Detection of serum biomarkers of HPV-16 driven oropharynx and oral cavity cancer in Brazil.

BACKGROUND: HPV-16 driven oropharynx/oral cavity squamous cell carcinomas prevalence varies globally. We evaluated the presence of HPV-16 ctDNA and HPV-16 E6 antibodies in samples obtained from participants treated at the Instituto do Cancer do Estado de Sao Paulo, ICESP, and from whom tumoral HPV DNA, HPV-16 E6*I mRNA, and p16INK4a status was also accessed. METHODS: HPV was genotyped by PCR-hybridization. All HPV DNA positive and ∼10 % HPV DNA negative cases underwent p16INK4a immunohistochemistry and E6*I RNA testing using a multiplex bead based protocol. HPV-16 ctDNA and anti-E6 antibodies were assessed by ddPCR (digital droplet PCR) and multiplex serology, respectively. RESULTS: The prevalence of HPV-16 in oropharynx carcinoma (OPC) cases was low (8.7 %) when considering solely HPV-16 DNA detection, and even lower (5.2 %) when taken into consideration the concomitant detection of HPV-16 E6*I RNA and/or p16INK4 (HPV-16 attributable fraction - AF). None of the oral cavity cancer (OCC) cases were detected with HPV-16 DNA. HPV-16 ctDNA was more commonly detected than HPV-16 E6 antibodies (29.8 % versus 10.6 %). Both serum biomarkers attained 100 % sensitivity of detecting HPV-16 AF OPC, however the specificity of the HPV-16 anti-E6 biomarker was higher compared to ctDNA (93.2 % versus 75.0 %). Finally, when both HPV-16 ctDNA and anti-E6 biomarkers were considered together, the sensitivity and specificity for HPV-16 OPC detection was 100 % and about 70 %, respectively, independently of analyzing HPV-16 DNA positive or HPV-16 AF tumors. CONCLUSIONS: Our findings corroborate that serum biomarkers are highly sensitive and specific biomarkers for detection of HPV-associated OPC.

Cumulative Coffee Consumption as a Protective Factor for Head and Neck Cancer in Brazil.

There is still no consensus in the literature regarding the role of coffee in head and neck cancer. Thus, we sought to analyze the cumulative consumption of coffee as a protective factor in the genesis of head and neck cancer in Brazil, one of the main coffee producing countries, from January 2011 to February 2017. We carried out a case-control study in 5 referral centers for head and neck cancer with 839 cases and 842 non-cancer hospital controls matched by sex, data collection center and age group. The results of logistic regression analysis showed that the cumulative consumption of >2 cups of coffee per day is an important protective factor (OR: 0.73, 95% CI: 0.5-0.9) against head and neck cancer. Smoking increased the risk by 22 times (OR: 22.19; 95% CI: 13.7-35.8) in individuals who smoke more than 50 packs per year, and the habit of ingesting more than 155 ml of alcohol per day represented approximately twice as high risk (OR: 2.20; 95% CI: 1.4-3.4). In summary, this study suggests that coffee consumption is associated with a lower chance of head and neck cancer.

JMJD1A, H3K9me1, H3K9me2 and ADM expression as prognostic markers in oral and oropharyngeal squamous cell carcinoma.

AIMS: Jumonji Domain-Containing 1A (JMJD1A) protein promotes demethylation of histones, especially at lysin-9 of di-methylated histone H3 (H3K9me2) or mono-methylated (H3K9me1). Increased levels of H3 histone methylation at lysin-9 (H3K9) is related to tumor suppressor gene silencing. JMJD1A gene target Adrenomeduline (ADM) has shown to promote cell growth and tumorigenesis. JMJD1A and ADM expression, as well as H3K9 methylation level have been related with development risk and prognosis of several tumor types. METHODS AND RESULTS: We aimed to evaluate JMJD1A, ADM, H3K9me1 and H3K9me2expression in paraffin-embedded tissue microarrays from 84 oral and oropharyngeal squamous cell carcinoma samples through immunohistochemistry analysis. Our results showed that nuclear JMJD1A expression was related to lymph node metastasis risk. In addition, JMJD1A cytoplasmic expression was an independent risk marker for advanced tumor stages. H3K9me1 cytoplasmic expression was associated with reduced disease-specific death risk. Furthermore, high H3K9me2 nuclear expression was associated with worse specific-disease and disease-free survival. Finally, high ADM cytoplasmic expression was an independent marker of lymph node metastasis risk. CONCLUSION: JMJD1A, H3K9me1/2 and ADM expression may be predictor markers of progression and prognosis in oral and oropharynx cancer patients, as well as putative therapeutic targets.

Epidermolytic Hyperkeratosis - case report

Abstract: Epidermolytic hipercetarose is a rare genodermatosis, with a prevalence of 1:100.000 to 1:300.000, with autosomal dominant inheritance. We report the case of a 5 year old girlwho presented an hypertrophic verrucous plaques in the neck, under arm, buttocks, knees, pelvis, legs, dorsum of the right foot and elbows. Histological examination of the skin lesions showed typical changes of epidermolytic hyperkeratosis. Because it is an autosomal dominant disorder with complete penetrance, the individual carrying the mutation will necessarily develop the disease. However, in 50% of cases postzygotic mutation occur. The case report emphasizes early diagnosis and differential diagnoses with ichthyosis and other bullous diseases of childhood, as well as discussing the therapeutic possibilities.

Extracranial neurogenic tumors of the head and neck, / Tumores neurogênicos extracranianos na cabeça e pescoço

ABSTRACT INTRODUCTION: Peripheric nerve tumors typically derive from Schwann cells of the peripheral nerve sheet. Since these tumors are uncommon, they should be considered in preoperative differential diagnosis. OBJECTIVE: To report the experience of a tertiary care department. METHODS: Forty-two patients with head and neck peripheral neurogenic tumors were retrospectively analyzed and evaluated from 1977 to 2013. The preoperative diagnosis was confirmed by biopsy or imaging study. RESULTS: The mean age was 41.7 and 15 patients (36%) were male. The mean size was 5.5 cm and 26 (61%) were located laterally in the neck. Most tumors (39.9%) presented as an asymptomatic neck mass. Most (39.9%) were resected through a neck approach. Cranial nerves were the commonest site of origin. CONCLUSIONS: Extracranial neurogenic tumors presented with a mean size of 5.5 cm, were located laterally in the neck, normally had their origin from cranial nerves, and their resection approach is cervical.

Resumo INTRODUÇÃO: Tumores dos nervos periféricos tipicamente derivam das células de Schwann da bainha dos nervos periféricos. Por serem incomuns, devem ser lembrados no diagnóstico diferencial pré-operatório. OBJETIVO: Relatar a experiência de serviço de referencia terciária. MÉTODO: De 1977 a 2013, 42 pacientes com tumores neurogênicos periféricos da cabeça e pescoço foram operados e analisados retrospectivamente. A confirmação diagnóstica pré-operatória deu-se por biópsia ou método de imagem. RESULTADOS: A média da idade foi de 41,7 anos, sendo 15 indivíduos (36%) do gênero masculino. O tamanho médio foi de 5,5 cm e 26 (61%) localizavam-se na face lateral do pescoço. A maior parte (39,9%) apresentou-se como tumor palpável assintomático. A maioria (39,9%) foi ressecadapor acesso cervical. A maioria originou-se de nervos cranianos. CONCLUSÕES: Tumores neurogênicos extracranianos apresentam-se com tamanho médio de 5,5 cm, na face lateral do pescoço, costumam originar-se de nervos cranianos e ser ressecados por via cervical.

Extracranial neurogenic tumors of the head and neck.

INTRODUCTION: Peripheric nerve tumors typically derive from Schwann cells of the peripheral nerve sheet. Since these tumors are uncommon, they should be considered in preoperative differential diagnosis. OBJECTIVE: To report the experience of a tertiary care department. METHODS: Forty-two patients with head and neck peripheral neurogenic tumors were retrospectively analyzed and evaluated from 1977 to 2013. The preoperative diagnosis was confirmed by biopsy or imaging study. RESULTS: The mean age was 41.7 and 15 patients (36%) were male. The mean size was 5.5cm and 26 (61%) were located laterally in the neck. Most tumors (39.9%) presented as an asymptomatic neck mass. Most (39.9%) were resected through a neck approach. Cranial nerves were the commonest site of origin. CONCLUSIONS: Extracranial neurogenic tumors presented with a mean size of 5.5cm, were located laterally in the neck, normally had their origin from cranial nerves, and their resection approach is cervical.

Epidermolytic Hyperkeratosis--case report.

Epidermolytic hipercetarose is a rare genodermatosis, with a prevalence of 1:100.000 to 1:300.000, with autosomal dominant inheritance. We report the case of a 5 year old girl who presented an hypertrophic verrucous plaques in the neck, under arm, buttocks, knees, pelvis, legs, dorsum of the right foot and elbows. Histological examination of the skin lesions showed typical changes of epidermolytic hyperkeratosis. Because it is an autosomal dominant disorder with complete penetrance, the individual carrying the mutation will necessarily develop the disease. However, in 50% of cases postzygotic mutation occur. The case report emphasizes early diagnosis and differential diagnoses with ichthyosis and other bullous diseases of childhood, as well as discussing the therapeutic possibilities.

FAS/FASL expression profile as a prognostic marker in squamous cell carcinoma of the oral cavity.

FAS/FASL altered expression may cause tumor protecting immunomodulation, with a direct impact on patient prognosis. FAS expression was studied in 60 squamous cell carcinomas of the oral cavity. FAS expression did not show a significant association with tumor histopathological characteristics, but was significantly associated with lymph node positivity. FAS expression was significantly associated with disease specific death and negative FAS expression was an independent risk factor, increasing risk 4 times when compared to positive expression. When FAS and FASL expression results were combined, we were able to define high, intermediate and low risk profiles. Disease-free and disease-specific survival were significantly correlated with FAS/FASL expression profiles. The high risk category was an independent marker for earlier disease relapse and disease-specific death, with approximately 4- and 6-fold increased risk, respectively, when compared to the low risk profile. Risk profiles based on FAS/FASL expression showed that high risk was significantly associated with increased disease relapse and death, as well as shorter disease-free or disease-specific survival. This categorization, added to patient clinical data, may facilitate the choice of therapy, minimizing treatment failure and increasing disease control.

FGFR4 profile as a prognostic marker in squamous cell carcinoma of the mouth and oropharynx.

BACKGROUND: Fibroblast growth factor receptor 4 (FGFR4) is a member of a receptor tyrosine kinase family of enzymes involved in cell cycle control and proliferation. A common single nucleotide polymorphism (SNP) Gly388Arg variant has been associated with increased tumor cell motility and progression of breast cancer, head and neck cancer and soft tissue sarcomas. The present study evaluated the prognostic significance of FGFR4 in oral and oropharynx carcinomas, finding an association of FGFR4 expression and Gly388Arg genotype with tumor onset and prognosis. PATIENTS AND METHODS: DNA from peripheral blood of 122 patients with oral and oropharyngeal squamous cell carcinomas was used to determine FGFR4 genotype by PCR-RFLP. Protein expression was assessed by immunohistochemistry (IHC) on paraffin-embedded tissue microarrays. RESULTS: Presence of allele Arg388 was associated with lymphatic embolization and with disease related premature death. In addition, FGFR4 low expression was related with lymph node positivity and premature relapse of disease, as well as disease related death. CONCLUSION: Our results propose FGFR4 profile, measured by the Gly388Arg genotype and expression, as a novel marker of prognosis in squamous cell carcinoma of the mouth and oropharynx.

HIF1-alpha expression predicts survival of patients with squamous cell carcinoma of the oral cavity.

BACKGROUND: Oral squamous cell carcinoma is an important cause of death and morbidity wordwide and effective prognostic markers are still to be discovered. HIF1α protein is associated with hypoxia response and neovascularization, essential conditions for solid tumors survival. The relationship between HIF1α expression, tumor progression and treatment response in head and neck cancer is still poorly understood. PATIENTS AND METHODS: In this study, we investigated HIF1α expression by immunohistochemistry in tissue microarrays and its relationship with clinical findings, histopathological results and survival of 66 patients with squamous cell carcinoma of the lower mouth. RESULTS: Our results demonstrated that high HIF1α expression is associated with local disease-free survival, independently from the choice of treatment. Furthermore, high expression of HIF1α in patients treated with postoperative radiotherapy was associated with survival, therefore being a novel prognostic marker in squamous cell carcinoma of the mouth. Additionally, our results showed that MVD was associated with HIF1α expression and local disease relapse. CONCLUSION: These findings suggest that HIF1α expression can be used as a prognostic marker and predictor of postoperative radiotherapy response, helping the oncologist choose the best treatment for each patient.

[Neck skin collision tumor]. / Tumor de colisão de pele do pescoço.

The collision or mixed tumor is a malignant neoplasm of the skin related to sun exposure and incidence rates of up to 1.5%. It displays a distinctive clinical behavior in relation to other malignancies of the skin and the histological diagnosis, characterized by the collision between a basal cell carcinoma and squamous cell carcinoma, i.e., two malignancies with distinct histologies and sharp interface between them. The case reported was of a male, 73-year-old patient, with two cervical lesions progressively growing in recent months. The chosen treatment was surgery. Histological examination showed the presence of squamous cell carcinoma adjacent to basal cell carcinoma. These tumors preferentially occur in light-skinned men in the fifth or sixth decades of life. Their most common location is in the head and neck, especially in the central part of the face. The differential diagnosis of basal-squamous carcinoma is defined by distinct histological criteria, since both tumors have similar clinical behavior. Local recurrence rates vary from 12% to 45%, whereas regional ones are of approximately 7.5%. The main prognostic factors are gender, surgical margins, perineural infiltration and lymph node status. The treatment of choice is resection, radiotherapy being indicated as adjuvant or to inoperable lesions. Local recurrence is the main limiting factor in disease-free survival, with poor results.

Tumor de colisão de pele do pescoço / Neck skin collision tumor

O tumor de colisão ou tumor misto é uma neoplasia maligna de pele, relacionada à exposição solar e com índices de incidência de até 1,5 por cento. Apresenta comportamento clínico peculiar, em relação às demais neoplasias malignas de pele e com diagnóstico histológico, caracterizado pela colisão entre um carcinoma basocelular e um carcinoma epidermóide, ou seja, duas neoplasias com histologias distintas e interface nítida entre ambas. O caso relatado foi de paciente do sexo masculino, 73 anos, com duas lesões cervicais de crescimento progressivo nos últimos meses. O tratamento realizado foi cirúrgico, com exame histológico demonstrando a presença de carcinoma de células escamosas contíguo ao carcinoma de células basais. O acometimento preferencial ocorre em homens de pele clara, na quinta ou sexta décadas de vida. Sua localização mais comum é na cabeça e pescoço, principalmente na parte central da face. O carcinoma basoescamoso é diagnóstico diferencial, definido através de critérios histológicos distintos, uma vez que ambas neoplasias apresentam comportamento clínico semelhante. Os índices de recidiva local variam de 12 por cento a 45 por cento, enquanto que é baixo na recidiva regional, de aproximadamente 7,5 por cento. Os principais fatores prognósticos são o gênero do paciente, margens cirúrgicas, infiltração perineural e status linfonodal. O tratamento de escolha é a ressecção, sendo a radioterapia indicada na sua adjuvância e lesões irressecáveis. A recidiva local é o principal fator limitante na sobrevida livre de doença que apresenta resultados pobres.

The collision or mixed tumor is a malignant neoplasm of the skin related to sun exposure and incidence rates of up to 1.5 percent. It displays a distinctive clinical behavior in relation to other malignancies of the skin and the histological diagnosis, characterized by the collision between a basal cell carcinoma and squamous cell carcinoma, i.e., two malignancies with distinct histologies and sharp interface between them. The case reported was of a male, 73-year-old patient, with two cervical lesions progressively growing in recent months. The chosen treatment was surgery. Histological examination showed the presence of squamous cell carcinoma adjacent to basal cell carcinoma. These tumors preferentially occur in light-skinned men in the fifth or sixth decades of life. Their most common location is in the head and neck, especially in the central part of the face. The differential diagnosis of basal-squamous carcinoma is defined by distinct histological criteria, since both tumors have similar clinical behavior. Local recurrence rates vary from 12 percent to 45 percent, whereas regional ones are of approximately 7.5 percent. The main prognostic factors are gender, surgical margins, perineural infiltration and lymph node status. The treatment of choice is resection, radiotherapy being indicated as adjuvant or to inoperable lesions. Local recurrence is the main limiting factor in disease-free survival, with poor results.

Case for diagnosis: (unilateral multiple piloleiomyoma).

Piloleiomyoma is a benign neoplasm arising from the erector pilorum muscle in the skin. It occurs in young adults of both genders. Lesions can be single or multiple and more frequently involve extremities. Pain may occur spontaneously or after physical stimulation. We describe a case of unilateral multiple piloleiomyoma in a young woman, complaining of itching lesions.

Caso para diagnóstico / Case for diagnosis

O piloleiomioma é uma neoplasia benigna originada do músculo eretor do pelo. Atinge adultos jovens, sem predileção por sexo. As lesões podem ser solitárias ou múltiplas, acometem mais frequentemente as extremidades e costumam apresentar dor espontânea ou após estímulos físicos. Descreve-se um caso de piloleiomioma múltiplo unilateral em paciente jovem do sexo feminino, com queixa de prurido nas lesões.

Piloleiomyoma is a benign neoplasm arising from the erector pilorum muscle in the skin. It occurs in young adults of both genders. Lesions can be single or multiple and more frequently involve extremities. Pain may occur spontaneously or after physical stimulation. We describe a case of unilateral multiple piloleiomyoma in a young woman, complaining of itching lesions.

How useful is the assessment of lymphatic vascular density in oral carcinoma prognosis?

BACKGROUND: Lymphatic vessels are major routes for metastasis in head and neck squamous cell carcinoma (HNSCC), but lymphatic endothelial cells (LECs) are difficult to recognize in tumor histological sections. D2-40 stains podoplanin, a molecule expressed in LECs, however, the potential prognostic usefulness of this molecule is not completely understood in HNSCC. We aimed to investigate the value of assessing peritumoral and intratumoral lymphatic vessel density (LVD) as prognostic marker for HNSCC. METHODS: Thirty-one cases of HNSCC were stained for D2-40 and CD31. LVD and blood vessel density (BVD) were assessed by counting positive reactions in 10 hotspot areas at x200 magnification. RESULTS: D2-40 was specific for lymphatic vessels and did not stain blood vascular endothelial cells. LECs showed more tortuous and disorganized structure in intratumoral lymphatic vessels than in peritumoral ones. No statistical differences were observed between peritumoral-LVD and intratumoral-LVD or between peritumoral-BVD and intratumoral-BVD. Tumor D2-40 staining was positively associated with lymphatic vessel invasion (p = 0.011). CONCLUSION: LVD is a powerful marker for HNSCC prognosis. We found significant differences in peritumoral and intratumoral D2-40 immunoreactivity, which could have important implications in future therapeutic strategies and outcome evaluation.

Padrão da disseminação regional linfática do carcinoma espinocelular da orofaringe / Pattern of distribution of cervical lymph node metastases in oropharyngeal squamous cell carcinoma

Introdução: o desenvolvimento de metástases para os linfonodos cervicais é o fator de maior impacto no prognóstico do carcinoma da orofaringe. Durante quase toda a segunda metade do século 20, o planejamento terapêutico do carcinoma da orofaringe incluía o tratamento radical (cirúrgico ou radioterápico) dos territórios de drenagem regional. Atualmente, é crescente a tendência à redução da extensão do esvaziamento cervical (EC), mesmo nos casos de linfonodos clinicamente positivos. Objetivo: avaliar o padrão e distribuição de metástases para linfonodos cervicais no carcinoma espinocelular (CEC) de orofaringe na busca do fundamento histopatológico para os EC seletivos. Casuística e Método: noventa e dois pacientes com CEC de orofaringe, submetidos a EC, no Serviço de Cirurgia de Cabeça e Pescoço do Complexo Hospitalar Heliópolis, entre 1994 e 2004, foram estudados retrospectivamente. Os blocos parafinados foram recuperados e as lâminas revistas por duas patologistas. Todos os pacientes receberam tratamento cirúrgico no primário e no pescoço, com intenção curativa. Os sítios da lesão primária eram a loja tonsilar (65 casos ? 70,65%), base de língua (16 casos - 17,39%), valécula (6 casos - 6,52%) e palato mole (5 casos - 5,43%). Realizou-se um total de 114 EC. O EC foi ipsilateral ou bilateral, sendo terapêutico foi realizado em 63 e oito pescoços e eletivo em 29 e 12 pescoços, no lado, respectivamente. A radioterapia pós-operatória foi indicada em 65% dos pacientes. Resultados: dos 92 pacientes, 66 (71,7%) apresentaram metástase linfonodal comprovada pelo exame histopatológico (pN+). Em lesões da loja tonsilar houve comprometimento dos linfonodos em 70,8% dos casos (19/46), na base da língua 77,3% (17/22) e no palato mole 60% (3/5) dos casos. Houve uma taxa de metástase oculta de 46,7% e de falso-positivos de 22,9%. O nível II estava comprometido em 96% dos casos N positivos. Observamos o comprometimento do nível I em apenas seis casos, todos de loja tonsilar e, em quatro deles, a mucosa oral estava envolvida pela lesão. O nível IV estava comprometido em 12 casos e todos apresentaram comprometimento conjunto de outros níveis. Em casos clinicamente N0, a incidência de metástase linfonodal para o nível I foi de 10% e para o nível IV foi de 3,3%. Em casos clinicamente N+, a incidência de metástase linfonodal para o nível I foi de 4,8% e para o nível IV de 17,8%. Conclusão: nos pacientes com CEC de orofaringe, o tratamento do pescoço N0 deve incluir os níveis I a III. O nível IV deve ser incluído quando houver comprometimento linfonodal dos níveis II ou III.

Introduction: the development of lymph node metastases is the most important prognostic factor in oropharyngeal carcinoma. During the second half of 20th Century the management of oropharyngeal carcinoma always included the radical treatment (by surgery or radiation therapy) of the neck. Nowadays there is a tendency to reduce the extension of the neck dissection even in cases with clinically positive lymph nodes. Objective: to evaluate the pattern of distribution of lymph node metastases in oropharynx squamous cell carcinoma (SCC) to justify the indication of selective neck dissection (ND). Materials and methods: data of 92 patients with oropharyngeal SCC who underwent ND, treated at the Head and Neck Surgery Service, Heliópolis Hospital, between 1994 and 2004 were retrospectively studied. The histological slides were reviewed by two pathologists. All patients underwent curative intent surgery on the primary site and neck. The primary sites were tonsilar fossa (65 cases - 70.65%), base of tongue (16 cases ? 17.39%), valeculla (6 cases - 6.52%) and soft palate (5 cases - 5.43%). A total of 114 ND were performed. Therapeutic ND (ipsilateral and contralateral, respectively) was performed in 63 and 8 necks, and elective ND in 29 and 12 necks. Postoperative radiation therapy was indicated in 65% of the cases. Results: Sixty-six patients (71.7%) had histological proven lymph node metastases (pN+). In the tonsilar fossa tumors, there were lymph node metastases in 70.8% of the cases (19/46), in base of tongue 77.3% (17/22) and in soft palate, 60% (3/5). There were occult metastases in 46.7% and 22.9% of false-positives. Level II was compromised in 96% of cases. Involvement of level I was observed in only 6 cases, all with primary tumor in tonsilar fossa and in 4, oral mucosa was involved by the tumor. Level IV was compromised in 12 cases and all of them had simultaneous involvement of other levels. In N0 cases the incidence of lymph node metastases to level I was 10% and to level IV was 3.3%. In N+ cases these incidences were 4.8% and 17.8% respectively. Conclusion: the treatment of N0 neck in oropharyngeal carcinoma should include levels I to III. Level IV have to be included when levels II or III are compromised.