Prognostic Markers and Driver Genes and Options for Targeted Therapy in Human-Papillomavirus-Positive Tonsillar and Base-of-Tongue Squamous Cell Carcinoma.

The incidence of Human-papillomavirus-positive (HPV+) tonsillar and base-of-tongue squamous cell carcinoma (TSCC and BOTSCC, respectively) is increasing epidemically, but they have better prognosis than equivalent HPV-negative (HPV-) cancers, with roughly 80% vs. 50% 3-year disease-free survival, respectively. The majority of HPV+ TSCC and BOTSCC patients therefore most likely do not require the intensified chemoradiotherapy given today to head and neck cancer patients and would with de-escalated therapy avoid several severe side effects. Moreover, for those with poor prognosis, survival has not improved, so better-tailored alternatives are urgently needed. In line with refined personalized medicine, recent studies have focused on identifying predictive markers and driver cancer genes useful for better stratifying patient treatment as well as for targeted therapy. This review presents some of these endeavors and briefly describes some recent experimental progress and some clinical trials with targeted therapy.

HPV-related papillary squamous cell carcinoma of the tonsil during treatment with fingolimod.

Fingolimod is a commonly used treatment for highly active relapsing-remitting multiple sclerosis (MS). We describe the case of a 50-year old man on fingolimod since 2011 who presented, in April 2017, with a voluminous swelling of the left tonsil. A left tonsillectomy was performed, and histological exam disclosed a papillary squamous cell carcinoma of the palatine tonsil, with an in situ hybridization positive for human papillomavirus (HPV)-16 DNA. Neither lymph nodes involvement nor other metastases were detected. Fingolimod was stopped as a precautionary measure in May 2017, and the patient currently continues his follow up at our Department. Immunocompromised patients are at risk for developing HPV-related malignancies probably in light of the suppression of T-cell immunity, therefore an increased risk for HPV activation in MS patients treated with disease modifying therapies (DMTs) characterized by a more pronounced immunosuppressant activity cannot be excluded. Given the absence of studies on larger cohorts of MS patients exposed to DMTs, additional monitoring for HPV infection during fingolimod treatment is not currently recommended. However, vigilance for this possible association is warranted.

Human polyomavirus and human papillomavirus prevalence and viral load in non-malignant tonsillar tissue and tonsillar carcinoma.

Human papillomaviruses (HPVs) are an acknowledged cause of a subset of oropharyngeal cancers, especially of tonsillar cancer. Similar to HPV, some human polyomaviruses (HPyVs), such as Merkel cell polyomavirus (MCPyV), have an oncogenic potential. Recently, several novel HPyVs have been discovered. The aim of our study was to determine viral DNA prevalence and viral DNA load of 13 different HPyVs in benign and malignant tonsillar tissue and to compare the data with those found for HPV. A total of 78 biopsies of palatine tonsils with a histologic diagnosis of non-malignant disease (chronic tonsillitis, tonsillar hyperplasia, n = 40) or tonsillar squamous cell carcinoma (n = 38) were included in the study. HPyV DNA prevalence and viral load were determined by virus-specific quantitative real-time PCRs. JCPyV (1/40, 2.5%) and WUPyV (3/40, 7.5%) were only found in non-malignant tonsillar tissue. HPyV7 and HPyV10 were only detected in one (2.6%) and seven (18.4%) of the 38 cancer biopsies, respectively. Both MCPyV (8/38, 21.1 vs. 4/40, 10.0%) and HPyV6 (2/38, 5.3 vs. 1/40, 2.5%) were found more frequently in cancer samples than in non-malignant tissue, but the differences were not significant. BKPyV, KIPyV, TSPyV, HPyV9, STLPyV, HPyV12 and NJPyV were not discovered in any of the samples. HPyV loads found in HPyV DNA-positive biopsies were very low with no difference between non-malignant and malignant samples (median load <0.0001 HPyV DNA copies per beta-globin gene copy, respectively). In contrast to HPyV, high-risk HPV types (HPV16/HPV18) were found significantly more frequently in tonsillar cancers than in non-malignant tonsillar tissue (17/38, 44.7 vs. 2/40, 5.0%, p < 0.001). Furthermore, high-risk HPV DNA loads were significantly higher in the cancer compared to the non-malignant samples (median load 11.861 vs. 7 × 10-6 HPV DNA copies per beta-globin gene copy, p = 0.012). While both HPV and HPyV may persist in tonsillar tissue, our data on HPyV DNA prevalence and load do not support a role of HPyV in tonsillar carcinogenesis, neither alone nor as co-infecting agents of HPV.

Association between unilateral tonsillar enlargement and lymphoma in children: A systematic review and meta-analysis.

Lymphoma is the most common head and neck malignancy in children, and palatine tonsils asymmetry is the most frequent clinical manifestation of tonsillar lymphoma. However, several studies with children with tonsillar asymmetry found no case of lymphoma, showing that the relationship of tonsillar asymmetry with lymphoma is unclear. In this review, we aimed to identify the association between tonsillar asymmetry and tonsillar lymphoma in children by conducting systematic reviews of the literature on children with palatine tonsil lymphoma and tonsillar asymmetry. Articles comprising the paediatric age group (up to 18 years) with information concerning clinical manifestations of tonsillar lymphoma or the diagnosis of the tonsillar asymmetry were included. The main cause of asymmetry of palatine tonsils was lymphoid hyperplasia, followed by lymphoma and nonspecific benign changes. The asymmetry of tonsils was present in 73.2% of cases of lymphoma. There was an association between asymmetric palatine tonsils and lymphoma, with a likelihood ratio of 43.5 for children with asymmetry of palatine tonsils and 8938.4 for children with asymmetry of tonsils and other signs of suspicion for malignancy. We also provide recommendations on the management of suspicious cases of palatine tonsil lymphoma.

Human papillomavirus, smoking status and outcomes in tonsillar squamous cell carcinoma.

It is now clear that the two separate entitles of tonsillar cancer, HPV induced and non-HPV induced (smoking induced), have significantly different presenting stage and outcomes. A significant proportion of patients with human papillomavirus positive tonsillar cancer have had exposure to smoking. We examined the combined effect of human papillomavirus and smoking on the outcomes and determined whether smoking can modify the beneficial effect of human papillomavirus. A total of 403 patients from nine centers were followed up for recurrence or death for a median of 38 months. Determinants of the rate of loco-regional recurrence, death from tonsillar cancer and overall survival were modeled using Cox regression. Smoking status was a significant predictor of overall survival (p = 0.04). There were nonstatistically significant trends favoring never smokers for loco-regional recurrence and disease specific survival. In addition, there was no statistically significant interactions between smoking and human papillomavirus (p-values for the interaction were 0.26 for loco-regional recurrence, 0.97 for disease specific survival and 0.73 for overall survival). The effect of smoking on loco-regional recurrence and disease specific survival outcomes was not statistically significant, nor was there significant evidence that the effect of smoking status on these outcomes was modified by HPV status. Irrespective of HPV status, however, smokers did have poorer overall survival than never-smokers, presumably due to effects of smoking that are unrelated to the primary cancer.

Solitary plasmacytoma of the tonsillar site associated with actinomyces infection: the possible role of IL-6.

ExtraMedullary Plasmacytoma (EMP) is a rare plasma cell tumor. It can occur in the upper aerodigestive tract and presents as a large nodule causing local compressive symptoms. A 79-year old woman presented to Otorhinolaryngology Department with progressive hearing loss and no other symptoms. Following PET/TC examination due to the suspicion of a lymphoproliferative disease, the patient underwent tonsillectomy and the diagnosis of solitary EMP was formulated. In addition to that, the histological examination of the tonsillar tissue revealed large colonies of filamentous bacteria, showing abundant sulphur granules and Splendore-Hoeppli phenomenon; these evidences indicating the presence of a chronic Actinomyces infection. Immunohistochemical analysis demonstrated a marked IL-6 immunoreactivity of the neoplastic plasma cells. Interestingly, a marked IL-6 immunoreactivity was also found in the tissue surrounding the Actinomyces colonies. In the present study we report for the first time a solitary EMP associated with Actinomycosis. It is tempting to speculate that the unsuspected and untreated Actinomyces infection, through chronic IL-6 production, could contribute to the neoplastic transformation of plasma cells.

Palatine tonsillar metastasis of lung cancer during chemotherapy.

Malignant tumors in the tonsils are usually primary. Metastases to the tonsils are extremely rare, with nearly one hundred cases reported. Herein we present an unusual case of palatine tonsillar metastasis of non-small cell lung cancer during chemotherapy. The patient was a 39-year-old man who was diagnosed as non-small lung cancer with IIIA4 staging and poor differentiated histology. After two cycles of vinorelbine and cisplatin based chemotherapy, a big mass was developed in the right palatine tonsil which was pathologically confirmed as the metastasis from the lung. There was no hemorrhage and complains except moderate foreign body sensations. No cervical lymphadenopathy and distal metastases to other organs such as brain and liver was found. Because of poor overall performance status, no radiotherapy was given. The disease progressed after docetaxel treatment. To the best of our knowledge, this is the first case with palatine tonsillar metastasis from non-small lung cancer during induction chemotherapy.

Gender and ethnic disparities in incidence and survival of squamous cell carcinoma of the oral tongue, base of tongue, and tonsils: a surveillance, epidemiology and end results program-based analysis.

BACKGROUND: Squamous cell carcinomas (SCC) of the oral tongue (OT) and of the base of the tongue and tonsils (BTT) differ with respect to etiology, treatment and prognosis. Human papillomavirus has been linked to the increased incidence of BTT, yet, the trends in incidence of BTT and OT tumors among gender and ethnic origin groups have not been well examined. We sought to examine the trend in gender-, ethnic origin- and age-specific incidence of these tumors over time. METHODS: Data were obtained from the Surveillance, Epidemiology and End Results Program of the US National Cancer Institute. We examined temporal trends in sex- and ethnic origin-specific incidence of SCC by calculating the annual percent changes followed by joinpoint analyses evaluating changes in trend. RESULTS: While BTT increased in age-adjusted rates among white males with a more pronounced increase observed in the mid-1990s, white females experienced a significant increase in incidence of OT tumors. Patients with advanced OT carcinoma had a significantly lower survival compared to those with advanced BTT disease; however, patients with early-stage OT tumors had a better survival compared to patients with BTT. CONCLUSIONS: While the increase in incidence of BTT tumors in white men is likely human papillomavirus driven, more studies are needed to elucidate the increasing incidence of OT tumors in white women. The differences in outcomes across ethnic origin groups are also described and discussed.

Tonsillary carcinoma after temozolomide treatment for glioblastoma multiforme: treatment-related or dual-pathology?

Glioblastoma multiforme is a primary malignant brain tumor with a prognosis of typically less than 2 years. Standard treatment paradigms include surgery, radiation therapy and temozolomide. Little data exists for temozolomide recommendations after the first 6 months. We present a case of a patient with glioblastoma multiforme treated with surgery, radiation and chronic temozolomide for 6 years. He continues to survive glioblastoma-recurrence-free, but developed tonsillary carcinoma. This case raises the question of whether this secondary solid-organ malignancy is treatment-related or dual pathology.

Human papillomavirus infection and oral cancer: a case-control study in Montreal, Canada.

The objective of the present study was to examine the association between human papillomavirus (HPV) infection and risk of developing oral cancer. The investigation followed a hospital-based case-control design. Cases consisted of newly diagnosed patients with squamous cell carcinoma of the oral cavity and oropharynx. Controls were frequency matched to cases on gender, age, and hospital. Subjects were interviewed to elicit information on putative risk factors. Oral exfoliated cells were tested for detection of HPV DNA by the PGMY09/11 polymerase chain reaction protocol. Serum antibodies against HPV 16, 18, and 31 viral capsids were detected using an immunoassay technique. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) of oral cancer according to HPV exposure variables. HPV DNA was detected in 19% of cases (14 out of 72), and 5% of controls (six out of 129). Among tonsil-related cancers (palatine tonsil and base of tongue) viral DNA was detected in 43% of cases (nine out of 21). The OR for tonsil-related cancers for high-risk HPV types was 19.32 (95%CI: 2.3-159.5), after adjustment for socio-demographic characteristics, tobacco, and alcohol consumption. The equivalent OR for HPV 16 seropositivity was 31.51 (95%CI: 4.5-219.7). The ORs of non-tonsillar oral cancers for high risk HPV DNA in oral cells and for seropositivity were 2.14 (95%CI: 0.4-13.0) and 3.16 (95%CI: 0.8-13.0), respectively. These results provide evidence supporting a strong causal association between HPV infection and tonsil-related cancers. The evidence for an etiologic link is less clear for non-tonsillar oral cancers.

Two types of squamous cell carcinoma of the palatine tonsil characterized by distinct etiology, molecular features and outcome.

To determine whether human papillomaviruses (HPV) positive tonsillar squamous cell carcinoma (SCC) represent a specific entity, we studied the prevalence of HPV association and of tobacco/alcohol exposure in a series of 52 cases of tonsillar SCC cases. p53, p16, and pRb levels, deregulated by viral oncoproteins were assessed. Forty patients reported tobacco/alcohol exposure, 10 reported no exposure. HPV DNA was found in 32/52 (62%) cases, (HPV16 genotype in 27). All patients with no history of tobacco-alcohol exposure presented HPV positive tumor (p=0.0008). A strong correlation was observed between positive HPV status, decrease in pRB and increase in p16 expression level. 5 year overall survival rate was higher in HPV16 positive patients than in HPV negative (71% versus 36%; p=0.023). HPV status remained a significant prognostic factor in multivariate analysis. Tonsillar SCC can thus be divided in HPV positive and negative subgroups with different oncogenesis and response to treatment.

The site of infection and ethnicity of the patient influence the biological pathways to HPV-induced mucosal cancer.

High-risk human papillomaviruses are the causative agents of cervical cancer and are also believed to be aetiologically involved in a subset of squamous cell carcinomas of the head and neck region, especially the tonsil. Cervical cancers arise through disruption of the pathways of p53 and the product of the retinoblastoma gene by the human papillomavirus oncoproteins E6 and E7. It is generally assumed that the same pathways are involved in human papillomavirus-induced carcinogenesis at other mucosal surfaces. However, the patterns of expression of cell cycle proteins targeted by human papillomavirus E6 and E7 in cancers from different anatomic sites have been inconsistent, due to either biologic or technological factors. In this study, 73 human papillomavirus, 16-positive cervical squamous cell carcinomas (35 from Australian and 38 from Chinese women) were analysed for the expression of p53, pRb, p16(INK4A), p21(CIP1/WAF1), p27(KIP1) and cyclin D1 by semiquantitative immunohistochemistry. Cervical cancers from Chinese women were found to be significantly more likely to overexpress p53, pRb, p21 and p27 than their Australian counterparts. These findings were compared with those from 31 human papillomavirus 16-positive tonsillar squamous cell carcinomas, all of Australian origin, tested using the same methodology. Comparisons of the tonsillar and combined cervical data showed that tonsillar cancers were significantly more likely to be p53-positive, whereas cervical cancers were significantly more likely to overexpress pRb, p16 and p27. When the tonsillar data were compared with cervical data from Australian women, the associations for p53 and pRb remained. These findings represent new evidence that the molecular pathways to human papillomavirus-induced mucosal cancer may be influenced by anatomic location and ethnicity.

Epstein-Barr virus and human papillomavirus infections and oropharyngeal squamous cell carcinomas.

Epstein-Barr virus (EBV) and human papillomavirus (HPV) are known to exhibit oncogenic potential. Target cells for both viruses include oropharyngeal elements. The present study investigated whether EBV or HPV infection are associated with palatine tonsil carcinoma (PTC) and/or tongue carcinoma (TC). The study included 28 adult patients with oropharyngeal squamous cell carcinoma, including 14 patients with PTC and 14 patients with TC. The control group included 20 healthy adult volunteers. Sera of all patients and controls were tested for IgG anti-EA antibodies, IgG anti-VCA antibodies, and IgG anti-EBNA antibodies. DNA extracted from the tumors was tested for the presence of EBV DNA and HPV DNA using PCR-ELISA. In parallel, the presence of EBV DNA was tested in the peripheral blood in all healthy individuals and patients. In addition, attempts were made to detect HPV 16 and HPV 18 using other PCR amplification techniques. Serum anti-EBV antibodies were detected in 24 patients (12 patients with PTC and 12 patients with TC). The frequency of detection of the antibodies did not significantly differ between the groups of patients and the control individuals. Most positive patients and controls demonstrated a serological pattern typical for past EBV infection. EBV DNA was identified in 12 cases of PTC and in 12 cases of TC (altogether 86% cases). In 10 PTC patients, 8 TC patients, and only 2 healthy individuals EBV DNA was detected in peripheral blood. HPV DNA was detected in only 3 cases (1 sample of PTC and 2 samples of TC). These results suggest that the etiopathogenesis of oropharyngeal cancers may be associated with EBV infection much more frequently than with HPV infection.

[Localized recurrence of acute lymphoblastic leukemia-L3 in the tonsil after 3-years' remission].

Recurrence of Burkitt's lymphoma (BL)/acute lymphoblastic leukemia (ALL)-L3 after a long-term remission is very rare. We herein report on a case of BL/ALL-L3 indicating solitary recurrence in the tonsil after a 3-year remission. A 50-year-old man was diagnosed as having Burkitt's type ALL-L3 with involvement of the stomach and abdominal lymph nodes. He was treated with intensive chemotherapy consisting of methotrexate and cyclophosphamide (ALL-BFM86 protocol), and a complete remission was achieved. After sustaining the remission for three years, a swelling of the right tonsil was observed, which was histologically diagnosed as Burkitt's lymphoma. No other organ involvement, including the bone marrow, was observed. The pattern of c-myc rearrangement of the tonsil demonstrated by southern blotting was identical to that of the bone marrow at initial presentation and the recurrence of primary ALL-L3/BL was thus confirmed. The patient was then treated with the ALL-BFM86 protocol and subsequently underwent high-dose chemoradiotherapy with autologous peripheral blood stem cell transplantation (PBSCT). He has now been in complete remission for more than 2 years after his PBSCT.

Post-transplant lymphoproliferative disease in tonsils of children with liver transplantation.

OBJECTIVE: To assess the incidence and characteristics of post-transplant lymphoproliferative disease (PTLD) in tonsils of the liver transplanted children. METHODS: All patients under 14 years of age recipients of a liver transplant at the institution and operated on for tonsillectomy under suspicion of malignancy were included in this study. RESULTS: Seven patients underwent surgery on their tonsils under suspicion of PTLD. One case of B-cell lymphoma, and three cases of polymorphic diffuse B-cell hyperplasia were found. This represents an incidence of 1.4% of PTLD in the tonsils of the 283 pediatric liver transplants performed at the hospital. CONCLUSION: The incidence of PTLD in tonsils after liver transplantation is very low at the institution. However, it is very important to follow-up allograft recipients for early diagnosis of this entity.

[The role of Epstein-Barr virus (EBV) infection in carcinogenesis of palatine tonsil carcinoma (PTC)]. / Rola wirusa Epsteina-Barr (EBV) w karcinogenezie u chorych na raka migdalka podniebiennego.

OBJECTIVES: Casual link of Epstein-Barr Virus (EBV) and endemically manifesting nasopharyngeal carcinoma has been already well documented. Our study, conducted in Karol Marcinkowski University of Medical Sciences in Poznan, aimed at examining whether EBV infection occurs also in patients with another tumor, palatine tonsil malignant neoplasms. METHODS: The studies were performed on 20 patients, aged 32 to 80 years, in whom tonsil malignencies was diagnosed by histological methods. The treatment of choice was surgery. Sera of the patients was tested for EBV DNA (Sharp Signal System; Digene), IgM-anti-EBV antibodies (Behring), IgG-anti-EA antibodies (ETI-EA-G; Dia Sorin) and IgG-anti-VCA antibodies (ETI-VCA-G; Dia Sorin). RESULTS: Serological exponents of reactivated EBV infection (serum IgG-anti-EA and IgG-anti-VCA antibodies) were observed in 12 patients. In parallel, ten of the patients demonstrated EBV DNA. In the remaining 8 patients, three manifested past EBV infection (positive IgG-anti-VCA) and five probed to be EBV negative. CONCLUSIONS: The results indicated, that tonsil malignancies may be associated with EBV infection.

Risk of malignant neoplasms in patients with pulmonary sarcoidosis.

BACKGROUND: For over 20 years the association between sarcoidosis and malignancy, particularly lymphoma and lung cancer, has been disputed with misclassification being the major concern. The aim of the present study was to analyse the incidence of malignancies in a cohort of patients with sarcoidosis by linkage to a nationwide population based cancer register. METHODS: The cohort comprised 254 patients followed for a median of 25 years until death, emigration, or 31 December 1992, whichever came first. The expected number of cancer cases was calculated using the annual age and sex specific cancer rates from the Danish Cancer Registry. RESULTS: Thirty six cancers were registered, three of which were misclassified as sarcoidosis, leaving 33 cancers compared with 23 expected (standardised incidence ratio (SIR) = 1.4; 95% CI 0.99 to 2.0). Five lung cancers were observed compared with 2.5 expected, yielding an SIR of 2.0 (95% CI 0.7 to 4.7). There was no incidence of lymphoma and only one case of leukaemia. There was a significant excess number of pharyngeal cancers based on two cases (SIR = 15.4; 95% CI 1.7 to 56). CONCLUSIONS: This study does not support the theory of an association between sarcoidosis and malignancy, and the main reason other studies have shown such an association is most likely to have been due to selection bias and misclassification.