Squamous Cell Carcinomas of the Head and Neck in Fanconi Anemia: Risk, Prevention, Therapy, and the Need for Guidelines

 

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Abstract

Fanconi anemia (FA) is a rare recessive DNA repair disorder that is clinically characterized by congenital malformations, progressive bone marrow failure, and increased incidence of malignancies, especially acute myeloid leukemia and squamous cell carcinomas of the head and neck (HNSCCs) and the anogenital regions. On a cellular level, typical features of the disorder are a high degree of genomic instability and an increased sensitivity to bi-functionally alkylating agents. So far, germ-line defects in 15 different FA genes have been identified. Some of these FA genes are also established as tumor susceptibility genes for familiar cancers.

In recent years, the prevention and therapy of HNSCCs in FA patients has become more important as the percentage of patients surviving into adulthood is rising. HNSCCs appear in very young FA patients without common risk factors. Since cisplatin-based chemotherapy in combination with radiotherapy, essential parts of the standard treatment approach for sporadic HNSCCs, cannot be used in FA patients due to therapy-associated toxicities and mortalities even with reduced dosing, surgery is the most important treatment option for HNSCCs, in FA patients and requires an early and efficient detection of malignant lesions. So far, no uniform treatment protocol for the management of HNSCCs in FA patients exists. Therefore, we propose that the information on affected FA patients should be collected worldwide, practical therapeutic guidelines developed and national treatment centers established.

Zusammenfassung

Die Fanconi-Anämie (FA) ist eine seltene rezessive DNA-Reparaturerkrankung, die klinisch durch angeborene Fehlbildungen, fortschreitendes Versagen des Knochenmarks und ein frühzeitiges und vermehrtes Auftreten von bösartigen Erkrankungen – insbesondere AML und Plattenepitelkarzinome in der Kopf-Hals-Region (HNSCCs) und ano-genitalen Bereich – charakterisiert ist. Auf zellulärer Ebene prägen eine hohe genetische Instabilität und eine erhöhte Sensitivität gegenüber kreuzvernetzenden Substanzen die Erkrankung. Bisher wurden Keimbahnmutationen in 15 FA-Genen identifiziert, wobei einige FA-Gene identisch mit bekannten Suszeptibilitätsgenen für familiäre Tumorerkrankungen sind.

In den letzten 10 Jahren hat der Anteil der FA-Patienten, die bis ins Erwachsenenalter überlebt, deutlich zugenommen. Bei diesen Patienten treten HNSCCs sehr früh und häufig ohne die üblichen Risikofaktoren auf. Cisplatin-basierte Chemotherapie in Kombination mit Bestrahlung, die bei sporadischen HNSCCs Therapiestandard ist, kann selbst mit reduzierter Dosis bei FA-Patienten aufgrund der assoziierten Toxizität und Mortalität nicht angewendet werden. Deshalb ist die chirurgische Tumorentfernung die wichtigste Therapieoption bei FA-Patienten, die allerdings eine effiziente Früherkennung der malignen Läsionen voraussetzt. Da derzeit kein einheitliches Diagnostik- und Therapieoptimierungsprotokoll für HNSCCs bei FA-Patienten existiert, sind Informationen von betroffenen Patienten weltweit zu sammeln, therapeutische Leitlinien zu entwickeln und nationale Behandlungszentren zu etablieren.

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