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

Critical Reviews in Oncology/Hematology 86 (2013) 191–199 Neurofibromatosis type 1, gastrointestinal stromal tumor, leiomyosarcoma and osteosarcoma: ...
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Critical Reviews in Oncology/Hematology 86 (2013) 191–199

Neurofibromatosis type 1, gastrointestinal stromal tumor, leiomyosarcoma and osteosarcoma: Four cases of rare tumors and a review of the literature C ¸ i˘gdem Usul Afs¸ar a,∗ , ˙Ismail O˘guz Kara a , Banu Kara Kozat b , Haluk Demiryürek c , Berna Bozkurt Duman a , Figen Doran d b

a Cukurova University Medical Faculty, Department of Medical Oncology, Adana, Turkey Adana Numune Education and Research Hospital, Department of Gastroenterology, Adana, Turkey c Cukurova University Medical Faculty, Department of General Surgery, Adana, Turkey d Cukurova University Medical Faculty, Department of Pathology, Adana, Turkey

Accepted 8 November 2012

Contents 1. 2. 3.

4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Patient 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Patient 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Patient 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Patient 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion and literature review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

192 192 192 192 193 193 193 193 196 197 197 198 199

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. ∗

Corresponding author. Tel.: +90 3223386060x3143. E-mail address: [email protected] (C ¸ .U. Afs¸ar).

1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2012.11.001

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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. © 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Neurofibromatosis type 1; GIST; Somatostatinoma; Osteosarcoma; Leiomyosarcoma

1. 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 [7–9]. NF1 patients have a high risk of developing STS, and particularly malignant peripheral nerve Table 1 Diagnostic criteria for NF1 as defined by the NIH Consensus Development Conference in 1988 [49]. -6 or more café-au-lait spots (>0.5 cm in children or >1.5 cm in adults) -2 or more cutaneous/subcutaneous neurofibromas or one plexiform neurofibroma -Axillary or groin freckling -Optic pathway glioma -2 or more Lisch nodules (iris hamartomas observed on slit lamp examination) -Bony dysplasia (sphenoid wing dysplasia, bowing of long bone, pseudarthrosis) -First degree relative with NF1

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].

2. 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 genetic alterations in these tumors were evaluated. Two of the cases evaluated had G˙ISTs, one had osteosarcoma and one had leiomyosarcoma. Pathology reports of these patients were assessed at the same hospital; Cukurova University of Medicine, Adana, Turkey.

3. Clinical material 3.1. 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 soft tissue mass in the left neck region. Histological findings from

C ¸ .U. Af¸sar et al. / Critical Reviews in Oncology/Hematology 86 (2013) 191–199

the resected specimen were consistent with neurofibroma. At age 17, he had a pathologic fracture in the femur. Magnetic resonance imaging (MRI) revealed extraskeletal growth of a tumor, and he underwent wide excision of the tumor attached to the femoral cortex followed by vascular reconstruction. Postoperative chemotherapy was performed using “CYVADIC” (cyclophosphamide, vincristine, doxorubicin, and dacarbazine). The patient is still alive. 3.2. Patient 2 A 51-year-old man who suffered from abdominal discomfort was found to have a tumor of the papilla of Vater, based on gastroduodenal endoscopy. The patient appeared in good health. A right subcostal scatris as well as multiple soft skin tumors and café-au-lait spots were observed over his entire body. Leucocytosis, significant increases in parameters of liver function (especially ALP, GGT), and mild increases in calcitonin and parathyroid hormone levels were detected, but there were no abnormal findings with respect to tumor markers. On his computed tomography (CT) scan, dilatation was observed in both the common and intrahepatic bile ducts, but there was no evidence of any tumor in the head of the pancreas. There was distributed contrast passage in the second duodenal part. Numerous submucosal tumors were observed in the duodenum; and jejunum on the endoscopy, and the patient had undergone a Whipple procedure with resection of the jejunal submucosal tumors. The tumor of the papilla of Vater had the histologic appearance of a dense proliferation of tumor cells in acinar form, from the duodenal mucosa to the muscle layer. Immunohistologically, the tumor cells stained intensely positive for somatostatin. The submucosal tumors of the duodenum and jejunum were positive for smooth muscle actin (SMA), s100, and CD34 and c-kit. They were diagnosed as GISTs. The patient was treated with imatinib and remains in his follow-up period. 3.3. Patient 3 A 55-year-old hypertensive woman who suffered from dyspnea; had undergone an echocardiography and was diagnosed with mitral stenosis. In her preoperative examination, multiple masses were found in the liver. Upon biopsy, malignant mesenchymal neoplasia; with leiomyosarcoma was detected and stained positive for vimentin, SMA and demsin. Multiple café-au-lait spots, neurofibromas in the left thigh, back and abdomen were found during physical examination. Levels of tumor markers in the blood, such as CEA, CA 15-3 and CA 19-9, were normal. A PET-CT scan, revealed multiple hypermetabolic lesions in the liver; and a hypermetabolic nodular lesion in the right inguinal region. Gastroscopy and colonoscopy results were normal. She had 7 pregnancies; 6 were alive, and one was dead. Upon diagnosis of metastatic leiomyosarcoma, she was treated with cisplatin and doxorubicine chemotherapy. She had diarrhea

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and febrile neutropenia once and died 1 year after diagnosis. 3.4. Patient 4 A 51-year-old man with NF1 suffered from abdominal discomfort, and had a history of previously experienced gastrointestinal bleeding three times. He had undergone a gastroenterostomy 3 years ago. On his new abdominal and pelvic CT, a mass was detected in the duodenal region. Four years ago, he had a gastroscopy that revealed multiple atypic localized duodenal ulcers and a leiomyoma in the second part of the duodenum. Gastrin and parathyroid hormone levels were normal. In his relatives, his daughter and his cousin were also diagnosed with NF1. In his last gastroscopy, a 1.5 cm bleeding nodular lesion in the bulbus part of stomach and multiple ulcers in the anastomosis region of the gastroenterostomy were found. Pathological examination showed GIST with c-kit expression; that was s-100 positive, Ki-67 and desmin negative, and had SMA-positive loci. In his diagnostic PET-CT scan, hypermetabolic lesions were found in the sternum, fifth and sixth costal areas, and the liver. The patient was treated with imatinib and complete response was detected. In his last PET-CT scan, there was no evidence of malignancy.

4. 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 Table 2. Our case is the youngest NF1 patient in the literature who had osteosarcoma. Our second case is a patient who had somatostatinoma of the papilla of Vater with multiple gastrointestinal stromal tumors. They are rare, with an estimated annual incidence of one per 40 million and a median age at onset of 54 years. Our patient was a 51-year-old man who was treated with surgery and imatinib therapy. Therefore, we reviewed 43 somatostatinoma cases in the literature in full text and summarized their clinicopathologic features in Table 4. The third case presented here is a patient with a very rare neoplasm, leiomyosarcoma. She had metastases at the time of diagnosis, and her prognosis was poor. We reviewed publications on 15 patients with leiomyosarcoma and NF1 (Table 3). The final case in this study was a patient with GIST and NF1. That patient’s comorbidity has been previously reviewed and genetic alteration (somatic mutations) due to NF was also previously evaluated. Our patient had c-kit expression; and as a result, was treated with imatinib.

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Table 2 Clinicopathologic features of osteosarcomas associated with NF1. Year

Author

Age (years)

Sex

1 2 3 4 5 6 7 8

2009 2006 2002 1996 1996 1994 1993 1984

Chowdry et al. Hatori et al. Cinamon et al. Sakaguchi et al. Miyoshi et al. Ferreira et al. Woodruff et al. Ducatman et al.

22 29 50 48 49

F F F M M F F F F M

20 28, 31 20, 31 32, 9

Clinical manifestation

Tumor size (cm)

Therapy

Associated tumors

Pain, swelling Pain, swelling

4×4 5×4×7

Resection, CT Resection, CT Pheochromocytoma, MPNST

Follow-up 2 months, died Parathyroid adenoma

10 × 7 × 7 Brain metastasis Mass at neck

10

Subtotal resection Resection Resection, RT Resection, CT, RT

MPNST MPNST MPNST

3 months Died Died, died Alive

Table 3 Clinicopathologic features of leiomyosarcomas associated with NF1. No

Year

Author

Age (years)

Sex

Clinical manifestation

Tumor size (cm)

Therapy

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

2009 2009 2007 2005 2004 2003 2002 1999 1999 1995 1994 1993 1992 1989 1977

Kluger et al. Jhas et al. Rodriguez FJ et al. Mezghani S et al. Maruta K et al. Borvorn S et al. Klijanienko J et al. Stigsen BM Bernardis V et al. Kawano N et al. Aoi T et al. Lieu AS et al. Ishizaki Y et al. Nortier J et al. Poleksic S.

47 14 62 42 72 51 23

F M M F F M M

6

Resection Resection, CT, RT RT

20 62

M M

48 54

F F F M

Menorrhagia Headache, vomiting Low back pain Chest pain Thigh pain, muscle weakness Leg weakness, foot drop Thoracal mass Bladder mass Nausea, vomiting Melana, abdominal pain Pancreatic mass Hematochezia

66

10 13 × 12 × 10 1

Resection Resection Resection

3 5

Resection, RT Resection Resection Resection, twice CT, RT

Associated tumors

Follow-up

MPNST

Alive Years, alive 3 weeks, died

Pheochromocytoma

8 months, died

10 years, alive

Leiomyomas Intestinal neurofibroma

Alive Alive

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No

Table 4 Clinicopathologic features of somatostatinomas associated with NF1. No

Year

Author

Age (years)

Sex

Clinical manifestation

Tumor size (cm)

Therapy

Associated tumors

1 2 3 4 5 6 7 8 9 10 11 12 13

1981 1982 1982 1983 1983 1983 1984 1985 1985 1986 1986 1986 1986

Johnson et al. Cantor et al. Griffiths et al. Dayal et al. Hough et al. Weder et al. Dawson et al. Hibi et al. Dayal et al. Dayal et al. Dayal et al. Zollinger et al. Wheeler et al.

53 49 60 41 59 32 70 51 40 64 29 36 54

F F F M M F F M M M M M F

Pain, jaundice Hypertension Hypertension Pain, melena Pain, jaundice Pain, vomiting Jaundice Pain Obstruction Pain, jaundice Jaundice Duodenal ulcer Hypertension

2.0 1.5 × 1.5 ND 4 × 3 × 2.5 3×2×2 1.5 1.0 2.0 × 1.8 × 1.5 2.0 1.5 2.0 1.0 2.0 × 1.5

Local resection Local resection No operation PD PD PD Found at autopsy PD PD ND PD Found at autopsy Local resection

18 months, alive Pheochromocytoma Pheochromocytoma

14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

1988 1988 1989 1989 1989 1991 1991 1992 1994 1996 1996 1998 2002 2004 2011 2010 2010

Swinburn et al. Swinburn et al. Ohtsuki et al. Robert et al. Klein et al. Yoshida et al. Farr et al. Hagen et al. Richenel et al. Kainuma et al. Tan et al. Reichardt et al. Usui et al. Suzuki et al. Williamson et al. Bukkems et al. Relles et al.

51 61 64 52 23 50 43 36 36 44 21 50 64 51

F M F M M M F F F F F F F M

2.0 ND 1.0 2.0 × 1.5 3.0 1 × 1 × 1 × 0.8 0.5 × 4.0 × 0.2 0.5 1.5 3.5 × 2.0 2.5 × 1.0 × 1.0 3.0 1.5 × 0.8 1.5 × 4.5

31 32 33 34 35

2010 2009 2009 2008 2008

Deschamps et al. Chetty et al. South et al. Sakorafas et al. Garbrecht et al.

48 43 31 49 36 39 49 35 60 37 63 50 28 47 45 56 42 53 57 48

M M M F M F F F M F F F F M F M F F F F

Pain, melena Obstruction Pain Jaundice Pain, jaundice Cachexia Jaundice Steatorrhea Steatorrhea Jaundice Amenorrhea, diarrhea, pain Pain Pain Pruritus, diarrhea Jaundice, pain Jaundice, diarrhea Melena Dysphagia Pain Jaundice Anemia Asymptomatic Incidental Pain Jaundice Pain Pain, diarrhea Vomiting, anemia Melana, diarrhea Pain, dysphagia Cholastasis Pheochromocytoma Pain, jaundice, anemia Jaundice Pain, diarrhea

1.5 5 0.7 1.5 5.5 2 3.5 2 1.7, 1.2 1.6 × 1.6 0.5

Local resection PD Local resection Local resection Unresectable Found at autopsy PD Local resection No operation PPPD PD after local resection Local resection Local resection PD PPPD PPPD PPPD Local resection PD, CT PD Local resection PD D PD PD Local resection SP, H DJ, M, CT PD, M Local resection Observation

2.5 2 2.2

PD PPPD PPPD

37 38 39 40 41 42 43

2008

2007 2006 2006 2006 2005 2004 2001

Nesi et al.

Bettini et al. Juergens et al. Morisawa et al. Caiazzo et al. Hendi et al. Fendrich et al. Green et al.

Alive 18 months, alive 5 years, alive 7 months, died 18 months, alive

Rectal carcinoid 25 days, died ND ND 4 months, died Pheochromocytoma Pheochromocytoma, paraganglioma Parathyroid adenoma,

Died of other diseases 3 months died 6 months alive Died of old age 4 months, alive 3 years, alive

Thyroid carcinoma

GIST GIST GIST GIST GIST Adenocarcinoma GIST Pheochromocytoma Leiomyoma 3 months, alive

2 years, alive 1 years, alive 2 years, alive 48 months, alive 2 years, alive 15 months, alive 1 years, alive 3 months alive ND 2 months, alive 6 months, alive 3 years, alive 6 months, alive 6 years, alive 4.4 years, alive 5 years, alive

13 years, alive Hypothyroidism GIST GIST

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36

3.5 2.4 × 1.8 1.5 × 1 4.5 × 5

Follow-up

1 year, died 4 years, alive 16 months, alive 7 years, alive

Appendix carcinoid 13 months, died Nephrolithiasis

9 months, alive

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ND, not described; D, duodenectomy; PD, pancreatoduodenectomy; PPPD, pylorus-preserving pancreatoduodenectomy; GIST, gastrointestinal stromal tumor; SP, splenopancreatectomy; H, hepatectomy; DJ, duodenojejunectomy; M, metastasectomy; CT, chemotherapy.

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5. 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 a prerequisite for understanding the complex molecular mechanisms underlying NF1 tumorigenesis [42]. Based on a search of the articles and reviews in the literature on NF1 and these rare malignant tumors; 45 articles about NF and osteosarcoma were found, and 26 articles about NF1 and osteosarcoma were found. Osteosarcoma is the most common, high-grade malignant bone tumor, where the neoplastic cells produce osteoid. An unusual case of a 29-year-old NF1 female has been reported: initially suffering from malignant peripheral nerve sheath tumor (MPNST), this tumor eventually developed into an osteosarcoma in the proximal femur [21]. The correlation between the histogenesis of osteosarcoma and the genetic abnormality in NF1 patients has not been elucidated. The finding of osteosarcomatous transformation in this case suggests divergent cellular differentiation of neuroectodermal tissue to mesenchymal malignant tumors in NF1 patients [21]. There have been some reports of osteosarcoma arising in patients with NF1 who have a parathyroid adenoma and hyperparathyroidism. There are also studies implying that the parathyroid hormone plays a role in the regulation and modulation of osteogenic sarcomas in vitro [20]. Osteosarcoma developed at an early age in patient 1 in this study, suggesting a possible relationship between NF1 and the development of a bone sarcoma. We recommend further research into this potential link. To date, no genetic relationship has been described between osteosarcoma and NF1. The most extensive previous review of periampullary and gallbladder tumors in patients with NF1 was published in 1989 by Klein et al. [22]. The authors identified 37 tumors in patients with NF1, and noted that 54% were found in the ampulla, 38% in the duodenum, 5% in the pancreas, and 3% in the gallbladder. Histologically, tumors were identified as – carcinoid (41%), neurofibroma (30%), neurofibrosarcoma (MPNST) and adenocarcinoma (8% each), neurilemoma (schwannoma) and paragangliomas (5% each), or ganglioneuroma (3%). Of the 20 tumors found at the ampulla of Vater, 60% were carcinoid [22]. Seventy-five articles were found in PubMed about NF and GIST. Among these studies were 76 reported cases of periampullary tumors in patients with neurofibromatosis, and only 43 cases of somatostatinomas. Of these 43 cases, the most common symptoms at presentation were jaundice, weight loss, pain, GI bleeding, and anemia [15,16]. This

is consistent with previous reports on ampullary carcinoids in both NF1 and non-NF1 patients. Adenocarcinomas (8%) were reported more frequently [9]. GISTs, the most common mesenchymal neoplasms of the gastrointestinal tract, are believed to originate from interstitial cells of Cajal or their stem cell-like precursors [12]. We can state that GIST is the most important and frequent nonneurological malignancy in NF1, and has a high frequency in NF1 patients (5% of all GISTs, likely representing the major subgroup at risk, so this percentage is not small but great). Consequently, the risk of NF1 patients for developing this malignancy is remarkably higher than the general population. GISTs typically occur in the stomach, duodenum and jejunum [23,24]. In NF1, GISTs tend to arise as multiples, may be benign or malignant, and can have both muscular and neural differentiation [25,26]. Zöller et al. reported that GISTs are detected in 7% of NF1 patients [19]. Previous reports have found that 22–31% of GISTs in NF1 patients are found in the duodenum, and approximately 60% of patients harbor tumors at multiple sites [13,23]. Although most GISTs harbor activating somatic mutations of KIT and PDGFRA, the absence of such mutations in NF1-associated GISTs (NF1-GISTs) may be indicative of a different pathogenetic mechanism [13,42]. Somatic NF1 mutations have been identified in the interstitial cells of Cajal (ICC) throughout the gastrointestinal tract, as well as in NF1GISTs lacking KIT or PDGRA mutations [42,43]. Therefore, further studies should be conducted to evaluate this possible link, which could change the classic treatment of GISTs in NF1 patients. The prediction of aggressive behavior for GISTs remains difficult. Features associated with malignant behavior include the following: tumor size (>5 cm), extragastric location within the GI tract, invasion of adjacent organs, cytologic grade/cell type (mixed cell types are more aggressive than spindle or epithelioid alone), foci of unequivocal tumor necrosis, tumor infiltration of the overlying mucosa, and high mitotic activity (at least five mitoses per 50 high-power fields) [27,28]. It is generally accepted that the presence of two or more of these features can be quite predictive of aggressive or malignant behavior. The tumors in patient 2 from this study did not fulfill any of the aforementioned criteria. GISTs are defined by their immunohistochemical expression of KIT (CD117), and are neoplasms that are distinct from leiomyosarcomas, neurofibromas, and schwannomas [36]. GISTs occur commonly in the elderly (median age 55–60 years), and rarely in children. NF1 associated GISTs are rare, and account for

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