Pheochromocytomas are rare neuroendocrine tumors. They could be adrenal vs. extra-adrenal, sporadic vs. familial, isolated vs. multifocal, or benign vs. malignant. MAX gene mutation has recently been recognized as an unusual cause of familial pheochromocytoma.
This article documents the first patient with simultaneous germline MAX mutation, pituitary prolactinoma, bilateral pheochromocytoma and mild primary hyperparathyroidism.
Could the germline MAX mutation be a direct cause of prolactinoma as well?
J of Endocrine Society
Pheochromocytomas are neuroendocrine tumors that can arise sporadically or be inherited as a familial disease, and they may occur in isolation or as part of a multitumor syndrome.
Familial disease typically presents in younger patients with a higher risk of multifocality. Recently, the tumor suppressor MYC-associated factor X (MAX) gene has been implicated as a cause of familial isolated pheochromocytoma and paraganglioma.
We describe a patient with a pituitary prolactinoma and bilateral pheochromocytomas who tested positive for a germline MAX mutation. Interestingly, the patient also had mild primary hyperparathyroidism that resolved upon resection of the pheochromocytomas despite the absence of parathyroid hormone staining in the tumors.
To our knowledge, this case is the first report of prolactinoma in a patient with a MAX mutation, which suggests the possibility of germline MAX mutations also contributing to the development of prolactinomas.
More from the publication:
Pheochromocytomas are rare tumors derived from neural crest cells in the adrenal medulla. Tumors overproduce catecholamines, leading to symptoms such as hypertension, palpitations, perspiration, headaches, pallor, and tremors. Studies have revealed that up to 20-40% of pheochromocytomas are familial.
FAMILIAL pheochromocytomas can be associated with genetic syndromes such as multiple endocrine neoplasia type 2 (MEN2, RET proto-oncogene mutation), von Hippel–Lindau disease (VHL mutation), and neurofibromatosis type 1 (NF1 mutation), but they may also present in ISOLATION, as in the case of succinate dehydrogenase complex (SDH A, B, C, D, and AF2), and transmembrane protein 127 (TMEM127) mutations. Comino-Méndez et al. recently identified mutations in the tumor suppressor MYC-associated factor X gene (MAX) as a cause of hereditary pheochromocytoma.
They examined 62 patients with pheochromocytomas and detected unique MAX mutations in eight families, totaling 12 affected patients.
An investigation of 1694 pheochromocytoma/paraganglioma patients without mutations in RET, VHL, SDHB, SDHC, SDHD, or TMEM127 identified germline MAX mutations in 23 patients and somatic MAX mutations in 4 of 245 tumors. These MAX mutation carriers included patients with bilateral pheochromocytomas, as well as multiple pheochromocytomas within the same gland. Another study of 153 pheochromocytoma/paraganglioma cases in patients presenting under age <40 years with multiple tumors identified genetic mutations in 73 patients (47%), one of which was a MAX mutation.
GERMLINE MAX mutations have been associated with pheochromocytoma, paraganglioma, and renal oncocytoma, whereas SOMATIC MAX mutations have been linked to formation of other tumors, including endometrioid carcinoma, colon carcinoma, and small-cell lung carcinoma.
Benign pituitary adenomas can be sporadic, familial, or part of a genetic syndrome. The most common inherited forms of pituitary adenoma are multiple endocrine neoplasia type 1 [menin 1 (MEN1), cyclin-dependent kinase inhibitor 1B (CDKN1B) genes], familial isolated pituitary adenoma [aryl hydrocarbon receptor–interacting protein (AIP) gene], and Carney complex [protein kinase cyclic adenosine monophosphate–dependent type 1 regulatory subunit α (PRKAR1A) gene].
Pituitary adenomas and pheochromocytomas/paragangliomas are rarely part of the same syndrome.
A recent report of 39 patients with pheochromocytoma/paraganglioma along with a pituitary adenoma detected germline mutations in SDHB/C/D, VHL, and MEN1 but failed to identify any MAX mutations. We describe a patient who presented with a pituitary prolactinoma, an endocrine disease not previously associated with MAX mutations, who was found to have bilateral pheochromocytomas and a germline MAX mutation.
We describe a patient who presented with a prolactinoma and was found to have bilateral pheochromocytomas and a novel MAX mutation. Although MAX mutations have been demonstrated to cause familial pheochromocytomas, to our knowledge, this is the first report of a pituitary adenoma in a patient with a MAX mutation. Immunohistochemistry revealing loss of the MAX protein in the patient’s pheochromocytoma cells suggests that this novel mutation of MAXwas responsible for tumorigenesis. Loss of heterozygosity studies would have been useful in confirming the loss of the normal MAX allele at the genetic level. Tissue from the pituitary tumor is not available for analysis; therefore, it is impossible to directly implicate a MAX mutation as a causative event for tumor formation. The pituitary adenoma could be a coincidental finding in this patient with a germline MAX mutation.
MAX has been shown to behave as a classical tumor suppressor gene, with loss of heterozygosity of the normal allele in tumors carrying pathogenic mutations. The MAX protein interacts with the MYC proto-oncogene and the MAX dimerization protein 1 (MXD1) family of proteins. MAX mutations appear to cause pheochromocytoma by failing to control MYC signals for cellular proliferation.
Consistent with findings from other pheochromocytomas harboring MAX mutations, our patient’s tumor secreted normetanephrine in a greater proportion than metanephrine. An interesting aspect of this case was the inconsistent uptake of [123I] MIBG in the adrenal lesions. The absence of [123I] MIBG positivity could reflect the varying degrees to which pheochromocytomas, particularly dedifferentiated tumors, accumulate MIBG.
On presentation, the patient had mild primary hyperparathyroidism, which normalized after removal of the pheochromocytomas. Rarely, pheochromocytoma can cause hypercalcemia, which is thought to be mediated either by a primary process of the parathyroid glands (associated with multiple endocrine neoplasia) or directly from the pheochromocytoma, likely due to secretion of parathyroid-related protein. Our patient’s hypercalcemia improved after adrenalectomy, without intervention to the parathyroid glands. Hypercalcemia mediated by parathyroid-related protein secreted from the pheochromocytoma would be expected to suppress PTH levels, but this was not the case in our patient. Therefore, we hypothesized that the pheochromocytoma might secrete PTH ectopically, but immunohistochemistry was negative for PTH; thus, the source of primary hyperparathyroidism remains unclear.
This case is important in that, to our knowledge, it is the first report of a pituitary tumor, specifically a prolactinoma, in combination with pheochromocytomas in a patient with a germline MAX mutation. It raises the question of whether MAX mutations could cause a syndromic disease involving pituitary tumors in addition to pheochromocytomas/paragangliomas. Because MAX mutations are rare events, observations from case reports are important to identify potentially related clinical sequelae.