The World Health Organization Reporting System for Pancreaticobiliary Cytopathology: Overview and Summary.

The recently published WHO Reporting System for Pancreaticobiliary Cytopathology (World Health Organization [WHO] System) is an international approach to the standardized reporting of pancreaticobiliary cytopathology, updating the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSC System). Significant changes were made to the categorization of benign neoplasms, intraductal neoplasms, mucinous cystic neoplasms, and malignant neoplasms considered low grade. Benign neoplasms, such as serous cystadenoma, categorized as Neoplastic: benign in the PSC system, are categorized as Benign/negative for malignancy in the WHO system. Pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, and gastrointestinal stromal tumor, categorized as Neoplastic: other in the PSC system, are categorized as Malignant in the WHO System in accord with their classification in the 5th edition WHO Classification of Digestive System Tumours (2019). The two new categories of Pancreaticobiliary Neoplasm Low-risk/grade and Pancreaticobiliary Neoplasm High-risk/grade are mostly limited to intraductal neoplasms and mucinous cystic neoplasms. Low-risk/grade lesions are mucinous cysts, with or without low-grade epithelial atypia. High-risk/grade lesions contain neoplastic epithelium with high-grade epithelial atypia. Correlation with clinical, imaging, and ancillary studies remains a key tenet. The sections for each entity are written to highlight key cytopathological features and cytopathological differential diagnoses with the pathologist working in low resource setting in mind. Each section also includes the most pertinent ancillary studies useful for the differential diagnosis. Sample reports are provided for each category. Finally, the book provides a separate section with risk of malignancy and management recommendations for each category to facilitate decision-making for clinicians.

A Histone Methylation-MAPK Signaling Axis Drives Durable Epithelial-Mesenchymal Transition in Hypoxic Pancreatic Cancer.

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial-mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation-MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell autonomous EMT in PDAC cells, which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a supporting role. Hypoxia-driven EMT could be antagonized in vivo by combinations of MAPK inhibitors. Collectively, these results suggest that hypoxia promotes durable EMT in PDAC by inducing a histone methylation-MAPK axis that can be effectively targeted with multidrug therapies, providing a potential strategy for overcoming chemoresistance. SIGNIFICANCE: Integrated regulation of histone methylation and MAPK signaling by the low-oxygen environment of pancreatic cancer drives long-lasting EMT that promotes chemoresistance and shortens patient survival and that can be pharmacologically inhibited. See related commentary by Wirth and Schneider, p. 1739.

Oncocytic carcinoma of the thyroid: Conclusions from a 20-year patient cohort.

BACKGROUND: Oncocytic carcinoma (OCA) was recently reclassified as a distinct differentiated thyroid carcinoma (DTC). Given its rarity, OCA studies are limited. This study describes the characteristics of OCA in a 20-year cohort. METHODS: Retrospective analysis of patients with OCA at a single tertiary care hospital from 2000 to 2021. RESULTS: Fifty-one OCA patients (22M:29F) were identified. The mean age at diagnosis was 60.3 years; 90% presented as palpable mass; 24% had a family history of thyroid cancer. None had vocal fold paresis. On ultrasound, most tumors were solid and hypoechoic. FNA (n = 14) showed Bethesda-4 lesions in 93%. All were treated surgically. Histologically, 63% demonstrated angioinvasion, 35% had lymphovascular invasion, and 15% had extrathyroidal extension. Radioactive iodine was used as adjunct therapy in 77%. CONCLUSION: OCA has distinct features that distinguish it from other DTCs, and additional focused studies will help clarify the aggressive nature, treatment options, and prognosis of the disease.

One procedure-one report: the Re-Imagine Cytopathology Task Force position paper on small tissue biopsy triage in anatomic pathology.

INTRODUCTION: Endoscopic biopsy procedures increasingly generate multiple tissue samples from multiple sites, and frequently retrieve concurrent cytologic specimens and small core needle biopsies. There is currently lack of consensus in subspecialized practices as to whether cytopathologists or surgical pathologists should review such samples, and whether the pathology findings should be reported together or separately. MATERIALS AND METHODS: In December 2021, the American Society of Cytopathology convened the Re-Imagine Cytopathology Task Force to examine various workflows that would facilitate unified pathology reporting of concurrently obtained biopsies and improve clinical care. RESULTS AND CONCLUSIONS: This position paper summarizes the key points and highlights the advantages, challenges, and resources available to support the implementation of such workflows that result in "one procedure-one report".

A brief review of the WHO reporting system for pancreaticobiliary cytopathology.

The World Health Organization (WHO), the International Academy of Cytology, and the International Agency for Research on Cancer have developed an approach to standardized reporting of pancreaticobiliary cytopathology. The WHO Reporting System for Pancreaticobiliary Cytopathology (WHO System) revises the Papanicolaou Society of Cytopathology (PSC) System for Reporting Pancreaticobiliary Cytology published in 2015 and replaces the 6 PSC categories with 7 categories: "Insufficient/Inadequate/Nondiagnostic"; "Benign/Negative for malignancy"; "Atypical"; "Pancreaticobiliary neoplasm, low risk/grade (PaN-low)"; "Pancreatic neoplasm, high risk/grade (PaN-High)"; "Suspicious for malignancy"; and "Malignant". In the PSC system, there is a single category for "Neoplastic" lesions that includes 2 groups, 1 for benign neoplasms and 1 named "Neoplastic-other", dominated by premalignant intraductal neoplasms primarily intraductal papillary mucinous neoplasms and low-grade malignant neoplasms (pancreatic neuroendocrine tumors (PanNET) and solid pseudopapillary neoplasms (SPN). In the WHO System, benign neoplasms with virtually no risk of malignancy are included in the "Benign" category and low-grade malignancies (PanNET and SPN) are included in the "Malignant" category, as per the 5th edition of the WHO Classification of Digestive System Tumors, while the non-invasive pre-malignant lesions of the ducts are divided by the cytomorphological grade of the epithelium into PaN-low and PaN-high with distinctly different risks of malignancy. Within each category, key diagnostic cytopathologic features and the ancillary studies for diagnostic and prognostic evaluation, as well as the implications of diagnosis for patient care and management, are outlined. Reporting and diagnostic management options recognize the variations in the availability of diagnostic and prognostic ancillary testing modalities in low- and middle-income countries.

Microsecretory adenocarcinoma of the external ear canal.

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor characterized by unique histomorphologic and immunohistochemical features as well as recurrent MEF2C::SS18 gene fusion. Since 2019, 24 cases have been reported in the literature, primarily arising in the oral cavity, with a single reported case arising in the parotid gland. Here, we present a case of MSA that arose in the external ear canal in an 89-year-old woman and was discovered during management of vertigo symptoms. Excisional biopsy of the lesion showed multiple fragments of squamous epithelium with hyperplastic changes and a distinct subepithelial infiltrating neoplasm composed of bland cells forming tubules and cords. Neoplastic cells expressed keratin, S100 protein, p63, and TLE1 and did not express p40, mammaglobin, pan-TRK, synaptophysin, or chromogranin by immunohistochemistry. SS18 gene rearrangement was shown with break-apart fluorescent in situ hybridization. Overall, the histomorphologic, immunohistochemical, and cytogenetic findings confirm a diagnosis of MSA arising in a unique extraoral location.

The World Health Organization Reporting System for Pancreaticobiliary Cytopathology.

The World Health Organization (WHO), the International Academy of Cytology, and the International Agency for Research on Cancer, with expert contributors from around the world, present an international approach to standardized reporting of pancreaticobiliary cytopathology. This reporting system is one of the first in a series from various body sites that mirror the WHO Classification of Tumours series and provides an evidence-based terminology system with associated risk of malignancy and diagnostic management recommendation per diagnostic category. The WHO Reporting System for Pancreaticobiliary Cytopathology (WHO system) revises the Papanicolaou Society of Cytopathology (PSC) system for Reporting Pancreaticobiliary Cytology published in 2015 and replaces the six-tiered system with a seven-tiered system: "insufficient/inadequate/nondiagnostic"; "benign (negative for malignancy)," "atypical," "pancreaticobiliary neoplasm of low risk/low grade," "pancreatic neoplasm of high risk/high grade," "suspicious for malignancy," and "malignant." The principal differences between the WHO and the PSC systems revolve around the classification of neoplasia. In the PSC system, there was a single category for "neoplastic" lesions that includes two groups, one for "benign neoplasms" [primarily serous cystadenoma] and one named "other," dominated by premalignant intraductal neoplasms (primarily intraductal papillary mucinous neoplasms) and low-grade malignant neoplasms [pancreatic neuroendocrine tumors (PanNETs) and solid pseudopapillary neoplasms (SPNs)]. In the WHO system, benign neoplasms with virtually no risk of malignancy are included in the "benign" category and low-grade malignancies (PanNET and SPN) are included in the "malignant" category, as per the WHO Classification of Digestive System Tumours, thus leaving in the "neoplasm" category primarily those noninvasive premalignant lesions of the ductal system. These neoplasms are divided by the cytomorphological grade of the epithelium into low risk/low-grade and high risk/high-grade, with distinctly different risks of malignancy. As with the PSC system, the WHO system advocates close correlation with imaging and encourages incorporation of ancillary testing into the final diagnosis, such as biochemical (CEA and amylase) and molecular testing of cyst fluid and bile duct brushings. Key diagnostic cytopathological features of specific lesions or neoplasms, ancillary studies for diagnostic and prognostic evaluation, and implications of diagnosis for patient care and management are discussed. In addition, the WHO system includes reporting and diagnostic management options that recognize the variations in the availability of diagnostic and prognostic ancillary testing modalities in low- and middle-income countries, where cytopathology is particularly useful and is increasingly available in the absence of histopathological services.

Recurrent IDH2 Mutations in Salivary Gland Striated Duct Adenoma Define an Expanded Histologic Spectrum Distinct From Canalicular Adenoma.

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.

Malignant undifferentiated and rhabdoid tumors of the gastroesophageal junction and esophagus with SMARCA4 loss: a case series.

Undifferentiated SMARCA4-deficient carcinoma of the esophagus and gastroesophageal junction is a rare, highly aggressive, and diagnostically challenging malignancy. Here we present a case series of high-grade undifferentiated malignant neoplasms of the esophagus and gastroesophageal junction that share SMARCA4 loss by immunohistochemistry and demonstrate a rhabdoid phenotype. Five cases are presented, including 4 men and 1 woman with an age range of 48-79 years. Interestingly, only one case showed intestinal metaplasia (Barrett's esophagus) and no cases demonstrated glandular dysplasia or glandular differentiation. In all, the lesional cells were immunoreactive with antibodies to keratins (3/5), CD34 (2/4), and CD138 (4/5). SMARCA4 expression was diffusely lost in all cases, whereas SMARCB1 expression was intact. OncoScan™ assay demonstrated loss of SMARCA4 in all cases analyzed. Additional OncoScan™ findings included abnormalities of CDKN2A in 2 of 3 cases, abnormalities of TP53 in 2 of 3 cases, and abnormalities of PTPRD in 2 of 3 cases, among other abnormalities.

Sinonasal Tumors With Neuroepithelial Differentiation (Olfactory Carcinoma): Delineation of Their Pathologic and Clinical Features With Insights into Their Relationship to Olfactory Neuroblastoma and Sinonasal Carcinoma.

Olfactory carcinoma is one of many names applied to sinonasal malignancies with histologic similarity to olfactory neuroblastoma (ONB) but cytokeratin expression or gland formation. It is unclear whether these neuroepithelial tumors represent a unified category and if they are separate from ONB and currently-recognized sinonasal carcinomas. This study aims to explore their clinicopathologic characteristics based on a large collective experience. A total of 53 sinonasal tumors with neuroepithelial differentiation were identified affecting 41 men and 12 women, median age 47 years (range: 12 to 82 y). The vast majority arose in the superior nasal cavity and presented at the high Kadish-Morita stage. Frequent histologic findings included (1) lobulated and solid growth, (2) rosettes and/or neurofibrillary stroma, (3) high-grade cytology, (4) complex, often ciliated glands, (5) nonfocal pancytokeratin expression, (6) neuroendocrine pos+itivity, and (7) variable S100-positive sustentacular cells. Twelve patients with available follow-up (48%) developed progressive disease at a median 8 months (range: 0 to 114 mo to progression), and 7 (28%) died of disease. Despite disparate historical terminology, neuroepithelial differentiation is a recurrent and recognizable histologic pattern that is associated with aggressive behavior in sinonasal tumors. While tumors with this phenotype may originate from olfactory mucosa, well-developed epithelial features warrant separation from conventional ONB and neural elements distinguish them from most sinonasal carcinomas. Although their full histogenesis remains uncertain and some heterogeneity may exist, we propose that this pattern is sufficiently distinctive to merit separate recognition as olfactory carcinoma. Use of consistent nomenclature may facilitate greater recognition of tumors with this phenotype and understanding of their pathogenesis and classification.

Myeloid Cell Infiltration Correlates With Prognosis in Cholangiocarcinoma and Varies Based on Tumor Location.

Cholangiocarcinoma (CC) is an uncommon malignancy with increasing incidence and dismal prognosis. We conducted a comprehensive analysis of the CC tumor immune microenvironment (TIME) based on tumor location to identify therapeutic targets. We hypothesized that the TIME of CC would vary by primary tumor location and that high tumor infiltration by CD8+ T cells and low infiltration by M2 macrophages would be associated with improved survival. A retrospective analysis was conducted of 99 CC tumor samples surgically resected between 2000 and 2014. Tissue microarrays were constructed from each tumor and stained by immunohistochemistry for 24 markers of immune cells, immune activation or inhibition, programmed cell death-ligand 1, and mesothelin. Most tumors were amply infiltrated with by CD4+, CD8+, and FoxP3+ T cells, as well as by myeloid cells. Mesothelin expression ≥1+ by immunohistochemistry was found in 68% of tumors. We identified higher densities of M1 macrophages in primary distal extrahepatic CC, as well as metastatic lesions. Mesothelin expression was also significantly higher in distal extrahepatic CC. There was no association with survival of infiltration by CD4+, CD8+, or FoxP3+ T cells, mesothelin expression, or programmed cell death-ligand 1 percentage expression, however, high CD14+ myeloid cells and high CD163+ M2 macrophages were associated with worse survival. In conclusion, the CC TIME is a heterogenous milieu highly infiltrated by innate and adaptive immune cells, which differs based on primary tumor location and between primary tumors and metastatic lesions. The correlation of intratumoral M2 macrophages and myeloid cells with a worse prognosis may suggest promising immunotherapeutic targets in CC.

Normal gastrointestinal tract inflammatory cells and review of select benign hematolymphoid proliferations.

The luminal gastrointestinal tract can be a site of robust immune response in which reactive lymphoproliferative processes can sometimes be difficult to distinguish from lymphoma. In this article, we review gastrointestinal tract normal resident inflammatory cells and common nonneoplastic lymphoproliferative responses with emphasis on their differential and links to lymphoma. Topics that are covered include lymphocytic esophagitis, gastric chronic inflammation, mucosa-associated lymphoid tissue, and ulceration, small intestinal lymphoid hyperplasia, celiac disease, microscopic colitis, inflammatory bowel disease, primary immunodeficiency, graft-versus-host disease, and anti-programmed cell death protein-1 effect. We additionally present the less common differential of histiocytic processes within the gastrointestinal tract. The aim of this paper is to serve as a reference for practicing pathologists facing lymphoid, lymphoplasmacytic, or histiocytic processes in the luminal gastrointestinal tract. We hope to help the practicing pathologist distinguish benign from malignant entities and identify features requiring further workup.

Unexpected PD-L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies.

Lack of effective immune infiltration represents a significant barrier to immunotherapy in solid tumors. Thus, solid tumor-enriched death receptor-5 (DR5) activating antibodies, which generates tumor debulking by extrinsic apoptotic cytotoxicity, remains a crucial alternate therapeutic strategy. Over past few decades, many DR5 antibodies moved to clinical trials after successfully controlling tumors in immunodeficient tumor xenografts. However, DR5 antibodies failed to significantly improve survival in phase-II trials, leading in efforts to generate second generation of DR5 agonists to supersize apoptotic cytotoxicity in tumors. Here we have discovered that clinical DR5 antibodies activate an unexpected immunosuppressive PD-L1 stabilization pathway, which potentially had contributed to their limited success in clinics. The DR5 agonist stimulated caspase-8 signaling not only activates ROCK1 but also undermines proteasome function, both of which contributes to increased PD-L1 stability on tumor cell surface. Targeting DR5-ROCK1-PD-L1 axis markedly increases immune effector T-cell function, promotes tumor regression, and improves overall survival in animal models. These insights have identified a potential clinically viable combinatorial strategy to revive solid cancer immunotherapy using death receptor agonism.

Galectin-3 Expression in High-Risk HPV-Positive and Negative Head & Neck Squamous Cell Carcinomas and Regional Lymph Node Metastases.

Despite higher stages at presentation, patients with high-risk (HR) HPV-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) have better survival rates compared to those with non-HPV-related (HPV-) disease. However, significant comorbidity and the number of patients who suffer failed treatment, recurrent disease, late metastasis, and death are increasing along with the incidence of HPV+ HNSCC. A cytotoxic T-cell-dependent immune response is required to clear these antigenic cancers. This provides a unique opportunity to employ immune modulators in therapy. Galectin-3 (Gal-3) is a lectin and glycoprotein involved in numerous immunosuppressive functions. Inhibitors are currently under clinical investigation for various diseases. Gal-3 expression was evaluated in HR-HPV+ and HPV- HNSCCs and regional lymph node metastases by tissue microarray. HR-HPV+ cases were more likely to be Gal-3-positive (Gal+) [50% (14/28)] than HPV- cases [18% (9/50), p = 0.004]. No difference in the number of Gal+ cases was identified between primary [30% (16/53)] and metastatic [28% (7/25)] cancers (p = 1); 53% (9/17) of primary HPV+ cancers were Gal+ and 45% (5/11) of metastatic HPV+ cancers were Gal+ (p = 1). Nineteen percent (7/36) of primary HPV- cancers were Gal+ and 14% (2/14) of metastatic HPV- cancers were Gal+ (p = 1). Gal-3 positivity was observed in a subset of HNSCC, suggesting a potential role for therapeutic inhibition in this tumor type. The significantly higher rates of expression seen in HR-HPV+ versus HPV- HNSCC suggest particular promise in the setting of HPV infection. The relatively consistent Gal-3 expression rates observed between metastatic and primary tumors argues against progressive Gal-3 expression in metastasis.

The cytologic and immunohistochemical findings of pancreatic mixed acinar-endocrine carcinoma.

BACKGROUND: The classification of epithelioid pancreatic neoplasms based on fine-needle aspiration (FNA) is important for proper management, as distinction of pancreatic neuroendocrine neoplasms from other similar appearing lesions can result in significantly different treatment. Mixed acinar-endocrine carcinomas (MAEC) are genetically related to acinar carcinomas and are treated as such. We reviewed cases of MAEC to better characterize their cytologic and immunohistochemical features. METHODS: Eight FNAs of MAECs were identified and reviewed. A chart review for each case was conducted. RESULTS: All patients were male, 42-68 years of age, and presented with either Stage 3 or 4 disease. Smear backgrounds of all cases showed naked nuclei without significant necrosis. The smears were cellular with cells arranged in either three-dimensional (3D) clusters with intervening capillaries or singly dispersed. Acinar formation was a prominent feature. Cells were round to oval with small to moderate amounts of delicate cytoplasm. The nuclei were round to oval with mild to moderate anisonucleosis with granular chromatin and small nucleoli. Apoptotic bodies and mitoses were noted in most cases, with Ki67 indices of 10%-48%. All tumors, by definition, demonstrated expression of trypsin and synaptophysin with variable chromogranin expression (50%). CONCLUSION: The cytology of acinar cell carcinoma shares features with aspirates of other nonductal adenocarcinoma neoplasms of the pancreas. A clue to the diagnosis is that tumors show high Ki67 indices and a diagnosis of MAEC should be excluded anytime a diagnosis of Grade 2 or 3 well-differentiated neuroendocrine tumor or high-grade neuroendocrine carcinoma is in the differential.

Antitumor effect of insulin-like growth factor-1 receptor inhibition in head and neck squamous cell carcinoma.

OBJECTIVES: The insulin-like growth factor-1 receptor (IGF1R) has been implicated in therapeutic resistance in head and neck squamous cell carcinoma (HNSCC), and small molecule tyrosine kinase inhibitors (TKIs) of IGF1R activity may have anticancer activity. Therefore, the relationship between survival and IGF1R expression was assessed for oral cavity (OC) cancer, and the antitumor effects of two IGF1R-TKIs, OSI-906 and BMS-754807, were evaluated in HNSCC cell lines in vitro. METHODS: Clinical outcome data and tissue microarray immunohistochemistry were used to generate IGF1R expression-specific survival curves. Immunoblot, alamarBlue proliferation assay, trypan blue exclusion viability test, clonogenic assay, flow cytometry, and reverse phase protein array (RPPA) were used to evaluate in vitro responses to IGF1R-TKIs. RESULTS: For patients with stage III/IV OCSCC, higher IGF1R expression was associated with poorer overall 5-year survival (P = 0.029). Both BMS-754807 and OSI-906 caused dose-dependent inhibition of IGF1R and Akt phosphorylation and inhibited proliferation; BMS-754807 was more potent than OSI-906. Both drugs reduced HNSCC cell viability; only OSI-906 was able to eliminate all viable cells at 10 µM. The two drugs similarly inhibited clonogenic cell survival. At 1 µM, only BMS-754807 caused a fourfold increase in the basal apoptotic rate. RPPA demonstrated broad effects of both drugs on canonical IGF1R signaling pathways and also inhibition of human epidermal growth factor receptor-3 (HER3), Src, paxillin, and ezrin phosphorylation. CONCLUSION: OSI-906 and BMS-754807 inhibit IGF1R activity in HNSCC cell lines with reduction in prosurvival and proliferative signaling and with concomitant antiproliferative and proapoptotic effects. Such antagonists may have utility as adjuvants to existing therapies for HNSCC. LEVEL OF EVIDENCE: NA Laryngoscope, 130:1470-1478, 2020.

Transcriptionally Active HPV and Targetable EGFR Mutations in Sinonasal Inverted Papilloma: An Association Between Low-risk HPV, Condylomatous Morphology, and Cancer Risk?

Sinonasal inverted papillomas (IPs) commonly recur, and transform to malignancy in 5% to 10% of patients. It has long been debated whether IPs are caused by high-risk or low-risk (lr) human papillomavirus (HPV) and whether the HPV is transcriptionally active. EGFR mutations have also been recently implicated in the pathogenesis of IP with an unclear relationship to HPV status. IP cases over a 10-year period were tested for p16 by immunohistochemistry and for transcriptionally active hrHPV and lrHPV by reverse-transcriptase real-time polymerase chain reaction and RNA in situ hybridization, respectively. EGFR tyrosine kinase domain Sanger sequencing was performed on all lrHPV RNA positive and 15 randomly selected lrHPV RNA negative IPs. Seven sinonasal nonkeratinizing squamous cell carcinomas (SCCs) without associated IP were included as controls. Of the 44 IPs, 5 (11.4%) were associated with SCC, all keratinizing type. All IPs and associated SCCs were negative for p16 and hrHPV. lrHPV RNA was detected in 5/42 (12%) cases, including 3/5 (60%) with associated SCC (P=0.009). All 5 lrHPV RNA positive IPs involved the nasal cavity, had a distinct, condylomatous morphology, and were EGFR wild-type. In contrast, 11/15 (73.3%) lrHPV RNA negative IPs that were sequenced had EGFR exon 19 or 20 mutations. All control nonkeratinizing SCCs were lrHPV RNA negative, but 5/7 (71.4%) were p16 and high-risk HPV RNA positive. This study shows that a subset of IPs involving the nasal cavity have transcriptionally active lrHPV, condylomatous morphology, and possibly increased risk of malignancy. Furthermore, lrHPV positivity is mutually exclusive with EGFR mutations, which suggests alternate mechanisms of pathogenesis.

Mismatch Repair Protein Deficiency/Microsatellite Instability Is Rare in Cholangiocarcinomas and Associated With Distinctive Morphologies.

OBJECTIVES: Although germline mutations of mismatch repair (MMR) genes (Lynch syndrome) are not typically associated with cholangiocarcinomas, the US Food and Drug Administration recently approved the use of pembrolizumab in patients with advanced solid tumors at all sites that show MMR deficiency or associated high microsatellite instability. METHODS: We analyzed 96 cases of intra- and extrahepatic cholangiocarcinomas for morphology using H&E and for MMR status using immunohistochemical staining. We submitted any results with MMR loss for microsatellite instability testing. RESULTS: We found that 6% of samples showed MMR deficiency. The best predictive factor was a nontypical infiltrating pattern of invasion (P < .0001). No patients with MMR deficiency had a history of a cancer typically associated with Lynch syndrome. CONCLUSIONS: Solid, mucinous, or signet-ring appearance of a cholangiocarcinoma should prompt MMR testing for immunotherapy options but should not necessarily raise concern about Lynch syndrome.