HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

Esophageal carcinoma masquerading as recurrent acute suppurative thyroiditis.

A 61-year-old woman had clinical features of acute suppurative thyroiditis that was recurrent and refractory to antibiotic therapy. The diagnosis of acute suppurative thyroiditis was established by a fine-needle aspiration biopsy procedure, yielding suppurative material from which anaerobic and aerobic bacteria grew. Subsequent investigation with a barium swallow study followed by esophagoscopy and biopsy confirmed extensive esophageal carcinoma with a fistulous tract extending into the perithyroidal region.

Postparathyroidectomy transient thyrotoxicosis.

Three patients are described who had spontaneously resolving transient thyrotoxicosis after resection of a parathyroid adenoma without thyroidectomy or an apparent thyroid abnormality before or during surgery. All had documented thyrotoxicosis that developed within 2 weeks after surgery, which was clinically symptomatic in two of three patients. The thyrotoxicosis was associated with subnormal radioactive iodine thyroid uptake when performed in the two symptomatic patients and was consistent with a postsurgical inflammatory etiology secondary to thyroid gland trauma during parathyroidectomy. In all patients, the clinical and biochemical evidence of thyrotoxicosis resolved within 2 months. Antithyroglobulin and antimicrosomal antibodies were not detected in the two patients who had a complete recovery 3 months after surgery. However, in the patient who had autoimmune thyroiditis, hyperthyroidism due to Graves' disease subsequently developed 19 months after parathyroidectomy and was associated with increasing titers of antithyroglobulin and antimicrosomal thyroidal autoantibodies. From these observations, we conclude that 1) spontaneously resolving transient thyrotoxicosis of varying severity may occur in some patients after parathyroidectomy, which could be secondary to intraoperative thyroid gland manipulation, and 2) while the occurrence of subsequent Graves' hyperthyroidism in a patient with underlying autoimmune thyroiditis may have been a coincidence, this observation also raises the possibility that thyroidal autoantigen released during parathyroidectomy may trigger the reactivation of autoimmune thyroid disease in a predisposed subject.

ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential?

The ret/PTC oncogene is unique to papillary thyroid cancer. Three forms of this oncogene, formed by translocation of three different genes to the tyrosine kinase domain of the ret protooncogene, result in constitutive kinase activation. Correlation with clinical outcome is controversial; ret/PTC-1 has been suggested to predict aggressive behavior. There is no morphological description of ret/PTC-positive tumors. We analyzed 60 thyroid carcinomas for ret/PTC expression to determine correlation with clinical history, disease stage, or tumor morphology. Ribonucleic acid extracted from frozen tissue was reverse transcribed; PCR was performed to amplify ret/PTC-1, 2, and -3. The TPC-1 cell line was the positive control for ret/PTC-1. All tumors were characterized morphologically. Clinical data were collected. The 57 papillary and 3 follicular carcinomas were resected from 44 female patients and 15 males. The average age at diagnosis was 46.2 yr (range. 24-83 yr). Three patients had a history of neck irradiation. At diagnosis, 11 patients had extrathyroidal tumor extension, 20 had lymph node metastases, and 1 had lung metastasis. Thirteen patients had tall cell papillary carcinomas; 3 tumors had focal insular or anaplastic dedifferentiation. The average follow-up was 13.4 months, during which 4 patients had recurrent disease. No deaths occurred. One papillary carcinoma (1.7%) was positive for ret/PTC-1, none was positive for ret/PTC-2, and 2(3.4%) were positive for ret/PTC-3. Although all 3 patients who had tumors containing ret/PTC rearrangements were under the age of 45 yr (range, 26-44 yr) and had small tumors (< 1.2 cm), 2 of these 3 patients presented with lymph node metastases, and the third had lymphatic invasion. ret/PTC oncogene expression did not correlate with radiation history. In summary, ret/PTC oncogene rearrangements were found in 3 of 60 (5%) thyroid carcinomas and were not present in tumors with aggressive morphological features. However, we found ret/PTC rearrangements in young patients (< 45 yr of age) with small thyroid carcinomas showing a predisposition for lymphatic involvement, suggesting a possible role in the development of this subgroup of tumors.

Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia.

Rearrangements involving the RET protooncogene have been implicated in the development of papillary thyroid carcinoma (PC). Transgenic mice, expressing thyroid-targeted RET/PTC-1, develop PC; but the clinical significance of this oncogene remains uncertain. We examined the expression of RET/PTC-1, -2, and -3 in human thyroid microcarcinomas and clinically evident PC to determine its role in early stage vs. developed PC and to examine the diversity of RET/PTC in multifocal disease. RNA was extracted from paraffin-embedded microcarcinomas and clinically evident PCs; the results obtained from paraffin-embedded tissue were confirmed on RNA from corresponding snap-frozen tissue of clinically evident PCs. RT and PCR was performed using primers for RET/PTC-1, -2, and -3; PGK-1 (the housekeeping gene) analysis was used to ensure integrity of the RNA and efficiency of the RT reaction. PCR products were resolved by gel electrophoresis, and Southern hybridization was performed with RET/PTC-1, -2, and -3 probes. A polyclonal antibody to the carboxyterminus of RET was used for immunohistochemistry on paraffin sections. Thirty-nine occult papillary thyroid microcarcinomas from 21 patients were analyzed. Of the 30 tumors (77%) positive for RET/PTC rearrangements, 12 were positive for RET/PTC-1, 3 for RET/ PTC-2, 6 for RET/PTC-3, and 9 for multiple RET/PTC oncogenes. In clinically evident tumors, 47% had RET/PTC rearrangements. Immunohistochemistry demonstrated close correlation with RT-PCR-derived findings. RET/PTC expression is highly prevalent in microcarcinoma and occurs more frequently than in clinically evident PC (P < 0.005). Multifocal disease, identified in 17 of the 21 patients, exhibited identical RET/PTC rearrangements within multiple tumors in only 2 patients; the other 15 patients had diverse rearrangements in individual tumors. Our results indicate that RET/PTC oncogene rearrangements may play a role in early-stage papillary thyroid carcinogenesis, but they seem to be less important in determining progression to clinically-evident disease. In multifocal disease, the diversity of RET/PTC profiles, in the majority of cases, suggests that individual tumors arise independently in a background of genetic or environmental susceptibility.

DNA histogram of parathyroid tissue in determining extent of parathyroidectomy.

In an attempt to better define hyperplasia from adenoma and for more accurate discernment of grossly normal but histologically abnormal presumed hyperfunctioning gland, parathyroid tissue obtained at operation was subjected to flow cytometric analysis producing DNA histogram. Seventeen abnormal specimens and seven normal specimens obtained from parathyroidectomy cases were placed in RPMI 1640 culture medium, treated to produce a monodispersed cell suspension, and stained with propidium iodide fluorescent dye to provide a measure of DNA content that could be graphically demonstrated. All cell cycles for affected cell populations could be demonstrated on DNA histogram in the G0G1, S, and G2M phases. Proliferative index was arbitrarily derived by combining percentages of G2M plus S phases. It was apparent that the value so derived showed a tendency for higher value for the abnormal parathyroid tissue but the overlap was sufficient so that no specific discriminating value could be placed on DNA histogram. While flow cytometry may not be of significant use in intraoperative identification of abnormal parathyroid tissue, the values obtained may indicate that a spectrum of activity occurs in hyperparathyroidism that cannot be fully appreciated at the present time and that may in the light of incomplete knowledge manifest itself in the clinical state of hyperparathyroidism and hypercalcemia. The findings of our flow cytometry study may indeed lend credence to the view that all hyperparathyroidism represents a four-gland hyperfunction although this does not support as a consequence routine subtotal parathyroidectomy but should stimulate further inquiry into the pathogenesis of primary hyperparathyroidism.

Sequelae of radiation facial epilation (North American Hiroshima maiden syndrome).

Radiation for benign problems of the head and neck area has been uniformly recognized as unacceptable practice. This includes epilation for facial hirsutism. Twelve such patients, recently encountered, have characteristic radiodermatitis facies and have demonstrated multisite neoplastic involvement--including skin, thyroid, parathyroid, salivary gland, oral cavity, facial skeleton, and breast--and have also undergone extensive dermatologic treatment of complications of radiodermatitis. There was one cancer death, and three patients are alive with cancer. Such patients have a superficial resemblance to the Hiroshima maiden group of young women who survived atomic bombing and experienced severe facial burns, necessitating extensive plastic surgery. As atomic survivors they are at increased risk for cancer of thyroid, salivary gland, lung, breast, bone marrow, and gastrointestinal tract. The North American Hiroshima maiden should warrant easy clinical recognition and require lifetime scrutiny for multisite neoplastic disease.

Hürthle cell tumor behavior: dilemma and resolution.

Thirty-four patients with the diagnosis of Hürthle cell tumor occurring from 1971 to 1984 were reviewed to help delineate an acceptable treatment policy. Twenty-nine of these occurred in the last 5 years of study so that extensive follow-up was not possible. Patients varied from age 17 years to 82 and consisted of five males and 29 females, most of whom had an asymptomatic solitary cold nodule. There was a 26% incidence of malignancy. One patient died of cancer caused by anaplastic change of underlying disease; this woman had refused surgery after an incisional biopsy specimen showed benign Hürthle cell tumor. Surgery consisting of lobectomy in 16 patients and near-total thyroidectomy in 18 was uncomplicated. No nodal surgery was necessary. Eighteen percent of patients had multicentric disease of which one half were malignant. Twelve percent of patients developed contralateral Hürthle cell tumor after lobectomy. Associated thyroid lesions occurred in 30% of patients, hyperparathyroidism in 10%. There are polar views in the literature on the management of these patients. While our own tumor experience has been reassuring, we feel that in view of the paucity of cases, those who view this tumor in a serious light deserve attention. Accordingly we advocate near-total thyroidectomy as a primary operation for those who are fit, lesser procedures for the disabled, and the difficult situation, and node sampling to detect early metastasis and improved survival in this group. It is apparent that further reporting of long-term follow-up experience is necessary for complete resolution of dilemmas in the treatment of this problem.

Pregnancy and surgical thyroid disease.

Twenty patients, aged 18 to 34 years, with thyroid nodular disease detected during pregnancy from 1981 to 1984 were referred for surgical management. An additional five patients are now in the process of investigation and preparation for surgical treatment. Of the 20 patients, four were hyperthyroid and operation was indicated for medical intractability. In the remaining 16 patients there were seven cancers, for a 43% rate, and three instances of metastatic nodal disease. Needle aspiration biopsy represented the most important maneuver in clinical diagnosis but if strictly interpreted could give rise to errors in management. Two of 20 patients underwent midtrimester surgery will no ill effect on pregnancy. Operations varied in extent, tailored to the presenting problem, and produced no major complication. One stillbirth occurred in a patient with cancer who did not undergo surgery who was managed throughout her pregnancy by thyroid feeding. Hyperthyroidism in pregnancy bears a significant risk to the fetus and with medical failure surgery can be both effective and safe. The occurrence of cancer in a goiter of pregnancy should be appreciated. The principles of management should be conservative, consisting of needle biopsy, thyroid feeding and follow-up, and surgery, if indicated, preferably reserved for the midtrimester or puerperium.

The factor of factor XI deficiency in thyroid neoplasia.

Forty-three patients with factor XI deficiency detected by prolonged partial thromboplastin times were reviewed over an 11-year period. They were predominantly Ashkenazim--18 men and 25 women--ranging in age from 20 to 92 years. Thirteen patients had a history of bleeding, and eight had a family history of factor XI deficiency. Six patients with thyroid disease with four significant tumors were found for a 9% incidence of associated neoplasia. These consisted of two adenomas and two papillary-mixed cancers in two men distinguished by an aggressive course by virtue of extensive nodal disease, local recurrence, and systemic metastases in whom factor XI was profoundly decreased. It would appear that there is an undue association of factor XI deficiency and thyroid neoplasia suggestive of a shared genetic disturbance. These cases illustrate the benefit of routine preoperative coagulopathy screening by use of prothrombin time, partial thromboplastin time, and platelet counts. Factor XI deficiency is an infrequent cause of excessive bleeding, and the operative morbidity of surgical management of affected individuals can be avoided by the use of fresh-frozen plasma before and after surgery.

Biologic basis for the treatment of microscopic, occult well-differentiated thyroid cancer.

BACKGROUND: Management of thyroid microcancer or occult well-differentiated thyroid cancer (OWDTC) is controversial. Our present study compared some clinical features of OWDTC and gross well-differentiated 10-mm thyroid carcinoma (GWDTC), which may offer a basis for treatment policy. METHODS: From 1964 to 2000, 1000 patients underwent thyroidectomy for thyroid cancer. We randomly selected 428 cases for study in which node sampling was carried out in 88% of GWDTC and 60% of OWDTC and who were demographically comparable. All data were obtained by chart review and analyzed by chi-square test. RESULTS: With the maximum limit of 10 mm for defining OWDTC, we found 113 such cases with a mean size of 6.1 mm and 315 GWDTC cases with a mean size of 27.6 mm. The incidence of metastatic nodal disease was 16.8% in OWDTC cases and 25.7% in GWDTC cases (P = .057). Distant metastases occurred in 1 of 113 (0.9%) cases of OWDTC and 11 of 315 (3.5%) cases of GWDTC (P = .149). After a mean follow-up time of 55.8 months, neck metastatic recurrent disease occurred in 3 of 113 (2.7%) cases of OWDTC and 7 of 315 (2.2%) cases of GWDTC (P = .770). OWDTC was found in 11.1% of the GWDTC group undergoing an operation. Multicentricity occurred in 31.9% of OWDTC cases and 35.9% of GWDTC cases (P = .447). No cause-specific death occurred. CONCLUSIONS: One cannot be dogmatic in treatment of microcancer, but one is justified in extending similar treatment principles for OWDTC as in GWDTC, which in our center usually indicates near-total thyroidectomy and consideration for radioactive iodine ablation.

Oral calcium load test: diagnostic and physiologic implications in hyperparathyroidism.

An oral calcium load test (CLT) (1 gm Ca/50 kg) was administered to 11 control subjects and 35 patients with overt hyperparathyroidism to assess its efficacy in diagnosis of hyperparathyroidism. All participants were placed on a low-calcium diet 3 days before the CLT. Intact parathormone and ionized calcium (Cai) levels were measured 0, 1, 2, and 3 hours after CLT. Initial Cai and parathormone (mean +/- SE) were 1.22 +/- 0.01 mmol/L and 2.94 +/- 0.03 pmol/L in the control group compared with 1.43 +/- 0.02 mmol/L and 10.6 +/- 2.2 pmol/L in the group with hyperparathyroidism. Both groups had a similar percent increase in Cai values (control, 5.9% +/- 0.8%; hyperparathyroidism, 6.3% +/- 0.6% (p greater than 0.1). A decline in parathormone levels of 47.6% +/- 2.8% in patients with hyperparathyroidism was significantly less than the 75.3% +/- 5.3% decline observed in control subjects (p less than 0.025). Three hours after CLT, parathormone was suppressed in control subjects, whereas a rebound occurred in patients with hyperparathyroidism. Postoperative CLT demonstrated a higher mean percent Cai increase and percent parathormone decline (Cai, 8.9% +/- 1.1%; parathormone, 67.9% +/- 1.8%) compared with preoperative values (Cai, 6.0% +/- 1.0%; PTH, 49.6% +/- 4.3%) (p less than 0.025), and 3 hours after calcium intake, parathormone remained suppressed, similar to control subjects. After surgery, three patients had elevated parathormone and low normal Cai levels and parathormone response to a CLT confirmed the diagnosis of secondary hyperparathyroidism. In conclusion, a CLT (1) can confirm the diagnosis of hyperparathyroidism and successful parathyroidectomy, (2) distinguished postoperative secondary from persistent primary hyperparathyroidism, (3) demonstrated nonautonomy of abnormal parathyroid glands with a parathormone response to a calcium load characterized by an earlier nadir, decreased suppressibility, and more rapid recovery, and (4) produced dynamic changes that did not distinguish patients with hyperparathyroidism from control subjects or hyperplasia from adenoma.

Aggressive thyroid cancer in low-risk age population.

Seventy-eight patients under the age of 40 (low-risk patients) who had undergone surgical treatment for well-differentiated thyroid carcinoma were referred from 1979 to 1986 to our hospital for adjuvant therapy. A subgroup of 37 patients, 14 with apparent aggressive cancer, was studied. This study group consisted of 27 female and 10 male patients with mixed papillary and follicular cancer, who ranged in age from 11 to 40 years. Nodal disease occurred in 27 (73%) patients and invasiveness in 30 (81%) patients and involved multiple areas in 9 (24%) patients. Recurrence occurred in 14 (38%) patients and visceral metastases occurred in eight (22%) patients. All patients underwent appropriate surgery, but microscopic residual disease was seen in 15 patients and gross residual disease in seven patients, so that 31 patients underwent iodine-131 therapy, and 17 of these patients also underwent external radiation therapy. Three patients died of their disease, whereas 24 (65%) patients are free of disease and 9 (24%) patients are alive with disease. An additional 7 (19%) patients were initially seen in the fifth to seventh decade after decades of neglected thyroid disease, which culminated in residual cancer and death. Although low-risk categorization for thyroid cancer appears valid, its rigid application in support of conservative treatment may lead to inadequate primary treatment and underdiagnosis of cancer in thyroid nodule disease in the low-risk age population.

Management implications from routine needle biopsy of hyperfunctioning thyroid nodules.

To evaluate the diagnostic and treatment consequences of using a routine needle biopsy procedure on all thyroid nodules without a radioisotopic scintigraphic study, 12 patients with documented hyperfunctioning thyroid nodules were retrospectively evaluated regarding the physical and cytologic observations obtained after a fine-needle (22 to 27-gauge) aspiration biopsy (FNB) procedure. Among the seven solid lesions, features of marked cellularity and nuclear pleomorphism were present in three and moderate sheets of epithelium in four raising the suspicion of underlying malignancy, while five mixed (cystic and solid) lesions were larger than 3 cm, hemorrhagic, and recurrent, with two having detectable sheets of epithelium. Evidence for concomitant lymphocytic thyroiditis was seen in five of 12 (42%) patients, and nine had positive serum antithyroid antibody titers as well. In conclusion, total reliance on FNB without scintigraphy could lead to operations on hyperfunctioning thyroid adenomas for suspected malignancy, of whom the vast majority would be benign, and could expose some unprepared patients with thyrotoxicosis to surgical morbidity. Routine thyroid hormone suppression therapy for apparently benign inflammatory or cystic degenerative lesions could also induce hyperthyroidism in patients with hyperfunctional or autonomous (nonsuppressible) nodules. When using an initial FNB approach, the need for thyroid function studies and scintigraphy before undertaking surgery or thyroid hormone feeding, as well as the consequences of omitting such studies, should be considered.

Intraoperative parathormone level measurement in the management of hyperparathyroidism.

To investigate the potential use of intraoperative intact parathormone measurements to predict curative parathyroidectomy, we measured ionized calcium (Cai) levels and parathormone levels in 33 patients with hyperparathyroidism who underwent exploratory bilateral neck surgery. Nineteen patients each had a solitary adenoma, 13 patients had hyperplasia, and one patient had four normal parathyroid glands. These results were compared to the results for 37 patients who underwent either thyroid lobectomy (TL) (n = 10) or near-total thyroidectomy (NTT) (n = 27) and of 14 control patients who underwent miscellaneous operations. Parathormone decline after curative parathyroidectomy was 86.4 +/- 1.2% (mean +/- SE), which was significantly greater than a decline of 25.7% +/- 9.8% in three patients with persistent postoperative hyperparathyroidism (p less than 0.01). Declines were 38.5% +/- 8.7% after TL (p less than 0.01), 52.2% +/- 5.9% after NTT (p less than 0.01), and 8.3% +/- 4.3% (p less than 0.01), in the control patients. An intraoperative Cai decline of 4.0% +/- 0.6% after curative parathyroidectomy did not differ significantly from the results after TL, NTT, or miscellaneous operations in the control patients. Patients with persistent postoperative hyperparathyroidism had the greatest decline in Cai levels (7.1% +/- 2.3%; p less than 0.05). From these data we conclude that (1) a decline in parathormone level of 70% or more 20 minutes after parathyroidectomy is predictive of cure, (2) thyroidectomy, even unilaterally, produces a significant decline in parathormone level that affects interpretation of intraoperative parathormone level changes, (3) Cai level because of its slow decline is not useful in predicting effective parathyroidectomy, and (4) measurement of intraoperative parathormone level changes should not be used as a substitute for exploratory bilateral neck surgery.

Pathologic nature of cystic thyroid nodules selected for surgery by needle aspiration biopsy.

Sixty euthyroid patients with cystic hypofunctioning thyroid nodules were selected for operation by the criteria of evidence of needle aspiration of cyst fluid with malignant cytologic findings, suspicion of malignancy on the basis of recurrent cyst fluid formation after at least two aspirations, or incomplete decompression after aspiration. Other factors such as size (greater than 3 cm in diameter), history of radiation, and cervical lymphadenopathy were given weight. Radiation exposure occurred in 14% of patients. Surgical pathologic findings revealed malignancy in 32%, adenoma in 43%, and colloid nodule in 25%, with a total neoplasia rate of 75%. The types of malignant tumors included six papillary, six mixed, three follicular, and four Hurthle. Surgical treatment included 26 near total thyroidectomies, 34 partial thyroidectomies, and four neck dissections without major morbidity or deaths. Cytologic false-negative rates were 50% cancer, 50% Hurthle cell 50%, and 60% adenoma, even after nucleopore filtration, emphasizing the value of surgical selection on the basis of cyst response to aspiration. Cytologic false-positive rate in the colloid group was 6% and 25% for false (solid) positive for echography. Bloody fluid occurred in all types of lesions but was more common in the cancer group. Thyroid ultrasonography does not appear to be an important way to assess thyroid nodular disease and has been, in our estimation, superseded by needle aspiration cytology. It should be recognized that cystic thyroid nodules, when selected for operation on the basis of the above mentioned needle biopsy and clinical criteria, have the same frequency of neoplasia and cancer as solid hypofunctioning thyroid nodules. Hence, it is recommended that all cystic lesions of the thyroid gland be assessed in accordance with such criteria to exclude underlying cancer.

Management considerations in Hürthle cell carcinoma.

BACKGROUND: Hürthle cell tumors still pose issues concerning diagnosis and management. METHODS: From 1984 to 1993 forty-seven patients underwent thyroidectomy, and they were diagnosed after operation to have presumptive Hürthle cell tumors. The surgical pathologic findings were reviewed. In the neoplastic group the chart was reviewed for clinical features and outcome. RESULTS: Thirty-one patients had nonneoplastic Hürthle cell nodules. Eleven (69%) of the 16 tumors were malignant affecting 11 women and five men ranging in age from 22 to 86 years. Two patients died of cancer for a 18% rate; one patient is alive with disease. Operations were uncomplicated. Factors for adverse outcome include tumor size greater than 4 cm, woman older than 60 years of age, and complete capsular invasion on surgical pathologic findings. CONCLUSIONS: Fine-needle aspiration biopsy demonstration of Hürthle cell lesion is an indication for operation, providing Hashimoto's thyroiditis is excluded. Our surgical practice (I.B.R.) is to perform total thyroidectomy for all Hürthle cell neoplasms, as well as jugular node sampling and adjuvant radioiodine for cancer. Stringent histologic interpretation is possible and necessary for true appreciation of Hürthle cell tumor incidence and behavior. Cancer mortality of 18% is greater than the rate (2%) of our well-differentiated thyroid cancer group.

Reevaluation of needle aspiration cytology in detection of thyroid cancer.

From July, 1978, to August, 1980, 379 patients with thyroid disease were assessed clinically and underwent scintiscanning and needle aspiration cytology. One hundred fifty-three patients were selected for operation, there were 138 solid lesions and 15 cystic lesions. Selection criteria included clinical factors as well as cytology results. There was a cancer rate of 33% and a neoplasia rate of 92%. In the solid lesions there was a 36% incidence of cancer, whereas the incidence was 27% in cystic lesions. There was a false positive rate of 1%. A false negative rate could be viewed in various ways. Twenty-four cancers were missed in benign cytology for an incidence of 25%; however if one excluded the cytologic abnormal group, as some authors do, labeling them as potential malignancies, false negative results occurred in the cytologic benign cases for a rate of 4% for the entire group. If noncystic benign lesions alone were considered, the false negative rate would be 1%. False negative reporting arises predominantly from the inability to differentiate follicular adenoma from adenocarcinoma in cytology. Other factors such as geographic miss cystic disease also play a role. If one is to avoid underdiagnosis and undertreatment of thyroid cancer, one should consider cellular aspirates as potentially malignant and subject to surgical excision. Needle aspiration cytology has an unassailable role in the management of the patient with thyroid disease but requires interpretation in the light of clinical and scintiscanning results.

High-dose radiation and the emergence of thyroid nodular disease.

High-dose radiation (in excess of 2500 rads or centiGray) to the head and neck area is reputedly infrequently associated with the emergence of thyroid nodular disease. Thirty-three patients who underwent high-dose radiation and who developed thyroid nodular disease have been described. Radiation was originally administered for hyperthyroidism in 11 patients, postmastectomy in five, oral cancer in three, Hodgkin's disease in three, facial hirsutism in three, hemangioma in three, cancer of the larynx in one, skin cancer in one, desmoid tumor of the neck in one, Ewing's tumor in one, and pituitary tumor in one. Treatment included radioiodine in 11, external radiation in 21, interstitial radiation in one, and combined radiation in one. Associated head and neck neoplasms included four parathyroid tumors, one osteogenic sarcoma of the maxilla, two basal cell cancers of the facial skin, and one parotid gland carcinoma. The study group consisted of five men and 26 women varying in age from 22 to 75 years, with a duration of latency of effect varying from 1.5 to 50 years. Thyroid disease consisted of 21 cancers, six adenomas, four colloid goiters, and two cases of thyroiditis resulting in four deaths caused by cancer, for a 20% mortality rate. Consideration of radiation beam behavior showed that isodose curve, penumbra effect, back scatter, and special field resulted in the thyroid gland receiving a low dose, namely under 2500 rads. Clinical factors such as an overlooked goiter, coincidental carcinoma, error in presumption of dose, and second primary malignancy were also considerations. True biologic radiation oncogenesis may have been seen in our radioiodine-treated group with hyperthyroidism as well as the group with Hodgkin's disease who underwent mantle irradiation. It is apparent that for whatever reason and by whatever means and by whatever mechanism, high-dose radiation to the head and neck area can result in significant thyroid disease, and patients undergoing such radiation should be followed with this in mind and considered for thyroid feeding on a prophylactic basis.

The role of surgery in the management of thyroid lymphoma.

The role of surgery in the management of patients with primary lymphoma of the thyroid gland has been addressed after review of 61 patients treated at Princess Margaret Hospital between 1958 and August 1982, 46 of whom had clinical stage I and II disease confined to the thyroid gland or lymph nodes or both above the diaphragm. Postoperative radiation therapy was used in 34 patients, radiation therapy and chemotherapy in 11 patients, and chemotherapy alone in 1 patient. Analysis of disease progression, local relapse, and distant disease recurrence indicated that postoperative residual disease bulk predicted strongly for both local and distant disease progression. Overall cause-specific survival was 59% at 5 years, with a relapse-free rate of 46% at 5 years. Of those with less than 2.5 cm of residual disease after surgery, 80% achieved lifelong local disease control compared with 40% for those with residual disease in excess of 2.5 cm after surgery. Distant relapse rates were 7% and 23% for those with less than 2.5 cm and greater than 2.5 cm after surgery, respectively. The long-term survival rate for those with disease progression during this period was approximately 10%, with a median survival expectancy of 18 months. It is suggested that those patients without an antecedent cytologically based diagnosis of lymphoma undergo biopsy and removal of operable tumor without compromise of parathyroid glands, recurrent laryngeal nerves, or appearance. Those patients with an existing cytologic diagnosis of lymphoma and bulky and/or inoperable tumor may be more effectively managed with a combined chemotherapy-radiation therapy program.