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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Parathyroid carcinoma

.

Department of Surgery, Karolinska Hospital, Stockholm, Sweden

The first published paper on a presumed parathyroid carcinoma was that by Mandl in 1925. The features described are still valid for a diagnosis of carcinoma such as symptomatic hypercalcemia, gross tumor adherent to an adjacent structure and recurrent disease (grade C). Since then, some 250 papers on parathyroid carcinoma have been published, mostly anecdotal reports or historic cohort or case series.

Incidence

Among patients with primary hyperparathyroidism (PHPT), the mean incidence of parathyroid carcinoma is 2% (range 0.3–5.6) (grade C). Centers that reported these figures are referral centers and the number of PHPT operations vary substantially between them (table I).

Table I. Incidence of parathyroid carcinoma.

Table I

Incidence of parathyroid carcinoma.

Diagnosis

General features

There are no clinical differences in a symptomatic patient suffering from benign or malignant PHPT. The treatment is no different except an en bloc resection is done if a contiguous structure is invaded. Females and males are equally affected and age of onset lies around 50 years (grade C). Among 95 patients in a collected series that were classified to have parathyroid carcinoma, the initial diagnosis was benign PHPT in 19% (grade C). Symptomatic hypercalcemia affects renal function, the skeleton, the crebebrum and results in polydipsia, polyuria, nephro- or ureterolithiasis and osteolytic bone changes that occur from long-standing elevated serum parathormone (grade C). Pancreatitis due to hypercalcemia occurs less often (grade C). Mood changes, such as fatigue, depression and muscular weakness are common findings. A palpable cervical mass occurs but was found in only 20% in the collective series of 95 patients (grade C). Symptomatic hypercalcemia is treated by rehydration, loop diuretics, calcitonin and, or bisphosphonates (1).

A diagnosis of parathyroid cancer is seldom made preoperatively. Only in the reoperative setting are localization studies of additional value, provided that unilateral neck exploration is not part of the routine procedure where different non invasive and invasive scanning modalities are used. Localization studies include, computed tomography, sestamibi scintigraphy, venous selective sampling (grade C).

Operative findings

The first operation offers the best opportunity for cure (grade C). All parathyroid tumors should be removed en bloc without breaking into their capsules in order to avoid seeding of parathyroid cells that may implant and cause locally recurrent disease (grade C). Making the distinction between benign parathyromatosis and a malignant tumor recurrence is very difficult (grade C). Whether more extensive operations including cervical lymph node dissections are beneficial is doubtful. Furthermore, the diagnosis of cancer during the initial operation may not be confirmed or even suspected (grade C). Macroscopically, parathyroid carcinomas are usually described as being firm, gray-whitish, and may be densely adherent or locally invasive (grade C).

Histopathologic findings

When the malignant diagnosis is based on histopathologic criteria only, there is a tendency to overdiagnose due to the fact that parathyroid carcinoma is such an unusual neoplasm (grade C). When a detailed morphologic study was done in the collective series of 95 patients, two groups of tumors were formed, one with unequivocal signs of malignancy (n = 56), i.e. invasive growth into neighboring structure, and or recurrent/ metastatic disease. The second group (n = 39), lacked these criteria but showed morphologic features of nuclear atypia, fibrous bands, mitotic figures in various frequency and combinations of these findings.

In particular, a marked nuclear atypia and frequent mitoses counted in high power field (HPF) were significantly more common among locally aggressive tumors. Also a significant association was seen between an aberrant DNA pattern, fibrosis and frequent mitoses (> 5/HPF). However, some tumors that did recur, lacked either one or more of these features in those sections that were studied (grade C).

Molecular markers

To increase the diagnostic accuracy, a number of molecular markers have been assessed to evaluate their validity as prognostic signs of malignancy and tumor aggressiveness but also to serve as an adjunct in cases where there was no clear cut invasion found or metastatic disease present. Data on somatic loss of TP53, loss of retinoblastoma protein expression, increased proliferate index measured by Ki67 immunostaining have so far not been found to be independently reliable (2, 3).

Recurrent metastatic disease

Cervical implantation from parathyroid carcinoma is the most common manifestation of recurrence and distant spread affects the lungs, the liver, the skeleton and the brain. Time to recurrence varies as parathyroid carcinoma can have a slow progressive course (grade C) (4). Because late recurrences occur, patients should be followed periodically for life.

There is unanimous support for reoperative procedures for both local and distant metastatic disease (grade C) (4).

The goal of medical treatment is to render the patient eucalcemic. Toxic and short term acting agents like mithramycin and calcitonin are not recommended for longer use. Bisphosphonates are better tolerated and are less toxic when used repeatedly. There are only anecdotal reports of the use of chemotherapy and radiotherapy regimens. These options must be assessed on an individual basis (1).

Prognosis

The clinical course varies from an aggressive rapidly recurrent disease to a slowly progressive disease. The initial procedure may have cured the patient if no recurrence is detected (grade C). In 40 patients with metastatic parathyroid carcinoma, the actuarial survival was 35% after five years. These figures can be compared to a 75% cumulative survival in the 95 patients with an initial cancer diagnosis (grade C) (4).

Conclusion

Parathyroid carcinoma occurs in a very low percent of patients with PHPT. The clinical picture of that resembles that of acute hyperparathyroidism and should be treated likewise. Surgical management by removal of all tumor en bloc offers the best chance for cure. The clinical course varies and late recurrences occur. Morphologically, some carcinomas show marked fibrosis, cellular atypia, and mitotic figures which often correlates with an aggressive clinical course. Cervical recurrences and metastatic disease can often be removed surgically and may render patients eucalcemic for extended periods of time.

References

1.
Belizikian JP, Singer FR (1994) Acute management of hypercalcemia due to parathyroid hormone and parathyroid hormone related protein. In: Belizikian JP, Levine MA, Marcus R (eds) The parathyroids. Raven Press, New York, pp 359–372 .
2.
Lloyd R V, Carney A J, Ferreiro J A, Long J, THompson G B, van Heerden J A. et al. Immunohistochemical analysis of the cell cycle asociated antigens Ki-67 and retinoblastoma protein in parathyroid carcinomas and adenomas. Endocr Pathol. (1995);4:279. [PubMed: 12114810]
3.
Farnebo F, Auer G, Farnebo L. et al. Evaluation of RB and Ki-67 immunostaining as diagnostic markers in benign and malignant parathyroid disease. World J Surg. (1999);23:68–74. [PubMed: 9841766]
4.
Sandelin K, Tullgren O, Farnebo L. et al. Evaluation of RB and Ki-67 immunostaining as diagnostic markers in benign and malignant parathyroid disease. World J Surg. (1999);23:68–74. [PubMed: 9841766]
5.
Sandelin K, Tullgren O, Farnebo L. Clinical course of metastatic parathyroid cancer. World J Surg. (1994);18:594–599. [PubMed: 7725750]
Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK7004

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