Hay, Ian

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.

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.

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).

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.

Abstract The ability to differentiate benign from malignant Hürthle cell thyroid neoplasms has provoked considerable controversy. This has significant therapeutic implications, since some have advocated total thyroidectomy for all of these lesions. The principal objectives of this study were: (a) to determine whether the histologic diagnosis of Hürthle cell adenoma could be reliably made, (b) to quantitate the risk of inappropriately labelling a Hürthle cell cancer as an adenoma, and (c) to ascertain whether the type of operative procedure affected the clinical course . We reviewed 272 patients who had undergone thyroid resection for benign Hürthle cell neoplasms at the Mayo Clinic from 1960 to 1980. All pathologic sections were rereviewed. Postoperative follow‐up was available on 233 patients (86%), with a mean of 8.9 years. A minimum of 5 years of follow‐up was obtained on 10% of the patients. Nodules ranged in size from 0.3 to 11 cm; 195 (55%) were 2 cm or larger. Surgical resection was limited to one side in 137 (50%) patients and involved both sides in 135 patients. No total thyroidectomies were performed. Evidence of malignancy—a local recurrence—developed in only 1 patient, and she died of unrelated causes. None of the 272 patients died of thyroid cancer, and none showed evidence of metastases. Our data is in agreement with most published reports, with only 6 (0.9%) of 642 reported patients being diagnosed incorrectly. These tumors can be accurately separated into benign and malignant. Routine total thyroidectomy for Hürthle cell adenomas is not justified .

Abstract The PAX8/PPARγ (PPFP) fusion-oncogene is moderately specific for follicular thyroid carcinomas (FTC). It remains unknown whether this can be translated into improved diagnosis, classification, or outcome prediction. We studied a cohort of well-characterized follicular adenomas (FA), FTC, and Hürthle cell carcinomas (HCC) from patients with complete clinical follow-up, to determine whether PPARγ immunohistochemistry (as a surrogate of PAX8/PPARγ expression) helps to distinguish FA from FTC and to assess its diagnostic accuracy as an adjunct to frozen section. We also correlated PPARγ staining with clinical outcomes to assess its role as a prognostic marker. PPARγ staining was more common in FTC (31 of 54; 57%) than in HCC (one of 23; 4%) or FA (four of 31; 13%) (P &lt; 0.000001). Adjunctive use of PPARγ immunohistochemistry improved diagnostic sensitivity of intraoperative frozen section from 84% to 96% (P &lt; 0.05) but reduced specificity from 100% to 90% (P &lt; 0.05). PPARγ staining was associated with favorable prognostic indicators (female gender, better tumor differentiation, and lesser risk of metastases). PPARγ staining may be helpful in the differential diagnosis of FA, FTC, and HCC, particularly when diagnostic sensitivity of histomorphology is reduced (e.g. during intraoperative frozen section). PPARγ staining also shows an association with favorable prognosis and may have a role in risk stratification.

AbstractChildhood papillary thyroid carcinoma is associated with more locally aggressive and more frequent distant disease than its adult counterpart. Recurrence rates tend to be higher in children, but cause‐specific mortality remains low. Optimal initial treatment of childhood papillary thyroid carcinoma should include total or near‐total thyroidectomy and central compartment node clearance. Modified neck dissections should be performed for biopsy‐proven lateral neck disease. Every effort should be made to maintain parathyroid and laryngeal nerve function. Radical neck dissections are to be avoided. Radioiodine remnant ablation (RRA), appropriate thyroid hormone suppressive therapy (THST), and judicious use of therapeutic doses of 131I are applied to achieve a disease‐free status, which is most often confirmed by negative neck ultrasonography, negative whole‐body scan (either withdrawal or recombinant human thyroid‐stimulating hormone‐stimulated), and extremely low levels of serum thyroglobulin. Appropriate utilization of 131I, THST, repeat surgery, external beam radiotherapy, and rarely chemotherapy may provide long‐term palliation and some cures in patients with recurrent/persistent disease. Follow‐up should be lifelong, and the care of children after age 17 should subsequently be transferred to adult‐care endocrinologists with expertise in managing thyroid neoplasia. Optimal surgical management can be achieved if adequate operations are routinely carried out by “high‐volume” thyroid surgeons with expertise in the care of children. Nowhere is a multidisciplinary approach (endocrinologists, surgeons, nuclear medicine physicians, pediatricians, pathologists, oncologists) more critical than in the long‐term management of papillary thyroid carcinoma that presents during childhood.

It is uncertain whether more extensive primary surgery and increasing use of radioiodine remnant ablation (RRA) for papillary thyroid carcinoma (PTC) have resulted in improved rates of cause‐specific mortality (CSM) and tumor recurrence (TR). Details of the initial presentation, therapy, and outcome of 2444 PTC patients consecutively treated during 1940–1999 were recorded in a computerized database. Patients were followed for more than 43,000 patient‐years. The 25‐year rates for CSM and TR were 5% and 14%, respectively. Temporal trends were analyzed for six decades. During the six decades, the proportion with initial MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scores <6 were 77%, 82%, 84%, 86%, 85%, and 82%, respectively (p = 0.06). Lobectomy accounted for 70% of initial procedures during 1940–1949 and 22% during 1950–1959; during 1960–1999 bilateral lobar resection (BLR) accounted for 91% of surgeries (p <0.001). RRA after BLR was performed during 1950–1969 in 3% but increased to 18%, 57%, and 46% in successive decades (p <0.001). The 40‐year rates for CSM and TR during 1940–1949 were significantly higher (p = 0.002) than during 1950–1999. During the last 50 years the 10‐year CSM and TR rates for the 2286 cases did not significantly change with successive decades. Moreover, the 10‐year rates for CSM and TR were not significantly improved during the last five decades of the study, either for the 1917 MACIS <6 patients or the 369 MACIS ? 6 patients. Increasing use of RRA has not apparently improved the already excellent outcome, achieved before 1970, in low risk (MACIS <6) PTC patients managed by near‐total thyroidectomy and conservative nodal excision.