Parathyroid carcinoma: a case report

Parathyroid carcinoma (PTC) is an extremely rare malignancy that typically presents with severe primary hyperparathyroidism (PHPT). More often the surgeon is confronted with the diagnosis after simple parathyroidectomy for presumed benign parathyroid adenoma. This results in unacceptably high recurrence rate ranging from 1/3-2/3 of patients. Faced with the rarity of the disease and lack of reliable preoperative diagnostic test; a high-index of preoperative and intraoperative suspicion of malignancy is warranted in patients with severe hyperparathyroidism as en-block-resection of the gland along with surrounding adherent tissue during the initial exploration offers the only potential cure of the disease. Herein, we present a 46-year-old lady who presented with severe form of PHPT, eventually proved to be caused by PTC. We will also review the literature related to this extremely rare tumor, highlighting the difficulties encountered in its management.

Keywords: parathyroid carcinoma, parathyroid cancer, hyperparathyroidism 

 

Since its first description by Fritz DeQuervian in 1904(1), PTC remained a diagnostic and therapeutic challenge. This challenge may become even more exaggerated with the advent of minimally-invasive parathyroid surgery (MIP-surgery). Herein, we present a 46-year-old lady who presented with severe PHPT, eventually proved to be caused by PTC. We will also review the literature related to this extremely rare tumor, highlighting the difficulties encountered in its management.

A 46 year old female patient; previously healthy, presented complaining of progressive back pain and polyarthralgia of 10 month duration, associated with polydipsia, fatigue, weakness, anorexia, weight loss, vague abdominal pain and constipation. Her family history was negative for endocrine diseases. Physical examination showed blood pressure of 220/130. There was a 3x4 cm mass in the inferior angle of right carotid triangle of the neck that was felt on swallowing. Pelvis X-ray showed multiple osteolytic lesions (figure I) and the lumbosacral spine X-ray showed generalized osteopenia. Lumbosacral CT scan showed bilateral fracture of pars interarticularis of L5 with mild degree of spondylolisthesis of L5 over S1.  MRI of the lumber spine was requested and it revealed a mild annular disc bulge at L4/L5 & L5/S1. Due to presence of the osteolytic lesions, the patient was admitted for study. Lab tests revealed hypercalcemia, hypophosphatemia with very high alkaline phosphatase (nine times the upper normal limit) (table I). Hand XR showed typical findings of parathyroid bone disease (osteitis fibrosa cystica) with erosions of distal phalanges; subperiosteal resorption and multiple bone cysts (fig. 2). Parathyroid hormone level was requested and it was found to be 1294; about 18 times the upper normal limit. The patient had no renal disease by renal ultrasonography (US) and normal urea and creatinine. Based on all these findings, the patient was diagnosed to have primary hyperparathyroidism. Neck US was thus requested and revealed 3x2.5 cm lobulated hypoechoic solid mass lesion related to lower pole of the right thyroid lobe. The Tc-99 MIBI parathyroid scan confirmed the presence of a functioning parathyroid tumor of the right inferior parathyroid gland (fig. 3).

Table I:  Laboratory results 

 

 

Based on this diagnosis; the patient underwent neck exploration. Operative findings include a 3.5x3x2.5 right inferior parathyroid gland weighting 11.8 grams which was whitish, hard and lobulated, and firmly adherent to carotid sheath and trachea (fig. 4&5). It was resected with difficulty en block with surrounding tissue. No lymphadenopathy was present. Histopathological examination of the resected tumor confirmed the diagnosis of parathyroid carcinoma (figure 6a-h). Five-years postoperatively, the patient was alive and free of recurrence.

PTC is a rare malignancy with an estimated incidence of 5.7 per 10,000,000 populations in USA in 2000-2003(2). It accounts for 0.7-5.5% of cases of primary hyperparathyroidism with the higher numbers reported in Italy and Japan. (3) It usually occurs in 4th-5th decade, with no gender predilection, unlike the much commoner parathyroid adenoma which typically affects women (female: male ratio of 3-4:1) in their 5th-6th decade. (2-4) We have searched our pathology database and found four cases of PTC diagnosed between 2000 and 2015. Although genetic predisposition, chronic renal failure and exposure to radiation have been suggested as etiologic factors, most patients have sporadic disease with no obvious etiologic factor. On the other hand, primary hyperparathyroidism is quite common with a prevalence of 0.1-0.3% in the general population. It’s usually diagnosed incidentally by hypercalcemia on routine chemistry lab test in asymptomatic patients.(5) Rarity of the disease poses the first challenge in management, with most of our knowledge derived from case reports, small case series and reviews.

Other Challenges encountered in management include 1) lack of reliable method for preoperative diagnosis 2) difficulty encountered in diagnosing parathyroid carcinomas even on permanent histopathological slides 3) no consensus on the most appropriate surgical intervention. Most importantly, en block resection of malignant parathyroid gland along with adherent surrounding tissue is the only potential curative treatment available with particular attention not to violate the tumor capsule, or else, local difficult to treat and potentially lethal recurrence is inevitable. Conversely, benign parathyroid adenoma can be easily excised using MIP-surgery.

A high degree of preoperative and intraoperative suspicion is thus warranted for optimal management of patients with parathyroid carcinoma.(6)

Patients with PTC typically presents with severe hyperparathyroidism with the classical description of “pain in bones, renal stones, abdominal groans & psychic moans”.  This contrasts well with benign parathyroid disease which is most commonly diagnosed by finding mild hypercalcemia in asymptomatic patients. The presence of severe hypercalcemia (>14mg/dL), highly elevated parathyroid hormone level (> 5 folds of upper limit of normal), palpable neck mass, vocal cord paralysis with no previous neck surgery, severe bone disease and/or renal disease raise the suspicion of malignancy. (7-10)

 Preoperative FNAC is contraindicated for the fear of tract seedling notwithstanding that it is useless in diagnosis. Intraoperative finding of large (>3cm) hard lobulated grey-white adherent tumor is also considered a worrisome sign and should be managed as parathyroid cancer. Frozen section is not warranted since it is difficult to diagnose PTC even on permanent section and it rarely add to management. (11-12)

Although the histopathological characteristics of PTC described in 1973 by Schantz and Castleman (13) are still used for diagnosis; none of them is pathognomonic pf PTC and occur frequently in typical and atypical parathyroid adenoma as well as in parathyromatosis. (14-15) Apart from distant or locoregional metastases; there is no absolute diagnostic criterion of malignancy on pathologic examination. However; taken together with the clinical presentation of severe hyperparathyroidism; parathyroid carcinoma should be considered and the patient should be followed up for a long time. To date; no staging system is adopted for this rare entity due to its rarity and lack of sufficient data regarding its biological behavior and prognosis. (16)

There is no consensus on the optimal surgical treatment of PTC, with reports ranging from simple parathyroidectomy to resection of the involved gland en-block with adherent surrounding tissue including the ipsilateral thyroid lobe to radical 4-gland exploration with or without modified neck dissection. (17-19) The risk of lymph node involvement has been reported to be low in most reviews and local recurrences occur primarily in the surrounding soft tissue rather than in lymph nodes. Additionally; lymph node involvement does not seem to poorly affect prognosis . (20-21)  In the absence of controlled randomized studies; en-block-resection of the gland along with adherent tissue and grossly abnormal lymph nodes offers a compromise avoiding the high recurrence rates associated with simple parathyroidectomy while minimizing the high complication rates associated with 4-gland exploration and neck dissection. The role of minimally-invasive parathyroid surgery is evolving; however, it’s still early to recommend it if the preoperative or intraoperative suspicion of carcinoma is high. (22-23)

Recurrence rate is high ranging from 1/3-2/3 of patients, particularly in patients operated with the assumption that they have adenoma and diagnosed on histopathological examination to have carcinoma. Recurrence typically occurs within 3-years from initial surgery, however, recurrences after 20-years of primary surgery has been reported (23-25). These tumors are slowly-growing and kill by the metabolic effects of severe hypercalcemia, rather than by tumor invasion. Surgical resection is indicated for locoregional recurrences and metastases when feasible, given the limited role of radiotherapy and chemotherapy. (17, 25) 

As in all fields of medicine, molecular biology is assuming an ever increasing importance. Parathyroid carcinoma is no exception and studies in this field are ongoing and may add to diagnosis and treatment of parathyroid carcinoma in the future.(25-28)

In the view of rarity of parathyroid carcinoma, lack of preoperative definite diagnosis and the high rate of treatment failure with less than aggressive en-block-resection, it is justified for the treating surgeon to assume the presence of parathyroid carcinoma in all patients with severe symptomatic primary hyperparathyroidism, with combined renal and bone disease, extremely high serum calcium and parathyroid hormone level or suspicious intraoperative findings. In the hand of experienced surgeon; this policy may reduce the recurrence rate without increasing potential complications. 

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