Thyroid poorly differentiated carcinoma metastatic to pancreas diagnosed by fine-needle aspiration and demonstrating a novel BRAF fusion.

Differentiating pancreatic duct adenocarcinoma from metastasis can be challenging by morphology alone. Metastasis from a classic papillary thyroid carcinoma can present as a poorly differentiated carcinoma and mimic pancreatic ductal adenocarcinoma's morphology.

Cytopathology of acinic cell carcinoma: A study of 50 cases, including 9 with high-grade transformation.

BACKGROUND: Although largely readily recognizable in tissue sections, acinic cell carcinoma (ACC) remains diagnostically problematic in fine-needle aspiration (FNA) cytopathology. The authors undertook an analysis of a large series of ACC aspirates, including acinic cell carcinoma with high-grade transformation (ACC-HGT). METHODS: The authors searched their cytopathology files for ACC cases with histopathologic confirmation. FNA biopsy was performed according to standard techniques. RESULTS: Fifty FNA biopsy cases of ACC (including 36 of parotid origin [72%]) from 41 patients (female to male ratio, 1.4:1; age range, 23-84 years; average, 54 years) met the study inclusion requirements. Primary neoplasm aspirates were most common (72%), and they were followed by recurrent tumors (16%) and metastases (12%). A precise cytologic diagnosis was made for 64%. Three of 9 ACC-HGT cases (33%) were correctly interpreted as such; 98% of conventional ACC cases were correctly graded as low-grade. With the Milan classification system, 74% fit into the malignant category. Ancillary testing was performed for only 36%. Conventional ACC had moderately to highly cellular smears; monotonous cells in aggregates and single forms; rounded nuclei; and microvacuolated, finely granular, oncocyte-like, or nonspecific cytoplasm. ACC-HGT smears contained larger nuclei, high nuclear to cytoplasmic ratios, coarse nuclear chromatin, and a loss of cytoplasmic granules/vacuoles. CONCLUSIONS: A correct diagnosis of ACC via FNA biopsy was made in almost two-thirds of the cases. With the Milan classification, 84% of the cases would have been classified as malignant or suspicious for malignancy. An absence of conventional serous acinar cell morphology in some cases as well as an absence of ancillary immunohistochemistry testing in almost two-thirds of the cases prevented even better diagnostic performance.

Classic polymorphous adenocarcinoma: Fine needle aspiration cytopathology of eight cases.

INTRODUCTION: The cytopathology and diagnostic accuracy of salivary gland (SG) polymorphous adenocarcinoma (PAC) is the subject of a limited number of reports. We undertook a review of our experience with fine needle aspiration (FNA) biopsy and PAC. MATERIALS AND METHODS: A search was made of our cytopathology files for PAC cases that also had histopathological confirmation. FNA biopsy smears and cell-blocks were performed and examined using standard techniques. RESULTS: Eight FNA biopsy cases of histologically proven PAC from 7 patients [F:M = 1.3:1, age 39-75 years, mean = 58] met study inclusion. Metastatic aspirates were most common (4), followed by 3 primary cases and 1 locally recurrent neoplasm. Primary FNA sites included hard palate (1 case), lip (1), and lateral tongue (1); all metastatic sites were in the neck. A precise cytologic diagnosis was made in 38% of cases; however, when applying the Milan classification system, 100% could be categorised as either malignant or of uncertain malignant potential. Ancillary immunohistochemical testing performed in 44% of the cases was non-specific. Cytologic smears showed cellular uniformity and structural variety of cell groups with tubular, branching, cribriform, and convex patterns as well as variable, but occasionally abundant globular myxoid stroma leading to confusion with adenoid cystic carcinoma. CONCLUSION: The imitative cytopathology of PAC with other SG neoplasms as well as its infrequency in routine FNA biopsy practice makes specific interpretation difficult, but using a classification system allows for appropriate patient management. Molecular testing in future specimens holds promise for enhancing diagnostic accuracy.

ROC analysis of p16 expression in cell blocks of metastatic head and neck squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma is associated with human papillomavirus (HPV) and often presents with early metastasis to cervical neck lymph nodes that are amenable to fine-needle aspiration (FNA). The most common method of HPV status determination is p16 immunohistochemistry (IHC). The literature suggests that a lower threshold is needed for p16 positivity on cell block. We examined and quantified p16 IHC staining on cell block and used receiver operating characteristics (ROC) curve analysis to determine an optimal cutoff value with high sensitivity and specificity. METHODS: Thirty-six FNAs of metastatic squamous cell carcinoma from cervical lymph nodes with p16 IHC were evaluated. The p16 stain was quantified in 5% increments and high-risk HPV mRNA in situ hybridization was performed as a gold standard test. Statistical analysis was performed. RESULTS: Interobserver variability was evaluated and was shown to be low with an intraclass correlation coefficient of 0.857. ROC analysis was performed and showed that a cell block p16 IHC cutoff of 15% yielded the highest sensitivity (80%) and specificity (81.8%). CONCLUSION: Our data show that a threshold of 15% p16 staining in cell block maximizes sensitivity and specificity.

The utility of high-risk human papillomavirus E6/E7 mRNA in situ hybridization in assessing HPV status on cell block.

INTRODUCTION: Assessment of human papillomavirus (HPV) status is critical to the treatment and prognosis of patients with oropharyngeal squamous cell carcinoma. Patients often present with enlarged cervical lymph nodes which are amenable to fine needle aspiration (FNA) and cell block creation. The most widely used method for assessing HPV status is the surrogate marker p16. Other HPV specific methods such as high-risk HPV E6/E7 mRNA in situ hybridization (ISH) have been shown to perform as well as p16 and are easier to interpret. Our study evaluates the utility of high-risk HPV mRNA ISH in cell block specimens. METHODS: Thirty-six cases of metastatic squamous cell carcinoma in cervical neck lymph node FNAs were identified over a 3-year period. All cases had p16 immunohistochemistry (IHC) performed on cell block. HR HPV mRNA ISH was performed on the cell block and compared to the p16 results. Additionally, p16 and HR HPV mRNA ISH status was assessed in those cases with corresponding surgical resections. RESULTS: HR HPV mRNA ISH confirmed the p16 IHC (either positive or negative) in 24 of the 36 cases (66.7%). Six false negative cases were p16 negative/HR HPV mRNA ISH positive. HR HPV mRNA ISH was positive in 75% of the four p16 equivocal cases. Two cases were p16 positive/HR HPV mRNA ISH negative. CONCLUSIONS: HR HPV mRNA ISH is no more difficult to perform in the IHC lab and is easier to interpret than p16 IHC. HR HPV mRNA ISH is a useful alternative to p16 in cell block specimens.

Merkel Cell Carcinoma of the Maxillary Sinus: An Unusual Presentation of a Common Tumor.

Merkel cell carcinoma is most commonly seen in the skin of sun exposed areas, particularly the head and neck and is associated with Merkel cell polyomavirus. Merkel cell carcinoma at an extracutaneous mucosal site of the head and neck is rare. We report a case of a 74-year-old women who presented with an enlarging thyroid mass found to be neuroendocrine carcinoma consistent with Merkel cell carcinoma (positive for synaptophysin, chromogranin, CK20). Subsequent work up revealed a maxillary sinus mass with extension into the nasal cavity. Biopsy was diagnostic for Merkel cell carcinoma (positive for synaptophysin, chromogranin, CK20 and Merkel cell polyomavirus). There are only case reports and small case series of Merkel cell carcinoma arising in the mucosal sites of the head and neck most commonly in the oral cavity, rarely the sinonasal mucosa. Merkel cell carcinoma metastasizing to the thyroid has only been reported in three other case reports, all from skin primaries. In addition to our case, we review the literature of extracutaneous sinonasal Merkel cell carcinoma and metastases to the thyroid.

Interobserver agreement in programmed cell death-ligand 1 immunohistochemistry scoring in nonsmall cell lung carcinoma cytologic specimens.

BACKGROUND: The evaluation of PD-L1 expression in nonsmall cell lung carcinoma (NSCLC) is becoming increasingly important given the effectiveness of PD-L1 inhibitors. Although cytologic specimens have been shown to be compatible with surgical specimens to evaluate PD-L1 immunohistochemistry (IHC), evidence of the reproducibility of PD-L1 in cytologic specimens is lacking. The aim of this study is to evaluate interobserver agreement in PD-L1 IHC in cytologic specimens. METHODS: PD-L1 IHC was performed on 86 NSCLC cytology specimens using Dako PD-L1 IHC 22C3 pharmDx. The digitally scanned whole slide images (WSI) were read by five pathologists. Each case was given a Tumor Proportion Score (TPS) and the results were compared between the observers. The interobserver concordance was assessed using 1% and 50% as cutoffs. RESULTS: TPSs were highly correlated among observers (Spearman correlation coefficient, 0.86-0.94). Using greater than 1% as a cutoff, interobserver agreement measured by Fleiss Kappa was 0.74 for all pathologists and Cohen's Kappa coefficient ranged from 0.49 to 0.83, consistent with moderate to substantial agreement. With a cutoff of greater than 50%, Fleiss Kappa was 0.79 for all pathologists and the kappa values ranged from 0.63 to 0.90, consistent with substantial to almost perfect agreement. Several pitfalls were identified by reviewing discordant cases, including staining in macrophages, stromal cells, and intratumoral heterogeneity. CONCLUSION: Our data suggest that TPS of PD-L1 IHC on cytology specimens is reproducible, with a better agreement when using 50% as the cutoff value. However, special attention is required when the TPS is near the 1% cutoff.

Mediastinal sarcomas: experience using fine needle aspiration cytopathology.

Fine needle aspiration (FNA) cytology is a sparsely used diagnostic method in the evaluation of mediastinal sarcomas in most medical centers worldwide with most literature citations regarding this category of malignancies consisting of small series and individual case reports. Most of these published studies highlight vascular sarcomas such as epithelioid hemangioendothelioma, and angiosarcoma, various subtypes of liposarcoma including well-differentiated liposarcoma, myxoid liposarcoma, and pleomorphic liposarcoma, malignant peripheral nerve sheath tumor, and sarcomas of uncertain differentiation, primary synovial sarcoma and the Ewing sarcoma family of tumors. This paucity of cytopathology reports regarding mediastinal sarcomas is in marked contrast to the almost daily application of endobronchial ultrasound (EBUS)-guided FNA biopsy for sampling mediastinal lymph nodes and mediastinal masses for primary and metastatic carcinomas which, of course, are considerably more common that any type of sarcoma in this location. EBUS, endoscopic ultrasound-guided (EUS) needle biopsy, and percutaneous image-guided biopsy using either core needle, fine-needle, or both can serve a potentially useful role for diagnostic sampling of mediastinal sarcomas, be they primary or metastatic. This review catalogues much of the published data regarding FNA cytopathology and its application to mediastinal sarcomas. An attempt is made to primarily highlight case series rather than individual case reports; however, due to the paucity of these, case reports are cited and discussed where appropriate.

Prevalence of High-Risk Human Papillomavirus in Tonsil Tissue in Healthy Adults and Colocalization in Biofilm of Tonsillar Crypts.

IMPORTANCE: The pathogenesis of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is currently an important topic of elucidation. The presence of latent HPV infection in tonsil tissue of healthy adults may provide an explanation for a component of this process and contribute to the understanding of HPV-associated squamous cell carcinoma oncogenesis of the oropharynx. OBJECTIVE: To determine the prevalence of oropharyngeal HPV and to determine the spatial relationship between the virus and crypt biofilm in tonsil tissue. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, cross-sectional study was carried out using samples obtained from tonsils that were archived at a university hospital following elective nononcologic tonsillectomy from 2012 to 2015. Samples consisted of formalin-fixed paraffin embedded samples of tumor-free tonsil tissue from 102 adults between the ages of 20 and 39 years. EXPOSURES: Human papillomavirus status was assessed by polymerase chain reaction, and high-risk subtypes 16 and 18 were assessed with quantitative polymerase chain reaction assay. Samples that demonstrated presence of HPV were then analyzed by in situ hybridization to localize the viral capsid protein. These samples were then stained with concanavalin A to establish biofilm presence and morphology. These samples were also stained with diamidino-phenylindole (DAPI) to visualize location of the virus in relation to cell nuclei. These data were then assembled for aggregate analysis to colocalize HPV in the biofilm of the tonsillar crypts. MAIN OUTCOMES AND MEASURES: Outcome measurements were determined prior to data collection and include prevalence of high-risk HPV types 16 and 18 in tonsil tissue of otherwise healthy adults, as well as demonstration with immunohistochemistry of HPV in tonsillar crypt biofilm. RESULTS: In 102 otherwise healthy adults (55 [53.9%] female; age range, 20-39 years), the overall prevalence of HPV in tonsils was 4.9% (n = 5); and high-risk type 16 or 18, 3.9% (n = 4). In this sample population, in situ hybridization colocalized HPV virus to the biofilm of the tonsillar crypts. CONCLUSIONS AND RELEVANCE: Biofilm is present in the tonsillar crypts in a considerable proportion of tonsil tissues and may be reproducibly identified. Human papillomavirus is demonstrated to colocalize to the crypt biofilm. This has important implications with respect to the determination of HPV prevalence rates in the oropharynx. It may also play a role in the pathogenesis of HPV-related oropharyngeal carcinoma.

Lobular neoplasia diagnosed on breast Core biopsy: frequency of carcinoma on excision and implications for management.

The appropriate follow-up and treatment for patients with a core biopsy diagnosis of lobular neoplasia (atypical lobular hyperplasia or lobular carcinoma in situ) remains controversial. Several studies have attempted to address this issue, with recommendations ranging from close clinical follow-up or surveillance to mandatory surgical excision in all cases. We report the findings at our institution, where virtually every core needle biopsy diagnosis of lobular neoplasia results in follow-up excision. The goal of the study was to identify potential predictors of upgrade to a more significant lesion. We identified 76 patients over a 15-year period with a core biopsy diagnosis of pure lobular neoplasia and no other high-risk lesions. Subsequent surgical excision identified 10 cases (13%) that were upgraded to carcinoma. Upgrade diagnoses included invasive ductal carcinoma (n=1), invasive lobular carcinoma (n=4), ductal carcinoma in situ (n=3), and pleomorphic lobular carcinoma in situ (n=2). All 10 upgraded cases had imaging findings suspicious for malignancy including irregular masses, asymmetric densities, or pleomorphic calcifications. Of the 10 upgraded cases, 7 were diagnosed as lobular carcinoma in situ on core biopsy. The data support a role for radiologic-pathologic correlation in the evaluation of suspicious breast lesions and suggest that the extent of lobular neoplasia in core biopsy specimens may be an indicator of the likelihood of upgrade to carcinoma.

Middle ear adenomas stain for two cell populations and lack myoepithelial cell differentiation.

Middle ear adenomas (MEAs) are benign neoplasms along a spectrum with neuroendocrine neoplasms (carcinoid tumors). Immunohistochemical (IHC) staining for myoepithelial markers has not been reported in these tumors. The archives of the Cleveland Clinic, University of Virginia and Armed Forces Institute of Pathology were retrospectively searched for tumors arising within the middle ear with material available for IHC staining. Twelve cases of MEAs, four cases of jugulotympanic paragangliomas (JPGs), 10 cases of ceruminous adenomas (CAs) and four cases of ceruminous adenocarcinomas (CACs) were obtained. IHC staining was performed for smooth muscle actin (SMA), p63, S-100 protein, cytokeratin 5/6 (CK5/6), and cytokeratin 7 (CK7). The MEAs were positive for: CK7 (92 %, luminal), CK5/6 (92 %, abluminal), p63 (83 %, abluminal), and negative for SMA and S-100 protein. The JPGs were negative for CK7, CK5/6, p63 and SMA; S-100 protein highlighted sustentacular cells. The CAs were positive for: CK7 (100 %, luminal), CK5/6 (100 %, abluminal), S-100 protein (80 %, abluminal), p63 (100 %, abluminal), and SMA (90 %, abluminal). CACs demonstrated two patterns, (1) adenoid cystic carcinoma-type: positive for CK7 (100 %, luminal), CK5/6, S-100 protein, p63, and SMA (all 100 %, abluminal); and (2) conventional-type: CK7 (50 % luminal), and no CK5/6, SMA, S-100 protein, or p63 expression. The IHC profile of MEAs suggests that these tumors harbor at least two cell populations, including luminal and basal cells. However, unlike ceruminous adenomas, MEAs lack true myoepithelial differentiation given the absence of S-100 protein and SMA staining in all cases.

Utility of autopsy in uncovering unexpected neuropathology.

Autopsy rates have declined in the last several decades for a variety of reasons. The purpose of this study is to compare autopsy neuropathologic findings from 2 periods to assess the prevalence of unexpected neuropathologic findings and unexpected neuropathologic diagnoses determined to be the major cause of death. Retrospective review of autopsies with examination of the central nervous system was performed in 2007 to 2008 (n = 289) and 1984 to 1985 (n = 328). Unexpected neuropathologic diagnoses were found at autopsy in 42.4% of cases from 1984 to 1985 vs 38.8% of cases from 2007 to 2008. The neuropathology was felt to contribute to the cause of death in 22% of cases from 1984 to 1985 vs 19.7% of cases from 2007 to 2008. Unexpected neuropathologic findings were the cause of death in 5.2% of cases from 1984 to 1985 vs 3.1% of cases from 2007 to 2008. These findings underscore the continued use of brain and spinal cord examination at autopsy despite advances in "modern" medicine.