October 2016

A 32 year-old woman with a nodule on her neck

Derrick Green, M.D., H. James Williams, M.D.

Overview

A 32 year-old woman presented to her primary care physician with the chief complaint of a nodule on her left neck.  Physical examination revealed a single firm nodule within the mid portion of the left thyroid gland.  A thyroid ultrasound was ordered and revealed a predominantly solid, hypoechoic mass within the left thyroid gland which was suspicious for a neoplasm. Based on the FNA results, a subsequent serum calcitonin was150 pg/mL. A CT scan revealed a mass within the right adrenal gland.  No other masses or lesions were identified.

Gross Description

Pathologic findings in the thyroid are shown in Figures 1 and 2. A subsequent right adrenalectomy revealed the pathologic findings in Figures 3 and 4. Genetic testing revealed a mutation.

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Figure 1. (H&E 2x) The tumor (arrow) forms a large mass which infiltrates through bands of fibrous tissue impinging upon adjacent normal thyroid.
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Figure 2. (H&E 10x) The tumor cells have abundant eosinophilic cytoplasm and are arranged in a predominantly spindle cell pattern with a few having a rounded, polygonal appearance. Amorphous eosinophilic material is scattered throughout the tumor (thin arrows). Adjacent benign thyroid is present at the bottom of the picture (thick arrow).
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Figure 3. (H&E 2x) The adrenal tumor is adjacent to normal adrenal cortex and periadrenal fat (small arrow). The tumor mass (large arrow) is seen arising from and replacing the adrenal medulla.
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Figure 4. (H&E 10x) The tumor cells have a “Zellballen” arrangement forming nests of cells with abundant basophilic cytoplasm and low N/C ratio.

Diagnosis

Which of the following genes/gene families is most likely involved in the pathogenesis of this syndrome?

Answer

Please select an answer above.

Discussion

The presence of medullary thyroid carcinoma and pheochromocytoma is seen in MEN (multiple endocrine neoplasia) type 2 and is associated with the RET proto-oncogene.  MEN 2 was originally described in 1968 as a case report involving a family with concurrent medullary thyroid cancer (MTC), pheochromocytoma, hyperparathyroidism, and Cushing’s syndrome.  Multiple endocrine neoplasia 2A (MEN 2A), also known as Sipple syndrome, is a hereditary syndrome characterized by MTC, pheochromocytoma, and primary hyperparathyroidism.1   The other multiple endocrine neoplasia syndromes include MEN I (Werner syndrome) and MEN 2B (Gorlin syndrome) each with their own characteristic constellation of tumors.  MEN I is characterized by pituitary adenomas, pancreatic neuroendocrine tumors, and parathyroid hyperplasia, while MEN 2B is characterized by MTC, pheochromocytoma, mucosal neuromas, and various skeletal abnormalities.1,2  In addition to the genetic testing performed, the lack of mucosal neuromas helped to exclude MEN 2B as they are present in close to 100% of cases of MEN 2B.3

The RET proto-oncogene has a gain of function mutation in most cases of MEN 2A which leads to the constitutive activation of the protein with subsequent unregulated cell growth.4  This the underlying molecular abnormality responsible for the disease manifestations.1 The RET gene encodes a transmembrane receptor tyrosine kinase and is located on chromosome 10q11.2  RET is expressed in cells derived from the neural crest, the branchial arteries, and the urogenital system.5  RET is also expressed in other disease entities including parathyroid carcinoma, lung adenocarcinoma, chronic myelomonocytic leukemia, and Hirschsprung disease.6  The clinical presentation may vary depending on which neoplasm predominates and thus causes symptoms.

Medullary thyroid carcinoma is often the first tumor to develop.  If MTC is the predominant neoplasm, most patients will present in the second to third decades of life with a solitary thyroid nodule.1  Both MEN 2A and MEN 2B carry a nearly 50% risk for the development of a pheochromocytoma, and in these cases about 50% will be bilateral.    The extra-adrenal counterpart to the pheochromocytoma is the paraganglioma.  If a pheochromocytoma is the initial tumor manifestation, the patient will likely present with symptoms of adrenergic overstimulation such as palpitations, headache, and diaphoresis due to the excessive secretion of epinephrine and norepinephrine by the tumor.   However, up to 25% of cases will be entirely asymptomatic.4  

The initial diagnostic workup of a person with MEN 2A includes:  referral to an endocrinologist and genetic counselor.  Laboratory testing for plasma calcitonin levels, catecholamines and metanephrines, and serum calcium and parathyroid hormone are performed.  A workup for metastatic disease in individuals with MTC includes a CT scan with contrast of the chest and abdomen.  An MRI of the liver is indicated if nodal disease is present or if the serum calcitonin is > 400 pg/mL.7

References

  1. Yulong L, Simonds WF. Endocrine neoplasms in familial syndromes of hyperparathyroidism. Endocrine Related Cancer. 2016; 23: R229-R247.
  2. Kniffin C, McKusick V, Colton M. Multiple Endocrine Neoplasia, Type IIA MEN2A #171400. OMIM [serial online]. 2014. http://www.omim.org/entry/1714003 Accessed July 27, 2016.
  3. Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome). Journal of Medical Genetics. 1996; 33(9): 779-82.
  4. Mazzaglia PJ. Hereditary pheochromocytoma and paraganglioma. Journal of Surgical Oncology. 2012; 106(5): 580-585.
  5. Pachnis V, Mankoo B, Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development. 1993; 119: 1005–1017.
  6. Wells Jr SA, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25(6): 567–610.
  7. Marquard J and Eng C. Multiple Endocrine Neoplasia Type 2. Gene Reviews. June 2015. http://www.cancer.net/cancer-types/multiple-endocrine-neoplasia-type-2/multiple-endocrine-neoplasia-type-2. Accessed July 27, 2016.