Haploinsufficiency by minute MutL homolog 1 promoter DNA methylation may represent unique phenotypes of microsatellite instability-gastric carcinogenesis.

Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis.

HPV+ oropharyngeal squamous cell carcinomas from patients with two tumors display synchrony of viral genomes yet discordant mutational profiles and signatures.

Human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV + OPSCC) is increasing in prevalence in the USA, as are cases of patients with multiple HPV + OPSCCs (mHPV + OPSCC). mHPV + OPSCCs present a unique opportunity to examine HPV + OPSCC mutation acquisition and evolution. We performed sequencing of the viral genome, somatic exome and somatic transcriptome from 8 patients each with 2 spatially distinct HPV + OPSCCs, and 37 'traditional' HPV + OPSCCs to first address if paired tumors are caused by the same viral isolate and next, if acquired alterations, and the underlying processes driving mutagenesis, are shared within pairs. All tumor pairs contained viral genomes from the same HPV type 16 sublineage and differed by 0-2 clonal single nucleotide polymorphisms (SNPs), suggesting infection with the same viral isolate. Despite this, there was significant discordance in expression profiles, mutational burden and mutational profiles between tumors in a pair, with only two pairs sharing any overlapping mutations (3/3343 variants). Within tumor pairs there was a striking discrepancy of mutational signatures, exemplified by no paired tumors sharing high APOBEC mutational burden. Here, leveraging mHPV + OPSCCs as a model system to study mutation acquisition in virally mediated tumors, in which the germline, environmental exposures, immune surveillance and tissue/organ type were internally controlled, we demonstrate that despite infection by the same viral isolate, paired mHPV + OPSCCs develop drastically different somatic alterations and even more strikingly, appear to be driven by disparate underlying mutational processes. Thus, despite a common starting point, HPV + OPSCCs evolve through variable mutational processes with resultant stochastic mutational profiles.

Synchronous primary neoplasia in patients with oropharyngeal cancer: Impact of tumor HPV status. A GETTEC multicentric study.

INTRODUCTION: Patients with oropharyngeal squamous cell carcinoma (OPSCC) display a significant risk of synchronous primary neoplasia (SPN) which could impact their management. The aims of this study were to evaluate the risk and distribution of SPN in OPSCC patients according to their HPV (p16) status, the predictive factors of SPN and the impact of SPN on therapeutic strategy and oncologic outcomes. MATERIAL AND METHODS: All OPSCC patients treated from 2009 to 2014 were included in this multicentric retrospective study. Univariate analyses were conducted using Chi-2 and Fisher exact tests. For multivariate analyses, all variables associated with a p ≤ 0.10 in univariate analysis were included in logistic regression models. RESULTS: Among the 1291 patients included in this study, 75 (5.8%) displayed a SPN which was preferentially located in the upper aerodigestive tract, lung and esophagus. Comorbidity level (p = 0.03), alcohol (p = 0.005) and tobacco (p = 0.01) consumptions, and p16 tumor status (p < 0.0001) were significant predictors of SPN. In multivariate analysis, p16+ status was significantly associated with a lower risk of SPN (OR = 0.251, IC95% [0.133;0.474]). Patients with a SPN were more frequently referred for non-curative treatment (p = 0.02). In patients treated with curative intent, there was no impact of SPN on the therapeutic strategy (surgical vs. non-surgical treatment). We observed no overall survival differences between patients with or without SPN. CONCLUSION: P16 tumor status is the main predictive factor of SPN in OPSCC patients. This study provides crucial results which should help adapt the initial work-up and the global management of OPSCC patients.

Kaposi Sarcoma With Intravascular Primary Effusion Lymphoma in the Skin: A Potential Pitfall in HHV8 Immunohistochemistry Interpretation.

Primary effusion lymphoma is a rare, clinically aggressive large B-cell neoplasm universally associated with human herpesvirus 8 that occurs in the setting of immune compromise. It is classically described as a lymphomatous effusion occurring within body cavities. Recently, however, solid tumor masses, and rarely an intravascular form, have been described. We report a case of a cutaneous intravascular primary effusion lymphoma occurring within ectatic vascular spaces of a Kaposi sarcoma skin lesion in a human immunodeficiency virus-positive adult. Human herpesvirus 8 immunohistochemistry was positive in the nuclei of the Kaposi sarcoma spindled cells as well as within large intravascular plasmacytoid cells. This unusual case highlights the importance of careful assessment of the nature of human herpesvirus 8-positive staining cells in an otherwise typical Kaposi sarcoma. A careful search for dual pathology in immune-compromised patients as well as the importance of histologic assessment of skin lesions in human immunodeficiency virus-positive patients is also highlighted.

Post-hysterectomy rare collision vulva tumor with long-term human papilloma virus infection composed of squamous cell carcinoma of the labia major and adenosquamous carcinoma of bartholin gland: A case report.

RATIONALE: Post-hysterectomy collision tumors of the vulva has rarely been reported. Though long-term HPV infection may induce vulva tumor, but the relationship between HPV infection and collision vulva tumor is not clear. And there are no clear rules of the post-hysterectomy cancer surveillance for human papilloma virus (HPV) long-term infections. So here we first report a case of post-hysterectomy rare collision vulva tumor with long-term HPV infection composed of squamous cell carcinoma of the labia major and adenosquamous carcinoma of bartholin gland and hope to bring new direction to our future research. PATIENT CONCERNS: A 48-year-old woman with long-term HPV infection, 3 years after hysterectomy, gravida 3, para 2, was admitted to our hospital with complaints of a 4-month history of an itching vulva ulceration. An anabrosis was located on the surface of the solid mass of the bartholin gland at the posterior part of the right labium and the right inguinal lymph nodes were palpable. Result of the incisional biopsy of the ulcer area at local hospital was atypical squamous cells couldn't exclude high-grade squamous intraepithelial lesion (ASC-H). Subsequently more authoritative pathological consultation results suggested squamous cell carcinoma of the vulva. DIAGNOSES: Post-hysterectomy collision vulva tumor with long-term HPV infection composed of squamous cell carcinoma of the labia major and adenosquamous carcinoma of bartholin gland. INTERVENTIONS: The extensive excision of the vulva, bilateral inguinal lymph nodes dissection, and local skin flap transposition surgeon was done to this patient. The final certificate diagnosis was: vulvar tumor T1bM0N0 composed of squamous cell carcinoma of the labia major and adenosquamous carcinoma of bartholin gland; HPV infection; post hysterectomy, and bilateral salpingectomy. OUTCOMES: The patient recovered well after surgery, and consequently received 6 courses of TC (paclitaxel + carboplatin) chemotherapy, and 9 months and 13 days followed up. So far patient recorded as complete response (CR). LESSONS: Collision vulva tumor occurred post-hysterectomy is extremely rare. It is most likely related to long-term HPV infection, which suggests us should to modify the manner of the post-hysterectomy cancer surveillance for HPV long-term infections. For patients with high-risk HPV infection, even if the cytology results are negative, we may should perform colposcopy and vulva biopsy more positively to prevent the disease from progressing into cancer. And the pathogenesis of relationship between HPV infection and collision vulva tumor is still need further investigation.

Cervical small cell carcinoma frequently presented in multiple high risk HPV infection and often associated with other type of epithelial tumors.

BACKGROUND: Small cell carcinoma of the uterine cervix is a rare and highly malignant tumor, and its etiopathogenesis is strongly related to high-risk HPV infections. METHODS: The clinicopathological data of 30 cases of cervical primary small cell carcinoma were retrospectively analyzed. In situ hybridization, polymerase chain reaction and reverse dot-blot hybridization were employed to detect HPV DNA in both small cell carcinoma and other coexisting epithelial tumors. Immunohistochemistry was used to detect the protein expression of p16 and p53. RESULTS: Amongst 30 patients with cervical primary small cell carcinoma, 15 patients simultaneously exhibited other types of epithelial tumors, including squamous cell carcinoma, adenocarcinoma, squamous cell carcinoma in situ, and adenocarcinoma in situ. Most tumor cells infected with HPV presented integrated patterns in the nuclei by in situ hybridization. HPV DNA was detected in every small cell carcinoma case (100%) by polymerase chain reaction and reverse dot blot hybridization. 27 cases (90%) harbored type 18, and 15 (50%) displayed multiple HPV18 and 16 infections. The prevalence of HPV 18 infection in small cell carcinoma was higher than in cervical squamous and glandular epithelial neoplasms (P = 0.002). However, similar infection rates of HPV 16 were detected in both tumors (P = 0.383). Both small cell carcinoma and other types of epithelial tumors exhibited strong nuclear and cytoplasmic staining for p16 in all cases. Three cases of small cell carcinoma revealed completely negative p53 immunohistochemical expression in 15 cases of composite tumors, which suggested TP53 nonsense mutation pattern. The pure small cell carcinoma of uterine cervix had similar mutation or wild type pattern for TP53 compared with composite tumor (P = 0.224). CONCLUSIONS: Cervical small cell carcinomas are often associated with squamous or glandular epithelial tumors, which might result from multiple HPV infections, especially HPV 16 infection. Multiple HPV infections were not correlated with tumor stage, size, lymphovascular invasion, lymph node metastasis, or prognosis. Furthermore, careful observation of specimens is very important in finding little proportion of small cell carcinoma in the composite lesions, specifically in cervical biopsy specimens, in order to avoid the missed diagnosis of small cell carcinoma.

Case of probable spontaneous regression of Merkel cell carcinoma combined with squamous cell carcinoma without surgical intervention.

Merkel cell carcinoma (MCC) is a rare but more lethal cutaneous cancer than melanoma. However, spontaneous regression of a number of MCC has been reported, although the cause of this regression remains unclear. In most cases, MCC regresses after a surgical procedure, for example, biopsy. Herein, we report a case of Merkel cell polyomavirus-negative MCC coincident with squamous cell carcinoma (SCC) that underwent true spontaneous regression without biopsy. One month after the patient's first visit, clinical examination revealed that the tumor had not grown, but its surface showed changes in texture and color. Histopathologically, the excised specimen was indicative of MCC coincident with SCC and showed extensive necrosis in the upper portion of the tumor, numerous caspase-3-positive apoptotic cells, an accumulation of CD68-positive foam cells and vascular invasion. These findings suggested that the tumor had regressed. We hypothesize that extensive coagulative necrosis resulting from an insufficient local blood supply triggered the shedding of some products or components of MCC and SCC, which in turn induced antitumor immunity against both lesions.

Extranodal natural killer/T-cell lymphoma, nasal type, in Senegal.

INTRODUCTION: The distribution of extranodal NK/T-cell lymphoma (ENKTCL) is highly inhomogeneous throughout the world. In Sub-Saharan Africa, despite the precocity of Epstein-Barr virus (EBV) infection and its endemicity, ENKTCL remains exceptionally reported. The purpose of this study was to report the epidemiological, clinical, paraclinical, and evolutionary characteristics of ENKTCL at the Aristide LeDantec University Hospital in Dakar, Senegal. METHODOLOGY: A 5-year retrospective review of all patients with histopathological, immunohistochemical, and in situ hybridization proven cutaneous lymphomas RESULTS: We collected seven cases corresponding to a frequency of 1.4 cases per year. ENKTCL accounted for 10.5% of all cutaneous lymphomas, ranking second after T-cell lymphomas. Men were predominantly affected (M : F ratio of 6), and the mean age was 38.5 years ± 4.06. The mean time before consultation was 7.3 months. The lymphomas affected primarily the nasal cavity in five cases and the skin in two cases. At admission, six patients had nasal mucosa involvement, which was isolated in three cases, associated with cutaneous lesions in three cases and lymph node involvement in three cases. CD56 was positive in only one case, and Eber transcribed RNA of EBV was expressed by in situ hybridization in all patients. DISCUSSION: To our knowledge, we have reported the first and largest series of ENKTCL in Sub-Saharan Africa. Our study shows an intermediate prevalence between that reported from Asia, Latin America, and the West. It was also noted a young age of patients, a prolonged diagnostic delay, a frequent negativity of CD56 marker, and a very poor prognosis of the disease in our region.

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.

Benign and malignant hybrid adnexal tumors in a patient with epidermodysplasia verruciformis.

Epidermodysplasia verruciformis (EV) is a genodermatosis characterized by overgrowth of flat warts, pityriasis versicolor-like lesions and an increased propensity for developing cutaneous squamous cell carcinomas due to abnormal susceptibility to infection with beta-human papilloma viruses. Adnexal tumors are not typically associated with EV. Here we report a spectrum of hybrid adnexal tumors with divergent eccrine and folliculosebaceous differentiation, and cytologic features ranging from benign to frankly atypical, in a patient with inherited EV.

Association of Multiple Primary Skin Cancers With Human Immunodeficiency Virus Infection, CD4 Count, and Viral Load.

Importance: Persons with human immunodeficiency virus (HIV) have a 2.8-fold higher risk than HIV-uninfected persons of nonmelanoma skin cancer (NMSC), defined as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Individuals with a prior NMSC history are at increased risk for subsequent NMSC, but the magnitude of risk and its relation to HIV disease-related factors, including CD4 count and viral load (VL), are unknown. Objective: To better understand how laboratory markers currently used to evaluate HIV disease progression may be associated with subsequent NMSC risk. Design, Setting, and Participants: This cohort study analyzed 455 HIV-infected and 1945 HIV-uninfected patients, all of them members of the Kaiser Permanente Northern California (KPNC) health care plan, diagnosed with at least 1 NMSC from 1996-2008 to determine risk of subsequent NMSCs in relation to CD4 count and VL. All participants were white, non-Hispanic persons 18 years or older who had had at least 1 NMSC during the 1996-2008 period. Participants entered the cohort at their first NMSC diagnosis and were observed through 2008. Incidence rates were calculated and adjusted hazard ratios were estimated using extended Cox regression models with recent CD4 count and VL analyzed as time-changing covariates. Main Outcomes and Measures: Measured CD4 count, VL, and subsequent NMSC (BCC and SCC). Results: The cohort comprised 455 HIV-infected participants (13 [3%] women) and 1952 HIV-uninfected participants (154 [8%] women). Median duration of observation was 4.6 years, and 16.5% (n = 390) either died (n = 35) or lost KPNC membership status (n = 355) without having a subsequent primary NMSC. Compared with HIV-uninfected persons, HIV-infected individuals were slightly younger (mean age, 52.5 vs 55.5 years), more likely men (97% vs 92%), more likely to have smoked (57% vs 45%), and less likely to be overweight/obese (50% vs 61%). The small observed differences by HIV status in matching characteristics (ie, age and sex) resulted from the restriction of the original cohort to those with at least 1 NMSC. Compared with uninfected individuals, those with HIV infection with a recent biomarker of more severe immune deficiency (CD4 count <200 cells/mL) had a 44% increased risk of subsequent NMSC overall and a 222% increase risk of SCC in particular, suggesting that subsequent SCC risk is associated with immune dysfunction. Conclusions and Relevance: HIV-infected persons compared with HIV-uninfected persons were are at higher risk for subsequent new SCC but not BCC, with a dose-response relationship between risk and lower CD4 counts and higher VLs. Subsequent new primary SCCs had a strong association with lower CD4 and higher VL among HIV-infected persons, suggesting that immune dysfunction might contribute to increased SCC risk. Clinical implications include targeted monitoring for SCC among HIV-infected individuals, particularly those with low CD4 counts or high VLs.

Coexistence of Lymphoepithelial Carcinoma of the Parotid Gland and Submandibular Gland Pleomorphic Adenoma.

Lymphoepithelial carcinoma is a variant of undifferentiated carcinoma with characteristic dense lymphoid stroma in which nasopharynx is site of predilection. Racial and geographic association and Epstein-Barr virus positivity in endemic areas are other characteristics of this rare neoplasm. Lymphoepithelial carcinoma accounts for only 0.4% of malignant salivary gland tumors. The authors present a patient with Epstein-Barr virus positive lymphoepithelial carcinoma of the parotid gland in a nonendemic region. Besides this, synchronous pleomorphic adenoma in the contralateral submandibular gland caused a challenge in making initial therapeutic decision.

Clinicopathological analysis of concomitant hepatic embryonal rhabdomyosarcoma and hepatocellular carcinoma.

Hepatic embryonal rhabdomyosarcoma (ERMS) is extremely rare. Here we report the simultaneous occurrence of hepatocellular carcinoma (HCC) and ERMS of the liver in a 40-year-old man without any symptoms. Macroscopically, the mass was composed of two different tumors. The large tumor was 4.5×4×4cm and was poorly circumscribed and soft in the central region of left lateral lobe of the liver with apparently focal necrosis. The small tumor, with diameter of 1cm, was adjacent to the large tumor without clear boundary. Histologically, the large tumor was composed of numerous spindle-shaped or round cells with brightly eosinophilic cytoplasm as well as pathologic mitosis. Immunohistochemical staining was positive for MyoD1 and myogenin in nuclear testing. However, in the small tumor, cells demonstrated hepatocyte differentiation and were focally positive for HepPar1. A diagnosis of concomitant ERMS and HCC of the liver was made. The patient received no adjuvant treatment after hepatic left lateral lobectomy. The regular follow-up observation conducted by imaging examinations displayed that there was no sign of recurrence or metastasis of the mass over 32 months. To our knowledge, this is the first case report of ERMS of the liver associated with HCC. The diagnosis can only be made by pathological examination. The primary therapy method for this tumor is operative resection.