Biologic Markers

Parathyroid cells are characterized by very low turnover. Parfitt proposed a model of tumor formation starting from a

FIGURE 63-1. Histologic section from a parathyroid carcinoma with enlarged nuclei and macronucleoli. (From Bondeson L, Sandelin K, Grimelius L. Histopathological variables and DNA cytometry in parathyroid carcinomas. Am J Surg Pathol 1993;17:825.)

set-point mutation leading to cell proliferation. Further mutational events that occur in the cell cycle can cause tumor formation that is either benign or malignant.30

An altered DNA content (i.e., nondiploid) has been associated with a proliferative state of the tumor as a result of genetic instability. It is considered one of the earliest cellular events during malignant transformation. Numerous studies have demonstrated a relationship between the DNA content of the tumor cell nuclei and the clinical outcome. Patients with diploid tumors fare better than those whose tumors contain an aberrant crude DNA content.3134 The ploidy pattern remains stable during tumor progression, as has been shown in studies of primary tumors and metastases. Quantitative DNA assessments have been performed in parathyroid carcinomas, and contradictory results were obtained.2'9'27-29-35"43 In the series of 95 cases, there was a clear association between an aberrant DNA content and an infiltrative growth pattern. The clinical course, measured as freedom from disease, also correlated with the DNA content.2 When the DNA content was related to morphologic and cytologic features, significant associations were found between aberrant DNA values and the presence of necrosis, nuclear atypia, and mitosis.29

The proliferative activity, measured as percentage of cells in S phase, was significantly higher in a group of 15 parathyroid carcinomas compared with 31 normal and benign tumors.39 A number of cell cycle markers such as mitotic figures have been used to assess the malignancy potential of parathyroid tumors. The cellular phosphoprotein

TABLE 63-2. Histologic and Cytologic Characteristics of all Tumors Reviewed

Parathyroid Cancer Equivocal Cases

TABLE 63-2. Histologic and Cytologic Characteristics of all Tumors Reviewed

Parathyroid Cancer Equivocal Cases

Features

= 56)

(u - 39)

Fibrosis

45

(80%)

22 (56%)*

Trabecular growth

11

(20%)

14 (36%)

Necrosis

20

(36%)

3 (8%)*

Nuclear atypia

35

(63%)

10 (26%)*

Pleomorphism

25

(45%)

6(15%)

Macronucleoli

29

(52%)

6(15%)«

Large nuclei

10

(18%)

3(8%)

Oxyphil tumor

6

(11%)

Mixed cell types

10

(18%)

6 (15%)

(n

= 50)

(fl = 36)

Mitoses

38

(76%)

10 (28%)*

<5/50 HPF

11

(22%)

4 (11%)

5-25/50 HPF

16

(32%)

2 (6%)1

>25/50 HPF

11

(22%)

4(11%)

"Significance levels by Fisher's exact test, P < 0.05. 1P< 0.010. <P< 0.001.

HPF = high-power field.

From Bondeson L, Sandelin K, Grimeiius L. Histopathological variables and DNA cytometry in parathyroid carcinomas. Am J Surg Pathol 1993; 17:820.

"Significance levels by Fisher's exact test, P < 0.05. 1P< 0.010. <P< 0.001.

HPF = high-power field.

From Bondeson L, Sandelin K, Grimeiius L. Histopathological variables and DNA cytometry in parathyroid carcinomas. Am J Surg Pathol 1993; 17:820.

p53 is a cell cycle regulator, and its role is to inhibit the progression of cells from Gi to S phase. Mutations of the p53 gene are common in human malignancies. However, neither benign nor malignant parathyroid tumors have been found to have p53 mutations.44 The parathyroid adenomatosis 1 gene (PRADHcyclin Dl) encodes a protein closely associated with the cyclins that are important cell cycle regulators. Approximately 5% of benign parathyroid tumors have shown rearrangements of the PTH gene and PRAD1 on chromosome 1145,46 same group of investigators reported that the retinoblastoma tumor suppressor gene RB, also a cell cycle regulator, was inactivated in parathyroid carcinomas. This was further supported by loss of expression, as determined by immunohistochemical staining. Conversely, benign parathyroid neoplasms showed no inactivation or loss of expression of RB.41 Frequent chromosomal imbalances were found in a series of 29 carcinomas studied with comparative genomic hybridization.48 The gene encoding HPT-JT is a tumor suppressor gene called PARAIBROMIN, and its location is mapped to Iq21-q32. There is reduced penetrance in females, and only 10% to 15% of patients manifest with a parathyroid carcinoma although serum calcium is markedly elevated.49 Two articles have reported the presence of somatic and germline mutations of the HRPT2 gene in sporadic parathyroid carcinoma.50,51

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