Head and Neck Pathology

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Representative hematoxylin-eosin (H&E) (A, C, E, G) and immunohistochemistry for MUC1 (B, D, F, H) in normal salivary gland tissue (A, B), grade I (C, D), grade II (E, F), and grade III (G, H) MECs
Relative expression levels of (A) miR-145 and (B) miR-21. Middle point: median; box: interquartile range (25th to 75th percentiles); whisker: range (excluding outliers). Each error bar is constructed using a 95% confidence interval of the mean
Kaplan-Meier curves of overall survival stratified with (A) tumor stage (P = 0.003), (D) grade (P < 0.001), and (G) MUC1 expression level (Low expression (IRS: 0 to 4) vs. high expression (IRS > 4)) (P = 0.04). Kaplan-Meier curves of cancer-specific survival stratified with (B) tumor stage (P = 0.004), (E) grade (P < 0.001), and (H) MUC1 expression level (Low expression (IRS: 0 to 4) vs. high expression (IRS > 4)) (P = 0.04). Kaplan-Meier curves of disease-free survival stratified with (C) tumor stage (P = 0.16), (F) grade (P < 0.001), and (I) MUC1 expression level (Low expression (IRS: 0 to 4) vs. high expression (IRS > 4)) (P = 0.01). Note: P-values are obtained using log-rank test
Article
  • Ali AbdolrahmaniAli Abdolrahmani
  • Neda Kardouni KhoozestaniNeda Kardouni Khoozestani
  • Farid Azmoudeh-ArdalanFarid Azmoudeh-Ardalan
  • Ahmad Reza ShamshiriAhmad Reza Shamshiri
Background Salivary gland mucoepidermoid carcinoma (MEC) poses a considerable risk of locoregional and distant metastasis after conventional treatments. There is an evident need for specifying prognostic biomarkers to identify patients who are in need of more intensive and prolonged follow-ups. This study aimed to assess the mucin 1 (MUC1) expression level and its potential regulatory microRNAs in salivary gland MEC and their prognostic potentials.Materials and Methods The expression of MUC1 in salivary gland MEC tissues was assessed in 47 samples using immunohistochemistry. Related microRNA (miR-145 and miR-21) were evaluated using quantitative Reverse Transcription PCR. The associations between MUC1 and microRNAs expressions and clinicopathological parameters were investigated.ResultsMUC1 expression levels positively correlated with histologic grade (p < 0.001), clinical stage (p = 0.04), risk of nodal metastasis (p = 0.02), as well as the likelihood of opting for radical treatment (p = 0.01). Increased expression of miR-21 (p < 0.001) and decreased expression of miR-145 (p < 0.001) were observed in MECs compared to normal salivary gland tissue. MiR-145 negatively (p = 0.01) and miR-21 positively (p = 0.01) correlated with MUC1 overexpression. Based on the univariate cox proportional hazard model, histologic grade and MUC1 expression level were significantly associated with disease-free, cancer-specific, and overall survival. However, the multivariable cox proportional hazard model indicated tumor grade as the only prognostic factor associated with disease-free survival.Conclusion Our results support the tumor suppressor role of miR-145 and the oncogenic role of miR-21 in salivary gland MEC. Also, MUC1 and miR-145 overexpression, as well as miR-21 suppression, show promising association with histologic tumor grade and clinical stage.
 
Hematoxylin and eosin images of three of the cases identified: A and B a basal cell adenoma, with the typical basaloid cytology and well-defined borders; C and D a basal cell adenocarcinoma, with an obvious infiltrative growth pattern, with nodules on desmoplastic stroma; and E and F a highly aggressive basal cell adenocarcinoma ex-pleomorphic adenoma with an invasive front that reached the dermis (E) and a residual hyalinized nodule of a pleomorphic adenoma within the tumor (F)
Survival probability along time (months) per primary location of the tumor (global p-value mentioned)
Survival probability along time (months) per surgery plus radiation vs surgery alone (global p-value mentioned)
Survival probability along time (months) per complete vs incomplete excision (global p-value mentioned)
Article
Background Basal cell adenoma (BCA) and adenocarcinoma (BCAd) are two of the least frequent salivary gland tumors. We describe the largest series of these neoplasms, spanning over a period of 50 years (1970–2020), diagnosed and treated in a single Institution. Methods Sixty-eight cases were identified. Clinical and pathological data were collected and correlated with outcome. Results Forty-one BCA and 27 BCAd were identified. BCA cases had almost pristine prognosis, with only a relapse in a tumor inadequately excised. Ten patients with BCAd developed metastases, and 14 died from the disease. The 2-year and 5-year survival was of 76% and 42%. Conclusions The importance of adequate excision is reinforced in BCA, with no recurrences occurring when margins were negative. Contrary to previous reports, BCAd was not associated with a good prognosis. A better understanding of the genetics of these neoplasms may identify therapeutic options when dealing with inoperable or metastatic disease.
 
Right palatine tonsil GLI1-amplified soft tissue tumor (Case 1). The tonsil is effaced by a cellular multinodular spindle cell proliferation arranged in loose fascicles (A, B, C, D) within a variably myxoid to hyalinized stroma, reminiscent of a nerve sheath tumor, solitary fibrous tumor, or monophasic synovial sarcoma. The tumor cells contain abundant eosinophilic cytoplasm and oval to spindled nuclei with mild nuclear pleomorphism. Additional features include dilated vessels (B), a sprinkling of intratumor lymphocytes, and focal epithelioid morphology (E, F) with a prominent capillary vasculature (F)
Base of tongue ACTB::GLI1 fusion-related soft tissue tumor (Case 2). A cellular proliferation of epithelioid cells arranged in nests and anastomosing trabecula (A–C) is seen beneath an ulcerated mucosal surface (A). Hyalinized stroma is variably present (B, C) along with occasional intratumoral lymphocytes (C). There is strong nuclear and cytoplasmic, block-like p16 immunoexpression in > 70% of tumor cells (D)
Oropharynx ACTB::GLI1 fusion-related soft tissue tumor (Case 3). Low power shows expanded nodules of monotonous epithelioid cells (A–C). Variably hyalinized stroma is seen between some of the lobules (B–C). Within the nodules, an arborizing thin-walled vasculature show perivascular tumor cell nests (D–E). Focal myxoid change with microcysts is noted (D). High power view demonstrates round to ovoid nuclei with clear to pale eosinophilic cytoplasm (F)
Dorsal tongue ACTB::GLI1 fusion-related soft tissue tumor (Case 4). Infiltrating lobules of epithelioid cells can be seen infiltrating beneath the epithelium (A–C) and protruding into a superficial blood vessel (A). Myxoid change with microcyst formation is focally present (B). Tumor cells are arranged in a perivascular distribution around intratumoral blood vessels (D–E). Strong nuclear and cytoplasmic block-like p16 immunoexpression seen in 50% of tumor cells (F). DDIT3 FISH (CytoCell break apart probe set; green 165 kb probe 5′ to the DDIT3 gene locus and red 146 kb probe 3′ to the GLI1 gene locus) was positive for rearrangement of the 12q13.3 region (G, left-hand image, arrows indicate the cells with split red and green signals). Custom FISH probe specifically spanning the GLI1 locus coupled with a CEN12 FISH probe was negative for GLI1 specific amplification (G, right-hand image, arrows indicate cells with two CEN12 signals and three GLI1 signals including split of at least one of the GLI1 signals secondary to rearrangement involving the GLI1 specific locus)
Ventral tongue GLI1-amplified soft tissue tumor (Case 5). Tumor cells are round to focally spindled (A–C) and separated by a variably hyalinized fibrovascular stroma. Strong nuclear and cytoplasmic block-like p16 immunoexpression in > 70% of tumor cells (D)
Article
Background GLI1 is a transcription factor protein that has recently gained recognition in a morphologically distinct group of epithelioid soft tissue tumors characterized by GLI1 fusions or amplifications. The head and neck region, particularly the tongue, is a common location for GLI1-altered tumors. DDIT3 break apart fluorescence in situ hybridization (FISH), commonly used to identify translocations in myxoid/round cell liposarcoma, has been used as a surrogate test to detect both fusions and amplifications of the 12q13.3 region encompassing DDIT3 and GLI1 gene loci. Methods We herein report 5 cases of GLI1-altered soft tissue tumors. Three arose in the oropharynx (base of tongue/vallecula, tonsil) and two arose in the tongue. Given the frequent oropharyngeal location and epithelioid morphology, p16 immunohistochemistry was performed on cases with available material. Commercially available DDIT3 break apart FISH, custom GLI1 specific FISH, and RNA sequencing were performed on select cases. Results Two cases showed amplification using DDIT3 FISH which was confirmed using GLI1 specific FISH. The remaining cases harbored ACTB::GLI1, one of which showed rearrangement of the 12q13.3 region by DDIT3 FISH with absence of amplification by GLI1 specific FISH. STAT6 immunoexpression was positive in the GLI1-amplified cases and negative in the GLI1-rearranged cases while MDM2 expression was positive in the 4 cases tested. CDK4 expression was strong and diffuse in the GLI1-amplified cases. p16 immunohistochemistry showed strong nuclear and cytoplasmic staining in 50–70% of tumor cells in all four tested cases. Conclusion Here we show that GLI1-altered soft tissue tumors are frequently positive for p16 and can occur in tonsillar regions of the oropharynx. As such, positive p16 immunohistochemistry alone cannot be used as evidence for the diagnosis of HPV-related squamous cell carcinoma as strong and diffuse p16 expression may also occur in GLI1-altered soft tissue tumors. Commercially available DDIT3 break apart FISH, which is readily available in many cytogenetic laboratories, may be useful as a sensitive surrogate test for GLI1 fusions and amplifications.
 
Study selection based on eligibility criteria
A. Adamantinomatous craniopharyngioma presenting an epithelium with peripheral palisading, nodular whorls, and microcystic areas termed reticulum stellate (HE/40X, objective lens); B. Papillary craniopharyngioma constituted by non-keratinizing squamous epithelium and containing loosely structured connective tissue (HE/40X, objective lens); C. Follicular ameloblastoma showing peripheral palisading of columnar cells with reverse polarity and central reticulum stellate pattern (HE/ 40x, objective lens); D. Plexiform ameloblastoma with anastomosing strands and cords of tumour cells (HE/40x, objective lens)
Article
Background Craniopharyngiomas and ameloblastomas are tumors of epithelial origin, mostly characterized by a benign course, slow growth and for being locally invasive. Some studies highlight the similarity of these neoplasms, especially regarding histopathological aspects. In this context, the aim of the present study was to carry out a systematic literature review correlating the clinical, radiographic, and histopathological aspects of these two tumors. Methods Searches were conducted at the Pubmed, Periódicos Capes, Scopus, Science Direct, Web of Science and Scielo databases, according to the following inclusion criteria: publications in English or Spanish, from the 2000s and 2021, comprising case report studies, case series and literature reviews. Results Considering clinical and radiographic aspects, it is evident that craniopharyngiomas and ameloblastomas exhibit few similarities. Histopathologically, however, adamantinomatous craniopharyngiomas are the type of tumor that most resembles ameloblastomas, both concerning the formation of palisade epithelial cords and epithelial formations. Regarding to recurrences in cases of craniopharyngioma, it appears that a more radical surgical resection is more related to a lower recurrence rate for both craniopharyngiomas and ameloblastomas. As for the outcome, it was observed that craniopharyngiomas have a greater relationship with possible systemic disorders. Conclusions This histopathological similarity is related to their origin, since both craniopharyngiomas and ameloblastomas share a relationship with the oral cavity, either partially, as in the case of craniopharyngiomas, or totally, as in ameloblastomas, not comprising the same lesion in different locations. It is important to note that the differential morphogenetic evidence observed herein between these lesions opens up a new field of study aiming at better treatment alternatives in the future.
 
Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flowchart
Risk of Bias assessment (a, b)
Forest plots; (a) Hazard Ratio, (b) Odd’s/Risk Ratio
Clinicopathologic co-relations; (a) Lymph node metastasis, (b) Recurrence of the primary tumor
Funnel Plot for assessment of Publication Bias
Article
Background Oral Squamous Cell Carcinoma (OSCC), a major debilitating illness demands focus in recent times due to a constant upsurge in cases and poor prognostic implications. An urgent mandate upon finding evidence of relevant prognostic markers is the need of the hour. This systematic review and meta-analysis, therefore, elect an objective assessment of Lymphatic Vessel Density (LVD) as a pertinent parameter governing OSCC prognosis. Methods The study protocol was registered at the International Prospective Register Of Systematic Reviews (PROSPERO). Databases were searched using the MeSH keywords for all study types following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The exposure under consideration was the evaluation of LVD in patients of OSCC. The outcome was measured as pooled Hazard/Odd’s/Risk ratios in survived versus non-survived OSCC population. The risk of bias assessment was performed using the QUIPS tool. Heterogeneity was assessed by Chi-square and I² statistics whereas publication bias was investigated using Egger’s test of significance. All the statistical analysis was conducted using STATA version 13.0. Results The initial search of 226 records were screened and filtered through the inclusion and exclusion criteria to achieve an outcome of 15 studies for qualitative synthesis out of which seven studies were eligible for meta-analysis. Pooled Hazard of enhanced Lymphatic Vessel Density was not found to be statistically significant (HR = 1.98, p = 0.553); contrary to the pooled Odd’s/Risk for patient survival which was statistically significant (RR = 1.33, p = 0.046). The I² test of heterogeneity was also significant (58.8%, p = 0.046). Conclusions This meta-analysis helps to generate pathfinding evidence for a noteworthy role of Lymphatic Vessel Density evaluation in suggesting OSCC prognosis.
 
Elevated cytotoxicity marker and KLRG1 gene expression in oral lichen planus oral mucosa. Analysis of oral mucosa biopsy samples gene expression in Gene Expression Omnibus datasets (A) GSE38616 and (B) GSE52130. Increased expression of KLRG1, multiple markers of T cell cytotoxicity (CD8A, granzymes, perforin), interferon gamma (IFNG) driven chemokine expression (CXCL9, CXCL10, CXCL11), including elevated KLRG1, and KLRG1 correlation with markers of T cell cytotoxicity CD8A and granzyme K (GZMK)
CD8 and KLRG1 + T cell infiltration in oral lichen planus oral mucosa. Oral mucosa biopsy sample immunohistochemistry shown for patient 9915 (A-C, low magnification; D-F high magnification), patient 10,115 (G-I), patient 9369 (J-L), and patient 9748 (M-O). Dense lymphocytic infiltrates at the epithelium and lamina propria junction show abundant CD8 + and KLRG1 + T cells
Basal layer and intraepithelial CD8 and KLRG1 + T cell infiltration. Oral mucosa biopsy immunohistochemistry shows intraepithelial, including the basal cell layer, infiltration with CD8 + and KLRG1 + T cells adjacent to keratinocytes. Arrows track specific cells across increasing magnification (left to right in all rows). (A-G) Patient 10,115, with CD8 (A-C) and KLRG1 (D-F) immunohistochemistry. (G-J) Patient 9844, with KLRG1 immunohistochemistry
Article
Background Oral lichen planus (OLP) is a chronic inflammatory disease affecting oral mucosa. Its pathogenesis includes T cell infiltration. T cells may be naïve or in response to antigen stimulation, progress through differentiation stages. The differentiated states of T cells in OLP mucosa have not previously been reported. Methods Available OLP microarray gene expression data from Gene Expression Omnibus were analyzed for markers of T cell cytotoxicity. Immunohistochemical studies of T cell subset markers CD4 and CD8 and the T cell differentiation marker killer cell lectin-like receptor G1 (KLRG1) were performed on paraffin embedded formalin fixed oral mucosa biopsy samples from 10 patients with OLP. Results Gene expression analysis of OLP oral mucosa samples disclosed increased transcript expression of KLRG1, CD8A, and granzyme K (GZMK). By immunohistochemistry, prominent CD4 + and CD8 + T cell infiltration was seen in all patient samples. KLRG1 + T cells were abundant, constituting a mean of 51% (range 40–65%) of the number of CD8 + T cells. KLRG1 + T cells localized at the epithelium and lamina propria junction, infiltrating both basal and intraepithelial regions and adjacent to both basal and intraepithelial keratinocytes. Conclusions OLP oral mucosa T cell infiltration includes KLRG1 + highly differentiated cytotoxic T cells, suggesting continued antigen exposure driving T cells to a highly differentiated phenotype. The known phenotype of these cells, together with microarray detected increases in cytotoxic molecules, suggests that highly differentiated cytotoxic T cells contribute to oral mucosa injury in OLP.
 
Inflammatory cells of a sinonasal polyp composed of a mixture of lymphocytes, plasma cells, neutrophils (black arrows), and predominant eosinophils > 10/HPF (red arrows). (H&E × 400)
Inflammatory cells of a sinonasal polyp composed of a mixture of lymphocytes, plasma cells, neutrophil clusters (black circle), and rare eosinophils < 10 /HPF (red arrow). (H&E × 400)
Article
Background With the advent of biotherapies, endotyping of chronic rhinosinusitis with nasal polyps (CRSwNP) is becoming more and more important to optimize therapeutic management. While the majority of CRSwNPs in the United States, Europe, and Japan exhibit type 2 eosinophil-dominant inflammation response, other parts of Asia display mixed patterns including neutrophil-dominant inflammation. Until now, no study has focused on the proportion of inflammation patterns in Morocco or anywhere on the African continent. We aim to fill this gap by studying tissue inflammatory response in our operated patients. Material and methods After searching the database of the pathology department, we retrieved from the archives the stained pathology slides of all our patients who underwent surgery for CRSwNP over 5 years from 2017 to 2021. We counted then the number of eosinophils in the lamina propria at high-power magnification to determine the predominant inflammatory pattern. Results A total of 35 reports were collected. We found that eosinophilic inflammation was predominant, accounting for 97% of the cases. Conclusions The CRSwNP endotype in our region would mainly be type 2. However, our results must be confirmed by multicenter studies involving a large number of patients.
 
Panoramic radiograph showing a multilocular radiolucent KA with areas of internal calcifications. CT imaging (insert) showed significant expansion and areas of cortical destruction
Panoramic radiograph (A) showing a multilocular KA affecting the left maxilla. Sagittal (B) and axial (C) CBCT images showed hyperdense areas of calcification and significant expansion, cortical perforation and sinus encroachment
Histopathologic features of keratoameloblastomas. A Solid and cystic tumour follicles in a fibrous connective tissue stroma (original magnification × 20). B Follicles containing abundant lamellated central keratin (original magnification × 40). C Epithelial lining suggestive of an OKC (original magnification × 100). D Other areas more reminiscent of the stellate reticulum (original magnification × 200). E Basal columnar cells with nuclear palisading and subnuclear vacuolisation (original magnification × 200). F Scattered dystrophic calcifications with a foreign body giant cell response (original magnification × 100)
Article
Background Keratoameloblastoma (KA) is an uncommon and controversial variant of ameloblastoma exhibiting central keratinisation. Due to their rarity, there is limited information in the literature on their clinical, radiologic and histologic features. This study adds seven additional cases of KA to the literature, and reviews the current published literature on this rare entity. Methods KAs were retrospectively reviewed over a 20-year period from three Oral and Maxillofacial Pathology Laboratories. Included cases were examined and the diagnosis confirmed under conventional microscopy. Immunohistochemistry with the use of a monoclonal antibody against calretinin was performed on included cases. The clinical, radiologic and histologic features of the seven new cases of KA were analysed and compared to existing cases in the literature. Results KAs presented at a mean age of 40 years with a nearly equal gender distribution and a mandibular predilection (65%). The majority (92%) of cases presented with localised swelling with associated pain in 32% of cases. Mixed density or internal calcifications were noted in 40% of cases. All tumours presented with bony expansion, with cortical destruction noted in 62% of cases. Histologically, all tumours consisted of solid and cystic follicles with surface parakeratinisation and lamellated accumulations of central keratin. In areas the cystic follicles had an epithelial lining suggestive of an OKC. There were focal luminal areas of loosely arranged polygonal cells reminiscent of the stellate reticulum. The basal cells consisted of columnar cells with evidence of palisading and prominent subnuclear vacuolisation. Of the cases treated via tumour resection, 27% presented with tumour recurrence. Conclusion This case series reports seven additional cases of KA, taking the total to 26 reported cases. The identification of subtle histologic features, including focal stellate reticulum-like central areas, subnuclear vacuolisation and lamellated-type central keratinisation, are key in diagnosing KA. The radiologic features will often indicate signs of aggressiveness such as cortical destruction, differentiating KA from OKC. All cases were completely negative for calretinin IHC, limiting its use in distinguishing KA from OKC. Further large series are needed to expand the current understanding of this rare variant of ameloblastoma.
 
Histologic features of salivary gland intraductal papillary mucinous neoplasm (SG IPMN). A A well-demarcated and circumscribed tumor is observed. B SG IPMN with mild cellular atypia. Tumor cells have monotonous basally-located nuclei and apical mucin. C SG IPMN with moderate cellular atypia. The papillary pattern becomes more complex and hypercellular than SG IPMN with mild cellular atypia. D SG IPMN with severe cellular atypia. Brisk mitotic activity is observed. The nuclear polarity is partially lost and cytoplasmic mucin is less remarkable than in SG IPMN with mild or moderate atypia. E Lymph node metastasis is detected. F The papillary growth protrudes from the orifice. G Invasion into surrounding parenchymal tissue with mucin extravasation is observed. H Non-neoplastic mucinous acinar cells are present in the neoplastic papillary growth
NKX3.1 immunohistochemistry in SG IPMN, its mimics, and normal salivary gland. H&E stain of SG IPMN (A) and corresponding NKX3.1 immunohistochemistry (IHC) (B). Tumor cells show diffuse and strong NKX3.1 expression. The expression is limited to the nucleus (inset). C Mucoepidermoid carcinoma and its NKX3.1 IHC (inset). All tumor cells including mucous cells are negative for NKX3.1, D Pancreatic IPMN morphologically resembles SG IPMN, but completely lacks NKX3.1 expression. E Normal mucinous acinar cells are positive for NKX3.1, while striated duct cells are negative. F Serous acinar cells are negative for NKX3.1
Immunohistochemical features of SG IPMN. The Ki-67 proliferation index is low in SG IPMN with mild atypia (A), while SG IPMN with severe atypia show a high Ki-67 proliferation index (B). Most SG IPMN cases lack p63-positive myoepithelial rimming (C, left portion) in contrast to normal mucinous salivary gland myoepithelial cells (C, right portion). A partial myoepithelial cell lining is observed in one SG IPMN case (D)
Chromatogram of DNA sequencing of AKT1 (case 3). While surrounding normal salivary tissue is AKT1 wild-type, tumor cells exhibited a c.49G > A (p.E17K) peak
Article
Background: Salivary gland intraductal papillary mucinous neoplasm (SG IPMN) is a recently proposed entity characterized by a papillary-cystic proliferation of mucin-producing cells. Because of overlapping histologic features and a clonal AKT1 p.E17K variant, SG IPMN has been presumed to be a precursor or a low-grade subtype of mucinous adenocarcinoma. NKX3.1 is a tumor suppressor gene located on chromosome 8p and is a known immunohistochemical marker of prostate epithelium and mucinous acinar cells of the intraoral salivary glands. Methods: We retrieved 12 SG IPMN cases, and performed histologic and genetic analysis. Given the association of SG IPMN with mucinous acinar cells, we also investigated the performance of NKX3.1 as a marker of this tumor entity. Results: Diffuse and strong NKX3.1 expression was observed in all SG IPMN cases (12/12, 100%) as well as in normal mucinous acinar cells. In contrast, mucoepidermoid carcinoma and pancreatic IPMN cases as well as normal serous acinar cells were negative for NKX3.1. Genetically, 11 of 12 cases (92%) harbored an AKT1 p.E17K variant. A novel PTEN frameshift deletion (p.G36Dfs*18) was detected in the other single case. At least one of the histologic features implying malignant tumors, such as severe cellular atypia, brisk mitotic activity, high Ki-67 proliferating index, lymphovascular invasion, and lymph node metastasis, was detected in 6 SG IPMN cases (50%). Conclusion: The findings suggest that SG IPMN is a low-grade subtype of mucinous adenocarcinoma which may be derived from mucinous acinar cells of the minor salivary gland.
 
T2-weighted MRI with hypointense tumor of the left parotid gland
Cell block from FNA of left parotid gland showing clusters of oncocytes
Oncocytoma and surrounding normal salivary gland tissue and adipose
Tubular/acinar formations within the oncocytoma
Article
Oncocytomas of the salivary gland are uncommon neoplasms that are characterized by polygonal cells with abundant granular eosinophilic cytoplasm and relatively uniform nuclei. They are benign in nature and have a low recurrence rate with complete surgical excision. Though uncommon, oncocytic and clear cell variants of malignant tumors may histologically mimic oncocytomas and identification of their distinguishing features is essential. A classic example of an oncocytoma is discussed.
 
Boxplot of interrater reliability measures for presence/absence of ENE between every two pathologists in round one and two. The plotted kappa coefficients are between pathologist 1 and 2, 1 and 3, 1 and 4, 2 and 3, 2 and 4, and 3 and 4. The rectangles represent the second and third quartiles, the horizontal line inside represents the median, and the horizontal lines outside represent the maximum and minimum
Bar chart with the count of observed histological slides graded from 0 to 4 according to Lewis’ ENE classification system
Lymph node with metastasis from p16+ oropharyngeal squamous cell cancer and pseudocapsule. According to our definition, this finding does not qualify as ENE. (hematoxylin–eosin)
Article
Background: Extranodal extension (ENE) in lymph node metastases is one of the most important prognostic factors in head and neck squamous cell carcinomas. Studies have shown inconsistency among pathologists in the assessment of ENE. The aims of this study were: (1) to determine the interrater and intrarater reliability and agreement in the assessment of ENE among Danish pathologists and (2) to test if a standardized assessment method may increase interrater agreement. Methods: Four Danish head and neck pathologists assessed ENE presence or absence in 120 histological slides from lymph nodes with oropharyngeal squamous cell carcinoma metastases (first round). Subsequently, guidelines were introduced to the pathologists and a new assessment was performed (second round). Finally, two of the pathologists assessed the slides to determine intrarater reliability and agreement (third round). Results: Interrater kappa coefficients varied between 0.57 and 0.67 in the first round and between 0.59 and 0.72 in the second round. The intrarater agreement between round 2 and 3 was 0.88 for pathologist 1 and 0.92 for pathologist 2 with resulting kappa coefficients of 0.76 (95% CI 0.64-0.88) and 0.84 (95% CI 0.74-0.94), respectively. Conclusion: We found a moderate level of reliability and agreement among pathologists for ENE in lymph node metastases from oropharyngeal squamous cell carcinomas. The intrarater reliability and agreement was generally higher than interrater measures. Interrater agreement was slightly improved by standardized assessment.
 
Clinical photograph of a mixed leukoplakic and erythroplakic lesion of the ventral tongue and floor of mouth. (Courtesy of Julie Gaskill, DDS, Bowling Green, Kentucky)
Morphologic features of an HPV-associated SCC with in situ and invasive carcinoma. A On low power, the tumor shows many large, rounded nests of blue cells with high N:C ratios, smooth borders, and lack of stromal desmoplasia. B On medium power, the nests are large and smooth and have minimal maturing squamous differentiation. C On high power, the cells of the invasive carcinoma have round to oval nuclei, minimal cytoplasm, nuclear pleomorphism, and brisk mitotic activity with a focus of necrosis. D This SCC in situ had the typical dense and brightly eosinophilic parakeratin and cells with high N:C ratios
Morphologic features of another case of invasive HPV-associated SCC with SCC in situ. A SCC in situ showing brightly eosinophilic parakeratin, bulbous rete, and cells with high N:C ratios throughout. B On higher power, there are prominent mitotic figures, apoptosis, and a “mitosoid” apoptotic body. C The invasive SCC in this case consisted of large, irregular nests with stromal desmoplasia, but the nests showed a mixture of higher N:C ratio areas interspersed with the keratinizing areas, the latter being haphazardly arranged. D On high power, the invasive carcinoma shows some nonkeratinizing features but also extensive maturing squamous differentiation
Morphologic features of another invasive HPV-associated SCC with SCC in situ. A The in situ carcinoma shows the typical features of HPV-associated dysplasia compared to the adjacent more normal epithelium (superior). B Low power view of the invasive tumor shows very large, irregular nests, some of which are very blue with high N:C ratio cells and others which are more keratinized with abundant, eosinophilic cytoplasm. C High power view of the blue areas of invasive tumor shows the typical features of nonkeratinizing SCC
p16 immunohistochemistry and high risk HPV RNA in situ hybridization. A p16 immunohistochemistry on the invasive SCC showing diffuse strong nuclear and cytoplasmic staining. B p16 immunohistochemistry on the in situ SCC showing diffuse strong nuclear and cytoplasmic staining. C RNA in situ hybridization on the invasive SCC showing granular, brown positive staining of the cytoplasm. D RNA in situ hybridization on the in situ SCC showing granular, brown positive staining of the cytoplasm
Article
Background HPV-associated oral cavity squamous cell carcinoma (SCC) is not well-characterized in the literature, and also has a clinical significance that is poorly understood. Methods We gathered a cohort of oral cavity (OC) SCC with nonkeratinizing morphology, either in the invasive or in situ carcinoma (or both), tested for p16 by immunohistochemistry and high risk HPV E6/E7 mRNA by RTPCR (reference standard for transcriptionally-active high risk HPV) and gathered detailed morphologic and clinicopathologic data. Results Thirteen patients from two institutions were proven to be HPV-associated by combined p16 and high risk HPV mRNA positivity. All 13 patients (100%) were males, all were heavy smokers (average 57 pack/year), and most were active drinkers (9/11 or 81.8%). All 13 (100%) involved the tongue and/or floor of mouth. All had nonkeratinizing features, but maturing squamous differentiation varied widely (0–90%; mean 37.3%). Nonkeratinizing areas had high N:C ratios and larger nests, frequently with pushing borders, and minimal (or no) stromal desmoplasia. The carcinoma in situ, when present, was Bowenoid/nonkeratinizing with cells with high N:C ratios, full thickness loss of maturation, and abundant apoptosis and mitosis. HPV was type 16 in 11 patients (84.6%) and type 33 in two (15.4%). Nine patients had treatment data available. These underwent primary surgical resection with tumors ranging from 1.6 to 5.2 cm. Most had bone invasion (6/9–66.7% were T4a tumors), and most (6/9–66.7%) had extensive SCC in situ with all 6 of these patients having final margins positive for in situ carcinoma. Conclusions HPV-associated OCSCC is an uncommon entity that shows certain distinct clinical and pathologic features. Recognition of these features may help pathologic diagnosis and could potentially help guide clinical management.
 
Article
Background Primary bone lymphoma is a rare type of lymphoid neoplasm with favorable prognosis, where Primary Non Hodgkin Lymphoma of bone (PB-NHL) is most common with the subtype. Amongst PB-NHL, diffuse large Bcell lymphoma represents the majority of cases. The mandible is a very uncommon site of involvement, presenting as a painful bone mass with high suspicion of osteomyelitis. Methods We report the case of a 45-year-old male with no significant past medical history who was admitted to the hospital with a large right jaw mass and pain after recent tooth removal. The original tissue biopsy was not diagnostic, and cultures were found to be negative for microorganisms. Due to enlargement of the mass, a fine needle aspiration (FNA) was done. At the time of rapid onsite evaluation of the FNA, atypical lymphoid cells were seen, and material was obtained for flow cytometry (FC) evaluation. This revealed an aberrant clonal B-cell population. The consequent immunohistochemical evaluation of original material supported the diagnosis of PB-NHL. After chemotherapy patient improved. Results After an extensive English language literature review, we identified and summarized the clinical presentations, diagnostic procedures, histopathologic features, treatment methods, and outcomes of forty-two cases of periodontal PB-NHL. Based on our findings, we propose a set of clinical features at initial presentation to increase the clinical suspicion of periodontal PB-NHL for practitioners. Conclusion Based on our institution’s experience and the literature review conclusions, we propose the University of Texas Medical Branch diagnostic approach for PB-NHL and suggest that FNA and FC should be utilized as the essential diagnostic component. The fast and efficient diagnosis of PB-NHL can facilitate the correct treatment and sufficiently improve patient care.
 
SDC-RF were entirely composed of highly infiltrative sheets (A), cords (B), and singly dispersed cells (C) with intraductal colonization in a subset of cases (D)
Perineural invasion (A) and lymphovascular invasion (B) were frequently seen, and mitotic figures including atypical mitotic forms (C) and necrosis (Figure D) were common
Tumor cells had eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli with a rhabdoid (A) to histiocytoid (B) appearance. As subset of cases had signet-ring features (C) with intracytoplasmic mucin vacuoles on mucicarmine stain (D)
All tumors were positive for AR (A) and GCDFP (B); the majority showed total loss of e-cadherin (C) or abnormal cytoplasmic localization (D)
NGS highlighted frequent PIK3CA and HRAS hotspot mutations with additional TP53 mutations, AKT1 hotspot mutation, and PTEN loss. Most cases also had CDH1 alterations, including a novel CDH1::CORO7 fusion
Article
Background Salivary duct carcinoma with rhabdoid features (SDC-RF) is a recently-described salivary gland tumor that bears striking histologic similarity to lobular carcinoma of the breast. While this tumor has an apocrine phenotype that supports classification as a variant of SDC, it infrequently arises in association with conventional SDC. Furthermore, discohesive architecture can be seen in non-apocrine salivary carcinomas, raising the possibility that discohesive growth should define a separate entity. In this study, we aimed to perform comprehensive molecular profiling of SDC-RF to better understand its pathogenesis and classification. Methods We documented the clinicopathologic features of 9 cases of SDC-RF and performed immunostains including AR, GCDFP, and e-cadherin on all cases. We also performed targeted next generation sequencing (NGS) panels on 7 cases that had sufficient tissue available. Results The SDC-RF represented 8 men and 1 woman with a median age of 67 years (range 63–83 years) and included 6 parotid, 2 buccal, and 1 submandibular primary. All tumors were uniformly composed of discohesive cells with abundant eosinophilic cytoplasm; signet-ring cell features were seen in 2 cases. All tumors were also positive for AR (100%) and GCDFP (100%), and 7 tumors (78%) displayed lost or abnormal e-cadherin. NGS highlighted concomitant PIK3CA and HRAS mutations in 4 tumors, with additional cases harboring TP53, PTEN, and AKT1 mutations. Furthermore, CDH1 alterations were seen in 6 cases, including a novel CDH1::CORO7 fusion. Among 5 patients with follow-up available, 3 (60%) developed local recurrence and widespread distant metastasis and died of disease at a median 20 months (range 10–48 months). Conclusions Overall, our findings confirm frequent CDH1 mutations and e-cadherin inactivation in SDC-RF, similar to discohesive tumors from other sites. We also highlight an apocrine molecular profile similar to conventional SDC. However, occasional AKT1 mutation and signet-ring features suggest SDC-RF may also be related to mucinous adenocarcinoma. As more salivary tumors with discohesive growth are identified, it may become clearer whether SDC-RF should remain in the SDC family or be recognized as a separate entity.
 
Sections from the neck mass revealed nonkeratinizing squamous cell carcinoma (A). The majority of the tumor was strongly, diffusely positive for p16 by IHC, but discrete regions were completely negative (B). High power H&E (C) and p16 IHC (D) images taken from the same area demonstrate the interface between the distinct tumor regions
Nonkeratinizing squamous cell carcinoma of the right tongue base (A), which was negative for p16 by IHC (B). The background mucosa showed a normal patchy pattern of p16 positivity (C)
RNA ISH for high-risk HPV was positive throughout the metastatic neck mass (A) and the base of tongue lesion (B)
Article
Background Oropharyngeal squamous cell carcinoma is frequently associated with high-risk HPV infection, which confers a good prognosis. Immunohistochemistry for p16 is used as a surrogate for HPV status, but discrepant results are occasionally seen. Here, we report a case with a unique pattern of partial loss of p16. Methods A 63 year old male presented with a base of tongue nonkeratinizing squamous cell carcinoma and a large metastatic neck mass. The primary lesion and multiple regions of the metastatic mass were assessed with p16 immunohistochemistry, RNA in situ hybridization for high-risk HPV, and HPV16 genome sequencing. Results The primary lesion was p16 negative, and the metastatic neck mass had large, confluent regions that were either strongly p16 positive or entirely p16 negative. All of these regions were positive for high-risk HPV with identical HPV16 genomes. Conclusion This unusual case illustrates a potential diagnostic pitfall, and it raises important questions regarding molecular mechanisms and prognostic implications of p16 staining in oropharyngeal squamous cell carcinoma.
 
Article
Background Lymph node metastasis (LNM) is a well-known prognostic factor in Oral Squamous Cell Carcinoma(OSCC). A biological marker that predicts the Lymph Node Metastasis (LNM) in OSCC cases is the need of the hour. A Disintegrin And Metalloproteinases (ADAMs), a family of proteins that exhibit a metalloproteinase domain play a pivotal role in the pathogenesis of tumor growth and metastasis. This study aims to evaluate whether ADAM 10 can be used as a predictor of lymph node metastasis in OSCC using immunohistochemistry. Method A total of 90 samples that were categorized into 3 groups were included in the present study. Group I consisted of 30 samples of the normal oral mucosa, and Group II consisted of 30 samples of OSCC without lymph node metastasis. Group III consisted of 30 samples of OSCC with lymph node metastasis. Esophageal Squamous Cell Carcinoma was used as external positive control. Immunohistochemical expression of ADAM10 in their corresponding stained sections was assessed and staining intensity was calculated. Results ADAM10 immunoreactivity was considered positive when located in cytoplasm or membrane or both. This method is similar to that used by Bamane et al. for OSCC cases. The mean value of the Staining Index score “AxB” was highest in Group III (7.90), followed by Group II (3.13) and least in Group I (0.27). These values were statistically significant. Conclusion Considering the findings of a higher percentage of ADAM10 positive cells, higher staining intensity, and higher staining index, the overexpression of ADAM10 can be used as an independent marker for OSCC patients to predict the lymph node metastasis.
 
a-c Fused axial PET and CT images shows diffuse uptake in thyroid gland which are symmetrically enlarged. Few nodular enhancing deposits are seen in the vicinity of the lesion compressing the bilateral neck vessels. Tracheal air column shows no significant luminal compromise
H & E stained linear cores from thyroid swelling (a) shows proliferation of neoplastic cells in diffuse sheets (b) shows few entrapped thyroid follicles (arrow) in tumor tissue (c) shows pleomorphic bizarre neoplastic cells (d) shows significant mitosis (arrow) and multilobated neoplastic cells
Immunohistochemistry (a) CK was negative in tumor cells while entrapped thyroid follicles were positive (arrow) (b) CD138 was patchy positive in tumor cells (c) and (d) shows kappa lambda by ISH highlighting kappa restriction, respectively
Serum protein electrophoresis showed distinct M-band in Gamma region. The M-band concentration is 0.67 g/dl
Article
Background Plasmacytoma involving thyroid gland is infrequent and can present as either primary extramedullary plasmacytoma or secondary to multiple myeloma. Methods and Results We present a case of 71 years old male who complained of a huge anterior neck swelling accompanied by dysphagia and dyspnoea. Fine needle aspiration cytology was suggestive of anaplastic carcinoma of thyroid (ATC), however, the subsequent histomorphology supported by immunohistochemistry (IHC) astoundingly favoured the diagnosis of plasmacytoma. Further evaluation revealed the presence of lymphadenopathy and single bone lesion in the present case which was rather suggestive of secondary involvement of thyroid to multiple myeloma. However, the case was unique in view of its presentation as a rapidly enlarging thyroid mass associated with stridor and cytomorphological findings which were of an undifferentiated malignancy favouring ATC. The use of a broad and judicious IHC panel clinched the final diagnosis of plasmacytoma. Conclusion The present case emphasizes the diligent use of IHC in such cases given different therapeutic and prognostic implications.
 
(Case1): A Microphotograph showing diffuse infiltrate of atypical lymphoid cells entrapping a nerve (H&E*, × 40). B, C Microphotographs showing diffuse sheets of monocytoid lymphoid cells admixed with scattered transformed cells in a prominent vaso-formative background. (H&E*, × 200, × 400). D Immunohistochemistry microphotograph showing tumor cells to be diffusely positive for CD20. E Immunohistochemistry microphotograph showing tumor cells to be focally (~ 30%) positive for MNDA, F Immunohistochemistry microphotograph showing residual germinal centres as highlighted by CD21 *Hematoxylin and eosin
(Case 2): A Microphotograph showing vague nodular infiltrate of atypical lymphoid cells (H&E*, × 40). B, C Microphotographs showing sheets of centrocyte-like cells admixed with few large transformed cells (H&E*, × 400, × 800). D Immunohistochemistry microphotograph showing tumor cells to be diffusely positive for CD20. E Immunohistochemistry microphotograph showing tumor cells to be strongly and diffusely positive for MNDA. F Immunohistochemistry microphotograph showing Mib-1 labelling index of ~ 10%. *Hematoxylin and eosin
(Case3): A PET-CT scan image showing soft tissue lesion in right buccal mucosa. B Microphotograph showing diffuse infiltrate of atypical lymphoid cells (H&E*, × 100). C, D Microphotographs showing sheets of centrocyte-like cells admixed with numerus large transformed cells (H&E*, × 400, × 600). E Immunohistochemistry microphotograph showing tumor cells to be diffusely positive for CD20. F Immunohistochemistry microphotograph showing tumor cells to be positive for Bcl2. *Hematoxylin and eosin
A Case1: Interphase-FISH with Abott Molecular IGH/BCL2 dual colour dual fusion probe microphotograph showing one copy of BCL2 (Red signals). B Case2: Interphase-FISH with Abott Molecular IGH/BCL2 dual colour dual fusion probe microphotograph showing two copies of BCL2 (Red signals) and two copies of IGH (Green signals). C Interphase-FISH with Abott Molecular BIRC3 (API2)/MALT1 dual colour dual fusion probe microphotograph showing 2 copies of BIRC3 (API2) (Green signals) and 4 copies of MALT1 (Red signals) indicating tetrasomy 18
Article
Background Diagnosis of MALT lymphoma in the oral cavity is challenging. There is a great overlap in the histopathologic, immuno-histochemical and molecular features of MALT lymphoma with reactive lymphoid proliferations. The literature shows a very few case reports of primary MALT lymphoma of oral cavity. Methods We discuss the histopathologic, immuno-histochemical, cytogenetic features, treatment and behavior of 3 cases of primary MALT lymphoma oral cavity along with review of literature. Results The age ranged from 40 to 57 years (male to female ratio = 2:1). The sites involved were hard palate, bilateral gingivobuccal sulcus and right buccal mucosa. The most common histology was centrocyte-like (2 cases). Lymphoepithelial lesions were absent. On immunohistochemistry, all tumors showed diffuse strong CD20 and bcl2 expression with strong and diffuse MNDA staining in one case. IgH; MALT1 translocation was not seen in any of these cases. One patient received local radiotherapy, one received steroids; while the case 3 received RCHOP (Rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine and prednisone) chemotherapy. Two patients had complete remission while one had recurrence. Conclusion MALT lymphoma of oral cavity shows a wide spectrum of morphology with presence of transformed cells, that may lead to misdiagnosis of DLBL. Treatment guidelines are not well established but a tendency to excise MALT lymphomas of oral cavity has been observed. Nevertheless, MALT lymphoma of oral cavity appears to be an indolent disease.
 
Histopathological and immunohistochemical findings of small cell neuroendocrine carcinoma. A undifferentiated tumor proliferation of trabeculated architecture, composed of small basophilic cells (hematoxylin and eosin stain, 100×); B small, round, atypical basaloid cells with scant cytoplasm (hematoxylin and eosin stain, 200×); C high nuclear-cytoplasmic ratio, ovoid‑ to spindle‑shaped nuclei, fine granular chromatin, inconspicuous nucleoli, and abnormal mitosis (hematoxylin and eosin stain, 400×); D–I, epithelial cell immunopositivity for AE1/AE3, EMA and CK18; J–M, neuroendocrine differentiation confirmed by immunopositivity for CD56, synaptophysin and neuron-specific enolase; N and O, strong Ki67 index
Independent variables (clinical-demographic features) associated with cumulative survival
Independent variables (histopathological features) associated with cumulative survival
Survival curve analysis of individuals with oral and maxillofacial neuroendocrine carcinoma
Article
The aim of the present study was to integrate the available data published in the literature on oral and maxillofacial neuroendocrine carcinomas concerning the demographic, clinical and histopathological features of this condition. An electronic search with no publication date restriction was undertaken in April 2021 in four databases. Eligibility criteria included reports published in English having enough data to confirm a definite diagnosis, always showing a neuroendocrine marker. Cases originating in the oropharynx, including base of the tongue and tonsils, were excluded. Outcomes were evaluated by the Kaplan–Meier method along with Cox regression. Twenty-five articles (29 cases) from nine different countries were detected. Mean patient age was 56.3 (± 17.5) years, with a slight male predilection. Symptomatology was present in 72.2% of informed cases. Regarding clinical presentation, a non-ulcerated nodule located in the gingiva with a mean size of 3.4 (± 2.0) cm was most frequently reported. Concomitant metastasis was identified in seven individuals. Histopathologically, most neoplasms were of the small cell type, and immunohistochemistry for both epithelial and neuroendocrine differentiation was used in 65.5% cases. Radical surgery was the treatment of choice in almost all cases, with or without adjuvant therapy. Mean follow-up was 20.5 (± 21.2) months, and only four patients developed recurrences. Eleven (44.0%) individuals died due to the disease. Ulcerated lesions were a prognostic factor. This study provides knowledge that can assist surgeons, oncologists, and oral and maxillofacial pathologists with the diagnosis and management of neuroendocrine carcinomas. Our findings demonstrated that the long-term prognosis of this lesion continues to be poor.
 
Axial and sagittal CT demonstrating an enlarged thyroid mass with posterior tracheal encasement
FNA biopsy of the thyroid demonstrating emperipolesis
A Histologic examination demonstrated diffuse large cells with irregular nuclei, vesicular chromatin, and prominent nucleoli in a background of apoptotic bodies (hematoxylin and eosin). B B-cells with diffuse positivity for CD20. C B-cells positive for Bcl-6. D High proliferation index by KI-67 (> 90%), indicating high cellular turnover
Article
The aim of this study is to present an elusive case of primary thyroid lymphoma (PTL), initially thought to be anaplastic thyroid carcinoma, then Rosai Dorfman disease, before the final diagnosis of PTL was made. An elderly female with hypothyroidism presented with compressive airway symptoms secondary to an enlarging neck mass. Imaging was suggestive of undifferentiated thyroid cancer. The initial biopsy was unexpectedly consistent with a lymphoproliferative disorder such as Rosai-Dorfman disease. A repeat biopsy with immunohistochemical analysis yielded a diagnosis of diffuse large B-cell lymphoma of germinal center subtype. The patient was spared thyroid surgery and started on appropriate chemotherapy. PTL is within the differential diagnosis that physicians must consider in a patient with a rapidly-enlarging neck mass. A clinical index of suspicion and early accurate diagnosis may spare the patient from unnecessary surgery that is required of most other non-hematopoeitic thyroid malignancies.
 
Clinical examination revealed a large ulceration located on the left hard and soft palate, extending posteriorly to the uvula and left glossopalatine arch
Macroscopic examination of the incisional biopsy specimen showing a tan soft tissue of 1.2 cm maximum diameter
Histopathologic findings (H&E; original magnification: ×200): a Oral mucosa specimen with surface ulceration infiltrated by a diffuse or vaguely nodular neoplastic proliferation; b Medium-sized and pale-staining cells with morphological characteristics of lymphocytes and scattered tangible-body macrophages in a stroma exhibiting vascular hyalinization. c Crash artifacts were also noticed. d Monomorphic oval shaped lymphocytes with finely dispersed chromatin intermixed with tangible-body macrophages. e High power view highlighting the cytological characteristics of the neoplastic population which exhibits an overall lymphoblastic appearance with increased mitotic activity. Perivascular hyalinization of a blood vessel is also noticed
Immunohistochemical evaluation (original magnification: ×200): Diffuse immunoreactivity of the neoplastic cells for CD20 (a), CD5 (b) and CCND1 (c)
Histopathologic findings of the new relapsed tumor in nasopharynx (original magnification: ×200): a Neoplastic proliferation of medium-sized lymphoid cells with blastoid features (H&E); b Immunohistochemical evaluation of Ki-67 showing > 50% immunopositivity
Article
Mantle cell lymphoma (MCL) is a well-defined, non-Hodgkin lymphoma of B-cell origin displaying diverse morphological phenotypes and variable disease course. The World Health Organization recognizes two aggressive histopathologic variants of this type of lymphoma: pleomorphic and blastoid MCL. To date, only few cases of MCL affecting the oral cavity have been reported. Additionally, the involvement of the oral and maxillofacial area by aggressive MCL subsets is considered extremely rare with only two patients reported in the English language literature to the best of our knowledge. Herein, we describe a 69 year-old male with a prior history of MCL of the right lateral pharyngeal wall developing a recurrent lesion extending to the palatal mucosa as diffuse ulceration and exhibiting histomorphological features of blastoid MCL. We also review the pertinent literature with emphasis on the diagnostic challenges and distinction between the different MCL variants.
 
Topographical distribution. A all odontogenic tumors, B ameloblastoma, C ameloblastic fibroma, D adenomatoid odontogenic tumor, E odontoma, F odontogenic myxoma, G cemento-ossifying fibroma. The figures represent numbers and percentages
Article
Several attempts have been made to classify odontogenic tumors; however, the need for a uniform international classification system led the World Health Organization (WHO) to present a classification of odontogenic tumors in 1971. We aimed to evaluate the number and types of odontogenic tumors examined at the Tokyo Dental College Hospital in Japan to determine the frequency and types of odontogenic tumors, based on the 2017 WHO classification system, as this information has not been reported previously in Japan. We also compared the results of our evaluation with those reported in previous studies. We conducted a clinicopathological evaluation of odontogenic tumors examined at the Tokyo Dental College Hospital between 1975 and 2020. This included an analysis of 1089 cases (malignant, n = 10, 0.9%; benign, n = 1079, 99.1%) based on the 2017 World Health Organization Classification of Head and Neck Tumors. We identified 483 (44.3%), 487 (44.7%), and 109 (10.0%) benign epithelial odontogenic, mixed odontogenic, and mesenchymal tumors, respectively. The most common tumor types were odontoma (42.5%) and ameloblastoma (41.9%). Of the 1089 cases, 585 (53.7%) and 504 (46.3%) were male and female patients, respectively. Ameloblastoma and ameloblastic fibroma occurred more commonly in male patients, whereas odontogenic fibroma and cemento-ossifying fibroma affected female patients primarily. The age at diagnosis ranged from three to 87 (mean, 29.05) years. In 319 (29.3%) patients, the age at diagnosis ranged from 10 to 19 years. Ameloblastoma and odontoma were the most common tumor types among patients in their 20s and those aged 10–19 years, respectively. In 737 (67.7%) and 726 (66.7%) patients, the tumors were located in the mandible and posterior region, respectively. Ameloblastoma was particularly prevalent in the posterior mandible. Odontogenic tumors are rare lesions and appear to show a definite geographic variation.
 
Papilloma with squamous and respiratory features demonstrating an exophytic architecture with focal papillary growth (arrow) (A). The multilayered stratified squamous epithelium transitions to ciliated pseudostratified columnar epithelium (B). Mucous cells are a prominent feature in this case (C). Neutrophilic infiltrates were a consistent finding (D)
Well-differentiated squamous cell carcinoma arising in association with the papilloma with squamous and respiratory features. The papilloma fragments on the left of image have both multilayered squamous epithelium admixed with ciliated respiratory epithelium, the well-differentiated squamous cell carcinoma fragments on the right of image have thicker epithelium with a glassier, keratinized appearance (A). In this intact fragment invasion by the well-differentiated squamous cell carcinoma is apparent as broad pushing pattern (B), perineural invasion was also identified in this case (asterisk) (C)
p16 immunohistochemistry demonstrated patchy expression in both the papilloma and well-differentiated squamous cell carcinoma and was considered to be negative in both components (A). Refer to Fig. 2A for the corresponding hematoxylin and eosin-stained section. Chromogenic in-situ hybridization for low-risk HPV subtypes is positive in both the carcinoma (B) and the papilloma component (C). There is dot-like positivity in the ciliated columnar cells as well (arrow) (D). Inset: Hematoxylin and eosin-stained section from the corresponding area
Article
There is limited literature detailing the histology of pharyngeal papillomas. Herein, we report our experience with papillomas occurring in the oro-and nasopharynx that have both squamous and respiratory features akin to the sinonasal Schneiderian papilloma. We retrospectively reviewed pharyngeal papillomas that were composed of both squamous and respiratory epithelium received at our institution between 2010 and 2020. Cases of sinonasal papillomas directly extending into the pharynx were excluded. Immunohistochemistry for p16 as well as RNA in situ hybridization to evaluate for 6 low-risk and 18 high-risk HPV genotypes were performed on all cases. Thirteen cases were included. Mean age was 61 with 12 males and 1 female. While often incidentally found, presenting symptoms included globus sensation, hemoptysis, and hoarseness of voice. Histologically, all tumors consisted of squamous and respiratory epithelium with neutrophilic infiltrates arranged in an exophytic/papillary architecture that was reminiscent of the exophytic type of Schneiderian papilloma. Immunohistochemistry for p16 was negative in all papillomas. 85% were positive for low-risk human papillomavirus (HPV) subtypes and all were negative for high-risk HPV subtypes. A well-differentiated, invasive squamous cell carcinoma was associated with two of the cases. Papillomas with squamous and respiratory features similar to the sinonasal exophytic Schneiderian papilloma can arise in the oro- and nasopharynx and like their sinonasal counterparts show an association with HPV. While many in this series were benign, they can be harbingers for invasive squamous cell carcinoma.
 
Histologic and immunohistochemical aspects of the six cases that stained positively for CD30 in the current study. A A HGBL (triple hit) demonstrating large and median sized neoplastic cells. B Diffuse staining of CD30 in > 20% of the neoplastic cells, although only a faint staining was observed. C An EBV + DLBCL NOS composed by large neoplastic B cells. D CD30 positivity was high and stained more than 20% of the tumor cells. E Oral DLBCL NOS (BCL2 neg., BCL6 neg. and MYC neg.) showing a diffuse growth pattern of neoplastic large B cells. F Less than 20% of tumor cells were faintly positive for CD30. G Oropharyngeal DLBCL NOS (BCL2 neg., BCL6 neg. and MYC neg.) containing large neoplastic cells and areas of necrosis and atypical mitotic figures. H This oropharyngeal DLBCL NOS was the only positive for CD30, but in only scattered neoplastic cells. I Oral DLBCL NOS (BCL2 neg., BCL6 neg. and MYC neg.) showing large neoplastic cells with one of more evident nucleoli and atypical mitotic figures. J CD30 was found in > 20% of neoplastic cells, although the staining intensity was weak in the majority of the neoplasm. K Oral DLBCL NOS (BCL2 not evaluated, BCL6 not evaluated and MYC not evaluated) showing a diffuse growth of neoplastic B cells. L CD30 strongly and diffusely stained > 20% of the tumor cells
Survival analyses of the sample investigated and the prognostic impact of CD30 expression using Log-rank univariate analysis. A Overall survival curve obtained for the whole sample (DLBCL NOS, HGBL and EBV + DLBCL NOS) demonstrating a five-year survival of 35.8%. B Univariate analysis showed that CD30-positive patients had five-year old overall survival rate of 60%, while CD30-negative patients was 32.3%. However, tis difference was not statistically significant (p = 0.28). C Investigating the prognostic impact of CD30 expression higher than 20% it was not found a statistically significant result either (p = 0.32), but the CD30-positive patients also showed a better prognosis (five-year survival 66.7 vs 32.3%, respectively). D Evaluating the overall survival of the DLBCL NOS cases only, we found a five-year survival rate of 38.2%. E The expression of CD30 in this group was not significantly associated with a higher survival (p = 0.19), but CD30-positive cases had a higher five-year survival (75%) than CD30-negative cases (32.3%). F A similar result was found when CD30 positivity in > 20% of the tumor cells was considered, although significance could not be achieved (p = 0.17) (CD30-positive 100% vs CD30-negative 32.3%)
Schematic representation of CD30 signals. The presence of the ligand that activates CD30 in the cell membrane can lead to the activation of the MAPK pathway and its components, culminating in the activation of the NF-κB gene in the neoplastic cell nucleus (left). Activation of tumor necrosis factor receptor-associated factor TRAF2 and TRAF5 in tumor necrosis factor receptor TNFR1 signaling, leads to the recruitment and activation of a series of factors. This pathway leads to IKK activation through IKKβ phosphorylation, allowing the translocation of NF-κB to the nucleus, favoring cell survival (central). Both lead to activation of the nuclear factor-kappa B, which triggers the transcription of anti-apoptotic factors, leading to cell proliferation and/or differentiation. Thus, activation of CD30 promotes neoplastic development in a series of human neoplasms. Due to its biological importance, the use of Brentuximab vedotin, an antibody–drug conjugate, releases into the cell anti-microtubule agent monomethyl auristatin E (MMAE), which induces cell cycle suspension and consequent apoptosis (right)
Article
Diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS) is the most frequent non-Hodgkin lymphoma subtype. This aggressive neoplasm may variably express the CD30 protein, which may be used as a therapeutic target for this tumor. However, CD30 expression in DLBCL NOS arising from the oral cavity and the oropharynx has not been investigated. Therefore, this study aims to determine the frequency of CD30 expression and its prognostic significance for patients affected by oral/oropharyngeal DLBCL NOS. Fifty cases were retrieved from pathology files and submitted to immunohistochemistry against CD30. Reactivity was accessed by two oral pathologists using two cut-off values (> 0% and > 20% of tumor cells) to determine positivity in each case. Clinical data were obtained from the patients’ medical files to investigate the prognostic potential of the protein. Seven high-grade B cell lymphomas and two EBV-positive DLBCL NOS were identified. We found one CD30-positive case in each of these two groups of lymphomas. Among the remaining 41 DLBCL NOS, other four cases (three in the oral cavity and one in the oropharynx) were positive for CD30, but only two expressed the protein in > 20% of tumor cells, both in the oral cavity. Survival analysis demonstrated that CD30-positive cases had a higher five-year overall survival rate (75%) than CD30-negative cases (32.3%), although a statistically significant result was not achieved (p = 0.19). Only a minor subset of oral and oropharyngeal DLBCL NOS express CD30 and these patients seems to have a higher survival rate.
 
Morphology and immunophenotype of primary thyroid SC with high-grade features. At the invasive front, the tumor formed solid sheets and nests and invaded the tracheal cartilage and respiratory mucosa (A, 40x). Multiple foci of comedo-type necrosis were identified (B, 200x). Cribriform areas with dense pink-red luminal secretions were divided by thick, dense, hypocellular and hyalinized stroma (C, 100x). Areas of epithelial tufting, papillae and bridges were noted (D, 200x). Tumor cells had ample amount of delicate eosinophilic vacuolated cytoplasm, mildly enlarged nuclei with open chromatin, and conspicuous nucleoli (E, 400x). Except for the minimal chronic infiltrate at the interface with the tumor, the adjacent thyroid parenchyma was unremarkable (F, 200x). SC was positive for mammaglobin (G, 200x) and S100 protein (H, 200x). Proliferation index labeled by Ki-67 was about 10% (I, 200x)
MSK-IMPACT assay was performed on the lung metastasis: exons 1–4 of ETV6 gene are fused with the exons 14–20 of NTRK3 gene resulting in ETV6–NTRK3 fusion
Article
Secretory carcinoma of the thyroid gland is histologically and genetically similar to its mammary and salivary gland counterparts. Unlike differentiated thyroid carcinomas of follicular cell origin, thyroid SC is not a thyroglobulin-producing tumor and would not be amenable to radioactive iodine therapy. Instead, these carcinomas may respond to targeted therapy with TRK inhibitors, which further emphasizes the importance of their recognition among morphologically similar thyroid entities. Based on eleven cases reported to date, most primary thyroid SC tend to present as locally advanced malignancies and are characterized by frequent recurrences and long-term survival. High-grade histologic features, increased mitotic count and necrosis have been described but their impact on clinical course and outcome remains unclear. We hereby report the case of a primary SC with high-grade features arising in the thyroid of a 49-year-old man, who was treated with Larotrectinib for his second recurrence. The patient achieved a durable response that lasted for 18 months but then he continued to progress and died of disease 181 months after the diagnosis.
 
Article
Frozen section evaluation of head and neck squamous cell carcinoma (SCC) is critical for margin status and subsequent patient therapy. In this study, we retrospectively reviewed the rate of frozen-permanent section discrepancies in blocks with two frozen section levels compared to ≥ three levels in oral cavity and oropharyngeal SCCs. A search of the cases with both intraoperative frozen sections and corresponding permanent sections for SCCs in the oral cavity and oropharynx was performed. Frozen sections and permanent slides were compared. The nature of discrepancies was assigned to one of the following: change in diagnosis, margin status, or distance of the tumor from the margin. The cause of the discrepancy was designated as one of the following: block sampling, gross sampling, interpretation, or technical error. The pathologist experience, frozen section technical experience, and intraoperative impact of each discrepancy were also evaluated. A total of 654 frozen and corresponding permanent blocks were assessed. For 532 of the frozen section blocks, two levels were cut, while 122 frozen section blocks had ≥ three levels. Thirty-five frozen-permanent section discrepancies were observed (5.4% of all blocks). Among these, 2.5% had a possible or definitive intraoperative impact. The percentage of discrepancies in the ≥ three levels group (5.7%) was slightly higher than the two-level group (5.3%), and this difference was not statistically significant. For the two-level group, the overall block sampling error rate was 4.5%. This was not significantly different from the 4.1% block sampling error rate seen in the ≥ three levels group. The rate of block sampling discrepancy did not show significant differences based on attending or frozen section technical experience. A change in margin distance (closer margin detected on permanent) occurred in 4% of the blocks and involved 16% of the patients. This review of oral cavity and oropharynx SCCs frozen/permanent section discrepancies shows that the error rate is not significantly different depending on the number of levels cut. The results suggest that always performing more than two frozen section levels may not yield a decreased discrepancy rate. A change in margin distance occurred quite frequently, but only in rare cases it had a definitive impact on the intraoperative management. Given the importance of correct intraoperative diagnosis in patient management, additional levels may be warranted depending on the clinical scenario.
 
Article
Tumour heterogeneity in oral cancer is attributed to the presence of cancer stem cells (CSCs). CSCs are the most migratory and metastatic cellular subpopulation within tumours. Assessment of CSC markers as significant predictors of lymph node metastasis may prove valuable in the clinical setting. Furthermore, analysis of this panel of putative stem cell markers in oral dysplasia may additionally inform of the likelihood for oral potentially malignant disorders (OPMDs) to progress to oral squamous cell carcinoma (OSCC). The present study aims to assess the significance of CSC markers in the progression of OPMDs to OSCC and assessment of lymph node metastasis in OSCC. CD44 and ALDH1 were assessed immunohistochemically in 25 normal, 30 OPMDs, and 24 OSCCs. CD44 is a membranous marker and ALDH1 is a cytoplasmic marker. The immunohistochemical expression of these markers were compared between OPMDs with and without dysplasia, as well as between low-risk and high-risk dysplasias. Similarly, expression was compared between OSCC with and without lymph node metastasis and among grades of OSCC. Positive CD44 expression was seen in all normal mucosal tissues. The expression decreased from normal epithelium to OPMDs but increased in OSCC. CD44 expression was positive in 21 cases of OSCC (87.5%) and reduced from well-differentiated to poorly differentiated OSCC. CD44 staining index was higher in OSCC without lymph node metastasis (3.59) when compared with OSCC with lymph node metastasis (1.33). There was a statistically significant difference observed in the ALDH1 staining index among three groups (p < 0.05), with highest expression seen in OSCC. Within OPMDs, the ALDH1 staining index was statistically higher in OPMDs with dysplasia as compared to OPMDs without dysplasia. Furthermore, the expression was higher in OPMDs with high-risk dysplasia when compared with low-risk dysplasia, but this was not statistically significant (p = 0.82). In conclusion, The CD44 positive population possesses properties of CSCs in head and neck carcinoma, and continuous shedding could be found after CD44 down-regulation. The present study reports differences in ALDH1 expression between OPMDs with and without dysplasia, dysplastic and non-dysplastic epithelia, and low-risk and high-risk dysplasia. These findings may suggest ALDH1 as a specific marker for dysplasia. CD44 demonstrated a difference in staining index in OSCC without lymph node metastasis versus OSCC with lymph node metastasis. These findings may suggest CD44 as a marker for lymph node metastasis. Both proteins may play key roles in the tumorigenicity of CSCs in OPMDs and OSCC.
 
Macroscopic features of the tumor. A The tumor grew on the left side of the soft palate with a superficial ulceration. B Residual tumor tissue was resected during second surgery, together with the left palatine tonsil
Low-power microscopic view of the tumor (H&E*). A The multilobular tumor grew underneath an ulcerated stratified squamous epithelium of the oropharyngeal mucosa. B Tumor cells extended into adjacent minor salivary gland. C Tumor cells infiltrated adjacent striated muscle tissue. D Perineural infiltration was noted. *Hematoxylin and eosin
Histomorphologic features of the tumor (H&E*). Nests of tumor cells were surrounded by thick or delicate fibrous septae (A). Arborizing capillary network was interspersed among tumor cells throughout the lesion (A, B). Tumor cells were relatively uniform, round to oval, occasionally spindled, and with bland basophilic oval nuclei and inconspicuous nucleoli (B, C). Several architectural patterns were seen. Tumor cells grew predominantly in a solid-trabecular (B) and a fascicular, myoepithelial carcinoma-like fashion (C, D). Less commonly, a reticular pattern with abundant myxoid stroma (E) and a pseudoglandular microcystic pattern (F) were seen. Focally, tumor cells displayed clearing of the cytoplasm with an infrequent perinuclear halo (G). The clear cell change escalated in some areas into a pseudolipoblast-like appearance with marked vacuolization of the cytoplasm (H). A focal lymphocytic infiltrate was seen throughout the tumor (H). *Hematoxylin and eosin
Immunohistochemical features of the tumor. A Immunohistochemical examination revealed focal and patchy S-100 protein expression (positive internal control in a nerve is seen in the upper right corner). B Similar pattern was seen with CD56 immunostain. C Diffuse and strong D2-40 positivity was present throughout the tumor. D Ki-67 stained up to 7% of cells in areas with sparse lymphocytes, while 20–25% of tumor cells were positive in lymphocyte-rich foci
PTCH1-GLI1 fusion transcript. Exon 1a of PTCH1 gene containing a Gli1 binding site (black arrow) is fused (red arrow) to exon 6 of GLI1 gene. Gli1 part of the fusion protein retains its FOXP coiled-coil domain (FOXP-CC) and three zinc fingers of C2H2 type (C2H2 Zn fingers), which may enable dimerization and binding to Gli1 target genes
Article
GLI1 fusions involving ACTB, MALAT1, PTCH1 and FOXO4 genes have been reported in a subset of malignant mesenchymal tumors with a characteristic nested epithelioid morphology and frequent S100 positivity. Typically, these multilobulated tumors consist of uniform epithelioid cells with bland nuclei and are organized into distinct nests and cords with conspicuously rich vasculature. We herein expand earlier findings by reporting a case of a 34-year-old female with an epithelioid mesenchymal tumor of the palate. The neoplastic cells stained positive for S100 protein and D2-40, whereas multiple other markers were negative. Genetic alterations were investigated by targeted RNA sequencing, and a PTCH1-GLI1 fusion was detected. Epithelioid mesenchymal tumors harboring a PTCH1-GLI1 fusion are vanishingly rare with only three cases reported so far. Due to the unique location in the mucosa of the soft palate adjacent to minor salivary glands, multilobulated growth, nested epithelioid morphology, focal clearing of the cytoplasm, and immunopositivity for S100 protein and D2-40, the differential diagnoses include primary salivary gland epithelial tumors, in particular myoepithelioma and myoepithelial carcinoma. Another differential diagnostic possibility is the ectomesenchymal chondromyxoid tumor. Useful diagnostic clues for tumors with a GLI1 rearrangement include a rich vascular network between the nests of neoplastic cells, tumor tissue bulging into vascular spaces, and absence of SOX10, GFAP and cytokeratin immunopositivity. Identifying areas with features of GLI1-rearranged tumors should trigger subsequent molecular confirmation. This is important for appropriate treatment measures as PTCH1-GLI1 positive mesenchymal epithelioid neoplasms have a propensity for locoregional lymph node and distant lung metastases.
 
Schematic of study flow
Representative images of PCR products. PCR analysis of GAPDH gene (A). Lane M: 100-bp DNA ladder marker, lane 1: negative control, lane 2: positive control, lanes 3–10: OSCC samples with GAPDH amplification. First step of nested PCR using MY09-MY011 primers (B). Lane M: 100-bp DNA ladder marker, lane 1: negative control, lane 2: positive control, lanes 3–10: representative OSCC samples. Second step of nested PCR using HPV1003-HPV1004 primers (C). Lane M: 100-bp DNA ladder marker, lane 1: negative control, lane 2: positive control, lane 3: PCR product of the first step negative control, lane 4: PCR product of the first step positive control, lanes 5–8: OSCC samples with positive results, lanes 9–12: OSCC samples with negative results
Representative images of p16INK4a immunohistochemical findings. Strong and diffuse p16INK4a nuclear and cytoplasmic immunostaining is present in ≥ 70% of tumor cells in p16INK4a-positive cases; original magnification 400× (A and B). Moderate and diffuse p16INK4a nuclear and cytoplasmic immunostaining is present in ≥ 70% of tumor cells in p16INK4a-positive cases; original magnification ×400 (C). Focal mild p16INK4a nuclear and cytoplasmic immunostaining is present in p16INK4a-negative cases; original magnification ×400 (D, E, and F)
Article
This study investigated the prevalence of human papillomavirus (HPV) infection in oral squamous cell carcinoma (OSCC) cases, as well as the association between HPV presence and p16INK4a expression, in Thai patients with OSCC. Eighty-one formalin-fixed paraffin-embedded specimens of OSCC were obtained. DNA extraction was performed; this was followed by nested polymerase chain reaction analysis to determine HPV DNA status, using consensus primers for the L1 region of HPV. HPV subtypes were determined by DNA sequencing. HPV-positive specimens and HPV-negative specimens from age- and sex-matched patients were subjected to immunohistochemical analysis to determine p16INK4a expression status. Of the 81 OSCC specimens, eight (9.9%) exhibited HPV DNA; DNA sequencing confirmed that the viral subtype was HPV-18 in all eight specimens. These eight HPV-positive specimens, as well as eight HPV-negative specimens from age- and sex-matched patients, were subjected to immunohistochemical analysis to determine p16INK4a expression status. Three of eight (37.8%) HPV-positive specimens and three of eight (37.8%) HPV-negative specimens showed positive p16INK4a expression findings. However, we did not find a significant association between HPV status and p16INK4a expression status in our OSCC samples. In conclusion, the prevalence of high-risk HPV was low in this group of OSCC patients; no association between HPV status and p16INK4a expression status was identified.
 
Gross appearance of low-grade fibromyxoid sarcoma. The tumor is circumscribed with firm grey, white cut surface
LGFMS of Neck. A relatively circumscribed tumor in the dermis with unremarkable overlying epidermis (A H&E*, 10×). Tumor interface with adnexal structures (B H&E*, 20×). Transition between alternate myxoid and collagenized areas (C H&E*, 40×). Whorled areas containing arcade of vessels and short fascicles of relatively bland spindle cells (D H&E*, 40×) *Hematoxylin and eosin
Hematoxylin and eosin-stained section shows higher magnification of giant collagen rosettes (A H&E*, 40×). MUC positivity in tumor cells (B)
Article
Low-grade fibromyxoid sarcoma (LGFMS) is an uncommon mesenchymal tumor usually arising in the lower extremities and trunk. Only rare examples in the head and neck region have been reported. Fifteen cases of head and neck LGFMS were retrieved. MUC4 was performed on all cases. Results for smooth muscle actins, β-catenin, desmin, S100 protein, Epithelial membrane antigen (EMA) and STAT6 immunohistochemistry, as well as FUS rearrangement status, were recorded when available. Sites included neck (8), supraclavicular region (4) and orbit (1), parapharyngeal space (1) and lower lip (1). The age of the patients ranged from 3 to 97 years (median, 26 years). Tumors displayed classical morphologic features of LGFMS, as described. All cases (15/15) were positive for MUC4, and all cases tested (4/4) harbored FUS rearrangement. Variable positivity for EMA was identified in one case. Follow-up was available in 11 patients, ranging from 2 to 240 months (mean 71.4 months; median, 44 months). Three tumors recurred locally; none metastasized. In conclusion, although distinctly uncommon, LGFMS may arise in the head and neck region and should be distinguished from other more common spindle cell tumors in these locations. The morphologic, immunohistochemical and molecular genetic features of head/neck LGFMS are identical to those occurring elsewhere. The long-term metastatic risk of LGFMS in these locations remains to be fully elucidated.
 
Article
Collision tumors, composed of two distinct benign or malignant neoplasms, are rarely reported in the oral cavity. We present a case of a 61-year-old female with an asymptomatic non-demarcated lump on the soft palate of unknown duration. An incisional biopsy revealed the presence of two neoplastic populations, a neurofibroma that was partially infiltrated by a polymorphous adenocarcinoma, low-grade variant. Total surgical excision was performed, with uneventful follow-up period. The development of collision tumors may be incidental, although molecular events may influence the pathogenetic mechanism of the phenomenon.
 
SARS-CoV-2 RNA expression in the middle ear and nasal cavity. Expression depicted as log10 fold difference, normalized to control COVID-19 negative tissue (P7 and P8, septal mucosa). All COVID-19 ME and nasal cavity samples demonstrated statistically higher levels of SARS-CoV-2 RNA expression compared to control except for the ME sample for P2 as indicated by ⁺(p < 0.05). A noninfectious positive control template yielded strong positive results in each assay (data not shown). For subjects P1 and P2, the viral loads in the nasal cavity were higher than those in the ME, as indicated by *(p < 0.05)
H&E and immunofluorescence staining of middle ear and nasal cavity tissues from COVID-19 and uninfected individuals. Histology A, E plus immunohistochemical localization of SARS-CoV-2 in epithelia of COVID-19 patients (B, F). Expression of ACE2 (C, G) was detected on surface epithelium identified by EPCAM (D, H). No SARS-CoV-2 staining was seen in COVID-19 negative tissues (I, J), although RBCs showed autofluorescence
Article
Viral infections have already been implicated with otitis media and sudden sensorineural hearing loss. However, the pathophysiology of COVID-19 as it relates to otologic disorders is not well-defined. With the spread of SARS-CoV-2, it is important to evaluate its colonization of middle ear mucosa. Middle ear and nasal tissue samples for quantitative RT-PCR and histologic evaluations were obtained from post-mortem COVID-19 patients and non-diseased control patients. Here we present evidence that SARS-CoV-2 colonizes the middle ear epithelium and co-localizes with the primary viral receptor, angiotensin-converting enzyme 2 (ACE2). Both middle ear and nasal epithelial cells show relatively high expression of ACE2, required for SARS-CoV-2 entry. The epithelial cell adhesion molecule (EpCAM) was use as a biomarker of epithelia. Furthermore, we found that the viral load in the middle ear is lower than that present in the nasal cavity.
 
The schema of prostate-specific membrane antigen (PSMA) receptor
Immunohistochemical findings of prostate-specific membrane antigen (PSMA) in pleomorphic adenoma (PA, upper) and Warthin tumor (WT, lower). Many cases show positive staining for myoepithelial and luminal cells in PA. All WTs show diffusely positive, but faint, staining
Immunohistochemical findings of prostate-specific membrane antigen (PSMA) in basal cell adenoma (upper) and adenoid cystic carcinoma (lower). Many cases show positive staining for myoepithelial and luminal cells
Immunohistochemical findings of prostate-specific membrane antigen (PSMA) in mucoepidermoid carcinoma (upper) and salivary duct carcinoma (lower). Many cases show positive staining for tumor cells
Immunohistochemical findings of prostate-specific membrane antigen (PSMA) in the normal salivary glands: submandibular gland (upper) and sublingual gland (lower). Many cases show positive staining for mucinous gland cells
Article
Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed in the prostate gland and prostate cancer. PSMA has been recently used in positron emission tomography/computed tomography (PET/CT) imaging and targeted alpha-radiation therapy (TAT) for prostate cancer. Recently, the tubarial gland, a type of minor salivary gland that is described as a new organ situated in the pharynx, is reported to express PMSA. Here, we studied the expression of PSMA in common benign and malignant salivary gland tumors. We performed immunohistochemistry for PSMA in 55 salivary gland tumors comprising 10 pleomorphic adenomas, 10 Warthin tumors, 9 basal cell adenomas, 9 adenoid cystic carcinomas, 9 mucoepidermoid carcinomas, and 8 salivary duct carcinomas. PSMA was expressed in 97% of benign tumors and 77% of malignant tumors. Moreover, PSMA was expressed in 59% of normal salivary glands adjacent to the tumor. PSMA is relatively expressed in salivary gland tumors and salivary glands. Therefore, salivary gland neoplasm, and normal salivary gland, possibly demonstrate the accumulation of PSMA in PET/CT. Thus, we need to monitor the side effects in the salivary glands during TAT for prostate cancer.
 
A PET-CT scan findings before neoadjuvant chemotherapy. B PET-CT scan findings after neoadjuvant chemotherapy
Surgical steps and reconstruction
Histologic findings. A Solid tumor nests with edematous and fibrinous stroma (100x, H&E). B Higher magnification of a solid area, comprising cells with vesicular nuclei, prominent nucleoli, and pale to eosinophilic cytoplasm. Occasional tumor cells show oxyphilic or plasmacytoid morphology. C Tumor area showing a microcystic pattern, reminiscent of a yolk sac tumor. D Some gland-like structures in an otherwise solid tumor area. E Extensive hyalinization near a residual tumor nest, a possible chemotherapy effect
Immunohistochemistry (IHC) studies. A SALL-4 staining demonstrates diffuse nuclear positivity in a yolk sac tumor-like area. B Glypican-3 is diffusely expressed in a yolk sac tumor-like area. C Keratin 5/6 staining shows membranous positivity in a solid area of tumor. D Keratin 7 staining shows focal membranous positivity in a solid area of the tumor. E Loss of nuclear expression of SMARCB1/INI1 is observed in both a solid tumor area and F a yolk sac tumor-like area
Article
SMARCB1 (INI1) deficient carcinoma (SDC) is a newly-described, aggressive, high-grade malignancy of the adult population. Rarely, these tumors demonstrate yolk sac differentiation. Treatment protocols are not defined due to the rarity of this entity. A 55 year-old-male presented with a tumor originating in the maxillary sinus. He was treated with neoadjuvant therapy followed by radical surgery and adjuvant treatment. We review the literature and discuss the course of disease and treatments of sinonasal SDC with yolk sac tumor differentiation. To our knowledge, this is the sixth reported case of sinonasal SDC with yolk sac tumor differentiation. This is the first publication describing the clinical course and efficacy of therapeutic interventions.
 
Clinicopathologic aspects of classic juvenile xanthogranuloma (case 4). A Clinical aspect of the lesion showing a pedunculated, pink nodule in the tip of the tongue. B, C Macroscopic aspect of surgical specimen displaying grayish color and homogenous yellow cut surfaces. D Low power photomicrograph showing a dense proliferation of histiocytic mononuclear cells (hematoxylin–eosin stain, original magnification ×100). E Note the multinucleated giant cell characterized by an arc of nuclei toward the outer membrane (hematoxylin–eosin stain, original magnification ×400). F. Mononuclear and giant cells showing strong and diffuse cytoplasmic positivity for CD63 (IHC, original magnification ×200; inset ×400) and G CD163 (IHC, original magnification ×200; inset ×400). H Focal positivity for Factor XIIIa (IHC, original magnification ×400). I Ki-67 (MIB-1) labeling index was approximately 5% (IHC, original magnification ×200; inset ×400)
Clinicopathologic aspects of non-lipidized juvenile xanthogranuloma (case 2). A Clinical aspect of the lesion showing a sessile, yellowish nodule in the lower labial mucosa. The underlying mucosa was intact. B, C Macroscopic aspect of surgical specimen displaying typical yellowish‐brown color and homogenous grayish-yellow cut surfaces. D Low power photomicrograph showing a well-circumscribed nodule composed predominantly of spindle cells in a multilobular pattern (hematoxylin–eosin stain, original magnification ×100). E Note the solid proliferation of spindle cells arranged in fascicular and storiform growth pattern and a few mitosis (hematoxylin–eosin stain, original magnification ×200; inset ×400). F Detail of epithelioid histiocytes showing marked cytoplasmic vacuolization (hematoxylin–eosin stain, original magnification ×400) and G Note strong and diffuse cytoplasmic positivity for CD63 (IHC, original magnification ×200; inset ×400) and H Factor XIIIa (IHC, original magnification ×400) I Numerous tumor cells positive for Ki-67 (IHC, original magnification ×200; inset ×400)
Article
Juvenile xanthogranuloma (JXG) is the most common form of non-Langerhans cell histiocytosis and oral mucosal involvement is exceedingly rare. Histiocytic disorders harbor activating mutations in MAPK pathway, including the report of BRAF V600E in JXG of extracutaneous site. However, no information is available for oral JXG. Herein, the clinicopathological and immunohistochemical features of five new oral JXG were evaluated in conjunction with literature review. Also, we assessed the BRAF V600E in oral samples. Five oral JXG were retrieved from pathology archives. Morphological and immunohistochemical analyses were performed. The BRAF V600E status was determined with TaqMan allele-specific qPCR. The series comprised of three female and two male patients, most of them adults, with a median age of 39 years (range 13–68 years). Clinically, the lesions appeared as asymptomatic solitary nodules, measuring until 2.5 cm, with more incident to the buccal mucosa. Morphologically, most of the cases presented classical histological features of JXG, with histiocytic cells consistent with the non-Langerhans cell immunophenotype. BRAF V600E was not detected in the cases tested. This is the first and largest published series of oral JXG affecting adults and a Brazilian population. The molecular pathogenesis of oral JXG remains unknown. Clinicians and pathologists must recognize JXG to avoid misdiagnoses with oral benign or malignant lesions.
 
Sclerosing polycystic adenoma of patient #1. A Well-circumscribed tumor separated from the surrounding uninvolved parotid parenchyma (lower right) showing an admixture of cystic structures and ducts embedded in a fibrotic stroma (H&E, 2 × 10 magnification). B Cysts and ducts lined by epithelial cells with variable granular, foamy, and apocrine morphology, the latter including cells with apical snouting (H&E, 4 × 10 magnification). C Acinar-type structures containing intracytoplasmic bright eosinophilic granules (H&E, 20 × 10 magnification)
Sclerosing polycystic adenoma of patient #2. A The overall histological features of sclerosing polycystic adenoma can be identified on a core biopsy (H&E, 2 × 10 magnification), including B the acinar-type structures containing intracytoplasmic brightly eosinophilic granules and C the cystic structures with a cell lining with variable morphology (H&E, 10 × 10 magnification). D The loss of nuclear expression of PTEN immunohistochemistry in the acinar and ductal cells with retain reactivity in the myoepithelial and stromal cells is a useful diagnostic aid (H&E, 20 × 10 magnification)
Spectrum of the apocrine intraductal epithelial proliferation in sclerosing polycystic adenoma of patient #1 showing: A Solid, B cribriform, and C micropapillary patterns (H&E, 10 × 10 magnification)
Carcinoma ex-sclerosing polycystic adenoma of patient #3. A Portions of the tumor show classical morphological features of sclerosing polycystic adenoma including: A Well-circumscribed tumor borders, admixture of cystic and ductal structures, and a fibrotic stroma (H&E, 2 × 10 magnification), as well as B acinar-type structures containing intracytoplasmic brightly eosinophilic granules (H&E, 4 × 10 magnification). C Intraductal epithelial proliferation with rigid cribriform architecture (H&E, 4 × 10 magnification) highlighted by D peripheral layer of myoepithelial cells positive for CK5/6) (4 × 10 magnification). E Another portion of the tumor shows a frankly invasive component associated with a prominent desmoplastic reaction. (H&E, 2 × 10 magnification). F The invasive carcinoma had features of a salivary duct carcinoma including abundant eosinophilic cytoplasm and large pleomorphic nuclei with prominent nucleoli (H&E, 10 × 10 magnification). G The invasive carcinoma showed loss of PTEN expression and H diffuse and strong reactivity for androgen receptor that in conjunction with the histologic features support a diagnosis of salivary duct carcinoma. (10 × 10 magnification)
Schematic diagram of TFG-PIK3CA fusion in the sclerosing polycystic adenoma of patient #4. TFG is located on 3q12.2 and PIK3CA on3q26.3. The break points were mapped exon 5 of TFG and exon 3 of PIK3CA
Article
Sclerosing polycystic adenosis, initially considered a non-neoplastic salivary gland lesion and classified as such in the 2017 WHO Classification of Head and Neck Tumors, has been the subject of controversy regarding its possible neoplastic nature. The reporting of recurrent PI3K pathway alteration represents evidence to support these lesions as being neoplastic and more appropriately referred to as sclerosing polycystic adenoma (SPA). Herein, we provide additional evidence that supports the classification of SPA as a true neoplasm. Eight cases of SPA were identified in our database and consultation files. All cases were subjected to PTEN immunohistochemistry (IHC) and next-generation sequencing (NGS). In addition, one patient underwent genetic counseling and germline testing. The cases included 5 men and 3 women with a mean age of 41 years (range 11–78) and all tumors arose in the parotid gland. One patient had multiple recurrences over a period of 2 years. Morphologically the tumors were circumscribed and characterized by an admixture of acini, ducts and cysts embedded in a fibrotic/sclerotic stroma. The cells lining the ducts and cysts showed variable granular, vacuolated, foamy and apocrine cytoplasmic features, as well as acinar cells contained intracytoplasmic brightly eosinophilic granules. The apocrine intraductal proliferations showed mild to moderate atypia in 6 cases. One case showed overt malignant morphology that ranged from intraductal carcinoma to invasive salivary duct carcinoma. Seven cases tested for PTEN IHC showed loss of nuclear expression in the acinar and ductal cells with retained PTEN expression in the myoepithelial cell and stroma. NGS detected PIK3CA or PIK3R1 genetic alterations in 7 cases, including a novel TFG-PIK3CA fusion. Coexisting PTEN mutations were seen in 4 cases, including in a patient with clinical stigmata of Cowden syndrome and confirmed by germline genetic testing. Our findings herein documented including recurrence of tumor, malignant transformation, high prevalence of PI3K pathway oncogenic alterations and the possible heretofore undescribed association with Cowden syndrome add support to classifying SPA as true neoplasms justifying their designation as adenoma, rather than adenosis.
 
Histomorphology of laryngeal neuroendocrine tumor (NET G2). a–d Tumors were monotonous in appearance and displayed a variety of patterns: trabeculae, cords, glandular, pseudopapillary, nests in a fibrovascular stroma; cGlomeruloid structures seen as cystic spaces lined by neoplastic cells, with abortive papillae protruding into the lumen, resembling renal glomeruli were identified in some cases; e clear cell morphology; f intranuclear grooves (inset) and inclusions (arrow); g hyaline globules; h Leisegang rings; i lymphoid aggregates
Immunohistochemical profile of laryngeal neuroendocrine tumor (NET G2). Neuroendocrine markers- synaptophysin (a), chromogranin (b), and INSM1 (c) were identified in all cases; d Ki67 labeling index of 18% in a case; e: calcitonin expression was present in 33% cases; f carcinoembryonic antigen immunoreactivity varied from focal to diffuse and was detected in 42.9%; g Tumor nuclei show positivity with Retinoblastoma antibody; h weak and focal expression of p53 in the tumor nuclei (wild-type pattern of staining)
Laryngeal neuroendocrine carcinoma. a, b Small cell neuroendocrine carcinoma (SCNEC). a Highly cellular tumor imparting a blue tumor appearance at low magnification. b Tumor cells possess round to elongate hyperchromatic nuclei, devoid of conspicuous nucleoli and scant cytoplasm; c–e Large cell neuroendocrine carcinoma (LCNEC). c, d Tumors cells show nests and irregular islands of basaloid cells in a desmoplastic stroma; e Tumor with undifferentiated morphology showing monomorphic cells with prominent nucleoli amidst necrosis; f Ki 67 labeling index of 95% in small cell carcinoma; g diffuse and strong overexpression of p53 (80% of positive cells) in SCNEC; h completely absent immunoexpression of p53 (null-type expression) in SCNEC with weakly positive stromal cells serving as an internal positive control; i complete loss of Rb staining in SCNEC with stromal cells serving as internal positive control; j Focal TTF1 immunoreactivity in LCNEC; k p53 overexpression in LCNEC (85% of positive cells); l Complete loss of Rb in LCNEC with positive internal control of stromal cells
Article
Laryngeal neuroendocrine neoplasms (NENs) are rare and heterogeneous, encompassing well-differentiated neuroendocrine tumors (NETs; grade 1, 2, and 3), neuroendocrine carcinomas (NECs, small cell and large cell types), and mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN). We aimed to study the clinicopathologic spectrum of these neoplasms. A retrospective review of all primary laryngeal NENs diagnosed from 2005 to 2017 was undertaken. Mitotic index was divided into < 2, ≥ 2–10, and > 10 mitoses/2 mm², with a Ki-67 labelling index of < 2%, ≥ 2–20%, and > 20% for the NET grade 1, 2 and 3 categories, respectively. A total of 27 patients were included. The median age at presentation was 60 years; the male-to-female ratio was 8:1. Supraglottis (n = 22) was the most frequently affected subsite. There were 9 NETs grade 2 (G2), and 18 NECs cases. There were no NET grade 1 or 3 cases in our cohort. Among the NETs G2, the morphology was epithelioid (2), plasmacytoid (3), clear (2), oncocytic (1), and rhabdoid (1). Unique ‘glomeruloid structures’ (n = 5), calcification (n = 3), lymphoid aggregates (n = 5), intranuclear inclusions (n = 2), hyaline globules (n = 3), and Leisegang rings (n = 2) were identified. NECs comprised 16 small cell neuroendocrine carcinoma and 2 large cell neuroendocrine carcinoma. On immunohistochemistry, tumor cells expressed AE1/AE3 (86%), synaptophysin (100%), chromogranin (100%), INSM1 (100%), calcitonin (33.3%). In the NEC group, p53 aberrant expression (87.5%), Retinoblastoma (Rb) loss (88.2%), and diffuse p16 immunoreactivity (66.7%) were additionally observed. Lymph-node metastasis was detected in 62.5% and 85.7%, while distant metastasis in 55.6% and 76.9%, respectively in NET G2 and NEC. Laryngeal NENs are aggressive neoplasms with a high rate of nodal and distant metastasis. Awareness of the wide pathologic spectrum of laryngeal NENs and appropriate use of IHC is needed to render an accurate diagnosis. Ki67 assessment is strongly recommended for laryngeal NEN prognostication
 
Relative distribution of stromal CAFsCOL11A1 scores among different tumour types. Stacked bar chart, visualizing the relative distribution of CAFsCOL11A1 scores in the analysed tumour types. Both the panCancer and the SGC collective are depicted. CAFsCOL11A1 scores are color-coded as indicated on the right-hand side. Cases that were not analysable are marked in grey. MuEp mucoepidermoid, SaDu salivary duct, ANOS adenocarcinoma NOS, EpMy epithelial-myoepithelial, AdCy adenoid cystic, Sec secretory, Basal basal cell, MyEp myoepithelial
COL11A1 mRNA expression by CAFs (CAFsCOL11A1) and tumour cells (TCCOL11A1). Top Row: CAFsCOL11A1 in SaDu (Score 4), MuEp (Score 3) and AdCy (Score 2). Middle row: CAFsCOL11A1 in normal colon mucosa (Score 0), ER + breast carcinoma (Score 3) and colon carcinoma (Score 2). Bottom row: TCCOL11A1 in MyEp (90%), EpMy (80%), AdCy (50%). 400x, reference bar: 50 µm
Comparison of SGC positive for CAFsCOL11A1 and TCCOL11A1 in SGC. A Dotplot, locating each carcinoma entity in a bidimensional manner according to the respective percentage of cases with TCCOL11A1 (x axis) and CAFsCOL11A1 (y axis). B Table demonstrating an anti-proportional pattern of COL11A1 expression in the above-mentioned tumour compartments. C Pie chart, illustrating the percentage of cases with CAFsCOL11A1, TCCOL11A1 or combined staining
Distribution of one COL11A1 peptide in TMA sections. Intensity box plots comparing the intensities of the shown m/z value for different primary sites (A) and SGC types (B). The horizontal line of the box part represents the mean intensity of the m/z value measured over all pixels. The blue dots represent pixel with spectra in which intensities of the m/z value are between the lower and upper quantile. The red dots represent pixel with spectra outside of these intervals. SGC salivary gland carcinoma, CRC colorectal carcinoma, LC lung carcinoma, MC mamma carcinoma, PC prostate carcinoma, SaDu salivary duct carcinoma, Acin acinic cell carcinoma, ANOS adenocarcinoma not-otherwise-specific, EpMy epithelial-myoepithelial carcinoma, MuEp mucoepidermoid carcinoma, MyEp myoepithelial carcinoma, Sec secretory carcinoma
Article
Procollagen 11A1 ( COL11A1 ) is a central component of the extracellular matrix in many carcinomas, which is considered to be mainly produced by cancer associated fibroblasts (CAFs). As COL11A1 expression correlates with adverse prognosis and is implicated in chemoresistance, it is a promising putative target. For the first time, we used RNA in-situ hybridization to systematically identify the cells that produce COL11A1 in the ten most prevalent carcinoma types, lymphomas (n = 275) and corresponding normal tissue (n = 55; panCancer cohort). Moreover, as most salivary gland carcinomas (SGC) display distinct stromal architectures, we also analysed 110 SGC. The corresponding protein formation of COL11A1 was determined by MALDI-TOF–MS-Imaging. We report that colon, breast and salivary duct carcinomas are highly infiltrated by COL11A1 positive CAFs (CAFs COL11A1 ) and might thus be promising candidates for antidesmoplastic or COL11A1 -targeted therapies. The amount of CAFs COL11A1 correlated significantly with tumour grade, tumour stage and nodal spread in the panCancer cohort. Significant associations between CAFs COL11A1 and vascular invasion, perineural spread and nodal spread were observed in the SGC cohort. Also, we discovered that tumour cells of intercalated duct derived SGC and CAFs produce COL11A1 in a mutually exclusive manner. Our findings represent a novel mode of extracellular matrix production in carcinomas and could be highly relevant in the future. Our findings elucidate the mode of COL11A1 expression in very different carcinoma types and may aid to categorise tumours in the setting of possible future COL11A1 -related therapies.
 
Article
We aimed to collect and analyze available cases of intraoral acantholytic squamous cell carcinoma (aSCC), that consisted of the authors’ cases and cases derived from the existing literature, with an emphasis on the pathological staging and patient outcome. Our research question was whether aSCC is more aggressive than conventional SCC. The literature was searched for documented cases of aSCC involving the intra-oral mucosa, excluding those from the lips and tonsils, and seven new cases were added from our files. The authors compared the obtained aSCC data to existing data for conventional SCC. Fisher Exact or Pearson’s χ2 tests were used for categorical variables. Fifty-five cases of intraoral aSCC were reviewed, of which 48 were retrieved from the literature. Analysis of the published cases was reinforced by contacting the authors of all the papers with incomplete data for further clarifications. The most common sites of aSCC were the tongue (24/55) and the maxilla/maxillary gingiva and/or palate (11/55). The overall survival rate was 36/53 (67.9%) with a mean follow-up period of 22 months against 62.5% for conventional SCC (p = 0.6). No statistically significant difference between the two variants of the tumor with respect to the oral cavity was detected. The differences in age, sex, survival rate, staging, and locations were not statistically significant. Based on the available data from 55 cases, there is no evidence to suggest that aSCC is more aggressive than conventional SCC in intraoral cases.
 
Case 1 showing a 1 cm right tongue ulcer (a); biopsy showing ulceration, granulation tissue and active inflammation (b and c, H&E stain); and T. Pallidum immunostain showing innumerable T. Pallidum spirochetes (d and inset) (b, 100x; c and d, 400x)
Case 2 showing a 1.4 cm lip white plaque (a); biopsy showing ulcerated squamous mucosa with adjacent pseudoepitheliomatous hyperplasia and a rich acute inflammatory infiltrate (b and c, H&E stain); and immunostain of T. Pallidum showing numerous T. Pallidum spirochetes (d and inset) (b, 100x; c and d, 400x)
Case 3 showing a 5 mm lateral tongue ulcer (a); biopsy showing surface ulceration with both acute and chronic inflammation and adjacent squamous epithelial hyperplasia (b and c, H&E stain); and immunostain of T. Pallidum showing many T. Pallidum spirochetes (d and inset) (b, 100x; c and d, 400x)
Article
Syphilis is a sexually transmitted infectious disease caused by Treponema pallidum and characterized by a complex and variable clinical presentation. Cases of unexpected oral syphilis presenting as non-healing ulcers are uncommonly reported. We report 3 cases (one female and two males, aged 35, 35, and 56 years, respectively) in which patients presented with non-healing oral ulcers. Biopsies revealed surface ulceration and a significant neutrophilic infiltrate rather than the more conventional plasma cell infiltrate seen with most reported syphilis infections, potentially leading to an inaccurate diagnosis. Treponema pallidum immunohistochemistry highlighted spirochetes within the epithelium, with additional diagnostic confirmation by serum T. pallidum particle agglutination assay. Sexual history documentation by the clinician with nonspecific oral ulcers is paramount to aiding diagnosis and leading to proper management. Further, it is important to perform immunohistochemistry for T. pallidum in oral biopsies from non-healing ulcers, especially when clinical history raises the differential diagnosis or when other clinical manifestations may support this consideration.
 
Article
Glandular tumors of jaw bones present, most often, histopathologic features of salivary gland and, rarely, of cutaneous glandular neoplasms. They are thought to originate from odontogenic epithelium. An unusual maxillary tumor presenting as a radiolucency in the periapical area of the right permanent lateral incisor of a 74-year-old male is presented causing root resorption. Preparations revealed occasionally branching tubular cords and ductal structures characterized, mostly, by a bilayer composed of luminal cuboidal to low columnar cytokeratin (CK) 7, Ber-EP4 and occasionally CK8/18 positive cells, and abluminal, CK5/6 positive, basal/basaloid cells revealing nuclear reactivity for p63/p40. Smooth muscle actin and calponin were negative, save for a single focus of calponin positive cells, confirming absence of myoepithelial support or epithelial mesenchymal transition. CK19 exhibited staining of both layers, the luminal being more intense. Eosinophilic secretory material and, occasionally, a luminal pellicle were decorated with CK8/18 and polyclonal carcinoembryonic antigen (CEA). CD1a identified only rare Langerhans’ cells and Ki67 decorated 1–2% of abluminal cell nuclei. Small solid nests of epithelial cells were also present. Infrequently, an apparent transition of a nest into a tubular structure was appreciated. The partially inflamed stroma featured multiple hyalinized acellular deposits consistent with amyloid, as confirmed by bright orange Congo red reactivity with apple-green birefringence, which reacted with odontogenic ameloblast-associated (ODAM) protein antibody but not with antibodies for amelotin and secretory calcium-binding phosphoprotein proline-glutamine rich 1. Based on the above, the diagnosis of tubuloductal/syringoid variant of central odontogenic fibroma with ODAM amyloid is favored.
 
Cytological findings in the FNA. A Monomorphic proliferation of dyscohesive cells, with scant cytoplasm and visible nucleoli, PAP stain (× 100). B Keratin immunocytochemistry (× 100). C TTF1 immunocytochemistry showing nuclear expression in a subset of cells (× 100)
Histological, immunohistochemical and FISH findings in the surgical specimen. A Neoplasm composed of small to medium sized cells with scant cytoplasm and enlarged nucleus with evenly distributed chromatin and inconspicuous nucleoli (H&E*). B Diffuse CD99 expression (× 100). C Absence of p40 expression (× 100), D FISH analysis showing EWSR1 gene rearrangement using a break apart probe. *Hematoxylin and eosin
Article
Extra-osseous Ewing sarcoma (ES) is a rare and aggressive malignant tumor found in a variety of organs. Primary ES of the thyroid is exceedingly rare and few cases have been documented to date. We describe the case of a 54-year old woman with a history of breast carcinoma in whom a unique hypermetabolic left thyroid nodule was identified during a follow-up PET-CT scan. An ultrasound examination showed a hypoechogenic nodule of 3.7 cm. A cytological diagnosis of poorly differentiated thyroid carcinoma was made, and a total thyroidectomy was performed. The surgical specimen revealed a poorly differentiated neoplasm composed of medium-sized cells with scant cytoplasm, expressing pancytokeratin, CD99 and NKX2.2 but lacking p63 and p40 expression. Molecular analysis revealed a EWSR1-FLI1 fusion transcript supporting the diagnosis of a primary extra-osseous ES of the thyroid. The patient received adjuvant chemotherapy and has no evidence of recurrent disease.
 
Article
Oral amelanotic melanoma (OAM) is a rare, non-pigmented mucosal neoplasm representing less than 2% of all melanoma. The present study analyses the available data on OAM and describes its clinicopathological features, identifying potential prognostic factors. Online electronic databases such as PubMed-Medline, Embase, and Scopus were searched using appropriate keywords from the earliest available date till 31st March 2021 without restriction on language. Additional sources like Google Scholar, major journals, unpublished studies, conference proceedings, and cross-references were explored. 37 publications were included for quantitative synthesis, comprising 55 cases. The mean age of the patients was 59.56 years, and the lesions were more prevalent in males than in females. OAM’s were most prevalent in the maxilla (67.2%) with ulceration, pinkish-red color, nodular mass, and pain. 2 patients (3.36%) were alive at their last follow-up, and 25 were dead (45.4%). Univariate survival analysis of clinical variables revealed that age older than 68 years (p = 0.003), mandibular gingiva (p = 0.007), round cells (p = 0.004), and surgical excision along with chemotherapy & radiation therapy (p = 0.001) were significantly associated with a lower survival rate. Oral Amelanotic Melanoma is a neoplasm with a poor prognosis, presenting a 6.25% possibility of survival after 5 years. Patients older than 68 years, lesions in the mandibular gingiva, round cells, and surgical excision along with chemotherapy and radiotherapy, presented the worst prognosis. However, they did not represent independent prognostic determinants for these patients.
 
a Tumour composed of odontogenic epithelium arranged in to interconnected strands. H&E × 10. b The tumour showed foci of dentinoid. H&E × 20
Radiologically the recurrent lesion presented as two multilocular radiolucencies
a In the recurrent anterior lesion, the cyst was lined by odontogenic epithelium, with an ameloblast like cell layer situated towards the capsule and hyper cellular epithelial whorls. H&E × 20. b The recurrent posterior lesion, exhibited multiple foci showing hypercellularity. H&E × 20
a A tumours composed of small epithelioid cells with hyperchromatic nuclei and minimal cytoplasms diffusely infiltrating in to bone. H&E × 4. b A photomicrograph showing epithelial whorls. H&E × 40. c Ameloblast like tall columnar cells with reverse polarity nuclei present throughout the tumour. H&E × 40. d A section showing areas reminiscent of Homer-Wright rosettes. H&E × 10
a Low power view of the lesion showing odontogenic epithelium arranged in to inter-connected strands. H&E × 10. b Solid areas of the tumour comprised of clear cells and ameloblast like cells. H&E × 40. c A few foci showed whorls of cells reminiscent of adenomatoid odontogenic tumour. H&E × 10
Article
Adenoid ameloblastoma is a hybrid odontogenic tumour showing histopathological features of both ameloblastoma and adenomatoid odontogenic tumour (AOT), with approximately 40 cases reported in the literature. The aims of the report are to illustrate the diagnostic challenges of adenoid ameloblastoma using three new cases and to analyze evidence in literature to consider adenoid ameloblastoma as a new sub type of ameloblastoma. A literature review was performed with the key words—adenoid ameloblastoma, hybrid/composite odontogenic tumours, hybrid ameloblastoma and adenomatoid odontogenic tumour, ameloblastoma with inductive changes, dentinoid and dentinoma to select the cases compatible with the diagnosis of adenoid ameloblastoma. Out of the 40 cases reported in literature, 31 cases with sufficient information and 3 new cases were analyzed. Out of the 34 adenoid ameloblastomas majority of tumours (76.5%) occurred in adults with age ranging from 25 to 55 years. Slight female predilection with a male:female ratio of 0.9:1 was observed. Approximately, 64.7% occurred in the mandible. Radiologically, 82.4% of adenoid ameloblastomas presented as radiolucent lesions while 47.1% occurred with ill-defined margins and cortical perforation at diagnosis. Histopathologically, 70.8% of tumours presented as plexiform ameloblastomas, while duct like structures/glandular structures were the commonest feature supportive of adenomatoid odontogenic tumour observed in overwhelming majority of 95.9% of adenoid ameloblastomas. 91.6% of tumours showed inductive change in the form of dentinoid. Further, 45.4% of the tumours developed at least one recurrence following surgical excision. The report presents literature review based evidence to show the existence of adenoid ameloblastoma, which is demographically similar to conventional ameloblastoma but with histopathological differences and presenting with higher rate/multiple recurrences, indicating its biological aggressiveness. Thus, we would like to propose the inclusion of adenoid ameloblastoma as a sub type of ameloblastoma in the next revision of the WHO odontogenic tumour classification.
 
Preoperative MRI showed a mass in the left buccal region with hyperintense signaling in T2 sequence (A) and partially contrast-enhancing and hypointense signaling in T1 sequence (B). Clinically, the mass was closely associated with the papilla of the parotid duct (C). Intraoperatively, the duct was found to run through the lesion which required a cannulation of the residual duct after total resection with a reinsertion of the duct posterior to its original location (D, E). F Gross specimen of the resected mass showing a well circumscribed glistening surface
A Overview of the histopathological specimen showing phylloides-like fibroepithelial lesion within dilated duct, covered by squamous oral mucosa (upper right field). B the lesion was composed of plump edematous to fibrous leaflet-like projections within the cystic cavity, covered by columnar respiratory-type epithelium continuous with the mucosal lining of the cystic duct. C Sebaceous elements and focal myxoid change are seen within the stroma. D The sebaceous glands merge with the lining epithelium (mid-lower field)
The epithelium lining the cystic duct (upper field) and the epithelial component covering the leaflets (lower field) are more or less similar (A), but the latter shows variable hyperplastic changes (B, right). C The mucus cell-containing epithelium (lower left) merges with eosinophilic columnar ciliated cells lacking mucous elements (C). D salivary-type serous acini closely associated with the epithelium covering the leaflets
The stromal component was mainly composed of fibroblastic spindle cells entrapping single fat cells at the periphery of the lesion (A). B higher magnification of the spindle cells, note ectatic vessels. C scattered multinucleated stromal giant cells were seen focally. Immunohistochemistry showed experssion of CD34 in the spindle cells (D) and the multinucleated giant cells (E). Desmin was expressed strongly in the giant cells (highlighting prominent dendritic cytoplasmic processes) and variably in the spindle cells (F)
Article
DICER1, a member of the ribonuclease III family, is involved in the biogenesis of microRNAs and, hence, it influences gene expression regulation. DICER1 germline (associated with the inherited DICER1 syndrome) or somatic mutations have been linked to tumorigenesis in histogenetically diverse benign and malignant neoplasms in different organs including pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, poorly differentiated thyroid carcinoma, thyroblastoma, intracranial sarcoma and gonadal Sertoli-Leydig cell tumors in addition to others. Moreover, rare botryoid (giant) fibroepithelial polyps may harbor this mutation. Herein, we describe the first reported case of a DICER1-mutated botryoid fibroepithelial polyp occurring within the parotid duct of a 65-year-old female who has no other features or family history of the DICER1 syndrome. Based on its distinctive morphology, we tested this lesion specifically for DICER1 mutations and confirmed the presence of a pathogenic DICER1 variant with a low allele frequency, consistent with a somatic mutation.
 
Lingual choristoma with gastric epithelium a physical examination reveals a well-demarcated, smooth surfaced mass on the dorsal midline of the tongue. b Histologically, the lesion is partially lined by squamous mucosa (arrow); focal erosion (arrowhead) is noted, while the deep layer is occupied by back-to-back glands (asterisk) (Hematoxylin and eosin, 4x). c These mucinous glands are consistent with pyloric-type glands (Hematoxylin and eosin, 20x). d Focal reactive atypia is identified in the area showing acute inflammation (Hematoxylin and eosin, 10x)
Article
The term ‘choristoma’ refers to normal appearing tissue in an abnormal location. We describe a case of choristoma with gastric epithelium of the dorsal tongue in a pediatric patient. Lingual choristomas are uncommon cystic or solid lesions which may demonstrate different types of tissue (e.g. gastric epithelium, respiratory epithelium, osseous and neuroglial tissue) histologically. Choristomas with gastric epithelium, also known as heterotropic gastric mucosa or foregut duplication cysts, are thought to arise from pluripotential cells of the embryonic foregut. They most frequently involve the anterior two-thirds of the tongue. Most patients are asymptomatic, but larger lesions may lead to feeding and breathing difficulties. Pathologic evaluation and surgical excision remain the mainstay of diagnosis and treatment, respectively. The pathologic characteristics of other congenital tongue lesions are also discussed.
 
Flow chart for article selection
Keratinizing squamous mucosa with surface corrugation and hypergranulosis (A) but with no identifiable cytologic atypia (B), presenting clinically as a well-demarcated leukoplakia of the attached gingiva (C). Thinly parakeratinizing and acanthotic mucosa (D) with no appreciable cytologic atypia or basal cell hypeplasia even in the presence of acanthosis (E) and presenting clinically as a well-demarcated leukoplakia of the ventral tongue (F). Keratinizing squamous mucosa with variable atrophy/acanthosis, hypergranulosis, and a lymphocytic host response at the interface (G), without cytologic atypia or lichenoid epithelial changes (H). The clinical presentation is of a well-demarcated leukoplakia of the ventral tongue with no reticulations. (A and G, original magnification × 40; B and E, original magnification × 100; D original magnification × 60; H original magnification × 200; hematoxylin and eosin stain)
Keratinizing squamous mucosa in two separate patients exhibiting epithelial atrophy, surface corrugation and hypergranulosis (A, D); epithelial atypia, chiefly in the form of nuclear hyperchromasia and increased nuclear/cytoplasmic ratio of basal and parabasal cells, is borderline for mild epithelial dysplasia (B, E); the clinical presentations are of leukoplakia with irregular but well-demarcated borders involving the ventrolateral tongue (C) and attached gingiva (F). (A and D, original magnification × 40; B and E, original magnification × 200; hematoxylin and eosin stain)
Chronic frictional/factitial keratosis (A–C) exhibiting shaggy parakeratosis with acanthosis and keratinocyte edema; parakeratosis is extensive and superficially colonized by bacteria. Benign alveolar ridge keratosis of retromolar pad (D–F) exhibiting hyperkeratosis with surface undulations and wedge-shaped hypergranulosis; epithelium is acanthotic with slender and elongated rete ridges are occasionally confluent at the tips without cytologic atypia. (B, E original magnification × 40, and C, F original magnification × 100; hematoxylin and eosin stain)
Within the 3 strikes to cancer model, intrinsically keratinizing stratified squamous epithelium in the absence of or with mild epithelial dysplasia corresponds to the breakthrough phase, high grade keratinizing dysplasia (moderate-to-severe epithelial dysplasia) corresponds to the expansion phase, and invasive carcinoma corresponds to the invasive phase. Three strikes to cancer diagram reproduced with permission from N Engl J Med 2015; 373:1895–1898, Copyright Massachusetts Medical Society
Article
The presence of epithelial dysplasia (ED) in oral leukoplakia is the single most important predictor of malignant transformation (MT). The majority of leukoplakias, however, do not show evidence of ED and yet MT of these lesions is well-recognized. These lesions have been referred to as “hyperkeratosis/hyperplasia, no dysplasia,” “keratosis of unknown significance” and “hyperkeratosis, not reactive (HkNR).” This study evaluates the MT rate of such leukoplakias. A literature review was performed to identify cohort studies on leukoplakias where (1) there was a recorded histopathologic diagnosis, (2) cases of “hyperkeratosis/hyperplasia, no dysplasia” comprised part of the cohort, and (3) follow-up information was available. There were 9,358 leukoplakias, of which 28.5% exhibited ED while 37.7% consisted of HkNR. Follow-up ranged from 15 to 73 months. The incidence of MT in leukoplakia exhibiting HkNR was 4.9%, compared to 15.3% for ED. Among oral squamous cell carcinomas (SCC) with previously biopsied, site-specific precursor lesions, 55.7% arose from ED/carcinoma in situ and 28.0% arose from HkNR. Leukoplakia exhibiting HkNR has a substantial MT rate, similar to that of mild ED, and must be recognized and managed appropriately to reduce oral SCC incidence.
 
Cytomorphology of secretory carcinoma of salivary gland. Highly cellular smear with cohesive, papillary-like clusters (a) with background histiocytes or singly dispersed neoplastic cells (f). The neoplastic cells have moderate amount of vacuolated cytoplasm and round to oval nucleus and smooth nuclear contour (b, c). Well-defined intracytoplasmic hyaline globules are noted in a portion of neoplastic cells (d, e by arrow)
Histopathology and selected immunostains of secretory carcinoma of salivary gland. Predominant microcystic architecture with intraluminal eosinophilic secretions and scant mucin are present a. Well-defined intracytoplasmic globular structures are present b and are highlighted by PAS-D stain (c). The tumor cells are diffusely positive for mammaglobulin (d) and vimentin (e), and focally positive for S100 (f), supporting the diagnosis of SC
Article
Secretory carcinoma (SC) of salivary gland, previously known as mammary analogue secretory carcinoma, is a rare low-grade malignancy harboring a diagnostic ETV6-NTRK3 gene fusion. SC of salivary gland shares histopathological, immunohistochemical and genetic characteristics with SC of the breast. There are several previous cytomorphological characterizations of SC of salivary gland reported in the literature. The most commonly reported patterns are of epithelial clusters with papillary architectural features, or of single dispersed epithelial cells on a background of abundant histiocytes. Tumor cells exhibit vacuolated eosinophilic cytoplasm and round to oval nuclei with regular nuclear contours and inconspicuous or small nucleoli. The cytomorphology of SC may closely mimic that of acinic cell carcinoma or low-grade mucoepidermoid carcinoma. Moreover, when cohesive epithelial clusters do not appear on the smears, it may be very difficult to distinguish dispersed tumor cells from histiocytes. In this article, we review the literature pertaining to SC cytomorphology and we report a fine needle aspiration biopsy case of SC in salivary gland showing well-defined intracytoplasmic hyaline globules, a feature that has not been previously reported. This novel cytomorphological feature may be helpful in distinguishing the tumor cells of SC from histiocytes and from other low-grade salivary gland tumors.
 
Top-cited authors
Lester D R Thompson
  • Permanente Medical Group
Margaret Brandwein-Gensler
  • University of Alabama at Birmingham
John M Wright
  • Texas A&M University
Donald Cohen
  • University of Florida
Leon Barnes
  • University of Pittsburgh