Periampullary tumors in a patient with pancreatic divisum and neurofibromatosis type 1: a case report

NF1 is the most common neurocutaneous syndrome, with a frequency of 1 in 2500 in the overall population [4]. Neurofibromatosis may increase the risk of multiple tumors [8]. The development of benign and malignant tumors is characterized by NF1, with the largest chance of developing symptomatic visceral tumors occurring within the first six years of life [9]. CALMs and overall skin pigmentation are the earliest signs, appearing within the first two years of life [10]. CALMs in the skin folds resemble freckles and are referred to as Crowe’s sign, the most specific indication for NF1 [11]. Excision may not be possible for people who have an excessive number of cutaneous neurofibromas. According to a Finnish study, at the age of 50, NF1 has a cumulative cancer risk of 38% and a lifetime cancer risk of 59.6%. However, equivalent values for the general population are 3.9% and 30.8%, respectively [12]. Because of this, a proper diagnosis is crucial at the prefrontal stage of a tumor and offers useful prediction guidance for tumor management [4].

This case report describes a patient who was identified with various neoplasms (NETs, GIST, and ampullary adenocarcinoma). The GIST and NETs were perhaps related to NF1, and the diagnosis was verified through germline genetic testing. Among the tumors identified, GIST is the most frequently observed gastrointestinal tumor in patients with NF1, accounting for 5–25% of all NF1 tumors [6, 13]. However, NF1-related GISTs show significant differences from sporadic GISTs. First, sporadic GISTs are mainly located in the stomach (50–70%), while NF1-related GISTs are mostly found in the small bowel (68%), and most NF1-related GISTs are of the spindle-cell type (75%), for which the prognosis is better than that of sporadic GISTs [14]. Second, mutations in the KIT and PDGFRA genes are rarely documented in NF1-associated GISTs, which are less malignant and risky tumors, and thus, imatinib treatment is usually unnecessary [13]. In addition to diagnosing NF1, the present patient was identified with an anatomical anomaly known as PD. PD is a congenital hypoplasia characterized by the absence or inadequate fusion of the ventral (main or Wirsung) and dorsal (marginal or Santorini) ducts during pancreatic development. It is most commonly observed on MRI or MRCP in patients with chronic pancreatitis [15, 16]. With a 10% frequency in the general population, PD is the most prevalent congenital abnormality of the pancreas. In approximately 5% of patients, it can manifest symptoms. Terumi et al. [17] collected 32 cases of PD, with 12.5% of the cases observed to have pancreatic tumors. Histological examination of the related pancreatic cancer revealed adenocarcinoma, with all tumors developing in the dorsal pancreas. Takuma et al. [18] examined 104 cases of PD and found that all pancreatic tumors originated from the dorsal pancreas and showed varying degrees of dorsal pancreatic duct dilatation. They hypothesized that long-term pancreatic duct obstruction induced by relative narrowing of the minor papilla could be a factor in oncogenesis. Although some NF1 individuals with periampullary tumors have been found to have PD, most of these people do not have any symptoms of the disease. According to Bertin et al. [19], the frequency of PD does not differ significantly between patients with idiopathic pancreatitis and those with no pancreatic disease (5%vs.7%), demonstrating that PD alone is not a cause of pancreatitis. According to a recent study, the risk for people with PD, idiopathic pancreatitis, and mutations in the CFTR gene is 12 times higher than that for people without those mutations. This simple PD should not be regarded as the pathogenesis of acute pancreatitis (AP)/chronic pancreatitis (CP) [20, 21]. The association between CFTR mutations or polymorphisms and PD might explain why the occurrence of both PD and CFTR mutations may develop into pancreatitis. However, no evidence exists that this developmental abnormality is directly related to cancer [15, 19].

The NF-1 gene is located at chromosome 17q11.2 [7, 22]. Neurofibromin, its gene product, is a tumor suppressor that inhibits RAS-GTP in the Ras-mediated signaling pathway. Neurofibromin inhibits cell proliferation pathways such as MAPK/ERK kinase (MEK), mitogen-activated protein kinase (MAPK), and cyclic adenosine monophosphate (cAMP)-mediated protein kinase A (PKA) [23, 24]. Patients with NF1 do not have a properly functional neurofibromin protein, which results in unregulated activation of RAS-GTP pathways, which leads to aberrant proliferation and the development of cancer [10, 25]. Although this autosomal dominant disorder is fully penetrant in adulthood, variable expressivity is common within families. This can be attributed to the wide range of mutations found in the NF1 gene [4]. The NF1 gene, which spans 350 kb of the genome, is highly vulnerable to many forms of mutations. Approximately 85–90% of these mutations are point mutations, 5–10% are microdeletions, and 2% are exon deletions or duplications [26]. Approximately 80% of the described mutations result in premature termination codons and truncation of neurofibromin [26‐28]. The present patient carried a termination mutation in exon 23 of the NF1 gene c.3052delT as well as a frameshift mutation in exon 10, c.1131del1134del.pI377fs, which predicts the occurrence of a premature stop codon and abnormal gene arrangement, resulting in the loss of all functional domains of the neurofibromin protein, which may be the cause of gastrointestinal tumors. Furthermore, Perrone hypothesized that in NF1 patients, increased susceptibility of both epithelial tissue (endocrine or exocrine) and nonepithelial tissue around the ampulla (endocrine or exocrine) leads to a higher risk of tumorigenesis and that extensive tumor excision is frequently required in treatment [29].