ANTICANCER RESEARCH 29: 2703-2706 (2009)

Clinical Characteristics of Laryngeal Cancer in BRCA-1 Mutation Carriers

EWA JAWOROWSKA1, CZESŁAWA TARNOWSKA1, JAKUB LUBIŃSKI1, PABLO SERRANO-FERNÁNDEZ2, TOMASZ HUZARSKI2, BOGDAN GÓRSKI2, BARTŁOMIEJ MASOJĆ2, JERZY JAKUBISZYN3, ALEKSANDRA KORYTOWSKA4, ANDRZEJ KRAM5, JERZY RABCZYNSKI6 and JAN LUBIŃSKI2

Departments of 1Otolaryngology and Laryngological Oncology, and 5Pathology, Pomeranian Medical University, 71-252 Szczecin; 2International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin; 3Department of Otolaryngology, District Hospital of Opole, 45-061 Opole; 4Department of Otolaryngology, District Hospital of Poznan, 60-479 Poznan; 6Department of Pathomorphology, Silesian Piasts University of Medicine, 50-368 Wrocław, Poland

Abstract. Background: The aim of this study was to analyze mutation carriers show a moderately increased probability of the occurrence of clinical features characteristic of breast developing cancer of several other organs including the colon, cancer type 1 susceptibility protein (BRCA-1)-dependent pancreas, prostate and stomach (3-6). Very few cases of tumors in a series of BRCA-1 mutation carriers with laryngeal cancer among BRCA-1 carriers have been reported, laryngeal cancer. Patients and Methods: The clinical features a situation that does not allow a definite conclusion on the of five laryngeal cancer patients with BRCA-1 mutations association between mutations and risk of cancer of the registered in our center were analyzed for: sex, age at larynx (4, 5, 7-9). In this paper, the potential association diagnosis, age at operation, tumor size and localization, between BRCA-1 mutation and laryngeal cancer was analyzed histopathological subtype and grading, lymph node and by checking the occurrence of clinical features characteristic distant metastases, mode of treatment and long term results of BRCA-1 dependent tumors in a series of laryngeal of the therapy. Results: The five patients were all men, with carcinomas from BRCA-1 families registered in our center. an average age at diagnosis of 52.4 years. The majority of the patients had clinical features typical of BRCA-1- Patients and Methods dependent tumors: four out of the five patients had advanced Patients. The clinical features of five patients were analyzed. Two staging at the time of diagnosis and in three of them the of them (1, 2) were identified by genotyping 430 unselected disorder disseminated within one year of follow-up. consecutive patients affected by laryngeal cancer diagnosed at the Conclusion: Since laryngeal carcinomas in men with BRCA- Department of Otolaryngology and Laryngological Oncology in 1 mutations show clinical features characteristic of BRCA-1 Szczecin (Poland) from 2001 to 2006. dependent tumors, it is reasonable to consider treatment An additional group of three laryngeal cancer patients (3-5) was modifications appropriate for this sub-group of tumors. collected from a general database of BRCA-1 mutation carriers at the International Hereditary Cancer Center (IHCC), Pomeranian Medical University, Szczecin, Poland. The patients in that database Breast cancer type 1 susceptibility protein (BRCA-1) were selected based on their familial relationship with patients mutations are associated with a very high risk of carcinomas affected by other types of cancer. Thus, they cannot be regarded of the breast and ovaries (1-2). Additionally, BRCA-1 either as consecutive or as unselected. The DNA obtained from peripheral blood was screened at the International Hereditary Cancer Center for the occurrence of at least one of the three constitutional BRCA-1 mutations dominant in Correspondence to: Ewa Jaworowska, Department of Otolaryngology Poland, C61G, 4153delA and 5382insC, covering over 90% of all and Laryngological Oncology, Pomeranian Medical University, ul. BRCA-1 mutations in Poland. Further details are described in Unii Lubelskiej 1, 71-252 Szczecin, Poland. Tel/Fax: +48 914253277, reports by Górski et al. (10, 11). e-mail: [email protected] The clinical characteristics were recorded for all five laryngeal cancer patients who were carriers of a BRCA-1 mutation. These Key Words: Laryngeal cancer, BRCA-1 mutation. included: sex, age at diagnosis, age at operation, tumor size and

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Table I. Clinical characteristics of laryngeal carcinomas in men with constitutional BRCA-1 mutations.

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Characteristic

BRCA1 Mutation C61G C61G C61G 5382insC 5382insC Age at diagnosis (years) 56 45 58 48 55 Tumor localization Supraglottis Supraglottis Glottis Glottis Glottis Tumor size T3 T4 T3 T3 T1** Lymph node metastases N2 N3 N0 N0 N0 Distant metastases M0 M0 M0* M0 M0 Grading 2/3 2/3 2 2 1 Proliferative rate*** 20 45 30 15 - Stage IV IV III III I Therapy TL, Radio TL, Radio TL, Chem* TL, Radio PL Laser

TL (Total laryngectomy), PL (partial laryngectomy), Radio (radiotherapy), Laser (laser therapy), Chem (chemotherapy), *chemotherapy after partial lobectomy, **reoperation (laserotherapy), ***number of mitoses per 10 fields 10×40. localization, clinical staging, histopathological subtype and grading, Discussion lymph node and distant metastases, mode of treatment and long- term results of the therapy. The present study is, to our knowledge, the first analysis of the clinical features of laryngeal carcinomas among carriers Results of BRCA-1 mutations. Thus, this series of a few cases is actually unique. The clinical and genetic characteristics are summarized in The clinical features typical for BRCA-1-dependent breast Table I. and ovarian carcinomas were found also in the majority of the BRCA-1 mutation C61G was detected in 3 patients (1-3) laryngeal carcinomas in the men with constitutional BRCA-1 and 5382insC in 2 patients (4, 5). All five patients were men, mutations. The carcinomas were characterized by earlier than with an average age at diagnosis of 52.4 years (range 45-58). average onset and aggressive progression. The average age at In all the cases squamous cell carcinomas of the larynx was diagnosis among the BRCA-1 carriers was 52.4 years in diagnosed. contrast to 58.3 years among unselected carcinoma of the In four out of the five patients (1-4) the tumor was larynx cases (12). Four out of the five patients had advanced already advanced at the time of diagnosis (stage III or IV). staging at the time of diagnosis and three of them developed Two of the patients (1, 2) showed postoperative local lymph disseminated disorders within one year of follow-up. node metastasis and despite combined therapy including The histopathological grading was described as 2/3 in two total laryngectomy, neck dissection to remove the local cases and as 2 in another two cases, however, in all of the lymph nodes and postoperative radiotherapy, both died tumors the pathologists reported a high proliferative rate of within one year after operation due to generalization of the 15-45 mitoses per 10 fields 10×40. malignancy. Knowledge of the spectrum of tumors associated with One patient (3) had a tumor of size T3 without lymph node BRCA-1 constitutional mutations has potentially great clinical metastases, however, 6 months after laryngectomy, a relevance. It has been well proven that BRCA-1 mutation metastasis in the right lung was detected. For this reason he carriers need special programs of prevention, surveillance and was subjected to a partial lobectomy and postoperative treatment for breast and ovarian cancer (13, 14). Especially chemotherapy (methotrexate). This patient has been regularly noteworthy and promising is the very high rate of complete monitored (for 6 months to date) without any recurrences. remissions of breast carcinomas in females with BRCA-1 One patient (4) also showed a tumor of size T3 without mutations following treatment with cis-platinum (15-17). lymph node metastases. After total laryngectomy and postoperative radiotherapy, he has been free of recurrences Conclusion for the last seven years. One patient (5) had a tumor of size T1 without lymph Laryngeal carcinomas in men with BRCA-1 mutation show node metastases, however after a first partial laryngectomy clinical features which are also characteristic of other tumors with laserotherapy, a new tumor was detected after six years in carriers of these mutations, thus it is reasonable to consider and the patient had to be subjected to a second partial treatment modifications for them such as participation in laryngectomy with laser therapy. clinical trials of monotherapy using cis-platinum.

2704 Jaworowska et al: Laryngeal Cancer with BRCA-1 Mutation

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