Bilateral pheochromocytoma with ganglioneuroma component associated with multiple neuroendocrine neoplasia type 2A: a case report

Composite pheochromocytoma/paraganglioma (CPC/PG) is a rare entity composed of classic PC/PG associated with other neurogenic tumors such as neuroblastoma, ganglioneuroblastoma, ganglioneuroma (GN), or malignant peripheral nerve sheath tumors (MPNST) [1]. In the literature, ganglioneuroma is the most reported component of composite tumors [2]. The adrenal medulla is the common site of these tumors, however, extramedullary locations (CPG) can be encountered. Cases of CPC/PG have been reported in association with neurofibromatosis (NF), gastrointestinal stromal tumors (GIST), multiple endocrine neoplasia (MEN), and von Hippel-Lindau syndrome (vHL) [2, 3]. The management and the prognosis of CPC/GN seem to be similar to their ordinary-type counterpart (PC/PG), but based on a few reported cases to date, little is known about their real behavior [2, 4, 5]. To the best of our knowledge, only four cases of CPC/PG associated with MEN 2 have been previously reported in the literature [6‐9]. The first case was reported by Brady et al. in 1997 in a 34-year-old man with MEN 2A. In 1998, Matias-Guiu et al. reported another case of CP in a 49-year-old man with MEN 2A. The two reported cases were located in the left adrenal medulla and the neurogenic components were ganglioneuroma and ganglioneuroblastoma, respectively. Cases associated with MEN 2B have also been reported. Charfi et al. reported in 2008 the first case of CP associated with MEN type 2B. More recently, in 2016, Yamasaki et al. reported a case of a composite retroperitoneal paraganglioma in a 59-year-old man.

We report here an additional case of CPC in a 40-year-old woman with MEN 2A. We discuss the clinicopathological issues and perform a review of the literature in order to improve understanding of this very rare type of tumor.

A 40-year-old Arabic woman presented with headache, palpitations, paroxysmal hypertension and weight loss, which she had had for 3 years. She had a history of treated type 2 diabetes. She had also a familial history of type 2 diabetes and MEN 2A. Her sister had undergone thyroidectomy and adrenalectomy for medullary carcinoma of the thyroid and pheochromocytoma. A physical examination showed an enlarged and firm thyroid mass which moved with swallowing, without cervical adenopathy. Our patient had no hypertension on admission. A cervical ultrasound scan found nodular heterogeneous calcified and cystic lesions of the thyroid gland, the larger lesion was located at the left lobe and measured 1.8 × 1.3 cm. An abdominal computed tomography (CT) scan revealed a left adrenal mass and a well-encapsulated nodule of the right adrenal gland (Fig. 1). The laboratory tests showed high levels of serum parathyroid hormone and calcitonin, normal levels of serum calcium, phosphorus, and Vitamin D. A 24-hour urine collection found elevated levels of norepinephrine, epinephrine, and methyldopa (Table 1). Because of our patient’s familial history of MEN 2A, a genetic mutational analysis for the RET proto-oncogene was performed at our hospital’s medical genetics department. The test was carried out on our patient’s peripheral blood. Her genomic deoxyribonucleic acid (DNA) was amplified by using polymerase chain reaction (PCR) and oligonucleotide primers for exon 11. A direct sequencing analyses showed a RET (rearranged during transfection proto-oncogene) germline mutation at exon 11 (codon 634), with a substitution of tyrosine by a cysteine residue (C1900T→C (C634R).

Our patient had undergone bilateral adrenalectomy, total thyroidectomy with cervical lymphadenectomy, and parathyroidectomy. A pathological examination confirmed the MEN 2A consisting of left medullary pheochromocytoma, right medullary composite pheochromocytoma-ganglioneuroma, medullary carcinoma of the thyroid (MCT) with lymph node metastasis, and parathyroid hyperplasia. Our patient recovered well after surgery and had no signs of disease 3 years after treatment.

Composite pheochromocytoma/paragangliomas (CPC/PG) are uncommon tumors combining the histologic features of the ordinary PC/PG with those of ganglioneuroma, ganglioneuroblastoma, neuroblastoma or peripheral nerve sheath tumors [2]. Paragangliomas (PG) are tumors derived from paraganglia located along the supradiaphragmatic (parasympathetic) nerves, the pre- and paravertebral sympathetic chains or sympathetic nerve fibers of the pelvic and retroperitoneal organs. Pheochromocytoma is a paraganglioma of the adrenal gland. Cells of both adrenal medulla and paraganglia derived embryologically from neural crest cells that migrated to other organs [2, 3]. This embryologic common origin allows understanding the histogenesis of composite tumors. In fact, neural crest cells migrate to other sites and mature into melanocytes, chromaffin cells, Schwann cells or ganglion cells [2, 10]. Disorders of crest cells migration or maturation at various stages of the cellular development are thought to lead to CPC/PG [2, 5]. The possibility of chromaffin cells to undergo divergent differentiation into neuronal elements is another hypothesis to explain histogenesis of CPC/PG [11].

Macroscopically, CPC/PG have similar features of ordinary pheochromocytoma, presenting generally, as solid and firm tumors, the cut section appearing gray-white, light tan, or dusky red [10, 12]. The histologic diagnosis of composite pheochromocytoma/paraganglioma (CPC/PG) must be based both on architecture and on cell populations deriving from neural crest. Any tumor component that does not share common embryological origin with paraganglia or adrenal medulla cells should be considered as a collision tumor [2, 12]. In addition, the presence of degenerating chromaffin cells, lymphocytes, or scattered neuron-like cells, should not be misinterpreted as CPC/PG, as they are occasionally found in ordinary PC/PG [6, 12]. On microscopic examination, the two components of the tumor are admixed or separate, usually the pheochromocytoma is the predominant component [6, 7]; but the case reported by Brady et al. was composed of approximately equal parts of PC and PG [6]. The PC cells are arranged in syncytial-like growth pattern (Zellballen pattern), or arranged in an alveolar, diffuse, trabecular or solid pattern. Spindle cells can also be found in the tumor. Cellular pleomorphism is often present, with admixture of large and small cells. Some cells with bizarre appearance with nuclear pseudoinclusion may be observed, but this is not criteria for malignancy [12]. The stroma and the vasculature of the tumor may be prominent, causing unhabitual appearance, with diagnostic challenge [2]. In our case, the PC component showed trabecular and diffuse pattern with a rich vasculature; cells with pseudoinclusion and spindle cells have been observed. The ganglioneuroma component was slightly demarcated from the PC component by dilated blood vessels. Immunochemistry is very helpful, to rule out differential diagnosis or to distinguish easily the different components of the CPC/PG. The cells of the PC/PG component stain positive for neuroendocrine markers such as chromogranin and synaptophysin; functional tumors are positive for catecholamine-synthetizing enzymes such as thyrosine hydroxylase (TH) or phenylethanolamine N-methyltransferase (PNMT). Tumor cells have also capacity to produce a large variety of neuropeptides like vasoactive intestinal peptide (VIP), bombesin, substance P, and so on. [2, 6, 7]. The neurogenic cells are positive for neuron-specific enolase (NSE), neurofilament (NF), but show weak or focal staining for chromogranin. The sustentacular cells and Schwann cells are positive for S-100 protein [6, 12]. There is no reliable biological marker that reflects the malignant potential of CPC/PG. Comstock et al. reported the absence of N-myc amplification in four cases of CPC, and concluded that CPC does not have adverse prognostic significance conferred by the neuroblastic elements [13].

Usually, CPC/PG are functional tumors, clinical symptoms are related to the type of hormones produced by the component of the tumor. Symptoms range from palpitations, headache, hypertension, and excessive sweat. These signs are due to excessive production of epinephrine or norepinephrine. Cases presenting with watery diarrhea have been described attributable to increased production of vasoactive intestinal peptide (VIP) [12]. According to Shawa et al., CPC/PG are similar clinically and radiologically, and their management should be so [14].

PC/PG, ordinary or composite types, are usually associated with certain hereditary disorders: von Hippel-Lindau syndrome (vHL), multiple endocrine neoplasia syndrome type 2A and 2B (MEN 2A and 2B), NF1 and the recently described familial paraganglioma syndrome [2, 12]. Several genes are involved in the pathogenesis of PC, such as the RET proto-oncogene, von Hippel–Lindau disease tumor suppressor (VHL), neurofibromatosis type 1 tumor suppressor (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits, TMEM127, and MYC-associated factor X (MAX) [4].

To the best of our knowledge, only four cases of CPC/PG associated with MEN 2 have been reported [6‐9] (Table 2). MEN type 2 is an autosomal-dominant disease with major components of MTC, PC, and hyperparathyroidism [7, 9]. There were two cases of MEN 2A and two cases of MEN 2B. The case reported by Matias-Guiu et al. was in fact a postmortem diagnosis on autopsy as the patient had died after an orthopedic surgery [7]. He had a RET germline mutation on the exon 11 at the codon 634, like our patient. In fact the vast majority of patients with MEN 2A carry a RET germline mutation on exon 10 or 11 [7, 9]. The MEN 2B represents less than 10% of the MEN 2 entity and has a more aggressive course. Patients with MEN 2B develop MTC, pheochromocytomas, developmental abnormalities, mucosal neuromas, and intestinal ganglioneuromas. They carry mostly a germline methionine-to-threonine mutation at codon 918 (M918T) in exon 16 of the RET proto-oncogene [9]. The case reported by Yamasaki et al. had a composite retroperitoneal paraganglioma with a M918T germline mutation of the RET proto-oncogene [9]. Patients’ age ranged from 27 years to 59 years, with a male predominance (three men for one woman). Our case was a woman aged 40 years. The adrenal medulla was the most common site of the tumors in the previously reported cases. However, the case reported by Yamasaki et al. had a retroperitoneal CPG. Our patient had bilateral pheochromocytomas with a CP at the right adrenal medulla. The neurogenic components of CPC/PG are, in decreasing frequency: ganglioneuroma, ganglioneuroblastoma, neuroblastoma, malignant peripheral nerve sheath tumors (MPNST), and neuroendocrine carcinoma [2].

The clinical course of CPC/PG is not clearly defined because of the rarity of these tumors. Patients usually present with clinical signs related to hormone hyperproduction, such as headache, palpitations or hypertension. It has been reported in the literature that the prognosis of composite tumors with neuroblastoma (NB), ganglioneuroblastoma (GNB) and MPNST is worse, and the clinical behavior is determined by these components [2]. The behavior of CPC/PG associated with MEN 2 seems to depend on the MCT. In fact, cases reported by Matias-Guiu et al. and Yamasaki et al., as well as our case, had metastasis from MCT [7, 9]. In general, the prognosis of patients with MEN 2 relies on the occurrence of the MCT, as the associated pheochromocytomas or other symptoms often have a benign course [15]. Recently, the American Thyroid Association (ATA) has updated its guidelines for the management of MTC [15]. In fact, the aggressiveness of MTC in MEN 2 depends on the type of RET proto-oncogene mutations, and a subsequent risk stratification has been suggested by the ATA. Patients with MEN 2A and C634 mutation on exon 11, like our patient, have a high risk of aggressive MTC. Patients with M918T RET mutation on exon 16, in patients with MEN 2B, have the highest risk. According to ATA’s guidelines, patients with a high-risk MEN 2 (ATA-H category), like our current patient, should be treated by surgery and their first-degree relatives should be offered genetic counseling and genetic testing for RET germline mutations [15]. In fact, such management has been proposed to our patient’s relatives but we do not know if they have had it done elsewhere, as they have not been screened at our center. The sister of our patient had also undergone surgery for MEN 2A years before; unfortunately, her sister (our current patient) had not been screened until she developed the complete disease syndrome with a locally advanced MTC.

CPC/PGs are very rare tumors and are supposed to have similar clinical behavior of ordinary pheochromocytoma/paraganglioma. The association with MEN 2 is uncommon. We have described here a case of a patient with CPC associated with MEN 2A, together with a review of the literature. Less than 100 cases of CPC/PG have been reported, emphasizing the need for further studies in order to know more about the epidemiological, diagnostic, and prognostic aspects of these rare tumors.