Neurofibromatosis type 1, gastrointestinal stromal tumor, leiomyosarcoma and osteosarcoma: Four cases of rare tumors and a review of the literature

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Abstract

Background

Neurofibromatosis type 1 (NF1) is a genetic syndrome that predisposes patients to benign and malignant tumor development. Patients with NF1 develop multiple neurofibromas that can transform into aggressive sarcomas known as malignant peripheral nerve sheath tumors. In contrast, malignant tumors unrelated to the nervous system rarely coexist with neurofibromatosis. The aim of this article was to present four cases of adult NF1 patients with malignant tumors unrelated to the nervous system as well as a bibliographic search for papers describing these tumors in NF1, focusing on osteosarcomas, gastrointestinal stromal tumors (GISTs), leiomyosarcomas and somatostatinomas and their genetic alterations in NF1.

Methods

Search engines such as PubMed and MEDLINE were browsed for English-language articles since 1989 using a list of keywords, as well as references from review articles. Search terms were NF1, osteosarcoma, leiomyosarcoma, somatostatinoma and GIST. Data were summarized in a table at the end of the Results section.

Results

In our four NF1 cases, there were one osteosarcoma, one leiomyosarcoma, one somatostatinoma and GIST and one GIST. NF1 was diagnosed at an adult age when these patients were admitted to our oncology department. The results generated by the literature search yielded 75 articles about NF and GIST. We summarized the clinical characteristics of 43 patients with NF1 and somatostatinoma. Forty-five articles involving NF and osteosarcoma were found, and of these, 26 involved NF1; from these articles, we identified the clinical features of 8 patients. Twenty-five articles were found concerning NF1 and leiomyosarcoma, and of those, we summarized the clinical features of 15 patients.

Conclusions

Here we reviewed somatostatinomas, GISTs, osteosarcomas and leiomyosarcomas occurring in NF1 patients. Patients with NF1 who present with gastrointestinal symptoms, should be carefully evaluated carefully with a high index of suspicion of potential GISTs, periampullary and duodenal tumors. Patients with pathological fractures or bone pain along with NF1 should be carefully screened for malignant bone tumors. Patients with NF1 can develop leiomyosarcoma less frequently than other malignancies, but the association of uterine leiomyoma and NF1 may not be fortuitous. Somatic mutations were defined for frequent tumors, including neurogenic tumors and GISTs but not for sarcomas due to the complexity of underlying mechanisms of the disease and tumorigenesis. Based on the findings; all NF patients can develop malignant tumors, including the less frequently observed ones. Therefore, we recommend that new genetic studies should be performed for rare malignancies in cases of NF1.

Introduction

NF1, or von Recklinghausen disease, is an autosomal dominant genetic disorder caused by mutations in the neurofibromin 1 gene, which encodes the tumor suppressor neurofibromin [1], [2]. NF1 is the most frequent subtype of neurofibromatosis (approximately 97% of NF patients), with an incidence of approximately 1 in 3500 live births [3].

NF1 is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple discrete dermal neurofibromas, and iris hamartomas known as Lisch nodules. Less commonly observed (but potentially more serious) manifestations of the disease include plexiform neurofibromas, optic and other central nervous system gliomas, malignant peripheral nerve sheath tumors (MPNST), vasculopathy, and osseous lesions. Bone dysplasia results in scoliosis [4], [5]. Neurological symptoms observed in NF1 include epilepsy, intellectual disability and difficulty learning. The diagnostic criteria for NF1 were defined by the NIH Consensus Development Conference in 1988 (Table 1).

The pathological manifestations of NF1 are extremely variable, even within a family. Mutations result in a predisposition to developing a variety of tumors of the central and peripheral nervous systems, as well as other malignancies. However, the occurrence of malignant tumors unrelated to the nervous system is rare [6]. GISTs, somatostatinomas, periampullary tumors, breast cancer, pheochromocytomas, and less frequently, soft tissue sarcomas (STS) and leukemia–myelodysplasia syndrome, are all observed in adults with NF1 [7], [8], [9]. NF1 patients have a high risk of developing STS, and particularly malignant peripheral nerve sheath tumors, often with aggressive clinical presentation and poor outcome [10]. In the literature, there is one report of a patient with NF1 who simultaneously, had polymyositis, asymptomatic pheochromocytoma, and primary hepatic leiomyosarcoma [11].

NF1-associated GISTs are not very rare, but account for less than 5% of all GISTs reported. NF1 patients are at higher risk for developing GISTs than the general population [12]. GISTs in NF1 patients have a high prevalence in the small intestine [13], [14].

Section snippets

Methods

Publications were identified by browsing search engines such as PubMed and MEDLINE for English-language articles since 1989 using a list of keywords; as well as identifying references from review articles. The following keywords were used for searching databases: NF1, osteosarcoma, leiomyosarcoma and GIST. Data were summarized as a table at the end of results. We evaluated four cases of NF1 with rare malignancies by searching patients’ folders, and treatment strategies were discussed. Possible

Patient 1

In our first patient; we report an unusual case of osteosarcoma, a high-grade malignant bone tumor, arising in the femur of an NF1 patient. The patient was a 17-year-old man who had café-au-lait spots and neurofibromatosis of the skin over his whole body, with von Recklinghausen disease (NF1) diagnosed by the authors. One of his brothers was also diagnosed with NF1 in our clinic. There was a consanguineous marriage between his parents. At the age of 16, he underwent marginal excision of a 2 × 1 cm

Results

We have summarized four patients with NF1 and rare tumors. The first patient presented with osteosarcoma of the femur at a very young age. In the literature there were 45 articles concerning NF and osteosarcoma; and there were 26 articles about NF1 and osteosarcoma. We searched the full text of 8 articles and identified patient characteristics. Age, sex, clinical manifestation, tumor size, therapy, other associated tumors (if present) and follow-up of osteosarcoma patients are summarized in

Discussion and literature review

Patients with NF1 are predisposed to the development of benign and malignant neoplasms, particularly those of neurogenic or neuroendocrine origin [18]. Zöller et al. reported a fourfold increase in the risk of developing a malignancy in patients with NF1 (24%); when compared to the general population [19]. While the identification of somatic mutations in NF1 patients has been problematic due to the extensive cellular heterogeneity of neurofibromas, the classification of NF1 somatic mutations is

Conclusion

In summary, we have reviewed GISTs, somatostatinomas, osteosarcomas, and leiomyosarcomas occurring in NF1 patients. Patients with NF1 who present with gastrointestinal symptoms; should be evaluated for typical causes, with increased suspicion toward potential periampullary and duodenal tumors. Patients who have pathologic fractures with NF1 should be carefully evaluated for malignant bone tumors. Patients with NF1 can develop leiomyosarcoma less frequently than other malignancies. As a result;

Reviewers

Dr Sven-Petter Haugvik, Department of Gastrointestinal Surgery, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, NO-0027 Oslo, Norway.

Assoc Professor Raffaele Virdis, University Hospital of Parma, Parma, Italy.

Professor Bernard Guillot, Hôpital Saint-Eloi (Montpellier), Dermatology, 80 Ave Augustin Fliche, F-34295 Montpellier, Cedex 5, France.

Dr Usul Afsar was born in İstanbul, Turkey, in 1978. She has graduated from Beyoğlu Anatolian High School, which is an English High School, with the third highest degree in 1995. She then attended the İstanbul University, Cerrahpasa Medical Faculty, from 1995 to 2001 and graduated with the second highest degree. From 2002 to 2004, she worked at İstanbul University, Cerrahpasa Medical Faculty, Department of Pharmacology and Clinical Pharmacology. From 2004 to 2010, she had her resident education

References (49)

  • F.M. Enzinger et al.

    Neurofibromatosis

    Soft tissue tumors

    (1995)
  • E. Bień et al.

    Therapeutic difficulties in soft tissue sarcoma occurring in children with neurofibromatosis type 1-own observations

    Medycyna Wieku Rozwojowego

    (2008)
  • A. Ferrari et al.

    Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1

    Cancer

    (2007)
  • K. Maruta et al.

    A patient with von Recklinghausen's disease associated with polymyositis, asymptomatic pheochromocytoma, and primary hepatic leiomyosarcoma

    Nippon Ronen Igakkai Zasshi – Japanese Journal of Geriatrics

    (2004)
  • M. Miettinen et al.

    Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis

    Archives of Pathology and Laboratory Medicine

    (2006)
  • M. Miettinen et al.

    Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases

    American Journal of Surgical Pathology

    (2006)
  • J. Andersson et al.

    NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics

    American Journal of Surgical Pathology

    (2005)
  • F.E. Eckhauser et al.

    Somatostatinoma

    Pancreas

    (1998)
  • Z.D. Goodman et al.

    Somatostatinoma of the cystic duct

    Cancer

    (1984)
  • N. Kluger et al.

    Pelvic mass in von Recklinghausen's neurofibromatosis: diagnostic issues: a case report

    Cases Journal

    (2009)
  • J.L. Ricci

    Carcinoid of the ampulla of Vater. Local resection or pancreaticoduodenectomy

    Cancer

    (1993)
  • M.E. Zöller et al.

    Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population

    Cancer

    (1997)
  • U. Cinamon et al.

    Neurofibromatosis type 1, hyperparathyroidism, and osteosarcoma: interplay?

    European Archives of Otorhinolaryngology

    (2002)
  • M. Hatori et al.

    Osteosarcoma in a patient with neurofibromatosis Type 1: a case report and review of the literature

    Tohoku Journal of Experimental Medicine

    (2006)
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    Dr Usul Afsar was born in İstanbul, Turkey, in 1978. She has graduated from Beyoğlu Anatolian High School, which is an English High School, with the third highest degree in 1995. She then attended the İstanbul University, Cerrahpasa Medical Faculty, from 1995 to 2001 and graduated with the second highest degree. From 2002 to 2004, she worked at İstanbul University, Cerrahpasa Medical Faculty, Department of Pharmacology and Clinical Pharmacology. From 2004 to 2010, she had her resident education in Internal Medicine Clinic at Ministry of Health, İstanbul Education and Research Hospital. Since 2010, she has been working at Cukurova University Medical Faculty, Department of Medical Oncology. She is still pursuing her education. She is interested in breast cancer, colorectal carcinoma, malign melanoma and rare cancers. Her research studies on these cancers are still ongoing. She had studied colorectal carcinomas as a fellow for 3 days at Ospedale San Martino, Medical Oncology Unit, Genova, Italy with Professor Alberto Sobrero in May 2012 with the group of Accademia Oncologica from Turkey.

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