Neurofibromatosis 1 with pheochromocytoma.

Von Hippel-Lindau (VHL) disease includes a wide spectrum of highly vascular tumors like pheochromocytoma, cysts and adenomas of the pancreas and kidney, endolymphatic sac and renal cell carcinoma. Molecular analysis of the VHL gene is vital in these patients and their kindred. Neuroendocrine pancreatic tumors are rare and are known for their malignant and metastatic potential. We discuss an interesting case of a young lady who had a strong family history of central nervous system and spinal tumors. Our patient presented with recently detected severe hypertension. She was found to have elevated urinary normetanephrine levels; radiological imaging revealed bilateral pheochromocytomas with a pancreatic lesion. On genetic analysis, a variation, c.IVS 2 + 3 A > G, was found in the intronic region following exon 2 of the VHL gene. This variant appears novel. This patient underwent bilateral adrenalectomy (right total and left cortical sparing), distal pancreatectomy and splenectomy. Histology was diagnostic for pheochromocytoma with a neuroendocrine tumor of the pancreas. The postoperative period was uneventful. She was advised genetic screening of all her first-degree relatives.

INTRODUCTION

Neurofibromatosis type 1 (NF1) affects approximately 1 in 3500 patients worldwide and is the most common phakomatoses reported. Phakomatoses are characterized by cutaneous pigmentary abnormalities and neoplastic growth of neural crest derived cells. NF1 is an autosomal dominant disorder characterized by multiple soft tissue neurofibromas, café au lait macules and Lisch nodules. NF1 patients have higher predilection to develop tumors like pheochromocytoma, paraganglioma, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumor. Pheochromocytoma is a tumor originating from adrenal medulla resulting in secondary hypertension. Most of the pheochromocytomas occur sporadically but familial predisposition is seen in cases of multiple endocrine neoplasia 2 (MEN2), NF1 and Von Hippel-Lindau (VHL) disease. Pheochromocytomas occur in 0.1–5.7% of patients with neurofibromatosis.[1]

Pheochromocytoma is rarely reported from our country and there are few publications involving small case series.[2-4] Ganesh et al. reported a series of 11 pediatric pheochromocytoma patients, where as Agarwal et al. reported a series of 93 patients over 15 years.[23] None of these data showed the occurrence of pheochromocytoma in association with NF1. We recently encountered an elderly lady who had prolonged history of neurofibromas and poorly controlled hypertension due to unilateral pheochromocytoma. Literature search revealed a single case report from India about the occurrence of pheochromocytoma in a patient with malignant peripheral nerve sheath tumor without NF1.[5] Pheochromocytoma with neurofibromatosis has not been reported earlier from India and hence we report the same in this article.

CASE REPORT

A 67-year-old lady presented with 6 month history of pain abdomen. The pain was localized to right lumbar region with dull aching in character and no specific exacerbating or relieving factors. Past medical history revealed that she noticed multiple nodular swellings on her body and face for past 50 years. Family history revealed similar nodular lesions in her father and sister with no major illness in them or other family members. She was diagnosed to have hypertension 8 years back and is currently requiring more than three antihypertensive drugs for optimal control. She did not have symptoms to suggest pancreatic neuroendocrine tumor. Examination showed blood pressure of 150/90 mmHg, multiple soft to firm nodular swellings over entire body including face (straight arrows), multiple macules (arrow heads) over arms, back, and generalized freckling of the skin (curved arrows) known as Crowe's sign [Figure 1]. There was no evidence of neck swelling/skeletal deformities/ophthalmic findings and abdominal examination was unremarkable. Ultrasonography abdomen revealed a mass lesion from right adrenal gland and CT scan showed a 4.6 × 3.8 cm mass arising from right adrenal gland with mixed consistency [Figure 2]. Her 24 h urinary metanephrines and normetanephrines were elevated. Investigations for medullary thyroid carcinoma and hyperparathyroidism were negative. The detailed work up is given in Table 1. She underwent right adrenalectomy with adequate preoperative preparation including prazosin and atenolol. Her intraoperative and postoperative courses were uneventful. During last review 1 month after surgery her blood pressure is now controlled with single drug and repeat urinary metanephrines returned to normal range.

Figure 1

Clinical photograph

Figure 2

Axial CT section of abdomen showing right adrenal mass

Table 1

Biochemical workup of the patient

DISCUSSION

We report a patient of unilateral pheochromocytoma in the background of neurofibromatosis type 1. Our patient is unique in several ways that she never had classical symptoms of pheochromocytoma, unilateral lesion in the setting of familial syndrome and presentation with pain abdomen at a delayed age in sixth decade of life. NF1 is due to mutation of neurofibromin gene on chromosome 17.[1] NF1 is characterized by cutaneous pigmentary abnormalities and neoplastic growth of neural crest-derived cells. Other phakomatoses with predilection for endocrinal tumors are tuberous sclerosis, Cowden's syndrome and Peutz-Jeghers syndrome.[6] Multiple endocrine syndromes were divided into two categories (MEN1, MEN2) initially based on the tumoral involvement. However, increasing awareness, genetic and hormonal screening expanded the spectrum to involve six syndromes with multiple subvariants.[7] They are MEN1, MEN2, VHL disease, NF1, Carney's complex (CC), and McCune-Albright syndrome (MAS). All of them meet the definition of multiple endocrinal organ involvement with hormonal overproduction. They affect endocrine and non-endocrine tissues and most of them have characteristic dermatological findings. Hormone overproduction is characteristic of MEN1 and 2 whereas others present with non-hormonal tumors. Our case presented neither with hormone overproduction nor with non-hormonal tumors and had a successful result post-adrenalectomy.

Pheochromocytoma is seen in about 1% of NF1 patients but the incidence increases to 20–50% in cases of NF1 with hypertension.[8] Although our patient had clinical features of NF1 and long standing history of hypertension requiring three drugs, the diagnosis was delayed due to the lack of symptoms of the disease. Recent reports showed that pheochromocytoma is seen in 7 out of 48 patients with NF1.[910] Clinical presentation remained similar to sporadic pheochromocytoma in six cases except for one case which was asymptomatic similar to our case. Previous published reports showed that pheochromocytoma occurs in third to fourth decade but our patient presented in sixth decade of life.[2-4910] NF1-associated pheochromocytoma has germline NF1 mutations that favor the cysteine serine-rich domain and behaves like a sporadic pheochromocytoma except for increased risk of malignancy.[11] They predominantly secrete epinephrine and present with classical episodic symptoms. Persistent hypertension is seen in about 60% of cases of NF1 with pheochromocytoma as seen in our patient. The tumors are generally localized to adrenals and are rarely malignant.[8] Adequate preoperative preparation is required with adrenergic blockers and surgery offers best cure rate. Postoperative complications include hypotension and hypoglycemia. A long-term follow up is required to monitor for recurrence in patients with genetic predisposition. A high index of suspicion is required for identification of such rare association. Data from observational studies suggest that all patients with NF1 and hypertension should undergo a biochemical testing for pheochromocytoma.[811]

CONCLUSION

To conclude, we report the atypical presentation of pheochromocytoma in an elderly lady with neurofibromatosis. Our case highlights the role of screening for pheochromocytoma in all patients of neurofibromatosis with hypertension.