well-known tumor entities. The routine use of next-generation sequencing has been instrumental in identifying novel fusions and tumor entities, which has helped bring the classification to a more objective and evidenced-based model. However, morphology remains critical in assessing the validity of these novel molecular findings, and most importantly, in assessing which of these findings will have an impact on the prognosis and treatment decisions for patients. The recognition of microsecretory adenocarcinoma (MSA) as a distinct low-grade malignancy of salivary glands, underpinned by MEF2C::SS18 , and a single possibly related case of SS18::ZBTB7A , recently expanded this growing list of distinctive tumors. It was not until now, however, that the morphology of the latter case was known to be unique and reproducible. The authors have now seen 4 of these distinctive tumors that show a combination of distinctive oncocytic cells forming compact glandular growth as well as amphophilic cells forming tubular growth, and suggest the appellation "microcribriform adenocarcinoma" (MCA). So far, these tumors appear to preferentially occur in nonoral sites (2 parotid, 1 submandibular gland, and 1 bronchial seromucous glands). By immunohistochemistry, they express S100 and SOX-10 with focal outer myoepithelial cells marked by circumferential p63, p40, and smooth muscle actin staining around some of the nests and tubules. The tumors show infiltrative growth within a hyalinized and myxoid stroma. Cytologically, they appear generally low grade, similar to MSA. The morphologic and molecular uniformity of these 4 microcribriform adenocarcinoma cases warrants their recognition, and while related to MSA, they are sufficiently different to be classified as a distinct tumor. So far, in limited follow-up, these tumors appear to be relatively indolent.
Asunto(s)
Adenocarcinoma , Proteínas de Fusión Oncogénica , Neoplasias de las Glándulas Salivales , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/patología , Factores de Transcripción/genéticaRESUMEN
Sinonasal teratocarcinosarcoma (TCS) is a rare tumor defined by intermixed neuroepithelial, mesenchymal, and epithelial elements. While its etiology was historically ambiguous, we recently reported frequent SMARCA4 loss by immunohistochemistry, suggesting that TCS might be related to SMARCA4-deficient sinonasal carcinomas. However, other molecular alterations including CTNNB1 mutation have been reported in TCS, and its full genetic underpinnings are unclear. Here, we performed the first comprehensive molecular analysis of sinonasal TCS to better understand its pathogenesis and classification. We collected 30 TCS including 22 cases from our initial study. Immunohistochemical loss of SMARCA4 was seen in 22 cases (73%), with total loss in 18 cases (60%). ß-catenin showed nuclear localization in 14 cases (64%) of the subset tested. We selected 17 TCS for next-generation sequencing with enrichment for partial or intact SMARCA4 immunoexpression. We identified inactivating SMARCA4 mutations in 11 cases (65%) and activating CTNNB1 mutations in 6 cases (35%), including 5 cases with both. Of 5 cases that lacked SMARCA4 or CTNNB1 mutation, 2 harbored other SWI/SNF complex and Wnt pathway alterations, including 1 with SMARCB1 inactivation and 1 with concomitant APC and ARID1A mutations, and 3 had other findings, including DICER1 hotspot mutation. These findings confirm that SMARCA4 inactivation is the dominant genetic event in sinonasal TCS with frequent simultaneous CTNNB1 mutations. They further underscore a possible relationship between TCS and sinonasal carcinomas with neuroendocrine/neuroectodermal differentiation. However, while SMARCA4 and ß-catenin immunohistochemistry may help confirm a challenging diagnosis, TCS should not be regarded as a molecularly defined entity.
Asunto(s)
Carcinoma , Carcinosarcoma , Neoplasias de los Senos Paranasales , Humanos , beta Catenina/genética , Carcinosarcoma/genética , Carcinoma/patología , Neoplasias de los Senos Paranasales/genética , Mutación , Biomarcadores de Tumor/análisis , ADN Helicasas/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Ribonucleasa III/genética , ARN Helicasas DEAD-box/genéticaRESUMEN
Mucoepidermoid carcinoma (MEC) is historically defined by a mix of squamoid, intermediate, and mucous cells, but we have recently encountered several cases lacking immunoreactivity for squamous markers p40, p63, and CK5/6 despite MAML2 fusions. This study will characterise these unique tumours. Ten MEC were collected arising from the parotid gland (n = 4), submandibular gland (n = 2), nasopharynx (n = 1), base of tongue (n = 1), bronchus (n = 1), and trachea (n = 1). Six tumours were low-grade, two intermediate-grade, one high-grade, and one demonstrated low-grade areas with high-grade transformation. Four cases were oncocytic, four had clear-cell features, two had spindle cell features, and one high-grade MEC had prominent solid, cord-like, and micropapillary features. The tumours were negative for p40 (10/10), p63 (10/10), and CK5/6 (9/9). Targeted RNA sequencing demonstrated CRTC1::MAML2 in five cases, CRTC3::MAML2 in two, and a novel MAML2::CEP126 in the unusual high-grade case. In two cases with insufficient RNA, MAML2 fluorescence in situ hybridisation (FISH) showed rearrangement. Genetically-confirmed MEC may lack overt squamous differentiation by histology and immunohistochemistry. While most cases harboured canonical fusions and fit within the spectra of MEC variants with oncocytic, clear cell, and/or spindle cell features, one had a novel MAML2::CEP126 fusion and unusual morphology. In MEC without squamoid cells, the use of immunohistochemistry may hinder, rather than aid, the correct diagnosis. In such cases, MAML2 analysis is most useful. The historical definition of MEC as a carcinoma with squamoid, intermediate and mucous cells should be revisited.