Section E

CASE

A 55 year old female patient consulted the ER due several fatigue nausea with changes on sensorium
for several days. PE: neck 5 cm x 5 cm mass hard nontender with palpable cervical lymph nodes. Serum
calcium 16 mg/dL

Questions:

What is the diagnosis?

Primary Hyperparathyroidism Secondary to Parathyroid Carcinoma

Parathyroid cancer accounts for approximately 1% of Primary Hyper Parathyroidism (PHPT) cases. It
may be suspected preoperatively by the presence of severe symptoms, serum calcium levels >14 mg/dL,
significantly elevated PTH levels (five times normal), and a palpable parathyroid gland.

What are the diagnostic workups?

An accurate diagnosis necessitates histologic examination. Major diagnostic criteria include vascular or
capsular invasion, trabecular or fibrous stroma, and frequent mitoses.

Treatment of parathyroid cancer consists of neck exploration, with en bloc excision of the tumor and
the ipsilateral thyroid lobe, in addition to the removal of contiguous lymph nodes (tracheoesophageal,
paratracheal, and upper mediastinal). The recurrent nerve is not sacrificed unless it is directly involved
with tumor. Adherent soft tissue structures (strap muscles or other soft tissues) should also be resected.

Modified radical neck dissection is recommended in the presence of lateral lymph node metastases.
Prophylactic neck dissection is not advised. If the diagnosis is made postoperatively, a decision must be
made regarding the adequacy of initial surgery based on a review of operative notes, pathology reports,
localization studies, and calcium and PTH levels. If any question exists, histologic review by another
experienced pathologist can be helpful.

Additional procedures can include ipsilateral thyroid lobectomy with resection of contiguous structures
and lymph nodes if the features are typical or the patient remains hypercalcemic. Patients with
equivocal pathologic findings and normocalcemia may be monitored closely. Reoperation is indicated
for locally recurrent or metastatic disease to control hypercalcemia.

Adjuvant radiation therapy should be considered in patients at high risk of local recurrence such as
those with close or positive margins, invasion of surrounding structures, or tumor rupture.

Radiation may also be used as primary therapy in unresectable disease or for palliation of bone
metastases. Chemotherapy is not very effective.

Bisphosphonates have shown some effectiveness in treating hypercalcemia associated with parathyroid
carcinoma. Cinacalcet hydrochloride, a calcimimetic, can reduce PTH levels by directly binding to the
CASR cells on the parathyroid gland and has been shown to be useful in controlling hypercalcemia in
patients with refractory parathyroid carcinoma.
Other promising approaches include antiparathyroid hormone immunotherapy, octreotide, and the
telomerase inhibitor azidothymidine, but additional investigations are needed in this area.

Discuss the pathophysiology of this condition?

The exact cause of PHPT is unknown, although exposure to low-dose therapeutic ionizing radiation and
familial predisposition account for some cases causing formation of mass in the parathyroid gland itself
that may increase the level of parathyroid hormone that elevates also the calcium level of the patient
while oncogenes and tumor suppressor genes have been linked to parathyroid carcinomas, especially
those involved in the control of cell cycle. There is no definitive evidence of a primary role but altered
expressions of these genes may play a part in the process of malignant transformation. Five genes with a
potential role in malignancy have been identified and studied: p53, breast carcinoma susceptibility
(BRCA2), cyclin D1/parathyroid adenomatosis gene 1 (PRAD1), retinoblastoma tumor suppressor gene
(RB) and hyperparathyroidism 2 tumor suppressor gene (HRPT2). The HRPT2 gene has provided the best
evidence. This gene is also responsible for the hyperparathyroidism with jaw-tumor syndrome (HPT-JT).
HPRT2 encodes a protein called parafibromin (parathyroid disease and fibro-osseous lesions) which is a
tumor suppressor protein. Cyclin D1 is highly expressed in parathyroid carcinomas, PCA specimens were
positive for cyclin D1 over expression compared with 39% (11/28) of the adenoma specimens. Cyclin D1
over expression may be a result of loss of parafibromin expression.