Hürthle cell neoplasms. Malignant potential

We studied the records of patients with Hürthle cell neoplasms seen at the University of California at San Francisco, from 1943 to 1982, because of controversy concerning the malignant potential of these tumors. Of our 84 patients, 71 had Hürthle cell adenomas (HCAs), nine had Hürthle cell change in chronic thyroiditis, and four had Hürthle cell carcinomas. Coexisting papillary thyroid carcinoma occurred in three patients with HCA. Twelve patients with HCAs had multiple lesions, five of which were bilateral. Patients with HCA were followed up for 675 patient-years, 45 for four years or more (maximum duration, 36 years). There were no recurrences or deaths among the patients with benign Hürthle cell tumors. Thus, patients with HCA had a benign course, and histologic examination results accurately reflected malignant potential.     

Follicular Histotypes of Oncocytic Thyroid Carcinomas Do Not Carry Mutations of the <Emphasis Type="Italic">BRAF</Emphasis> Hot-spot

Background The BRAF V600E mutation is the most prevalent genetic aberration in papillary thyroid carcinomas (PTCs), and it is found exclusively in RET/PTC-negative tumors. In oncocytic (Hürthle cell, oxyphilic) thyroid tumors, the presence of RET/PTC rearrangements is associated with either the conventional papillary histotype or the “solid” Hürthle cell tumors, whereas all predominantly follicular oncocytic carcinomas do not harbor RET/PTC chimeras. Although 12% of tumors of the follicular variant of PTC carry BRAF mutations, none of the few oncocytic follicular thyroid adenomas (oncoAd) or carcinomas (oncoFTC) published worldwide tested positive. An aspired molecular-based classification of oncocytic thyroid tumors is in need of additional evidence on BRAF mutations in the follicular histotype. Methods A series of 44 oncocytic thyroid tumors with well-documented clinicopathological data was subjected to BRAF mutation analysis (complete exon 15) by automated sequencing. Results The series of oncocytic thyroid tumors consisted of 21 adenomas (oncoAds: 17 females, 4 males; mean age, 54.5 years; range, 27–80 years), 20 follicular carcinomas (oncoFTCs: 14 females, 6 males; mean age, 61.4 years; range, 39–80 years), and 3 “classic” papillary carcinomas (oncoPTCs: 3 females; mean age, 58.1 years; range, 46–70 years; 3x T2 tumors). The follicular variants of oncocytic cancers are divided into 11x T2, 5x T3, and 4x T4 tumor stages (International Union Against Cancer [UICC] TNM 5th edition). None of the 44 neoplasms of the presented series demonstrated genetic alterations in the BRAF hot-spot region (exon 15, codons 599–601). Congruently, 0/10 oncoAd and 0/20 oncoFTC described in the literature so far carried BRAF V600E mutations. Conclusions Our results add to the evidence that, in contrast to follicular variants of oncoPTCs, predominantly follicular oncocytic thyroid tumors harbor neither RET/PTC rearrangements nor BRAF mutations. Furthermore, the findings support the concept that oncocytic neoplasms of the thyroid gland are oncocytic counterparts of the respective histotype (adenoma, FTC, PTC, or poorly differentiated thyroid carcinoma) rather than a separate tumor entity. Molecular characterization of oncocytic thyroid malignancies for RET/PTC or BRAF genetic alterations may help with (preoperative) classification and prognostic evaluation of these tumors.     

Surgical therapy for thyroid carcinoma: a review of 1249 solitary thyroid nodules

A total of 1249 "cold" solitary thyroid nodules were excised at the Brigham and Women's Hospital from 1948 through 1987. Of these nodules, 241 showed malignant conditions: 123 were papillary, 42 were mixed papillary-follicular, and 43 were pure follicular carcinomas. There were also 23 anaplastic, 8 medullary, and 3 Hürthle cell carcinomas. These patients were followed up from 3 to 31 years, with a mean range of 10 years. Fifty-three patients with well-differentiated tumors underwent total thyroidectomies, and 179 underwent subtotal thyroidectomies (excluding anaplastic, medullary, and Hürthle cell tumors). Regional lymph node involvement was commonly found but appeared not to affect survival; tumor size and local spread and extent of thyroid gland involvement did affect survival. A small percentage of well-differentiated thyroid tumors do, in time, undergo anaplastic change that leads to metastasis and death. There was no 30-day mortality rate. The late mortality rate was 2% for papillary and 14% for follicular carcinomas. Papillary tumors are becoming more common. Older aged patients and male patients appear to carry poorer prognoses for survival. The total thyroidectomy procedure has not improved survival over subtotal thyroidectomy and carries a higher complication rate.     

Molecular evidence of anaplastic transformation in coexisting well-differentiated and anaplastic carcinomas of the thyroid

Anaplastic thyroid cancer is a rare but nearly universally fatal tumor. Epidemiologic data suggest that many anaplastic thyroid carcinomas arise from transformation of preexisting or coexisting well-differentiated thyroid carcinomas. At the molecular level, the mutations responsible for the anaplastic transformation are incompletely understood, although the mutational events are thought to involve tumor suppressor genes. To examine transformation from a well-differentiated thyroid carcinoma to anaplastic carcinoma, we studied coexisting well-differentiated (Hürthle cell and papillary carcinoma) and anaplastic tumors with a molecular genotyping panel of tumor suppressor genes associated with thyroid neoplasia. The patterns of allelic loss in our results showed that the majority of cases have a core of conserved mutations in the two morphologically distinct areas and substantial increases in mutation rates in the anaplastic components.     

Encapsulated papillary neoplasms of the thyroid. A study of 14 cases followed for a minimum of 10 years

Fourteen cases of encapsulated papillary thyroid neoplasm in which extracapsular extension was not observed and a minimum of 10 years follow-up was available are herein presented. The cases were divided into three categories: encapsulated papillary carcinomas (five cases), which had cytologic features typical of papillary thyroid carcinoma (vesicular or indented nuclei) and an entirely or predominantly thick capsule with capsular invasion; encapsulated papillary neoplasms of undetermined malignancy (seven cases), in which the cytologic features were also typical of papillary carcinoma but the capsule was predominantly thin (less than 0.1 mm thick) or was thick without capsular invasion; and follicular adenomas with papillae (two cases), which resembled follicular adenomas cytologically (rounded, stippled nuclei and Hürthle cell change) but contained a significant number of papillary structures (both cases had an entirely or predominantly thin capsule). The only evidence of malignant behavior in the entire series was a cervical lymph node metastasis in one case of encapsulated papillary carcinoma; the "encapsulated papillary neoplasms of undetermined malignancy" were so labeled because other authors have reported "encapsulated papillary carcinomas without capsular invasion" and it was therefore thought that the malignant potential of this category is as yet best considered undefined.     

Characterization of the neoplastic potential of solitary solid thyroid lesions with Tc-99m-Pertechnetate and Tc-99m-sestamibi scanning

Background: Radionuclide scans that use Tc-99m-pertechnetate or I-123 currently lack the specificity to assess the malignant potential of solitary solid lesions of the thyroid gland. Tc-99m-sestamibi scanning was used to determine the neoplastic potential of thyroid lesions. Methods: Patients with lesions of the thyroid underwent Tc-99m-sestamibi imaging to assess the neoplastic potential of their thyroid lesions, identified as solitary and cold by radionuclide imaging with Tc-99m-pertechnetate. Tc-99m-sestamibi uptake was correlated with fine-needle aspiration cytology or surgical pathology. Results: Twenty-seven patients were evaluated using Tc-99m-pertechnetate and Tc-99m-sestamibi scans: 14 had right thyroid lesions, and 13 had left thyroid lesions. Of 27 patients, 10 had a positive Tc-99m-sestamibi scan: one Hürthle cell adenoma, one papillary carcinoma, six follicular adenomas, and two nodular goiters. Of 27 patients, 17 had a negative Tc-99m-sestamibi scan: one follicular carcinoma, one papillary carcinoma, two follicular adenomas, one Hürthle cell adenoma, one metastatic adenocarcinoma, one medullary carcinoma, four nodular goiters, and six colloid nodules. Positive Tc-99m-sestamibi scan identified neoplasms with a sensitivity of 53%, a specificity of 83%, and a positive predictive value of 80%. Conclusions: Tc-99m-sestamibi scanning lacks sufficient sensitivity for diagnosis of solitary thyroid nodules. Future work may define a role for its use in recurrent or metastatic thyroid neoplasms. Presented at the 47th Annual Cancer Symposium of The Society of Surgical Oncology, March 17–20, 1994, Houston, TX.     

Hürthle cell carcinoma of the thyroid.

Even though Hürthle cell carcinoma is a distinct histologic entity, the clinical course of these patients is similar to that of patients with follicular carcinoma of the thyroid and they should be so treated. This review covers a study of thirty-five previously untreated patients with Hürthle cell cancer of the thyroid.     

Hürthle cell tumors: a twenty-five-year experience

During a 25-year period (1959 through 1983), 54 patients with Hürthle cell tumors were treated and monitored at the University of Chicago Medical Center. Thirty percent were men and 70% were women; mean age at diagnosis was 46.7 +/- 13.2 years (range: 19 to 69 years). Tumors were grouped into three categories at the time of initial diagnosis: group 1, grossly malignant (four patients, or 7.5%); group 2, intermediate (partial capsular and/or subcapsular vascular invasion) (10 patients, or 18.5%); and group 3, benign appearing (40 patients, or 74%). Twenty-one (39%) of the patients had a history of low-dose, external radiation to the head and neck in childhood (including three of four grossly malignant lesions). A separate non-Hürthle cell thyroid carcinoma was found within the thyroid gland in 22 (50%) of the patients--79% were papillary and 21% were follicular carcinomas. In half of these, there was a history of childhood irradiation. During a mean follow-up period of 8.4 years (range, 22 days to 35 years), three additional Hürthle cell tumors were recognized as malignant after metastases were discovered--two were originally classified as intermediate lesions and one was in the benign-appearing group. Thus, seven of 54 of our patients (13%) had Hürthle cell carcinomas. One of the seven patients died of widespread metastases after 35 years, and the other six are currently free of disease. We believe that therapy of these lesions should be individualized. Total thyroid ablation (surgical procedure followed by radioiodine therapy) is appropriate for frankly malignant Hürthle cell cancers, for all Hürthle cell tumors occurring in patients who received low-dose childhood irradiation, for associated papillary or follicular carcinomas, and in those patients who exhibit partial capsular or subcapsular vascular invasion. On the other hand, single, well-encapsulated, benign-appearing Hürthle cell tumors may be treated by lobectomy and careful follow-up, since the chance that they will later exhibit malignant behavior is low (2.5% in our series and 1.5% among patients described in the recent literature).     

Hürthle cell carcinoma: A malignancy of low-grade potential.

BACKGROUND: Hürthle cell carcinoma of the thyroid is a variant of follicular carcinoma, which has been considered by many as a more aggressive disease than the usual well-differentiated carcinoma of the thyroid. Others, however, have found Hürthle cell carcinoma to be a low-grade malignancy with little morbidity or mortality. METHODS: This is a retrospective report on all patients with Hürthle cell carcinoma diagnosed during the years 1951-1997 by the authors. The behavior of the disease and results of treatment were analyzed biostatistically and the outcome was compared with that of patients with pure follicular carcinoma treated during the same period. RESULTS: Forty-two patients were diagnosed with Hürthle cell carcinoma and 153 with follicular carcinoma during this period (2.8% and 10.3% of all differentiated carcinomas of the thyroid, respectively). The rate of local recurrence and disease-related mortality were both 9.5%, compared with 3.2% & 15.7%, respectively, for the follicular cancers. There was a trend for better outcome in patients younger than 55 years of age, in patients with tumors under 4 cm in size, and in patients treated by total thyroidectomy. Distant metastases occurred in four patients (9.5%) and were the cause of disease-related mortality in three. CONCLUSIONS: When treated assertively, Hürthle cell carcinoma of the thyroid, an oncocytic variant of follicular carcinoma, has a favorable outcome, similar to that of pure follicular carcinoma. Uniting those two entities in a future classification and reporting should be considered.     

Increasing the effectiveness of radioactive iodine therapy in the treatment of thyroid cancer using Trichostatin A,a histone deacetylase inhibitor

BACKGROUND: Radioactive iodine is used to identify and treat recurrent and metastatic thyroid cancer of follicular cell origin. Between 30% and 40% of thyroid cancers are either resistant or become resistant to radioactive iodine. Increased sodium-iodide symporter (NIS) and decreased Pendrin (PDS) activity may be associated with increased radioactive iodine effectiveness. In this investigation the effects of Trichostatin A (TSA), a histone deacetylating inhibitor, on human thyroid NIS and PDS gene expression was investigated. METHOD: Cell lines from papillary, Hürthle, and follicular cell carcinomas were treated with TSA for 72 hours at concentrations up to 100 ng/mL. NIS and PDS gene expression was determined using quantitative RT-polymerase chain reaction. RESULTS: . NIS messenger RNA expression in cell carcinomas was increased 107- (1.8-307) and 217- (5.7-408) fold in papillary, 39- (20-63) and 58- (37-80) fold in Hürthle, and 459- (178-810) and 781- (412-1229) fold in follicular after treatment with 50 and 100 ng/mL of TSA, respectively. PDS messenger RNA expression in cell carcinomas was decreased 0.22- (0.05-0.45) and 0.27- (0.09-0.47) fold in papillary, 0.53- (0.46-0.60) and 0.54- (0.44-0.64) fold in Hürthle, and 0.32- (0.26-0.39) and 0.56- (0.47-0.64) fold in follicular, after the same treatment. CONCLUSIONS: In thyroid cancer cell lines, TSA dramatically increased NIS gene expression and reduced PDS expression. The increased NIS expression and reduced PDS expression may make radioiodine therapy more effective in patients with thyroid cancer, especially when the tumors have no or low uptake of radioiodine.     

Clear cell change in primary thyroid tumors. A study of 38 cases

Thirty-eight primary thyroid neoplasms with extensive (greater than or equal to 50%) clear cell changes were studied. These were divided into four categories: 1) Hürthle cell tumors, 10 cases; 2) follicular tumors, 17 cases (two of them having a signet-ring or lipoblast-like appearance); 3) papillary carcinomas, seven cases; and 4) undifferentiated carcinomas, four cases. These were compared with eight cases of renal cell carcinoma metastatic to the thyroid. Factors resulting in the cytoplasmic clear cell changes were: 1) formation of medium-sized vesicles, many of apparent mitochondrial derivation; 2) accumulation of glycogen (with or without accompanying fat); and 3) deposition of intracellular thyroglobulin. Vesicle formation was the most common cause of clear cell change in Hürthle cell and follicular tumors; glycogen accumulation in papillary, undifferentiated, and metastatic tumors; and thyroglobulin deposition in the subgroup of follicular tumors with a signet-ring or lipoblast-like appearance. However, several exceptions were noted. The results of this study refute the commonly held belief that all thyroid tumors containing clear cells are malignant, and do not support the concept of "clear cell carcinoma" of the thyroid as a specific microscopic entity. We believe that the natural history of thyroid tumors containing clear cells is more dependent on their basic cytoarchitectural features than on the presence, amount, or type of clear cells, and we suggest for these tumors to be evaluated for carcinoma by using standard morphologic criteria for their respective types. The importance of thyroglobulin staining for the differential diagnosis with metastatic renal cell carcinoma is emphasized, but the pitfalls inherent to this technique are also pointed out.     

Genetic markers in thyroid tumors.

Tissue from nine patients with malignant tumors and two with benign tumors was cultured briefly before cytogenetic analysis. The tumors included one goiter and one Hürthle cell adenoma, one lymphoma, one medullary carcinoma, two Hürthle cell cancers, and five papillary cancers, varying widely in clinical staging and histologic differentiation. When assessed, DNA content was aneuploid in two of six malignant tumors. Various culture conditions (oxygen levels, dissociation methods, and media) were evaluated; the end points were growth, cell differentiation, and time to first harvest. Clonal aberrations were detected in one of four successfully harvested papillary cancers: they consisted of trisomy 7 and a rearrangement of chromosome 10. The rea (10) seen in 22 of 27 cells involved bands q11-21. Two other papillary tumors and a medullary cancer (a family member with multiple endocrine neoplasia type IIA) showed tetraploidy and nonclonal numerically aberrant cells. A lymphoma and two benign lesions showed no cytogenetic abnormality. The tumor with rea (10) is of special interest because abnormalities of 10q have been reported repeatedly in thyroid tumors, including two cases of papillary thyroid tumors with a structural aberration similar to that of the presented case. This rearrangement could affect the ret-proto-oncogene, localized to 10q11.2 which is activated in some papillary thyroid carcinomas.     

Nuclear DNA content and prognosis in Hürthle cell tumours of the thyroid gland

The prognostic value of nuclear DNA content in Hürthle cell tumours of the thyroid was studied in 23 patients with more than 10 years follow up. Eleven of these neoplasms were classified as Hürthle cell carcinoma and 12 as adenoma. DNA measurements in morphologically identified single tumour cells were performed either on fine needle aspiration biopsy material or on histological sections from the primary tumours. The nuclear DNA content identifies those patients with a good versus a bad prognosis. These results correlate well with the findings in earlier studies about papillary, follicular and medullary thyroid tumours.     

Expression of Vascular Endothelial Growth Factor and Presence of Angiovascular Cells in Tissues from Different Thyroid Disorders

Background

Vascular endothelial growth factor (VEGF) is involved in tumor angiogenesis and other pathophysiological processes.

Materials and methods

We studied the localization of VEGF in human thyroid tissues to clarify its involvement in proliferative processes in a variety of thyroid disorders. Immunohistochemical analysis using purified rabbit polyclonal anti-human VEGF or anti-human CD34 antibody and a streptavidin–biotin peroxidase complex detection system was performed on 58 tissue specimens from 53 patients with different thyroid disorders and 5 normal thyroid glands.

Results

Vascular endothelial growth factor was not detected in normal thyroid follicular cells. However, some thyroid tumor cells expressed VEGF in the cytoplasm (papillary carcinoma, 10/18; follicular carcinoma, 1/3; medullary carcinoma, 2/2; follicular adenoma, 3/11; adenomatous goiter, 2/4). In benign follicular adenoma and adenomatous goiter, weak expression of VEGF was found in small areas of the tumor, whereas in malignant thyroid tumors, it was strongly expressed in many cells. However, VEGF was not expressed in anaplastic carcinoma, malignant lymphoma, or Graves’ disease. Angiovascular cells stained with CD34 antibody in tissues from different thyroid disorders reflected statistically significant differences in papillary carcinoma, follicular adenoma, and Graves’ disease compared with normal thyroids, and such cells showed a trend toward increases in medullary carcinoma and adenomatous goiter. In contrast, low vascularity was observed in anaplastic carcinoma, malignant lymphoma, and follicular carcinoma.

Conclusions

Because VEGF probably functions as a hypoxia-inducible angiogenic factor, overexpression of this mediator, concomitant with hypervascularity, may be induced more strongly in malignant thyroid tumors, which need more oxygen to proliferate, than in benign follicular tumors. However, neither VEGF nor CD34 was expressed in anaplastic thyroid carcinoma, which is an extremely poorly differentiated malignant tumor. CD34 but not VEGF was expressed in the hyperplastic thyroid tissues of Graves’ disease composed of nontransformed cells. Thus, the expression of VEGF concomitant with CD34 is suggested to reflect both the transformation and differentiation state of malignant tumors.     

Reoperative thyroid surgery.

BACKGROUND. Patients with thyroid cancer are sometimes denied repeat thyroid operations for fear of an increased risk of complications. METHODS. We therefore reviewed our experience in 114 patients with benign or malignant thyroid tumors who underwent 116 thyroid reoperations with or without other procedures. All patients had undergone at least one prior thyroid operation and 16 patients had undergone from two to four thyroid operations before referral. The initial histologic diagnosis before reoperation was thyroid carcinoma in 79 patients, papillary carcinoma in 47 patients, follicular carcinoma in 17 patients, medullary carcinoma in 9 patients, and Hürthle cell carcinoma in 6 patients. Benign disease was present in 35 patients. In 62 patients with cancer, reoperations were performed because of suspected persistent or recurrent disease; one of these patients underwent two reoperations by us. In 17 patients reoperation was to complete total thyroidectomy, primarily so that radioactive iodine could be used to scan for and treat metastatic disease. RESULTS. Among the 116 reoperations, 102 were completion total thyroidectomy, 8 were near-total or subtotal thyroidectomy, and 6 were completion lobectomy. Histologic examination at reoperation revealed thyroid carcinoma in 51 cases (64%) among the 79 patients who had undergone 80 operations for previous thyroid cancer. Recurrent or persistent cancer was present in 49 of 63 (78%) reoperations for patients with papillary, medullary, and Hürthle cell cancer but in only 2 of 17 (12%) patients with follicular cancer. Cancer also occurred in 8 cases (22%) of the 36 reoperations in 35 patients who initially had benign lesions. Complications included one permanent and one transient palsy of the recurrent laryngeal nerve; both occurred on the side of a previous partial or subtotal lobectomy. Other complications included temporary hypoparathyroidism in four patients, seromas in two patients, and a keloid in one patient. CONCLUSIONS. This study documents that reoperations can be performed with minimal morbidity. Thus patients should not be denied the chance to undergo removal of a persistent tumor or the remnant normal thyroid tissue because of the fear of complications.     

Molecular Genetics of Thyroid Tumors and Surgical Decision-making

The study of thyroid tumor genetics has great relevance to surgeons and facilitates understanding tumor pathogenesis, prediction of tumor behavior, and management decisions. The genes implicated can be broadly categorized as oncogenes or tumor-suppressor genes. The RET oncogene has well established roles in the development of both papillary (PTC) and medullary (MTC) thyroid carcinoma. Genetic screening for germline RET mutations in members of multiple endocrine neoplasia type II (MEN-II) families is now widely performed, and prophylactic thyroidectomy in gene carriers is advisable at an early age. Patients with apparently sporadic MTC can also be screened to rule out familial disease. The demonstration of a RET rearrangement in a patient's PTC may have prognostic significance, but as yet there are no management implications. The thyrotropin receptor (TSH-R) and Gsα become oncogenic through point mutation and are associated with the development of toxic thyroid adenomas. The ras oncogene is implicated in the early stages of development of several thyroid tumor types. Tumor-suppressor genes also have a role in thyroid tumor formation. The p53 gene appears to be involved in the process of transformation to the anaplastic phenotype and the PTEN gene in the development of follicular adenomas but not carcinomas. There is still limited evidence for the so called adenoma–carcinoma sequence of the thyroid follicular cell. Loss of heterozygosity studies have enabled identification of tumor-suppressor genes, and their findings suggests differences in the pathogenesis of PTCs compared with follicular cancers. Surgical decision-making will benefit from these basic molecular advances, which rapidly translates into improved patient management.     

Papillary Thyroid Carcinoma Variants

Papillary thyroid carcinomas are the most common thyroid cancers and constitute more than 70% of thyroid malignancies. The most common etiologic factor is radiation, but genetic susceptibility and other factors also contribute to the development of papillary thyroid carcinoma. The most common variants include conventional, follicular variant and tall cell variant. However, many other uncommon variants have been described including oncocytic, columnar cell, diffuse sclerosing and solid forms. Immunohistochemical staining with TTF-1 and thyroglobulin is very useful in confirming the diagnosis of papillary thyroid carcinoma especially in metastatic sites. Markers such as HBME-1 and CITED1 can assist in separating some difficult cases of follicular variants of papillary thyroid carcinomas from follicular adenomas. Molecular studies have shown that the BRAF V600E mutation is found mainly in papillary and anaplastic thyroid carcinomas. Other molecular markers such as HMGA2 and insulin-like growth factor II mRNA binding protein 3 have been used recently as molecular tests to separate papillary thyroid carcinoma and its variants from follicular adenomas and other benign thyroid nodules.     

Hürthle cell lesions in thyroid neoplasms

A study of nine cases of Hürthle cell lesions of the thyroid seen in a period of five years at Al-Adan Hospital, Kuwait, is presented. Chart review of physician's contact, patient follow-up and histopathological review showed two cases (22%) were due to Hürthle cell hyperplasia only, and seven (78%) were Hürthle cell tumours, of which Hürthle cell carcinoma was seen in three cases (33%) and Hürthle cell adenoma in four (44%). Of the four cases with adenoma, three (33%) had solitary lesions and one had an associated papillary carcinoma. The extent of primary surgical treatment did not affect the prognosis of adenoma. It is suggested that lobectomy with isthmectomy should be sufficient treatment for Hürthle cell adenoma, while more radical surgery should be reserved for cases with accepted malignant criteria.