Human Papillomavirus (HPV)-Related Carcinoma of the Oropharynx with Squamous Cell and Adenoid Cystic Carcinoma-Like Features: Report of a Case.

We describe the heretofore unreported case of an HPV-related carcinoma of the palatine tonsil with distinct areas of squamous cell- and adenoid cystic carcinoma-like differentiation in a 54-year old patient. The morphological, immunophenotypic and molecular findings of the tumor are illustrated. We discuss the parallels between the tumor and HPV-related multiphenotypic sinonasal carcinoma (HMSC) which is well-known to exhibit adenoid cystic carcinoma-like features. A review of the literature of high-risk HPV-associated non-squamous carcinomas of the oropharynx is presented.

CYLD-mutant cylindroma-like basaloid carcinoma of the anus: a genetically and morphologically distinct class of HPV-related anal carcinoma.

Rare reports of anal carcinoma (AC) describe histologic resemblance to cutaneous cylindroma, but mutations in the tumor suppressor CYLD, the gene responsible for familial and sporadic cylindromas, have not been systematically investigated in AC. Here, we investigate CYLD-mutant AC, focusing on molecular correlates of distinct histopathology. Comprehensive genomic profiling (hybrid-capture-based DNA sequencing) was performed on 574 ACs, of which 75 unique cases (13%) harbored a CYLD mutation. Clinical data, pathology reports, and histopathology were reviewed for each CYLD-mutant case. The spectrum of CYLD mutations included truncating (n = 50; 67%), homozygous deletion (n = 10; 13%), missense (n = 16; 21%), and splice-site (n = 3; 4%) events. Compared with CYLD-wildtype AC (n = 499), CYLD-mutant ACs were significantly enriched for females (88% vs. 67%, p = 0.0001), slightly younger (median age 59 vs. 61 years, p = 0.047), and included near-universal detection of high-risk HPV sequences (97% vs. 88%, p = 0.014), predominantly HPV16 (96%). The CYLD-mutant cohort also showed significantly lower tumor mutational burden (TMB; median 2.6 vs. 5.2 mut/Mb, p < 0.00001) and less frequent alterations in PIK3CA (13% vs. 31%, p = 0.0015). On histopathologic examination, 73% of CYLD-mutant AC (55/75 cases) showed a striking cylindroma-like histomorphology, composed of aggregates of basaloid cells surrounded by thickened basement membranes and containing characteristic hyaline globules, while only 8% of CYLD-wildtype tumors (n = 34/409) contained cylindroma-like hyaline globules (p < 0.0001). CYLD-mutant carcinomas with cylindroma-like histomorphology (n = 55) showed significantly lower TMB compared with CYLD-mutant cases showing basaloid histology without the distinctive hyaline globules (n = 14) (median 1.7 vs. 4.4 mut/Mb, p = 0.0058). Only five CYLD-mutant cases (7%) showed nonbasaloid conventional squamous cell carcinoma histology (median TMB = 5.2 mut/Mb), and a single CYLD-mutant case showed transitional cell carcinoma-like histology. Within our cohort of ACs, CYLD mutations characterize a surprisingly large subset (13%), with distinct clinical and genomic features and, predominantly, a striking cylindroma-like histopathology, representing a genotype-phenotype correlation which may assist in classification of AC.

A clinicopathological and molecular analysis of cervical carcinomas with basaloid features.

AIMS: To investigate the relationship between adenoid basal carcinoma (ABC), adenoid cystic carcinoma (ACC) and squamous cell carcinoma (SCC) in the uterine cervix. METHODS AND RESULTS: We analysed the clinicopathological and molecular features in two pure ABCs, 15 SCCs with ABC-/ACC-like features and seven basaloid SCCs (BSCCs) by chart review, immunohistochemistry, human papillomavirus (HPV) RNA in-situ hybridisation and fluorescence in-situ hybridisation. All patients were alive with no evidence of disease, except for one patient with ACC-like features who died of disease at 18 months post diagnosis. The mixed carcinomas comprised variable SCCs and ABC-/ACC-like components displaying vague transitional zones. All components consistently showed diffuse p16, p63 and SOX2, variable cytokeratin (CK)7 and CK17 and rare Ber-EP4 and MYB expression; there was a substantially lower Ki67 index in pure ABCs and the ABC-like components. The ACC-like components showed no myoepithelial differentiation (SMA, calponin and S100) and MYB gene fusions. CK7, CK17 and Ber-EP4 were characteristically stronger in BSCCs than in the mixed carcinomas (P < 0.01). High-risk HPV (HR-HPV) E6/E7 mRNA was detected in 12 mixed carcinomas and seven BSCCs, but not in pure ABCs. The HR-HPV mRNA expression was higher in the SCC components and BSCCs than in the ABC-like components of mixed carcinomas (P < 0.05). CONCLUSIONS: The ACC-like components in mixed carcinomas probably represent the morphological mimics of salivary ACCs. ABC-like components may be the potential precursor of the ACC-like and SCC components. HR-HPV oncogenes may play a role in the pathogenesis of SCCs with ABC-/ACC-like features.

Polyomavirus JCPyV infrequently detectable in adenoid cystic carcinoma of the oral cavity and the airways.

Our objective was to assess the presence of three polyomaviruses, namely SV40, JCPyV, and BKPyV, and human papillomaviruses (HPV) in adenoid cystic carcinomas (ACC) of the minor salivary glands (MiSG) in the head and neck region. The study comprised 68 MiSG ACC patients operated during 1974-2012 at the Helsinki University Hospital (Helsinki, Finland). Medical records and 68 histological samples were reviewed. Polyomaviruses were detected with quantitative PCR and the DNA-positive samples were further analyzed for the presence of viral tumor T antigen (T-ag) with immunohistochemistry. HPV genotyping was performed with a Multiplex HPV Genotyping Kit. Only JCPyV DNA was found in ACC samples, being present in 7 (10.3%) out of the 68 samples. The viral load of JCPyV was low varying between 1 to 226 copies/µg DNA. The JCPyV-positive samples originated from trachea (two samples), paranasal sinuses (one), and oral cavity (two). Additionally, JCPyV positivity was found in one lung metastasis of a tracheal tumor and one local disease failure of an oral cavity tumor. Three JCPyV DNA-positive samples showed weak nuclear staining for large T-ag. In conclusion, only JCPyV but not SV40, BKPyV, or HPV was found in ACC from the upper and lower airways. JCPyV copy numbers were low which might support its role as a "hit and run agent" in ACC carcinogenesis.

Strong SOX10 expression in human papillomavirus-related multiphenotypic sinonasal carcinoma: report of 6 new cases validated by high-risk human papillomavirus mRNA in situ hybridization test.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is associated with high-risk HPV (HR-HPV) infection. Using HR-HPV messenger RNA (mRNA) in situ hybridization (ISH), we reported 6 new HMSC cases and compared their histopathology with that of sinonasal adenoid cystic carcinoma. Using p16 immunohistochemistry (IHC) and HR-HPV ISH, we retrospectively identified 6 HMSC cases. All HMSC cases were positive for HR-HPV mRNA ISH and p16 IHC. Two HMSC cases had overlying atypical squamous epithelium, and 1 had invasive squamous cell carcinoma (SCC). All HMSC cases were SOX10 positive, whereas the overlying atypical squamous epithelium and the SCC were SOX10 negative. One atypical HMSC-like case was also identified, which was positive for HR-HPV mRNA ISH, HR-HPV DNA ISH, and SOX10 IHC, but negative for p16 IHC. This study showed that HR-HPV mRNA ISH was a useful tool to diagnose HMSC and had stronger signals compared with HR-HPV DNA ISH. HR-HPV E6/E7 mRNA could be identified in the overlying atypical squamous epithelium and the invasive SCC. A combination of p16 and SOX10 IHC will be a useful screening panel for HMSC followed by confirmatory HR-HPV mRNA ISH test.

Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma: A Case Report Documenting the Potential for Very Late Tumor Recurrence.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma is a peculiar sinonasal tract tumor that demonstrates features of both a surface-derived and salivary gland carcinoma. Implicit in its name, this tumor has a consistent association with high-risk HPV, particularly type 33. It was first described in 2013 under the designation of HPV-related carcinoma with adenoid cystic carcinoma-like features. However, since its initial description additional cases have emerged which demonstrate a wide morphologic spectrum and relatively indolent clinical behavior. Herein we report our experience with a case of HPV-related multiphenotypic sinonasal carcinoma that was initially classified as adenoid cystic carcinoma in the 1980s. The patient recurred after a 30-year disease free interval. RNA in situ hybridization confirmed the presence of high-risk HPV in both her recurrence and her initial tumor in the 1980s, which allowed for reclassification as HPV-related multiphenotypic sinonasal carcinoma. Our case adds to the literature of this relatively newly described entity and supports the indolent clinical behavior of this neoplasm but also demonstrates a potential for very late local recurrence.

Case report: HPV-related carcinoma with adenoid cystic-like features of the sinonasal tract.

Human papillomavirus-related carcinoma with adenoid cystic-like features is a newly described histologic variant of sinonasal tract carcinoma. The implications of this sinonasal malignancy is still being evaluated. There are a limited number of cases reported in the literature, and thus we seek to further characterize this patient population and review the histologic features of this malignancy with the following two cases. The behavior of this entity is as yet uncertain. Laryngoscope, 128:1515-1517, 2018.

HPV-related Multiphenotypic Sinonasal Carcinoma: An Expanded Series of 49 Cases of the Tumor Formerly Known as HPV-related Carcinoma With Adenoid Cystic Carcinoma-like Features.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a peculiar neoplasm that is restricted to the sinonasal tract, exhibits features of both a surface-derived and salivary gland carcinoma (particularly adenoid cystic carcinoma), and is associated with high-risk HPV. Given the limited number of published cases, the full clinicopathologic spectrum of this neoplasm is unclear. Here, we present an updated experience of 49 cases. All cases of HMSC were obtained from the authors' files. Immunohistochemistry for p16, c-kit, and myoepithelial cell markers (S100, actin, calponin, p63, and/or p40) was performed along with RNA in situ hybridization for HPV (type 33-specific as well as a high-risk cocktail). Fluorescence in situ hybridization studies for fusions of MYB, NFIB, and MYBL1 was performed on a subset of cases. Clinical follow-up was obtained from medical records. A total of 49 cases of HMSC were collected. Twenty-eight (57%) were from women and 18 (43%) from men, ranging in age from 28 to 90 years (mean, 54 y). Of 40 cases with detailed staging information, 43% of HMSCs presented with a high T-stage (T3 or T4). Histologically, most grew predominantly as solid nests of basaloid cells exhibiting high mitotic rates and frequent necrosis, with histologic and immunohistochemical evidence of myoepithelial differentiation. Most cases also demonstrated foci of cribriform and/or tubular growth, along with an inconspicuous population of ducts. Thirty-four (69%) cases demonstrated an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa. Less consistent histologic features included squamous differentiation within the invasive tumor (n=6), sarcomatoid transformation (n=5) including overt chondroid differentiation (n=3), and prominent epithelial-myoepithelial carcinoma-like growth (n=3). All cases were positive for p16 by immunostaining and HPV by RNA in situ hybridization. Thirty-three (67%) were positive for HPV 33. No cases tested for MYB, MYBL1, or NFIB gene fusions were positive. In the 38 cases with follow-up data, (mean follow-up, 42 mo) 14 recurred locally and 2 metastasized (lung, finger). There were no regional lymph node metastases, and no tumor-related deaths. HMSC is a distinct sinonasal neoplasm characterized by myoepithelial differentiation, frequent surface epithelial involvement, and the presence of high-risk HPV (especially type 33). Although it classically exhibits a cribriforming pattern that closely resembles adenoid cystic carcinoma, our expanded series highlights a histologic spectrum that is much broader than previously recognized, warranting a change in terminology. HMSC usually presents as a large and destructive sinonasal mass with high-grade histologic features, but it paradoxically behaves in a relatively indolent manner, underscoring the importance of distinguishing HMSC from true adenoid cystic carcinoma, squamous cell carcinoma, and other histologic mimickers.

Human papillomavirus-related carcinoma with adenoid cystic-like features: a series of five cases expanding the pathological spectrum.

AIMS: Human papillomavirus (HPV)-related carcinoma with adenoid cystic-like features is a newly described entity of the sinonasal tract. In this study, we evaluated histomorphology, immunophenotype and molecular testing to identify potentially helpful features in distinguishing it from classic adenoid cystic carcinoma (AdCC). METHODS AND RESULTS: We retrospectively collected five HPV-related carcinomas with adenoid cystic-like features and 14 AdCCs of the sinonasal tract. All histological slides were retrieved for morphological evaluation. As comparing with AdCC, HPV-related carcinomas with adenoid cystic-like features were associated with squamous dysplasia of surface epithelium (80% versus 0%, P < 0.01) and the presence of a solid growth pattern (100% versus 29%, P = 0.01), but less densely hyalinized tumour stroma (20% versus 86%, P = 0.02). Squamous differentiation in the invasive tumour was seen in three HPV-related carcinomas with adenoid cystic-like features, two of them showing abrupt keratinization and one with scattered non-keratinizing squamous nests. Diffuse p16 staining in ≥75% of tumour cells was noted in all HPV-related carcinomas with adenoid cystic-like features but in only one AdCC (100% versus 7%, P < 0.01). High-risk HPV testing gave positive results in all HPV-related carcinomas with adenoid cystic-like features (four associated with type 33 and one associated with type 16) but not in AdCCs. MYB rearrangement was tested in four HPV-related carcinomas with adenoid cystic-like features, and all were negative. CONCLUSIONS: This study has further clarified the histological spectrum of this tumour type, and reports the first HPV type 16-related case. Diffuse p16 staining followed by HPV molecular testing is useful in distinguishing HPV-related carcinomas with adenoid cystic features from classic AdCCs.

Sinonasal adenoid cystic carcinoma: Treatment outcomes and association with human papillomavirus.

BACKGROUND: The purpose of this study was to review long-term outcomes of sinonasal adenoid cystic carcinoma (ACC) and to clarify its association with human papillomavirus (HPV). METHODS: The medical records of 23 patients with sinonasal ACC treated with primary surgical resection between 1998 and 2013 were reviewed. Tissue specimens were available for 17 patients. The p16 testing was performed using immunohistochemistry (IHC), and HPV infection was determined using quantitative polymerase chain reaction (PCR) with primers targeting the E6/E7 region. RESULTS: Two of the 17 samples showed strong and diffuse p16 staining, whereas the remaining 15 cases showed p16-positivity isolated to the luminal cells. Only one of the p16-positive cases was positive for HPV. The 5-year local failure, disease-free survival (DFS), and overall survival (OS) were 51%, 52%, and 62%, respectively. CONCLUSION: Local failures are common with advanced sinonasal ACC, and the association of HPV with true sinonasal ACC is low.

Human Papillomavirus-Associated Neoplasms of the Head and Neck.

Human papillomavirus (HPV) is an essential causal factor in a subset of head and neck neoplasms, most notably oropharyngeal squamous cell carcinoma, for which HPV infection has important diagnostic, prognostic, and therapeutic implications. This article summarizes the current understanding of HPV-associated neoplasms of the head and neck, including the recently described carcinoma with adenoid cystic-like features. Salient clinical, gross, and microscopic features are discussed, and the utility of specific ancillary studies is highlighted.

Prevalence and associated survival of high-risk HPV-related adenoid cystic carcinoma of the salivary glands.

Adenoid cystic carcinoma (SACC) is a rare malignancy, but a frequent subtype in minor and major salivary glands. The molecular alterations or biomarkers that underlie its development and progression as well as therapy outcomes are poorly characterized. The main study goal was to investigate reliable biomarkers and patient-related factors that may have impact on recurrence and long-term survival of SACC. The prevalence of human papilloma virus (HPV) in SACC was determined by HPV-DNA genotyping and p16 immunostaining. Epithelial growth factor receptor (EGFR), p53 and Ki-67 expression were also evaluated. Twenty-eight (42%) of 67 patients were HPV-DNA positive. Kaplan-Meier analysis indicated that SACC patients with metastases (P=0.03) had a poor overall survival (OS) and a shorter recurrence-free survival (P<0.001). Positive resection margins significantly predicted shorter recurrence-free survival (P=0.01). In the multivariate analysis, non-metastatic disease (P=0.033) and p16 positivity (P=0.005) have shown their prediction value for OS while non-metastatic disease (P=0.002), HPV positivity (P=0.041) and negative resection margin predicted a better recurrence-free survival. The present study documents for the first time the positivity for HPV infection and overexpression of certain markers (p16, Ki-67, EGFR and p53) used in diagnostics in SACC as well as characterizes clinical entities. These factors might be exploited in the future as biomarkers for its prognostic value. Using the clinical and pathological basis for predicting different outcomes could significantly facilitate SACC stratification and potentially directing treatment.

Lower Female Genital Tract Tumors With Adenoid Cystic Differentiation: P16 Expression and High-risk HPV Detection.

Lower female genital tract tumors with adenoid cystic differentiation are rare, and data on their relationship with high-risk human papillomavirus (HPV) are limited. Here we report the clinicopathologic features from a case series. Tumors with adenoid cystic differentiation, either pure or as part of a carcinoma with mixed differentiation, arising in the lower female genital tract were evaluated by means of immunohistochemical analysis for p16 expression and in situ hybridization using 1 or more probes for high-risk HPV (a high-risk probe covering multiple types, a wide-spectrum probe, and separate type-specific probes for HPV16 and HPV18) and when possible by polymerase chain reaction for high-risk HPV. Six cervical carcinomas with adenoid cystic differentiation admixed with various combinations of at least 1 other pattern of differentiation, including adenoid basal tumor (epithelioma and/or carcinoma), squamous cell carcinoma (basaloid or keratinizing), and small cell carcinoma were identified in patients ranging in age from 50 to 86 years (mean, 73 y; median, 76 y). All of these tumors were characterized by diffuse p16 expression. High-risk HPV was detected in 5 of 6 tested cases: 4 cases by in situ hybridization (all positive for HPV-wide-spectrum and HPV16) and 1 by polymerase chain reaction (HPV45). Seven pure adenoid cystic carcinomas (6 vulvar and 1 cervical) were identified in patients ranging in age from 27 to 74 years (mean, 48 y; median, 48 y). All of these tumors were characterized by variable p16 expression ranging from very limited to more extensive but never diffuse. No high-risk HPV was detected in any of these pure tumors. Lower female genital tract carcinomas with adenoid cystic differentiation appear to comprise 2 pathogenetically distinct groups. Cervical carcinomas with mixed differentiation, including adenoid cystic, adenoid basal, squamous, and small cell components, are etiologically related to high-risk HPV and can be identified by diffuse p16 expression. Pure vulvar and cervical adenoid cystic carcinomas appear to be unrelated to high-risk HPV and are distinguished from the mixed carcinomas by nondiffuse p16 expression.

Co-existing of adenoid cystic carcinoma and invasive squamous cell carcinoma of the uterine cervix: a report of 3 cases with immunohistochemical study and evaluation of human papillomavirus status.

BACKGROUNDS: The aim of this study was to describe the clinicopathological characteristics and high-risk human papillomavirus (HPV) infection status in patients diagnosed with co-existing of adenoid cystic carcinoma (ACC) and invasive squamous cell carcinoma (SCC) of the uterine cervix. METHODS: Three patients were identified from the pathology databank of Peking Union Medical College Hospital from year 2000 to 2014. Immunohistochemistry and in situ hybridization (ISH) were employed in this study. RESULTS: The patients were aged 64, 77 and 63 years (average, 68 years old). All the patients were postmenopausal women who presented with bloody or watery vaginal discharge. The cervical cytology screening results were all suspicious for high-grade squamous intraepithelial lesion (HSIL). The subsequent cervical colposcopy biopsies all showed cervical intraepithelial neoplasia III (CINIII). One patient received only a cervical conization, whereas the other two patients underwent hysterectomy. The immunohistochemical results showed that the ACC compartments were positive for CK7 and CD117; the cases of SCC were negative for CK7 and CD117. P63 staining was strongly positive and diffuse throughout the SCC compartments, whereas only patchy positive areas were observed in the ACC. MYB exhibited strong nuclear staining in the ACC and SCC compartments but negative staining in the endocervical gland. In situ hybridization (ISH) signals for high-risk HPV DNA and mRNA were present in the two compartments of all three patients. The patients had no evidence of disease at an average follow-up time of 21.6 months. CONCLUSION: High-risk HPV was present in both the ACC and SCC compartments in all three patients.

Human papillomavirus and salivary gland neoplasia: a p16INK4 immunohistochemical and in situ hybridisation study.

OBJECTIVE: This study aimed to evaluate the association between human papillomavirus infection and salivary gland tumours in a Scottish cohort. METHODS: Specimens from a range of salivary gland tumours operated on between 1997 and 2012 were studied. A tissue microarray constructed from tissue blocks was subjected to p16INK4 (cyclin-dependent kinase inhibitor 2A) immunohistochemistry and in situ hybridisation using probes specific for human papillomavirus, including types 16 and 18. RESULTS: A total of 61 tumours (benign and malignant) were deemed suitable for the study. p16INK4 staining yielded three (4.9 per cent) positive samples: one small cell carcinoma, one squamous cell carcinoma and one poorly differentiated carcinoma. Human papillomavirus in situ hybridisation demonstrated a positive signal in the latter sample only (1.6 per cent). CONCLUSION: This study demonstrated a very low human papillomavirus detection rate in salivary gland tumours. It can therefore be concluded that human papillomavirus infection is unlikely to play a role in salivary gland neoplasia. Rare human papillomavirus positive cases should be carefully evaluated to exclude the possibility of a metastatic lesion.

Coexistent squamous cell carcinoma and adenoid basal carcinoma in the uterine cervix and infection with human papillomavirus (HPV 31).

OBJECTIVE: Adenoid basal carcinoma (ABC) is an uncommon neoplasm of the uterine cervix. ABC can be accompanied by carcinoma in situ or invasive carcinoma. Most cases are discovered accidentally during radical hysterectomy. ABC is associated with a high risk of human papillomavirus infection (HPV), most often HPV 16 infection. CASE REPORT: We present a rare case of an 86-year-old Taiwanese married woman who suffered from bloody vaginal discharge and occasional lower abdominal pain and received cervical biopsy. The pathological report revealed squamous cell carcinoma (SCC) of the uterine cervix. After radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymph node dissection, the final pathological report revealed SCC coexisting with ABC, and both of the components were infected by HPV 31. After receiving radiotherapy, she maintained outpatient department follow-up. CONCLUSION: A literature review revealed that this was a rare case of combined ABC-SCC associated with HPV 31 infection. In this case, the ABC component did not affect the tumor stage because it was confined to the cervix. However, we must avoid overestimating the clinical stage because the ABC component is thought to be a benign lesion.

Antitumor effects of telomerase-specific replication-selective oncolytic viruses for adenoid cystic carcinoma cell lines.

We evaluated the antitumor effect of a telomerase-specific replication-selective adenovirus (Telomelysin, OBP-301) for adenoid cystic carcinoma (ACC) in vitro and in vivo. Adenovirus E1 gene expression was controlled by human telomerase reverse transcription (hTERT). Infection of ACC cells by OBP-301 induced high E1A mRNA expression and subsequent oncolytic cell death in a dose-dependent manner. Using OBP-401 (TelomeScan), a genetically engineered adenovirus that carries the GFP gene under the control of the cytomegalovirus (CMV) promoter at the deleted E3 region of OBP-301, ACC cells expressed bright GFP fluorescence as early as 12 h after OBP-401 infection. The fluorescence intensity gradually increased in a time-dependent manner, followed by rapid cell death due to the cytopathic effect of OBP-401, as evidenced by the floating, highly light-refractive cells using phase-contrast microscopy. Effects of intratumorally injected OBP-401 against established Acc2 xenograft tumors were seen in BALB/c nu/nu mice. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Our data clearly indicated that telomerase-specific oncolytic adenoviruses have significant therapeutic potential against human ACC in vitro and in vivo. These results suggest that treatment with OBP-301 and OBP-401 may improve the quality of life of oral cancer patients.