The receptor tyrosine kinase RET encoded by the RET proto-oncogene located on chromosome 10, plays a relevant role in the development of the kidney and nervous system.^1,2 RET fusions and activating mutations are associated with thyroid cancer and multiple endocrine neoplasia type 2 respectively.¹ Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal dominant cancer syndrome associated with the M918T mutation in 95% of cases, and is associated with medullary carcinoma of the thyroid in 100% of the cases with a lifetime risk of 50% of developing pheochromocytoma.³ This report aims to show an uncommon case of MEN2B in a young female who developed bilateral pheochromocytoma.

Case Description

The patient was a 24-year-old female diagnosed with MEN2B and medullary thyroid cancer history managed with thyroidectomy 9 years before. Owing to several metastases, the patient underwent multiple neck lymph node resections, a lower left pulmonary lobectomy, and bilateral hip surgery related to pathological fractures.

After long-term followup by the Endocrinology Department, the patient was referred to the Urology Department due to radiological features of bilateral pheochromocytoma on enhanced-abdominal computerized tomography scan.

In the physical examination, the most relevant findings were the asymmetrical chest, scoliosis, and marfanoid habitus. Biological markers were within normal parameters except for urinary metanephrines (1,919 μg/24 hours).

After implementing a multidisciplinary approach, both adrenal glands were removed by laparoscopic surgery without complications during the procedure.

The Pathology Department reported a moderately differentiated pheochromocytoma in both adrenal glands (figs. 1 and 2) with a Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) score of 3 (pattern 1, cellularity 2, necrosis 0, capsular invasion 0, proliferation index Ki 67 0).

Figure 1. Macroscopic image from right and left adrenal glands.

Figure 2. A, panoramic microphotograph of pheochromocytoma (arrow). B, arrowhead shows no invasion within vascular structures in capsule. C, immunohistochemistry images without Ki-67 cell proliferation.

After a 2-year followup, the patient is under surveillance in a good health status: cancer-free with no adrenergic symptoms related to the previous manifestation of pheochromocytoma.

Discussion

The incidence of MEN2B is around 2 per million live births per year.³ For this reason, information in international literature is scarce. Medullary thyroid carcinoma develops during childhood in 100% of the cases, and it’s the main cause of death.³ It is of such great concern that the guidelines of the American Thyroid Association recommend a thyroidectomy before the age of 1 in those children carrying the M918T mutation.³ Unfortunately, the average age of a diagnosis of thyroid carcinoma is in the second decade of life. However, surgery should be considered as the first line of treatment. A followup is mandatory in all patients due to the risk of metastasis and other clinical features such as pheochromocytoma, which is diagnosed at around 25 years of age in MEN2B patients.³ Outcomes are based on microscopic features. The histological pattern, cellularity, necrosis, vascular or capsular invasion, Ki67 labeling index, and types of catecholamines are the parameters used for the GAPP score. A poorly differentiated histologic type has a GAPP score from 7 to 10 which is associated with a metastatic disease rate of 88.2%.⁴ A high GAPP score is characterized by a large and irregular cell nest, high cellularity (more than 250 cells in unit of 10×10 mm micrometer using a high-power field [×400]), necrosis, capsular or vascular invasion, and Ki67 positive in more than 3%, and in the presence of noradrenaline.⁴

The RET protein comprises 2 intracellular tyrosine kinase subdomains: TK1 and TK2. The TK2 domain germline mutation is associated with 95% of MEN2B cases (codon 918), and this specific mutation is related to aggressive cancer behavior and poor outcomes.¹ From all MEN2 cases, MEN2B accounts for 5%, and the codon 918 mutation on exon 16 has been assigned to the higher risk category for aggressive medullary thyroid carcinoma.¹ RET is activated in cancer through chromosomal rearrangements that generate fusion genes containing the kinase domain of RET. RET fusions activate downstream pathways that mediate ligand-independent constitutive activation of the RET kinase and increase RET expression (KIF5B-RET) from 2- to 30-fold.¹ The mechanism responsible for the rearrangements of RET is believed to be the unsuccessful repair of DNA double-strand breaks through nonhomologous end joining and break-induced replication. RET rearrangements were identified for the first time in papillary thyroid cancer in 1987. Recent research suggests that these rearrangements can occur in up to 10% to 20% of papillary thyroid cancers.

Conclusion

MEN2B syndrome is an uncommon clinical condition associated with RET mutations. Medullary thyroid carcinoma accounts for 3% to 5% of thyroid cancer cases, and 25% are related to RET proto-oncogene mutation. In MEN2B patients, medullary thyroid tumors are the main cause of death, and their aggressive behavior is related to M918T mutations. Early thyroidectomy in children (before 1 year of age) is able to modify the clinical course and long-term outcome. A followup in 100% of patients its mandatory owing to a high risk of metastasis and pheochromocytoma.