Impact of HPV status on immune responses in head and neck squamous cell carcinoma

Oral oncology

2022 Feb 24

Qureshi, HA;Zhu, X;Yang, GH;Steadele, M;Pierce, RH;Futran, ND;Lee, SM;Méndez, E;Houghton, AM;
PMID: 35219073 | DOI: 10.1016/j.oraloncology.2022.105774

The main objective of our study was to understand the impact of immune cell composition and the tumor-reactivity of tumor infiltrating lymphocytes (TIL) in HPV-positive (HPV+) and HPV-negative (HPV-) head and neck squamous cell carcinoma (HNSCC). TIL cultures were established from primary HNSCC tumors, the T cell subsets were phenotypically characterized using flow cytometry, and Interferon (IFN)-γ ELISA assay was used to determine TIL function. NanoString Immune Profiler was used to determine an immune signature by HPV-status, and multiplex immunohistochemistry (MIHC) was used to quantify immune cell distributions and their spatial relationships. Results showed that HPV+ and HPV- HNSCC had similar capacity to expand IFN-γ reactive TIL populations, and these TIL populations had similar characteristics. NanoString analysis revealed increased differential expression of genes related to B cell functions in HPV+ HNSCC, which were significant at a Benjamini-Yekutieli adjusted p-value of < 0.001. MIHC also displayed increased CD8+ T cell and CD19/CD20+ B cell densities in the tumor region of HPV+ HNSCC as opposed to HPV- HNSCC (p < 0.01). Increases in a combined metric of tumor B cell content and stromal plasma cell content was associated with increased progression-free survival in HPV- HNSCC patients treated with immune checkpoint inhibitor therapy (p = 0.03). In summary, TIL populations expanded from HPV+ and HPV- HNSCC displayed similar IFN-γ reactivity. However, we identified a strong B-cell signature present within HPV+ HNSCC, and higher B and plasma cell content associated with improved PFS in HPV- HNSCC patients treated with immune checkpoint inhibitors.

Clinicopathological features of squamous cell carcinoma of the oral cavity and oropharynx in young patients

Br J Oral Maxillofac Surg.

2018 Apr 05

Martinez RCP, Sathasivam HP, Cosway B, Paleri V, Fellows S, Adams J, Kennedy M, Pearson R, Long A, Sloan P, Robinson M.
PMID: 29628167 | DOI: 10.1016/j.bjoms.2018.03.011

Our aim was to examine the clinicopathological features of squamous cell carcinoma (SCC) of the oral cavity and oropharynx in a group of young patients who were dignosed during a 15-year period (2000-2014). Patients' clinical details, risk factors, and survival were obtained from medical records. Formalin-fixed, paraffin-embedded, tissue was tested for high-risk human papillomavirus (HPV). The results were compared with those of a matching group of older patients. We identified 91 patients who were younger than 45 years old, and the 50 youngest patients were studied in detail. The male:female ratio was 2:1, with more tumours located in the oral cavity than in the oropharynx (35 compared with 15). HPV-related SCC was restricted to the oropharynx. When matched for site, stage and HPV status, five-year overall survival was similar in young and matched older patients (log-rank test, p=0.515). Our findings suggest that young patients with oral SCC have a disease profile similar to that of older patients with the condition. It is plausible that prognostic information generally available for oral cancers is applicable to young patients with the disease.

The Role of Integration and HPV Status in Malignant Transformation of Inverted Papillomas

J Neurol Surg B Skull Base

2022 Jan 01

Stepp, WH;Kimple, AJ;Ebert, CS;
| DOI: 10.1055/s-0042-1743610

Introduction: Inverted papillomas (IPs) are rare, benign, sinonasal tumors with the ability to undergo malignant transformation. While rare, they are the most common type of papilloma within the sinonasal cavity and represent up to 5% of primary nasal cavity tumors. There have been many studies attempting to define a causal link between HPV and malignant transformation of IPs with mixed results. Additionally, these tumors have a high recurrence rate, and their malignant transformation potential has spurred significant investigation into their etiology, disease course, and treatment. Prior meta-analyses of HPV-mediated transformation of IPs have suggested a nearly 50% prevalence of HPV in IPSCC and strong bias toward the high-risk virus types, HPV16 and HPV18, in IP malignant transformation. In this study, we have identified a large, retrospective cohort of benign IPs, IP-SCC, and control sinonasal polyp tissues that have been tested for high-risk HPV types to determine the prevalence in both benign and malignant IPs. Methods: A total of 94 IP tumors, 22 IP-SCC, and 13 sinonasal polyps were stained with HPV16/18 RNAscope and imaged with fluorescence to determine HPV status. Formalin-fixed slides were processed via standard antigen retrieval protocols and anti-HPV RNA staining was performed. Imaging was performed via confocal and bright-field microscopy. Results: We demonstrated significant HPV-positivity in IP-SCC versus benign IP tumors (p

Prognostic factors for human papillomavirus-positive and negative oropharyngeal carcinomas.

Laryngoscope.

2018 Mar 14

Yin LX, D'Souza G, Westra WH, Wang SJ, van Zante A, Zhang Y, Rettig EM, Ryan WR, Ha PK, Wentz A, Koch W, Eisele DW, Fakhry C.
PMID: 29536542 | DOI: 10.1002/lary.27130

Abstract

OBJECTIVES/HYPOTHESIS:

Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) are distinct disease entities. Prognostic factors specific to each entity have not been adequately explored. Goals for this study were: 1) to determine whether HPV-positive and HPV-negative OPSCCs have distinct prognostic factors, and 2) to explore the prognostic significance of sex and race in OPSCC after HPV stratification STUDY DESIGN: Retrospective case series.

METHODS:

A retrospective review of 239 incident OPSCC patients from 1995 to 2012, treated at Johns Hopkins and University of California-San Francisco was conducted. Women and nonwhite races were oversampled. All analyses were stratified by tumor HPV in situ hybridization status. The effects of sex and race on survival were considered in Kaplan-Meier and unadjusted and adjusted Cox regression models.

RESULTS:

One hundred thirty-four (56.1%) OPSCC patients were HPV positive. On univariate analysis, women had better overall survival than men among HPV-positive (hazard ratio [HR]: 0.47, 95% confidence interval [CI]: 0.20-1.07; P = .06) but not HPV-negative (HR: 0.73, 95% CI: 0.43-1.24; P = .24) OPSCCs. On multivariate analysis, women with HPV-positive OPSCCs remained at lower risk of death (adjusted hazard ratio [aHR]: 0.34, 95% CI: 0.12-0.96; P = .04). Survival did not vary significantly by race among HPV-positive patients. Among HPV-negative patients, Hispanic patients had significantly better survival in unadjusted (HR: 0.27, 95% CI: 0.08-0.91; P = .04) but not adjusted (aHR: 0.93, 95% CI: 0.11-7.36; P = .94) analysis.

CONCLUSIONS:

Women with HPV-positive OPSCC may have improved overall survival compared to men. Sex does not play a prognostic role in HPV-negative OPSCC. There are no differences in prognosis by race among HPV-positive or HPV-negative patients.

[Uterine POLE mutant endometrioid carcinoma combined with human papilloma virus-associated cervical adenocarcinoma: A case report and literature review]

Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences

2023 Apr 18

Cao, F;Zhong, M;Liu, CR;
PMID: 37042153 | DOI: 10.19723/j.issn.1671-167X.2023.02.026

Independent primary uterine and cervical adenocarcinoma are rare and difficult to identify their origins, which makes treatment decision difficult. A 46-year-old female with endometrioid carcinoma and adenocarcinoma, human papilloma virus (HPV)-associated of the uterine cervix was reported. The patient presented with increased menstrual flow, contact bleeding and watery leucorrhea for more than one year, and the imaging findings showed abnormal uterine morphology, irregular margins, and multiple abnormal signals in uterine cavity and myometrium, which suggested multiple leiomyomas of the uterus. The signal intensity in the right muscle layer was markedly enhanced, suggesting a smooth muscle tumor of uncertain malignant potential. A large number of cystic hypointensity was seen in the cervix, and multiple cysts were considered. The initial preoperative diagnosis was multiple leiomyoma of the uterus, and a hysterectomy operation was planned. During the operation, the uterus was sent for frozen sections. There was a mass in the endometrium of the fundus, with a soft grayish-red cut surface and a clear border with the myometrium, and there was a grayish-white nodule in the cervix with a hard grayish-white cut surface. The two masses were well demarcated from each other, and the distance between them was 30 mm. The result of the frozen sections indicated the malignant tumor of the endometrium, and the extended hysterectomy+pelvic lymphadenectomy+partial resection of the greater omentum was performed. After the operation, the paraffin sections were sent to the Department of Pathology of the Peking University Third Hospital for histochemistry, POLE gene sequencing and HPV RNAscope tests, and the final diagnosis was a synchronous endometrioid carcinoma (POLE-mutant according to the WHO classification) and an adenocarcinoma, HPV-associated of the uterine cervix. Now the patient had been treated with 2 cycles of chemotherapy and her condition was fine. Through the analysis of the histological, immunohistochemical and molecular detection results of this case, the importance of applying HPV RNAscope and TCGA molecular typing in the diagnosis of cervical adenocarcinomas and endometrial carcinomas was emphasized. At the same time, gynecologists should not blindly rely on intraoperative frozen sections, and should pay attention to preoperative pathological examination, and make appropriate operation methods according to the results in order to prevent passivity in the surgery.

Squamous Cell Carcinoma of the Tongue in a Patient on Ustekinumab as the Treatment of Psoriasis

Clin Res Dermatol

2018 Aug 10

Chen HH, Wang CS.
PMID: - | DOI: 10.15226/2378-1726/4/3/00161

Ustekinumab is a human monoclonal antibody selectively targeting the shared p40 subunit of interleukin-12 (IL-12) and IL-23. Its efficacy for the treatment of psoriasis has been well documented in previous trials. We report a rare case of a patient who developed Squamous Cell Carcinoma (SCC) of the tongue after the commencement of ustekinumab as the treatment of plaque type psoriasis. To our knowledge, no link between ustekinumab and tongue SCC has been demonstrated before. Our report suggests that ustekinumab may induce the development of oral SCC in predisposed individuals.

SMARCB1 (INI-1)-deficient Sinonasal Carcinoma: A Series of 39 Cases Expanding the Morphologic and Clinicopathologic Spectrum of a Recently Described Entity.

Am J Surg Pathol.

2017 Apr 01

Agaimy A, Hartmann A, Antonescu CR, Chiosea SI, El-Mofty SK, Geddert H, Iro H, Lewis JS Jr, Märkl B, Mills SE, Riener MO, Robertson T, Sandison A, Semrau S, Simpson RH, Stelow E, Westra WH, Bishop JA.
PMID: 28291122 | DOI: 10.1097/PAS.0000000000000797

To more fully characterize the clinical and pathologic spectrum of a recently described tumor entity of the sinonasal tract characterized by loss of nuclear expression of SMARCB1 (INI1), we analyzed 39 SMARCB1-deficient sinonasal carcinomas collected from multiple medical centers. The tumors affected 23 males and 16 females with an age range of 19 to 89 years (median, 52). All patients presented with locally advanced disease (T3, n=5; T4, n=27) involving the sinuses (mainly ethmoid) with variable involvement of the nasal cavity. Thirty patients received surgery and/or radiochemotherapy with curative intent. At last follow-up, 56% of patients died of disease 0 to 102 months after diagnosis (median, 15), 2 were alive with disease, and 1 died of an unrelated cause. Only 9 patients (30%) were alive without disease at last follow-up (range, 11 to 115 mo; median, 26). The original diagnosis of retrospectively identified cases was most often sinonasal undifferentiated carcinoma (n=14) and nonkeratinizing/basaloid squamous cell carcinoma (n=5). Histologically, most tumors displayed either a predominantly basaloid (61%) or plasmacytoid/rhabdoid morphology (36%). The plasmacytoid/rhabdoid form consisted of sheets of tumor cells with abundant, eccentrically placed eosinophilic cytoplasm, whereas similar cells were typically rare and singly distributed in the basaloid variant. Glandular differentiation was seen in a few tumors. None of the cases showed squamous differentiation or surface dysplasia. By immunohistochemistry, the tumors were positive for pancytokeratin (97%), CK5 (64%), p63 (55%), and CK7 (48%); and they were negative for NUT (0%). Epstein-Barr virus and high-risk human papillomavirus was not detected by in situ hybridization. Immunohistochemical loss of SMARCB1 (INI1) expression was confirmed for all 39 tumors. Investigation of other proteins in the SWI/SNF complex revealed co-loss of SMARCA2 in 4 cases, but none were SMARCA4 deficient or ARID1A deficient. Of 27 tumors with SMARCB1 fluorescence in situ hybridization analysis, 14 showed homozygous (biallelic) deletions and 7 showed heterozygous (monoallelic) deletions. SMARCB1-deficient sinonasal carcinoma represents an emerging poorly differentiated/undifferentiated sinonasal carcinoma that (1) cannot be better classified as another specific tumor type, (2) has consistent histopathologic findings (albeit with some variability) with varying proportions of plasmacytoid/rhabdoid cells, and (3) demonstrates an aggressive clinical course. This entity should be considered in any difficult-to-classify sinonasal carcinoma, as correct diagnosis will be mandatory for optimizing therapy and for further delineation of this likely underdiagnosed disease.

Detection of HPV infection in head and neck squamous cell carcinoma: a practical proposal.

Virchows Archiv, 1–9.

Dreyer JH, Hauck F, Oliveira-Silva M, Barros MH, Niedobitek G. (2013).
PMID: 23503925 | DOI: 10.1007/s00428-013-1393-5.

Detecting human papillomavirus (HPV) infection in head and neck squamous cell carcinoma (HNSCC) is clinically relevant, but there is no agreement about the most appropriate methodology. We have studied 64 oropharyngeal carcinomas using p16 immunohistochemistry, HPV DNA in situ hybridisation (ISH) and HPV DNA polymerase chain reaction (PCR) followed by pyrosequencing. We have also evaluated a new assay, RNAscope, designed to detect HPV E6/E7 RNA transcripts. Using a threshold of 70 % labelled tumour cells, 21 cases (32.8 %) were p16 positive. Of these, 19 cases scored positive with at least one HPV detection assay. Sixteen cases were positive by HPV DNA-ISH, and 18 cases were positive using the E6/E7 RNAscope assay. By PCR and pyrosequencing, HPV16 was detected in 15 cases, while one case each harboured HPV33, 35 and 56. All p16-negative cases were negative using these assays. We conclude that p16 expression is a useful surrogate marker for HPV infection in HNSCC with a high negative predictive value and that p16-positive cases should be further evaluated for HPV infection, preferably by PCR followed by type determination. Using RNase digestion experiments, we show that the RNAscope assay is not suitable for the reliable discrimination between E6/E7 RNA transcripts and viral DNA.

Exposure to microbial metabolite butyrate prolongs the survival time and changes the growth pattern of HPV16 E6/E7-immortalized keratinocytes in vivo

The American journal of pathology

2021 Jun 29

Li, M;McGhee, EM;Shinno, L;Lee, K;Lin, YL;
PMID: 34214507 | DOI: 10.1016/j.ajpath.2021.06.005

Human papillomavirus (HPV) is a ubiquitous human pathogen that can be cleared by host immunity. Nonetheless, a small percentage of the patients develop persistent infection with oncogenic HPV, which poses an increased risk of developing HPV-associated malignancy. While cell-mediated immunity is a known systemic factor, local factors that influence persistent HPV infection have not been fully investigated. HPV-related head/neck cancers have a strong site preference for the oropharynx, suggesting the existence of unique local factors that promote HPV-induced oncogenesis. The human oropharynx often harbors anaerobic bacteria that produce a variety of byproducts, including butyrate. Because butyrate is a potent epigenetic modulator, it could be an environmental factor influencing the development of HPV-positive oropharyngeal malignancy. In this study, we showed that butyrate treatment changed the property of HPV16 E6/E7-immortalized keratinocytes. In vitro, the treatment increased the cells' migration ability, slowed the growth, and increased the genotoxic resistance. When implanted in the syngeneic mice, the treated keratinocytes survived longer and exhibited a different growth pattern. The survival advantage obtained after butyrate exposure potentially can increase the susceptibility of HPV-infected oropharyngeal keratinocytes to further malignant transformation. Our results suggest that tonsillar bacteria's fermentation products may play an important role in the long-term persistence of high risk-HPV infection, which is a critical risk factor for developing HPV-positive oropharyngeal malignancy.

Reprint of: Female Urethral Carcinoma: A contemporary review of the clinicopathologic features, with emphasis on the histo-anatomic landmarks and potential staging issues

Human pathology

2023 Mar 01

Lagarde-Lenon, MS;Aron, M;
PMID: 36894368 | DOI: 10.1016/j.humpath.2023.02.011

Primary female urethral carcinoma (PUC-F) accounts for less than 1% of all genitourinary malignancies and comprises a histologically diverse group of tumors that are usually associated with poor prognosis. The carcinomas documented at this site include adenocarcinoma (clear cell adenocarcinoma, columnar cell carcinoma, and Skene gland adenocarcinoma), urothelial carcinoma (UCa), and squamous cell carcinoma (SCC). Recent studies have shown adenocarcinomas to be the most common type of primary urethral carcinoma in females. As most of the urethral carcinomas morphologically resemble carcinomas arising from surrounding pelvic organs or metastases, these should be ruled out before making the diagnosis of PUC-F. These tumors are currently staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system. However, the AJCC system has limitations, including the staging of tumors involving the anterior wall of the urethra. Staging systems like the recently proposed histology-based female urethral carcinoma staging system (UCS) takes into account the unique histological landmarks of the female urethra to better stratify pT2 and pT3 tumors into prognostic groups, that correlate with clinical outcomes including recurrence rates, disease-specific survival and overall survival. Further larger multi-institutional cohorts are however required to validate the results of this staging system. There is very limited information regarding the molecular profiling of PUC-F. Thirty-one percent of clear cell adenocarcinomas have been reported to show PIK3CA alterations, whereas 15% of adenocarcinomas show PTEN mutations. Higher tumor mutational burden and PD-L1 staining have been reported in UCa and SCC. Although multimodality treatment is usually recommended in locally advanced and metastatic disease, the role of immunotherapy and targeted therapy is promising in select PUC-F cases.

Detection of human papillomavirus (HPV) in clinical samples: Evolving methods and strategies for the accurate determination of HPV status of head and neck carcinomas

Oral Oncology, 2014 - Elsevier

Westra WH
PMID: 24932529 | DOI: 10.1016/j.oraloncology.2014.05.004

Much recent attention has highlighted a subset of head and neck squamous cell carcinomas (HNSCCs) related to human papillomavirus (HPV) that has an epidemiologic, demographic, molecular and clinical profile which is distinct from non-HPV-related HNSCC. The clinical significance of detecting HPV in a HNSCC has resulted in a growing expectation for HPV testing of HNSCCs. Although the growing demand for routine testing is understandable and appropriate, it has impelled an undisciplined approach that has been largely unsystematic. The current state of the art has now arrived at a point where a better understanding of HPV-related tumorigenesis and a growing experience with HPV testing can now move wide scale, indiscriminant and non-standardized testing towards a more directed, clinically relevant and standardized approach. This review will address the current state of HPV detection; and will focus on why HPV testing is important, when HPV testing is appropriate, and how to test for the presence of HPV in various clinical samples. As no single test has been universally accepted as a best method, this review will consider the strengths and weaknesses of some of the more commonly used assays, and will emphasize some emerging techniques that may improve the efficiency of HPV testing of clinical samples including cytologic specimens.

The human Papillomavirus twilight zone- Latency, immune control and subclinical infection

Tumour virus research

2023 Jun 23

Doorbar, J;
PMID: 37354969 | DOI: 10.1016/j.tvr.2023.200268

The incorporation of HPV DNA testing into cervical screening programs has shown that many HPV-positive women are cytologically normal, with HPV-positivity fluctuating throughout life. Such results suggest that papillomaviruses may persist in a latent state after disease clearance, with sporadic recurrence. It appears that virus latency represents a narrow slot in a wider spectrum of subclinical and possibly productive infections. Clinical studies, and animal model infection studies, suggested a key role for host immune surveillance in maintaining such asymptomatic infections, and although infections may also be cleared, most studies have used the term 'clearance' to describe a situation where the presence of HPV DNA falls below the clinical detection level. Given our knowledge of papillomavirus immune evasion strategies and the restricted pattern of viral gene expression required for 'basal cell' persistence, the term 'apparent clearance' and 'subclinical persistence' of infection may better summarise our understanding. Subclinical infection also encompasses the lag phase, which occurs between infection and lesion development. This is dependent on infection titre, with multifocal infections developing more rapidly to disease. These concepts can usefully influence patient management where HPV-positivity occurs sometime after the onset of sexual activity, and where vertical transmission is suspected despite a lag period.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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