The risk of tumours including pheochromocytoma and gastrointestinal stromal tumour (GIST) has been reported to be higher in neurofibromatosis type 1 (NF1) patients. The concomitant occurrence of these two tumours was rare in NF1 patient and most were symptomatic. In this case report, we describe the case of a 47-year-old man with NF1 who presented with microscopic haematuria. Neither hypertension nor any gastrointestinal symptoms were reported by the patient. While investigating for haematuria, left adrenal mass and arterial enhancing lesions in the small bowel were incidentally documented during computerised urography. The patient subsequently underwent a left adrenalectomy and small bowel resection. The pheochromocytoma and multiple GIST tumours were diagnosed based on pathology. Here, we discuss the rare association of pheochromocytoma and GIST and the asymptomatic presentation of those tumours in an NF1 patient. We further suggest that in NF1 patients a heightened level of vigilance can help identify this infrequent combination.
- adrenal disorders
- small intestine cancer
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Neurofibromatosis type 1 (NF1) or Von Recklinghausen’s disease is an autosomal dominant genetic disorder with a prevalence of 1 in 3000 individuals.1 Hallmarks of NF1 include café-au-lait spots, neoplasms of the peripheral and central nervous systems and cutaneous neurofibromas. The diagnosis of NF1 is based on criteria established by US National Institutes of Health (NIH) Consensus Conference in 1997.2 NF1 is caused by NF1 tumour suppressor gene mutations on chromosome 17q11.2 resulting in the loss of function of neurofibromin, the protein which acts as a tumour suppressor, downregulating the Ras proto-oncogene pathway.3 When an NF1 mutation is present, the reduction of neurofibromin can activate mechanistic target of rapamycin and mitogen-activated protein kinase pathways, increasing the risk of various tumours, both benign and malignant.4 5 Pheochromocytoma is one of the tumours reported to be linked to NF1. The incidence of pheochromocytoma is approximately 0.1%–5.7% in NF1 patients; that incidence increases to 20%–50% in NF1 patients with hypertensive status.6 Gastrointestinal stromal tumour (GIST), soft tissue sarcomas arising within the stromal compartment of the gastrointestinal tract, is another type of tumour which has been described in NF1 patients with an estimated incidence of 13.5%–33%.7–9 Approximately 20% of patients with GIST are asymptomatic.10 As a result, the diagnosis of GIST is often missed. The co-occurrence of pheochromocytoma and GIST among NF1 patients is rare, with only approximately 15 documented cases reported in the English language to date. This article describes an NF1 patient with that uncommon clinical presentation: simultaneous occurrence of multiple GISTs and pheochromocytoma.
A 47-year-old man with NF1 presented with a history of recurrent microscopic haematuria. Renal ultrasound showed a left renal cyst compatible with Bosniak classification IIF. CT urography confirmed a 1.2 cm renal cortical cyst at the mid-pole of the left kidney. A large left adrenal mass with central cystic degeneration measuring 5×4.9×5.1 cm with 39 HU on plain scan was incidentally found. In addition, multiple round and lobulated arterial enhancing lesions of various sizes were documented at the posterior wall of the third part of the duodenum and the small bowel loop in the left lower abdomen and pelvic cavity (figure 1). An endocrinologist was consulted for the investigation of the adrenal mass. Physical examination found the patient’s blood pressure was 135/80 mm Hg. There was axillary freckling, plexiform neurofibroma at the nose and multiple neurofibromas ranging in size from 1 to 4 cm as well as more than six 1–3 cm spots of café-au-lait macules located all over his body (figure 2). His family history showed his mother, sister and son had similar lesions on their bodies. The patient reported no history of paroxysm, abdominal pain or gastrointestinal bleeding. Results of routine biochemical investigations, including complete blood count, electrolytes, blood glucose as well as kidney and liver function, were within normal limits. Assessments of the functional status of the adrenal mass were performed. The 24-hour urine metanephrine and normetanephrine were significantly elevated (table 1).
The patient had been provisionally diagnosed with NF1 and left pheochromocytoma with questionable lesions at the third part of the duodenum suspected of being GISTs. The differential diagnosis of a large with central cystic degeneration of left adrenal mass includes pheochromocytoma and adrenocortical carcinoma. In this case, it was possible to distinguish pheochromocytoma from adrenocortical carcinoma based on urine metanephrine and normetanephrine tests. Apart from GISTs, the other possible differential diagnosis for arterial enhancing lesions in small bowel includes neurofibroma, schwannoma, neuroendocrine tumour and adenocarcinoma at small bowel.
The patient underwent a left adrenalectomy along with a small bowel resection from the third part of duodenum to approximately 100 cm below the level of the ligament of Treitz for pathological diagnosis. Perioperative management for pheochromocytoma was carried out, including appropriate blood pressure and other metabolic profile monitoring during the perioperative period.
Outcome and follow-up
The resected tumour from the left adrenal gland measured 7.5×5.5×4.5 cm and weighted 81 g. A cut section revealed a well-defined solid reddish-brown tumour with capsulation and a 2.5×2 cm haemorrhagic space within the tumour. The small bowel specimen measured 13×2.5×3 cm and showed several firm nodular masses on the serosal surface, ranging from 0.3 cm to 2.5×2.5×2 cm, scattered throughout the specimen. Cut surfaces revealed well-defined solid whorled-like fleshy tan tissue.
Microscopic examination of the left adrenal mass showed profound nuclear pleomorphism with large nests of tumour cells arranged as small nests or Zellballen-type growth pattern, showing histological features of pheochromocytoma (figure 3). Nodules from the small bowel showed spindle cell neoplasm with abundant pale to eosinophilic fibrillar cytoplasm in a syncytial pattern and elongated nuclei with inconspicuous nucleoli. Macroscopic tumour perforation was also seen. Immunohistochemical (IHC) staining was strongly positive for CD117 and Ki-67 stain indicating approximately 1% immunoreactivity and confirming the diagnosis of high-risk GISTs based on modified NIH criteria (figure 4).
At the 1-month postoperative follow-up, 24-hour urine metanephrine and normetanephrine had declined significantly, back to normal values. Blood pressure remained normal without any anti-hypertensive mediation; the patient reported no gastrointestinal symptoms. Enhancing masses in the left adrenal gland and in the small bowel loops were no longer detected in CT scans of the abdomen at the 3-month postoperative follow-up. The oncologist recommended periodic follow-up by CT scan of the abdomen for surveillance of potential recurrence of GISTs. Written informed consent for publication of the patient’s medical information was obtained from the patient.
In this case, we presented an NF1 patient with unilateral pheochromocytoma and small bowel GISTs which had been incidentally found during CT investigation. Intriguingly, this case had unique clinical features which are (1) lacking in typical presentations of both pheochromocytoma and GISTs and (2) a rare combination of NF1 coexisting with pheochromocytoma and GISTs.
This case was diagnosed as NF1 in adulthood based on four of the seven clinical criteria in the NIH Consensus Statement: (1) six or more café-au-lait spots of more than 15 mm, (2) axillary freckling, (3) multiple neurofibromas throughout body and (4) having first-degree relatives diagnosed with NF1 (his mother, sister and son).2 NF1 is an autosomal dominant syndrome with a wide range of clinical characteristics including an increased prevalence of benign and malignant tumours throughout the body.
In NF1 patients, the risk of having pheochromocytomas is 10 times higher than in the general population.7 Almost 80% of NF1 patients with pheochromocytoma have suggestive symptoms, for example, tachycardia, hypertension and palpitations.11 In addition, the reported size of pheochromocytomas in NF1 patients is significantly smaller than in non-NF1 patients (2.75 cm vs 5.90 cm) due to earlier screening and incidental discovery of tumours in NF1 patients.12 Screening for pheochromocytoma is generally recommended only for NF1 patients with an onset of hypertension.2 6 However, in the present case, the patient had no obvious clinical symptoms of pheochromocytoma, including hypertension, and his tumour was larger than that reported in the previously cited study. It could be presumed that this case had a late tumour identification. Therefore, it should not be routinely assumed that a lack of symptoms or hypertension is an indication of the absence of pheochromocytoma. To preclude late pheochromocytoma detection, extra vigilance in biochemical screening of NF1 patients is suggested.
It has been reported that in NF1 patients the risk of GIST, a rare tumour in the myenteric plexus arising from Cajal cells, is 150 times greater than in the general population.10 13 Approximately 80% of patients with GIST are symptomatic, including abdominal mass, abdominal pain, gastrointestinal bleeding and bowel obstruction.14 In contrast to sporadic GIST, NF1-related GISTs tend to be multifocal, located in the small bowel and are commonly diagnosed incidentally. They also have a higher frequency of spindle cell morphology and a higher expression of CD34.10 15 In the present case, the GISTs were multifocal and located in the small bowel. However, this case exhibited CD117 expression rather than CD34 expression. Additionally, the patient reported no gastrointestinal manifestations which could be accounted for by earlier detection of the small GIST lesions.
To the best of our knowledge, in addition to the present case, only 15 cases of co-occurrence of pheochromocytoma and GIST in NF1 patients have been reported in the English language.16–27 Most of those cases presented with symptoms of either pheochromocytoma or GIST. The characteristics of each of those patients are shown in table 2. The combination of these two tumours without a background of NF1 had been described as Carney-Stratakis dyad. However, in this dyad, most of the patients had paraganglioma rather than pheochromocytoma, which was not the situation in our case.28 Possible theories regarding this rare association have been proposed in multiple studies. For example, Kimura et al suggested that the loss of neurofibromin due to the NF1 mutation can lead to abnormal proliferation of Schwann cells resulting in marked proliferation of chromaffin cells which, in turn, causes pheochromocytoma.29 Gorgel et al stated that the activation of the RAS proto-oncogene pathway in NF1 patients causes Cajal cell proliferation, resulting in GIST development.19 This causal relationship was confirmed through identification of somatic NF1 mutations in interstitial cells of Cajal in the gastrointestinal tract.30
Surgical removal is the definitive therapy for pheochromocytoma and was performed in the present case. Following surgery, lifelong surveillance for recurrent of pheochromocytoma should be conducted.31 Regarding GIST, about 60% of patients are cured with surgery alone, particularly those with low-to-moderate risk GIST. In those with high-risk GIST (such as our patient), in addition to surgery, imatinib mesylate should be prescribed to suppress CD117 receptors and thus to prevent tumour recurrence or metastasis.32 However, due to non-medical obstacles, imatinib was not prescribed for this patient. For that reason, in this case more intensive surveillance is needed for early detection of recurrence or metastasis of GISTs.
In NF1 patients, the co-occurrence of both pheochromocytoma and GIST is considered unusual. A high level of suspicion is essential for such a rare combination to be recognised. Although rare, NF1 patients with hypertension and any gastrointestinal symptoms should be thoroughly screened for both pheochromocytoma and GIST. Even NF1 patients who are normotensive, pheochromocytoma should be explicitly excluded before the patient undergoes surgery for GIST in order to reduce life-threatening perioperative complications. This is necessary as most NF1 patients with pheochromocytoma are asymptomatic. Early detection of GIST is also crucial because of the risk of complications from tumours, for example, bleeding and bowel obstruction. Additionally, lifelong monitoring of recurrence of both types of tumours should be conducted in NF1 patients following treatment.
Pheochromocytoma and gastrointestinal stromal tumour (GIST) in neurofibromatosis type 1 (NF1) patients are a rare association.
In hypertensive NF1 patients, pheochromocytoma should be investigated before any surgical procedure is performed as appropriate perioperative management of pheochromocytoma can reduce the risk of life-threatening complications during surgery.
In NF1 patients with gastrointestinal symptoms, GIST should be investigated in order to provide early treatment and proper surveillance.
Even in NF1 patients with no hypertension and no gastrointestinal symptoms pheochromocytoma and/or GIST can still occur. Clinical practitioners should keep in mind that further careful evaluation may be warranted with NF1 patients.
The authors are grateful to G Lamar Robert, PhD and Chongchit Robert, PhD for reviewing the manuscript.
Contributors NV conducted the literature review, designed and wrote the first draft of the manuscript. SK provided the pathological report and wrote the manuscript. PW conducted the literature review and edited the manuscript. WM was responsible for planning the case, conceived the original idea, conducted literature review and provided critical revision of the manuscript for important intellectual content. All the authors have read and approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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