The clinical course, histopathology, and tumor DNA distribution patterns were analyzed in 95 patients with parathyroid cancer. The median follow-up was 6 years (range 1-25 years). Eighteen patients received a benign diagnosis at their first operation. The initial procedure was tumor resection in 42 patients and tumor resection plus partial or total thyroidectomy in 40 patients. Forty patients developed recurrent disease and 36 patients underwent 1 to 9 re-operations. Cervical recurrence and lung metastases were most commonly encountered. The median time from the first operation to recurrence was 33 months (range 1-228 month). Twenty-one patients died of parathyroid cancer a median of 28 months following discovery of their first recurrence. The histopathological reevaluation confirmed unequivocal parathyroid cancer, i.e., infiltration and/or metastases, in 41 cases. Fifty-four cases lacked these criteria but showed various forms of atypia. Image cytometry demonstrated tumor aneuploidy in 26 of 39 cases with definite cancer by histological criteria, compared to the 13 of the 52 with equivocal histological diagnosis. Twelve patients with aneuploid tumors and 7 patients with euploid tumors died of parathyroid cancer. In a multivariate analysis, patients treated with extensive surgery, i.e., tumor resection and unilateral or bilateral thyroidectomy, had a longer survival and a longer relapse-free period. Other factors of importance for survival were age and histopathology. Histopathology and an aberrant nuclear DNA content were important factors for the time to recurrence. We conclude that histopathology alone is unable to confirm a cancer diagnosis in the absence of infiltration and/or metastases. Because recurrence may occur late, patients should be followed closely. Even repeated surgical interventions have proven beneficial.

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The role of viral oncoprotein expression in the maintenance of cellular transformation was examined as a function of time through controlled expression of simian virus 40 T antigen (TAg). Expression of TAg in the submandibular gland of transgenic mice from the time of birth induced cellular transformation and extensive ductal hyperplasia by 4 months of age. The hyperplasia was reversed when TAg expression was silenced for 3 weeks. When TAg expression was silenced after 7 months, however, the hyperplasia persisted even though TAg was absent. Although the polyploidy of ductal cells could be reversed at 4 months of age, cells at 7 months of age remained polyploid even in the absence of TAg. These results support a model of time-dependent multistep tumorigenesis, in which virally transformed cells eventually lose their dependence on the viral oncoprotein for maintenance of the transformed state.