Mixed HPV-related Neuroendocrine Carcinoma and HPV-related Squamous Cell Carcinoma of the Base of Tongue in a Patient With Incidental Identification of Synchronous Metastatic Papillary Thyroid Carcinoma.

BACKGROUND: While it is not uncommon in patients with head and neck cancer to present with multiple metachronous primary neoplasms, rarely do these present as a singular mass composed of intertwined, histologically distinct malignant tumors. Sometimes referred to as collision tumors, these entities are poorly understood and only appear in a handful of case studies in the literature. CASE REPORT: Here we present a 58-year-old male diagnosed with a human papillomavirus-related collision tumor consisting of oropharyngeal squamous cell carcinoma and small-cell neuroendocrine carcinoma, as well as an incidentally discovered metastatic thyroid papillary carcinoma, despite an unremarkable thyroid gland. The patient underwent transoral robotic base-of-tongue resection and partial pharyngectomy with selective neck dissection followed by chemoradiotherapy. At the 18-month follow-up the patient was doing well. His thyroid was normal and no recurrent or metastatic carcinoma was identified on the computed tomography and positron-emission tomography/computed tomography imaging findings. CONCLUSION: To the best of our knowledge, this is the first such case in English literature. This case demonstrates the importance of tumor morphology and immunohistochemical testing in HPV-related oropharyngeal carcinomas, despite the overall good prognosis of such tumors, due to the possibility of synchronous or colliding primary neoplasms.

Co-expression of SOX2 and HR-HPV RISH predicts poor prognosis in small cell neuroendocrine carcinoma of the uterine cervix.

BACKGROUND: Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is a rare cancer involving the human papilloma virus (HPV), and has few available treatments. The present work aimed to assess the feasibility of SOX2 and HPV statuses as predictive indicators of SCNEC prognosis. METHODS: The associations of SOX2 and/or high-risk (HR)-HPV RNA in situ hybridization (RISH) levels with clinicopathological characteristics and prognostic outcomes for 88 neuroendocrine carcinoma (NEC) cases were analyzed. RESULTS: Among these patients with SCNEC, SOX2, P16INK4A and HR-HPV RISH expression and SOX2/HR-HPV RISH co-expression were detected in 68(77.3%), 76(86.4%), 73(83.0%), and 48(54.5%), respectively. SOX2-positive and HR-HPV RISH-positive SCNEC cases were associated with poorer overall survival (OS, P = 0.0170, P = 0.0451) and disease-free survival (DFS, P = 0.0334, P = 0.0309) compared with those expressing low SOX2 and negative HR-HPV RISH. Alternatively, univariate analysis revealed that SOX2 and HR-HPV RISH expression, either separately or in combination, predicted the poor prognosis of SCNEC patients. Multivariate analysis revealed that the co-expression of SOX2 with HR-HPV RISH may be an independent factor of OS [hazard ratio = 3.597; 95% confidence interval (CI): 1.085-11.928; P = 0.036] and DFS [hazard ratio = 2.880; 95% CI: 1.199-6.919; P = 0.018] prediction in SCNEC. CONCLUSIONS: Overall, the results of the present study suggest that the co-expression of SOX2 with HR-HPV RISH in SCNEC may represent a specific subgroup exhibiting remarkably poorer prognostic outcomes compared with the expression of any one marker alone.

Human Papilloma Virus 18-Positive Submucosal Small Cell Neuroendocrine Carcinoma of the Vagina: An Immunohistochemical and Genomic Study.

Primary vaginal neuroendocrine carcinoma (NEC) is extremely rare among female genital tract tumors. Here, we report 2 cases of vaginal small cell NEC (SCNEC) using immunohistochemistry and next-generation sequencing (NGS) analysis. The 2 patients were in their mid-to-late 70s, presented with abnormal vaginal bleeding and had a vaginal submucosal mass. The biopsied or resected tumors showed a typical neuroendocrine morphology consisting of solid nests of atypical tumor cells, with no specific organoid patterns, and proliferating in the vaginal submucosa. Immunohistochemical analysis showed strong and diffuse expression of chromogranin A, synaptophysin, and p16, but no thyroid transcription factor 1 expression. Additionally, both cases were positive for human papillomavirus (HPV) 18. An NGS-based cancer panel analysis revealed that the tumors carried NF1 and AR mutations, but no major driver mutations were detected. The results of this study suggested that HPV18 infection is linked to vaginal SCNEC.

p16 immunostaining in cytology specimens: its application, expression, interpretation, and challenges.

INTRODUCTION: p16 immunostaining is considered as a surrogate marker for human papillomavirus (HPV)-related head and neck squamous cell carcinomas (HNSCC). Herein, the utility of p16 is evaluated in cytology specimens. MATERIAL AND METHODS: The electronic data of a large academic institution was searched for cytology cases accompanied by p16 (2014-2018). Cases were categorized based on body sites. P16 staining was quantified (negative [0%], focal/patchy, or diffusely positive [>70%]). HPV testing was correlated where available. RESULTS: A total of 372 cases were included (male:female, 239:133). The largest differences in application of p16 between men and women were in head/neck cases (209 versus 59) and the abdominal cases (1 versus 33), respectively. p16 diffuse staining is seen in most squamous cell carcinomas, small cell carcinomas, and gynecologic serous carcinomas. p16 expression was patchy or negative in most adenocarcinoma, neuroendocrine carcinoma, spindle cell neoplasms, and benign conditions. HPV testing was done on 217 cases including 138 cases with strong p16 (127 HPV+/11 HPV-), 20 cases with focal/patchy P16 staining (6 HPV+/14 HPV-) and 59 cases with negative p16 staining (3 HPV+/56 HPV-). CONCLUSIONS: Diffuse p16 staining aids in the diagnosis of HPV-related carcinomas, particularly HPV-related HNSCC, across the body and according to sex. In contrast, focal/patchy p16 staining does not correlate with HPV status across various body sites. In conclusion, intensity of p16 matters and should be correlated with cytomorphology, clinical history, and ancillary studies (eg, p40 immunostaining) for an accurate diagnosis and preventing diagnostic pitfalls.

High-grade Neuroendocrine Carcinomas of the Vulva: A Clinicopathologic Study of 16 Cases.

Vulvar high-grade neuroendocrine carcinomas (HGNECs) are rare and primarily thought to represent Merkel cell carcinoma (MCC). We present the clinicopathologic features of 16 such cases, the largest series to date. Patients were most often White, postmenopausal, and symptomatic from a palpable vulvar mass/nodule. Tumors ranged from 0.7 to 6 cm and most commonly involved the labium majus. Majority of the cases were pure HGNECs (15/16) with small cell (SC) morphology (14/16); 2 were large cell neuroendocrine carcinomas, of which 1 was combined with moderately differentiated adenocarcinoma. All tumors expressed synaptophysin. Of the 14 HGNECs with SC morphology, 6 were CK20-positive MCCs with characteristic CAM5.2 and neurofilament (NF) expression. Five of these MCCs were positive for Merkel cell polyoma virus large T-antigen (MCPyVLTAg). In contrast, 6 HGNECs with SC morphology were negative for CK20, NF, and MCPyVLTAg and classified as SCNECs. High-risk human papilloma virus was positive in all SCNECs and negative in all MCCs. One case of HGNEC with SC morphology could not be entirely characterized due to lack of tissue for ancillary testing. Five of 12 (42%) cases had a discrepant diagnosis initially rendered. Most patients (10/15) presented with International Federation of Gynecology and Obstetrics stage III or IV disease. Usual sites of metastasis included inguinal lymph node, liver, bone, and lung. Twelve patients underwent surgery with adjuvant chemotherapy and/or radiation therapy, 1 received adjuvant immunotherapy, and 1 patient received neoadjuvant chemotherapy followed by surgery and adjuvant radiation therapy. Median overall survival was 24 months (range: 7 to 103 mo), and overall 5-year survival was 12% (95% confidence interval: 1% to 39%). In summary, vulvar HGNECs are rare, aggressive neoplasms that can be further subclassified into MCC, SCNEC, and large cell neuroendocrine carcinoma. CK20, CAM5.2, NF, TTF-1, MCPyVLTAg, and high-risk human papilloma virus facilitate the distinction of MCC from SCNEC. Proper identification of vulvar HGNECs is critical for patient management.

Is Merkel Cell Carcinoma of Lymph Node Actually Metastatic Cutaneous Merkel Cell Carcinoma?

OBJECTIVES: The possibility of a so-called primary lymph node neuroendocrine carcinoma has been described in the literature. Here we evaluate cases fitting such a diagnosis and find that the cases demonstrate a convincing and pervasive pattern consistent with metastatic Merkel cell carcinoma. METHODS: Six cases of primary lymph node Merkel cell carcinoma and one case of metastatic neuroendocrine carcinoma at a bony site, all with unknown primary, were sequenced using a combination of whole-exome and targeted panel methods. Sequencing results were analyzed for the presence of an ultraviolet (UV) mutational signature or off-target detection of Merkel cell polyomavirus (MCPyV). RESULTS: Four of six primary lymph node cases were positive for a UV mutational signature, with the remaining two cases positive for off-target alignment of MCPyV. One case of neuroendocrine carcinoma occurring at a bony site was also positive for a UV mutational signature. CONCLUSIONS: We find no evidence to corroborate the existence of so-called primary Merkel cell carcinoma of lymph node.

Poorly differentiated neuroendocrine carcinoma of the head and neck: human papillomavirus tumour status/p16 status and impact on overall survival.

AIMS: Poorly differentiated neuroendocrine carcinoma (PDNEC) of the head and neck is a rare high-grade neuroendocrine neoplasm. Human papillomavirus (HPV) status and p16 status are as yet unclear among PDNECs, owing to a lack of statistical analysis. The objective of the present study was therefore to evaluate their potential clinicopathological associations, and their prognostic impact on overall survival in PDNECs of the head and neck, regardless to HPV genotype. METHODS AND RESULTS: All cases of PDNEC of the head and neck between 1998 and 2019 were identified from the database of the Lyon university hospital pathology department (n = 21); for these cases, p16 immunohistochemistry and HPV in-situ hybridisation were performed. Published cases of PDNEC of the head and neck with assessment of HPV status and p16 status were identified in PubMed (n = 57). Local and published cases were pooled for analysis. HPV positive (HPV+) tumour status was found to be significantly associated with oropharyngeal localisation (P < 0.001) and overexpression of p16 (P < 0.001). Multivariate analysis, adjusted on tumour site, histological subtype, p16 status, HPV status, and source of the case, showed that oropharyngeal localisation [hazard ratio (HR) 3.031, 95% confidence interval (CI) 1.257-7.310] and being a small-cell variant (HR 2.859, 95% CI 1.150-7.109) were significant predictors of worse overall survival; HPV+ tumour status was associated with better overall survival (HR 0.388, 95% CI 0.146-0.995). CONCLUSIONS: HPV+ tumour status was associated with oropharyngeal PDNECs and with a better prognosis.

High-Grade Neuroendocrine Carcinoma of the Head and Neck: Human Papillomavirus Status and PD-L1 Expression.

BACKGROUND: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma represents an important subgroup of head and neck cancer, but HPV occurs also in the less common neuroendocrine carcinomas (NEC). The PD-1/PD-L1 pathway appears to be activated in pulmonary NEC and correlates with a higher mutation burden, but the potential of NEC to respond to checkpoint inhibitors is unknown to a large extent. OBJECTIVES: To determine the HPV status of NEC of the head and neck region and to investigate the expression of PD-1 and its ligands PD-L1 and PD-L2. METHODS: Surgical tumor samples from 2006 to 2017 were analyzed. HPV status was determined by p16 immunohistochemistry (IHC) and multiplex PCR. IHC using the Cologne Score was performed for PD-1, PD-L1, and PD-L2. RESULTS: Seven NEC tumor samples were analyzed, three of them showed HPV type 18. Expression of PD-1 and PD-L1 differed widely and showed no correlation to HPV status. IHC showed an overexpression of PD-L2 in most of the patients. CONCLUSIONS AND SIGNIFICANCE: A multicentric analysis of NEC is needed to further evaluate the role of HPV as well as immunocheckpoints with regard to inflammatory immune response in genesis and clinical course of this rare tumor entity. Biomarkers for selection of novel treatment regimens, including immunotherapeutic approaches, are warranted.

Head and neck carcinoma of unknown primary.

In adult cervicofacial pathology, carcinoma of unknown primary is defined as lymph-node metastasis the anatomic origin of which is not known at the time of initial management. It constitutes up to 5% of head and neck cancers. Presentation may suggest benign pathology, delaying and confusing oncologic treatment. Diagnostic strategy in cervical lymph node with suspicion of neoplasia requires exhaustive work-up to diagnose malignancy and, in 45% to 80% of cases, depending on the series, to identify the primary site. Histologic types comprise squamous cell carcinoma, thyroid carcinoma, adenocarcinoma, neuroendocrine carcinoma and undifferentiated carcinoma. Association is sometimes found with human papilloma virus or Epstein Barr virus, guiding treatment. The objective of the present study was to provide clinicians with the necessary diagnostic tools, based on the current state of clinical, imaging and pathologic knowledge, and to detail treatment options.

HPV-associated neuroendocrine carcinomas of the head and neck in FNA biopsies: Clinicopathologic features of a rare entity.

BACKGROUND: The majority of human papillomavirus (HPV)-associated oropharyngeal carcinomas are squamous cell carcinomas; however, there are rare reports of HPV-associated neuroendocrine carcinomas (HPV-NECs) in the upper aerodigestive tract. The aim of this study was to characterize the diagnostic features of fine-needle aspiration (FNA) cases of head and neck HPV-NEC. METHODS: Cytology cases of HPV-NEC were identified over a 3-year period from 2 institutions. Clinical, cytomorphologic, and ancillary test results were evaluated. RESULTS: Five FNA cases of HPV-NEC were identified from 4 patients with cervical lymph node metastases with primaries in the oropharynx (n = 2), nasopharynx (n = 1), and larynx (n = 1). Three cases showed mixed small cell and large cell neuroendocrine morphologies; 1 case was a small cell carcinoma, and the last case appeared as a large cell neuroendocrine carcinoma. All tumors were strongly positive for synaptophysin and p16 and negative for p63/p40. Two cases tested for INSM1 showed diffuse nuclear staining. HPV was confirmed by in situ hybridization in 4 cases, and HPV-18 was detected by polymerase chain reaction in the fifth case. Retinoblastoma (Rb) staining was moderate to weak (5/5), and p53 was weakly positive (5/5). CONCLUSIONS: Head and neck HPV-NEC is a rare, aggressive entity that can show mixed small and large cell features and p16 upregulation; p53 and Rb are variable with limited diagnostic utility. Because p16 positivity can be nonspecific, confirmatory HPV testing is required and may be helpful in determining the primary site for neuroendocrine carcinoma of an unknown primary. The accurate diagnosis of HPV-NEC is also important because of its worse prognosis in comparison with HPV-associated squamous cell carcinoma.

Identification of high-risk human papillomavirus and Rb/E2F pathway genomic alterations in mutually exclusive subsets of colorectal neuroendocrine carcinoma.

Colorectal neuroendocrine carcinomas, both small cell and large cell types, are highly aggressive tumors with poor prognosis compared with colorectal adenocarcinoma. The molecular drivers of neuroendocrine carcinoma are best defined in small cell lung cancer, which shows near-universal genomic alterations in TP53 and RB1. The genetics of colorectal neuroendocrine carcinoma remain poorly understood; recent studies demonstrated infrequent RB1 alterations and genetics closely resembling colorectal adenocarcinoma. To better define the molecular pathogenesis of colorectal neuroendocrine carcinoma, we performed capture-based next-generation sequencing on 25 cases and evaluated for expression of p53, Rb, p16, and high-risk human papillomavirus (HR-HPV) subtypes using immunohistochemistry, in situ hybridization, and polymerase chain reaction. Rb/E2F pathway dysregulation was identified in nearly all cases (23/25, 92%) and occurred via three distinct mechanisms. First, RB1 genomic alteration was present in 56% (14/25) of cases and was accompanied by Rb protein loss, high p16 expression, and absence of HR-HPV; these cases also had frequent genomic alterations in TP53, the PI3K/Ras and Wnt pathways, as well as in DNA repair genes, with 4/14 cases being hypermutated. Second, 16% (4/25) of cases, all left-sided, had TP53 alteration without RB1 alteration; half of these harbored high-level amplifications in CCNE1 and MYC or MYCN and arose in patients with ulcerative colitis. Finally, 28% (7/25) of cases, all rectal or anal, lacked genomic alterations in RB1 or TP53 but were positive for HR-HPV. Our data demonstrate that Rb/E2F pathway dysregulation is essential in the pathogenesis of colorectal neuroendocrine carcinoma, akin to neuroendocrine carcinomas in other anatomic sites. Moreover, colorectal neuroendocrine carcinomas stratify into three distinct molecular subgroups, which can be differentiated based on Rb protein and HR-HPV status. HR-HPV infection represents a distinct mechanism for Rb and p53 inactivation in cases lacking genomic alterations in either gene. Differential treatment strategies for hypermutated and HPV-driven cases could improve patient outcomes.

Epstein-Barr Virus-Positive Large Cell Neuroendocrine Carcinoma of the Nasopharynx: Report of One Case and Review of the Literature.

Epstein-Barr Virus (EBV)-positive neuroendocrine carcinoma (NEC) of the nasopharynx is exceedingly rare, only two cases have been reported in the literature. While EBV infection is strongly associated with nasopharyngeal carcinoma, which is carcinoma with squamous differentiation, the link between EBV and NEC is not well known, and can be diagnostically challenging. In this study, we report the third case of EBV-positive large cell NEC of nasopharynx with neck lymph node metastasis. The patient was treated with combined radiation and chemotherapy and showed complete clinical and radiological response. Similar treatment response has been reported in another patient with high stage EBV-positive large cell NEC, suggesting that EBV status is an important prognostic factor. Recognition of this rare tumor is important for disease management and patient prognosis. We also review the literature about the clinical and pathologic presentation of neuroendocrine tumors of nasopharynx.

[Neuroendocrine carcinoma of cervix: a clinicopathologic study of 82 cases].

Objective: To investigate the clinicopathological characteristics and prognostic factors of neuroendocrine carcinoma (NEC) of the cervix. Methods: Eight-two patients diagnosed as NEC of cervix from 2008 to 2016 at West China Second University Hospital were analyzed retrospectively including HE slide review, immunohistochemistry and HPV genotyping. Survival analysis was performed using Kaplan-Meier and Cox regression model. Results: The age of the patients ranged from 16 to 75 years with mean age of 43 years. According to International Federation of Gynecology and Obstetrics (FIGO) clinical stage, 52 cases were in stageⅠ, 10 cases in stageⅡ, 14 cases in stage Ⅲ and 6 cases in stage Ⅳ. The tumor size ranged from 0.5 to 6.5 cm, with an average of 3.6 cm. Upon histopathologic review, 74 tumors were classified as small cell carcinoma; 7 tumors as large cell NEC, and 1 as atypical carcinoid. Further evaluation showed 52 cases (63.4%) with deep stromal invasion, 73 cases (89.0%) with lymph-vascular invasion, and 28 cases (34.2%) with pelvic and (or) para-aortic lymph nodes involvement. Immunohistochemical staining showed neuroendocrine markers Syn, CD56, NSE, S-100 protein and CgA were positive in 93.9%, 84.2%, 74.4%, 64.6% and 51.2% of cases, respectively. The results of HPV-DNA detection were positive in 72 cases, high-risk HPV types were 70 cases and 49 cases were HPV18 positive. The median follow-up time was 37 months (range, 6-101 months). Twenty-nine cases were found recurrence or metastasis, including 23 cases of death. The univariate analysis demonstrated that the tumor size, lymph node metastasis, infiltration depth, FIGO stage and whether the lesion confined to the uterus were significant prognostic factors(P<0.05). Cox multivariate analysis showed that lymph node metastasis and FIGO stage were independent prognostic factors of NEC(P<0.05). Conclusions: NEC of the cervix is a highly aggressive malignancy with poor prognosis. The tumor is associated with HPV infection, especially type 18. Small cell NEC is the most common type of cervical NEC. Diagnosis is based on histological and immunohistochemical examination. Lymph node metastasis and FIGO stage are the independent factors affecting prognosis.

Human Papillomavirus-Related Neuroendocrine Carcinomas of the Head and Neck.

Human papillomavirus (HPV)-related head and neck carcinoma (HNC) represents an important subgroup of head and neck cancer that is characterized by a consistent microscopic appearance and a favorable prognosis. A growing experience with HPV testing, however, has uncovered variants that deviate from the prototypic HPV-HNC with respect to morphology. While these HPV-HNCs may deviate morphologically from the prototype, they do not appear to stray far from the favorable clinical outcome assigned to HPV-positive status. In effect, HPV positivity trumps traditional prognostic features predicated on morphology such as tumor grade and histologic subtype when it comes to predicting clinical behavior. For the diagnostic pathologist, the pedestrian task of tumor grading and subtyping would seem to be of little prognostic or therapeutic relevance when it comes to HPV-HNC. Recognition and documentation of neuroendocrine differentiation is a most notable exception. Forms of HPV-HNC have now been reported that morphologically resemble small cell carcinoma (SCC) and large cell neuroendocrine carcinoma (LCNEC) of other sites, and that immunohistochemically exhibit neuroendocrine differentiation. Despite the presence of HPV, these SCCs and LCNECs share the same aggressive clinical behavior of their counterparts in the lung and other sites where the high grade neuroendocrine phenotype is associated with early distant spread and poor overall survival. Consequently, the high grade neuroendocrine phenotype should be regarded as an aggressive form of HPV-HNC where tumor morphology displaces HPV positivity as the most important prognostic feature.

Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix.

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS, Erbb2, c-Myc, NOTCH1, BCL6, or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN, RB1, BRCA1, BRCA2, and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor.

Epstein-Barr Virus-Positive Large Cell Neuroendocrine Carcinoma of the Nasopharynx: Report of a Case with Complete Clinical and Radiological Response After Combined Chemoradiotherapy.

Neuroendocrine carcinomas of the head and neck are rare and are classified as well differentiated, moderately differentiated, and poorly differentiated carcinomas with the latter category being subdivided into small cell and large cell neuroendocrine carcinoma (LCNEC). While most carcinomas in the nasopharynx are associated with Epstein-Barr virus (EBV), there has been only one previous report demonstrating a link between EBV and LCNEC of the nasopharynx. In this report we describe a second case of EBV-positive LCNEC arising in the nasopharynx with bilateral cervical metastases. The patient was treated with a combination of radiation and chemotherapy which resulted in a complete clinical and radiological response. The patient is still disease free 3 years after presentation. The results of this case suggest that EBV-positive LCNEC is sensitive to chemoradiotherapy and as a result may have better prognosis than EBV-negative LCNEC arising in the nasopharynx or other sites.

Cervical Carcinoma With Divergent Neuroendocrine and Gastrointestinal Differentiation.

Neuroendocrine carcinomas of the uterine cervix are rare tumors with aggressive behavior. They comprise <4% of cervical carcinomas. They may coexist with both adenocarcinoma and squamous cell carcinoma of cervix. Signet ring carcinoma of cervix is a rarer entity and less than 20 cases have been described in the literature. We present a case of a 34-year-old female who presented with systemic thrombosis, splenic mass and a cervical mass which on biopsy showed divergent differentiation of primitive large cell neuroendocrine carcinoma with signet ring cells. The cervical tumor was positive for human papilloma virus 16/18 by in situ hybridization, confirming cervical origin of the tumor. This unusual presentation and morphology needs to be recognized and appropriately evaluated when patients present with tumors of unknown origin in metastatic sites.

An extremely rare case of Epstein-Barr virus-associated gastric carcinoma with differentiation to neuroendocrine carcinoma.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVGC) is defined as a neoplasm comprising monoclonal proliferation of EBV-infected gastric epithelial cells. Although the typical histology is gastric carcinoma with lymphoid stroma (GCLS), the histologic features of the tumor vary. We report herein the case of a 78-year-old man with multiple simultaneous EBVGCs revealing different histopathologic morphologies; one was mixed adenoneuroendocrine carcinoma (MANEC), and the other was GCLS. Both tumor types exhibited positive results for EBV in situ hybridization. To the best of our knowledge, this represents the first report of EBVGC showing neuroendocrine differentiation. Immunohistochemistry also revealed a loss of gastrointestinal features, including CDX2, MUC5AC, and MUC6 expression, among tumor cells from the neuroendocrine component of the MANEC. We describe the pathologic features of this rare neoplasm and discuss the mechanisms underlying the neuroendocrine differentiation of EBVGC cells, along with providing a brief review of the literature.

A systematic review and meta-analysis on the attribution of human papillomavirus (HPV) in neuroendocrine cancers of the cervix.

BACKGROUND: There remains uncertainty about the role of human papillomavirus (HPV) infection in causing small-cell neuroendocrine carcinoma (SCNC) and large-cell neuroendocrine carcinoma (LCNC) of the cervix. To clarify the role of HPV in the development of SCNC and LCNC, we conducted a systematic review and meta-analyses. METHODS: PubMed and Embase were searched to initially identify 143 articles published on or before June 1, 2017. Studies were limited to methods that tested for HPV in the cancer tissue directly to minimize misattribution. Thirty-two studies with 403 SCNC and 9 studies of 45 LCNC were included in the analysis. RESULTS: For SCNC, 85% (95% confidence interval [95%CI]=71%-94%) were HPV positive, 78% (95%CI=64%-90%) were HPV16 and/or HPV18 positive, 51% (95%CI=39%-64%) were singly HPV18 positive, and 10% (95%CI=4%-19%) were singly HPV16 positive. In a subset of 5 SCNC studies (75 cases), 93% were positive for p16INK4a by immunohistochemistry and 100% were HPV positive. For LCNC, 88% (95%CI=72%-99%) were HPV positive, 86% (95%CI=70%-98%) were positive for HPV16 or HPV18, 30% were singly HPV18 positive (95%CI=4%-60%), and 29% (95%CI=2%-64%) were singly HPV16 positive. CONCLUSIONS: In conclusion, most SCNC and LCNC are caused by HPV, primarily HPV18 and HPV16. Therefore, most if not all SCNC and LCNC will be prevented by currently available prophylactic HPV vaccines.

p16 overexpression in high-grade neuroendocrine carcinomas of the head and neck: potential diagnostic pitfall with HPV-related carcinomas.

High-grade neuroendocrine carcinomas (HGNECs) of the head and neck have the morphological appearance of undifferentiated carcinomas and could be histologically similar to human papillomavirus (HPV)-associated non-keratinizing squamous cell carcinomas of the head and neck. The aim of the study is to characterize histologically, immunohistochemically, and virologically these unusual neoplasms. Nineteen HGNECs of the head and neck (1 oropharyngeal, 5 sinonasal, 7 of the larynx, and 6 of the parotid gland) were reviewed and analyzed with a immunohistochemical panel, with special emphasis on cell cycle proteins. The tumors were tested for HPV by in situ hybridization (GenPoint HPV, Dako) and PCR (SPF10-DEIA-LiPA25). Merkel cell polyomavirus was studied using the antibody CM2B4. Fifteen HGNEC were of small cell and 4 of large cell type. Most of the tumors (14/19, 73.7 %), including all the pure small cell carcinomas, showed a strong and diffuse positive staining for p16. Eleven of them (78.5 %) had Rb loss and a low or absent cyclin D1 expression. All cases were negative for HPV and polyomavirus. Most patients were smokers, diagnosed at advanced stages of the disease, and had a poor outcome, with a 5-year survival of 18 %. In conclusion, HGNECs of the head and neck are infrequently related to HPV infection, but usually show strong, diffuse positive p16 immunostaining due to Rb pathway dysregulation. Awareness of this immunohistochemical pattern of expression may avoid a potential diagnostic pitfall with HPV-associated non-keratinizing squamous cell carcinomas, which have a better prognosis.