Grant, Clive S.

AbstractWhereas excisional surgery and radiotherapy have resulted in a favorable outcome when non‐Hodgkin's lymphoma of the thyroid (NHLT) is confined to the thyroid gland, controversy persists over the potential advantage of aggressive debulking in favor of diagnostic biopsy alone when disease cannot be completely resected. Our aims in this study were to delineate the present role of surgery in NHLT in pre‐operative staging, the impact of the extent of resection on achieving complete remission and cause‐specific survival, and patterns of failure. All 62 patients who underwent primary surgery for NHLT at the Mayo Clinic between 1965 and 1989 were analyzed. By postoperative staging, 50 patients were stage IE or IIE. Overall survival was 53% and 46% at 5 and 10 years; 80% for stage IE confined to the thyroid, 58% for stage IE‐extrathyroid, 50% for stage IIE, and 36% for stages IIIE and IVE. Complete remission was achieved in 88% of patients who underwent diagnostic biopsy plus adjuvant therapy alone compared to 85% for patients in whom debulking plus adjuvant therapy was used. There was no difference in cause‐specific survival in these two groups or in cause‐specific survival in two subgroups who achieved complete remission. Relapse after complete remission occurred in 12 (26%) of 46 patients, only 2 of whom survived long‐term after salvage therapy. The role of surgery in NHLT is diminishing and advances that will increase complete remission and relapse‐free survival will not likely involve more aggressive surgical resections.

AbstractThree hundred and eighty‐four consecutive patients with primary hyperparathyroidism (HPT) were surgically treated at a single institution during the 2 year period 1983 through 1984. Two patients were found to have benign familial hypocalciuric hypercalcemia and a single patient had parathyroid carcinoma. In the remaining 379 patients, the cure rate was 99.5%, the operative mortality 0.3%, persistent vocal cord paralysis 0.8%, and permanent hypocalcemia 0.3%. This data supports a liberal policy regarding cervical exploration in patients with HPT and questions any policy of observation without surgical intervention.

AbstractIdentification of multiple clinical and pathologic prognostic factors in differentiated thyroid cancer has permitted some degree of risk stratification. However, these clinical indices fail to distinguish potential intrinsic differences in tumor virulence. The nm23 gene has been identified as a potential metastasis suppressor gene that is homologous to nucleoside diphosphate kinases. Studies in human breast cancer have shown a significant inverse correlation between nm23 levels and nodal involvement/tumor recurrence. Given the possible clinical utility of a marker of metastatic potential in the management of thyroid carcinoma, we examined 34 thyroid neoplasms and a human medullary thyroid cancer (MTC) cell line (TT) for nm23 expression. Normalized nm23 expression was assessed by Northern analysis of tumor RNA. nm23 Expression (tumor expression/TT cell expression, mean ±SE) was 1.14 ±0.15* in MTCs (n =5), 0.70 ±0.10* in follicular cancers (n=6), 0.51 ±0.11 in papillary cancers (n=19), and 0.31 ±0.03 in follicular adenomas (n=4) (*p< 0.05 when compared to adenomas). Within histologicgroups, we found no correlation between nm23 expression and nodal involvement or distant métastases. Our results indicate that thyroid neoplasms of different histologies express varying levels of the nm23 transcript. Although nm23 expression seems diminished in metastatic breast cancer, it appears not to be the case in metastatic thyroid cancer. The nm23 gene may therefore have different roles in the evolution and metastases of different neoplasms.

AbstractIn the absence of distant disease, the pathologic diagnosis of malignancy in pheochromocytoma or paraganglioma is impossible. In an effort to establish the true incidence of recurrence in this disease, we have analyzed long‐term follow‐up (average, 15.8 years) of 98 patients who underwent complete resection of localized, noninvasive, histologically‐benign pheochromocytomas and paragangliomas at our institution between 1960 and 1976.Eighty‐eight patients had nonfamilial, sporadic pheochromoctyoma/ paraganglioma. Nine had multiple endocrine neoplasia (MEN) type 2 (2A: 7, 2B: 2), and 1 had familial pheochromocytoma. Seventy‐nine patients had single pheochromocytomas; 10 had single extraadrenal tumors (paragangliomas); and 9 had multicentric or bilateral adrenal tumors.Six patients (6.5%) developed recurrent pheochromocytoma after documentation of normal postoperative urinary catecholamine levels. One of these patients had MEN 2A. The recurrences developed at intervals from 5 to 13 years following initial resection. These were distant in 3 patients, local in 2, and both local and distant in a single patient. None of the recurrences occurred in the 13 patients who, on pathologic rereview, had either local or vascular invasion. No paraganglioma recurred.Life‐long follow‐up of all patients who have had pheochromocytomas or paragangliomas resected is mandatory.

AbstractDistinguishing cellular follicular adenomas (FA) from minimally invasive follicular carcinomas (FC) continues to plague even experienced thyroid pathologists. DNA ploidy analysis has been promoted as a means of making this differentiation; however, the finding of DNA aneuploidy in FA has caused concern that they may demonstrate potential for malignant behavior or should even be reclassified as low‐grade noninvasive cancers. In histologically‐proven FC, nuclear DNA content has been claimed to have predictive power equivalent to that of all other prognostic factors combined. The aims of the present study, therefore, were to define the DNA ploidy characteristics of FA and FC, to assess the diagnostic potential of cell‐cycle parameters, and, in FC, to investigate the prognostic role of such measurements.We measured DNA content of 124 tumors (60 FA, 64 FC). DNA pattern was normal (diploid) in 75% of FA and 45% of FC, tetraploid/polyploid (T/P) in 13% of FA and 25% of FC, and aneuploid in 12% of FA and 30% of FC. FC was histologically verified in 39% of DNA normal, 67% of T/P, and 73% of aneuploid tumors. DNA index, S‐phase, G2M, and S‐phase plus G2M were analyzed and were not helpful in differentiating between FA and FC. No patient with FA developed tumor recurrence. In FC (excluding the Hürthle cell variant), no significant differences were found among the 3 DNA ploidy groups with respect to either cancer death or tumor recurrence; however, combining the Hürthle cell variant of follicular carcinomas with pure follicular carcinomas, the presence of distant metastases, DNA aneuploidy, and patient age were the only independently significant prognostic variables. Based on these data, while not valuable for determining the presence of malignancy, DNA ploidy determination is of major prognostic value in follicular carcinomas (including the Hürthle cell variant).

AbstractDuring a 30‐year period (1951–1981), seventeen patients underwent bilateral adrenalectomy for established adrenal medullary disease with catecholamine excess. Fourteen patients had the MEN IIa syndrome and 3 had the MEN IIb syndrome. There was no major operative morbidity and no operative mortality.One patient died 23 months after initial operation because of metastatic pheochromocytoma. The remaining patients were followed for a mean of 129 months and all were personally interviewed. Three patients had 7 uneventful pregnancies. Twelve patients underwent 23 other surgical procedures requiring general anesthesia during the followup period without any morbidity. Two patients have metastatic pheochromocytoma; 3 have clinical metastatic medullary thyroid carcinoma; 5 patients have high calcitonin values and 6 patients are in excellent health at intervals of 15, 27, 58, 110, 134, and 373 months following resection. The need for adrenal replacement therapy has not caused significant problems in any patient.The results of this study confirm that bilateral total adrenalectomy is a safe modality for the treatment of adrenal medullary disease in this syndrome and that it does not produce significant long‐term morbidity.

AbstractThe surgical management of pancreatic islet cell carcinomas poses a complicated set of questions resulting from their rare occurrence and the difficulty in establishing a diagnosis in early cases or, conversely, the problems inherent in dealing with metastatic disease. However, because their biologic behavior is rather indolent, a real opportunity exists not only for cure but also for meaningful palliation. These goals apply both to the tumor itself and the effects of the hormones they may secrete. The challenge facing the multidisciplinary management team in general, and the surgeon specifically, is to achieve the optimal combination of surgical resection and other treatment options. While the precept of aggressive excision applies to most islet cell carcinomas, it is not universally applicable. In contrast to other islet cell tumors, insulinomas are overwhelmingly benign, and are well treated by enucleation or limited pancreatic resection. Although based on relatively few cases, cytoreductive surgery seems beneficial for malignant insulinomas. Advances that have occurred over the past decade in Zollinger‐Ellison syndrome have markedly altered surgical management. Medication which reliably prevents ulcer formation has permitted the surgical perspective to be redirected from end organ ablation to curative tumor excision. Multicentricity and metastases, however, limit the extent to which cure can actually be achieved. Patients with vasoactive intestinal peptide‐producing tumors and glucagonomas are very rare, and when possible, should undergo tumor resection to correct the severe hormonally caused metabolic derangements. Increasingly recognized are islet cell carcinomas that do not produce clinical syndromes. They may be confused with ductal carcinomas, but when resected, lead to distinctly superior survival rates among patients.

AbstractIn most cases of persistent or recurrent hyperparathyroidism (HPT), the pathological parathyroid (PT) will be in the neck or accessible through the cervical approach, and in only a small percentage will median sternotomy be required. We present 3 cases of persistent HPT where the PT tissue was in the middle mediastinum. We acknowledge that this is a rare occurrence and that it cannot be explained adequately by standard embryological teaching. In cases requiring formal mediastinal exploration, the mediastinal exploration is not complete unless the middle mediastinum is carefully explored to exclude ectopic PT tissue.

AbstractThe prediction of outcome in the rare Hürthle cell tumor of the thyroid continues to present a problem to surgeons and pathologists. To better clarify the distinctions between benign and malignant tumors, we have measured DNA content by flow cytometry on isolated cell nuclei derived from archival paraffin‐embedded tissue blocks of 125 Hürthle cell tumors operated from 1943 to 1985 at the Mayo Clinic, Rochester, Minnesota, U.S.A. Nuclear DNA ploidy patterns were divided into 3 groups. A DNA normal (diploid) pattern was found in 55% of 75 Hürthle cell adenomas and in 26% of 50 Hürthle cell cancers; a DNA tetraploid/polyploid pattern was found in 11% of benign, and 14% of malignant tumors. An abnormal DNA stemline was detected in 34% of benign and 60% of malignant tumors. Hürthle cell cancer was the histologic diagnosis in 24% of the DNA normal, 47% of the DNA tetraploid/polyploid, and 54% of the DNA aneuploid tumors. None of the patients with adenomas developed tumor recurrence. However, 20% of the euploid and 40% of the aneuploid tumors developed local or distant recurrences. Survival to thyroid cancer death was significantly correlated with DNA ploidy status (p=0.02) but did not correlate with either tumor size or histologic grade. To date, deaths from thyroid cancer have been confined to patients whose tumors were DNA aneuploid. We would conclude that determination of DNA ploidy status may not aid the surgical pathologist in the diagnosis of Hürthle cell cancer. However, when a patient's Hürthle cell cancer is DNA aneuploid, there is significant risk of death from thyroid cancer.