Carcinoma of the thyroid with a mixed medullary, papillary, follicular, and undifferentiated pattern

While papillary and follicular thyroid carcinomas are frequently mixed, this is a case of a medullary, papillary, follicular, and undifferentiated carcinoma of the same gland. In addition, all four tumor types were metastatic to regional lymph nodes. The patient described herein did not demonstrate features of the multiple endocrine neoplasia type 2 syndrome. Immunoperoxidase staining for calcitonin and thyroglobulin was positive in the follicular and medullary areas of tumor. Because the embryologic origin of the thyroidal follicular cells is from the endoderm and the origin of the parafollicular cells of the medullary carcinoma is from the ectodermal neural crest, this case seems noteworthy for demonstrating mixed metastatic tumor of composite embryologic origin. Alternatively, this case may represent an extension of what has recently been termed differentiated thyroid carcinoma, intermediate type by Ljungberg and co-workers.     

High carcinoembryonic antigen level following cancer surgery: another way to detect thyroid medullary carcinoma

INTRODUCTION: Thyroid medullary carcinoma is usually detected in the presence of an isolated thyroid nodule or in the context of a family disease: familial thyroid medullary carcinoma or multiple endocrine neoplasia type 2A. EXEGESIS: Here we report a third means of detection: an unexplained rise in carcinoembryonic antigen levels after cancer surgery. In each case, the carcinoembryonic antigen increase led to the assessment of the caicitonin plasma level and to a thyroid echography being performed. Thyroid medullary carcinoma was confirmed in every case after surgery. CONCLUSION: Even though the association of thyroid follicular carcinoma with familial adenomatous polyposis is common, the association of thyroid medullary carcinoma with breast or colonic carcinoma remains exceptional and probably accidental. Due to the seriousness of the thyroid medullary carcinoma, it is mandatory to look for it in the event of an unexplained rise in the carcinoembryonic antigen level, by assessing the calcitonin plasma level.     

Orbital metastasis as primary manifestation of thyroid carcinoma.

A 59-year-old woman with unknown primary tumor developed progressive painless left upper eyelid swelling and exophthalmos. Computed tomography (CT) showed a well-circumscribed left orbital mass producing bone lysis. Immunohistologic staining of the incisional biopsy specimen was positive for thyroglobulin, suggesting an orbital metastasis from thyroid carcinoma. At this time, thyroglobulin was high (1400 ng/dL). Total thyroidectomy with lymph node dissection disclosed a follicular carcinoma with microscopic foci of papillary variant follicular carcinoma. Two months after radioiodine treatment, the CT showed a regression of the orbital tumor mass with concomitant decrease in thyroglobulin (428 ng/dL). Although orbital metastases of thyroid carcinoma are uncommon, thyroid carcinoma has to be considered as a potential primary tumor in a patient with an orbital metastasis.     

Advances in the follow-up of differentiated or medullary thyroid cancer

The long-term survival of patients with thyroid cancer and the possibility of tumour recurrence up to 30-40 years after the achievement of a disease-free status illustrate the importance of lifelong follow-up in these individuals. This Review discusses the most innovative aspects of follow-up protocols for patients with differentiated thyroid cancer, that is, of papillary or follicular hystotype, and those with medullary thyroid cancer. Particular focus is placed on the relevance of new ultrasensitive assays for thyroglobulin measurement and the option of using recombinant human TSH to stimulate thyroglobulin secretion. Methods to compensate for the loss of diagnostic significance of serum thyroglobulin levels in patients with differentiated thyroid cancer and circulating anti-thyroglobulin antibodies are highlighted, as well as the role of the postoperative calcitonin stimulation test and the clinical relevance of determining the doubling time of calcitonin and carcinoembryonic antigen in patients with medullary thyroid cancer. Moreover, this Review gives some insights into the role of molecular thyroid cancer testing, both for prognostic and for therapeutic purposes. Finally, a general overview of traditional imaging procedures, such as neck ultrasonography, CT, MRI and bone scintigraphy, is provided alongside a comparison with new nuclear imaging tests such as PET.     

Imaging of locally recurrent and metastatic thyroid cancer with positron emission tomography.

Serum thyroglobulin and imaging have been routinely used in the evaluation of thyroid cancer patients suspected of having metastatic or recurrent disease. A more sensitive technique capable of identifying the sites of disease not detected by current imaging methods might improve overall management. The objective in this study was to demonstrate the feasibility of using positron emission tomography (PET) for the detection of recurrent thyroid cancer. Thirty patients with a history of either papillary/follicular or medullary thyroid cancer suspected of having locally recurrent or metastatic cancer on the basis of elevated or rising blood markers were evaluated with PET. Imaging studies were performed with the radiotracer [F-18] fluorodeoxyglucose (FDG). A retrospective review of other imaging results was performed and compared to the PET results. PET was able to identify locally recurrent or metastatic papillary/follicular disease in all 24 patients studied with elevated or rising thyroglobulin. Similar results were obtained in 6 patients with medullary cancer recurrences in the presence of elevated calcitonin. In cases where follow-up data was obtainable (17/24 papillary/follicular cancers and 4/6 medullary cancers), disease was confirmed either directly by surgery and/or indirectly through changes or persistence of laboratory findings. The results support the hypothesis that in the presence of elevated blood markers indicative of recurrent thyroid cancer, PET may prove valuable as an adjunctive imaging test for identifying disease and influencing management in cases where conventional imaging fails to detect suspected disease.     

Unusual metastasis of differentiated thyroid carcinoma

Distant metastases of differentiated thyroid cancer are usually localised in the lung and bone; less common sites of metastases are the brain, liver, and skin. To find it in other sites it is exceptional. This work shows the clinical, histological and therapeutical characteristic of primary tumour in three cases of non-typical distant metastases of differentiated thyroid cancer. Follicular thyroid carcinoma was displayed in two cases, the first presented one metastases in right adrenal gland and the second in left kidney. Both cases were initially treated only with hemithyroidectomy, without posterior radioiodine. In one case, elevated serum thyroglobulin did not receive radioiodine treatment because Whole-Body Scintigraphy was negative. The thirst case was a papillary thyroid carcinoma treated with total thyroidectomy, ablative radioiodine and suppressor therapy with levothyroxine. However, posterior evolution was unfavourable and tumour presented metastases in common and less common sites like choroid. Histological study showed tall cell variant of papillary thyroid carcinoma. In summary, when the initial treatment of well-differentiated thyroid carcinoma it is inaccurate, it is possible to find common and less common sites metastases. Some variants of papillary thyroid carcinoma, like tall cell, have a worse prognosis and they can present metastases in less common sites.     

Is thyrotropin-releasing hormone as reliable a calcitonin stimulant as pentagastrin in medullary thyroid carcinoma?

Calcitonin determination is of central importance in the diagnosis and follow-up of medullary thyroid carcinoma. Stimulation tests must be applied, particularly for early recognition of familial medullary thyroid carcinomas and for early diagnosis of relapses/metastases, since the basal calcitonin levels are still within the normal range initially. The pentagastrin stimulation test has proven to be the most effective one, though it is associated with considerable adverse effects. TRH is also able to stimulate calcitonin secretion in medullary thyroid carcinoma. The present study examines the value of TRH stimulation compared with pentagastrin stimulation in patients with occult or manifest metastases of medullary thyroid carcinoma. Both patients with occult metastases displayed a marked calcitonin increase after pentagastrin stimulation, but not after TRH stimulation. While calcitonin increased after pentagastrin in the two patients with manifest metastases, TRH produced a clear rise in only one of them and even caused the serum calcitonin concentration to drop continuously in the other one. Thus, TRH cannot be regarded as a reliable calcitonin stimulant in medullary thyroid carcinoma.     

A novel chromosomal translocation t(3;5)(q12;p15.3) and loss of heterozygosity on chromosome 22 in a multifocal follicular variant of papillary thyroid carcinoma presenting with skin metastases

Classic genetic rearrangements in papillary carcinoma of the thyroid involve the RET- or TRK proto-oncogenes. We report a novel chromosomal translocation t(3;5)(q12;p15.3), confirmed by fluorescence in situ hybridization, in a multifocal follicular variant of a papillary carcinoma of the thyroid in a 79-year-old woman, with skin metastases as a presenting symptom. Three years earlier, another cutaneous metastasis on her scalp was misdiagnosed as hidradenoma. Four tumour foci were recognized in the thyroid, two with a follicular variant of papillary carcinoma. To detect loss of heterozygosity, 14 chromosomes were investigated with 59 microsatellite markers. A clonal relationship was detected between the two foci of tumour in the thyroid gland containing follicular variant of papillary carcinoma and one of the skin lesions tested, all demonstrating loss of heterozygosity (LOH) in the same region of chromosome 22. Based on earlier reports, the low rate of LOH detected is in agreement with the diagnosis papillary carcinoma of the thyroid. Whole body scintigraphy performed after ablative therapy with radioiodine revealed multiple metastases in the lungs and skeleton. After repeated radioiodine therapy, thyroglobulin under thyroxine suppression became undetectable and post-therapeutic scintigraphy revealed important regression of metastases.     

Factors related to the survival of papillary and follicular thyroid carcinoma patients with distant metastases.

There is limited clinical information comparing presentations and results of treatment of papillary and follicular thyroid carcinoma patients with distant metastases. We retrospectively analyzed data of 1,257 thyroid cancer patients who received their treatment and follow-up at Chang Gung Memorial Hospital. We found 992 patients with papillary carcinoma and 205 patients with follicular thyroid carcinoma. Of these, 68 patients with papillary thyroid carcinoma (6.9%) had distant metastases at the time of diagnosis or during the follow-up period. Of the follicular thyroid carcinoma patients, 69 (33.7%) had distant metastases. Of the 68 patients with papillary carcinoma, only 33 were categorized as stage IV at the time of diagnosis. Nine of the patients were categorized as clinical stage I carcinoma, 10 as stage II, and 16 as stage III. Sixteen patients (23.5%) died during the study period, all but 2 of thyroid cancer. Twelve of the 68 patients were disease-free after treatment. Of the 69 patients with follicular thyroid carcinoma, 58 were categorized as stage IV at the time of diagnosis. Six of the patients were categorized as clinical stage I carcinoma, 2 as stage II, and 3 as stage III at the time of diagnosis; all of these patients deteriorated to stage IV during the follow-up period. Of the 42 patients with follicular thyroid carcinoma involving bone, 24 presented with bone metastases during the initial diagnosis. After treatment, 25 of 69 patients with follicular carcinoma died of follicular carcinoma. Only 3 patients were disease-free after the treatment. In patients with follicular carcinoma, only tumor size was an important prognostic factor. In this study, 8 patients categorized as clinical stages I to III at the time of operation had thyroglobulin (Tg) levels less than 5 ng/mL and developed distant metastases during the follow-up period. In conclusion, at diagnosis a large group of Asian patients with metastatic well-differentiated thyroid cancer was more likely to have follicular than papillary histology, and that, as expected, metastases from follicular cancer were present earlier and more frequently, were more likely to involve bone, were more likely to be associated with mortality, and were linked to tumor size but not gender. Also unlike some other reports, treatment producing a low Tg did not always produce a good outcome. More aggressive surgical procedures may be able to improve outcomes.     

Recurrent differentiated thyroid cancer without elevation of serum thyroglobulin.

Thyroglobulin (Tg) is a reliable tumor marker in patients with well-differentiated thyroid cancer (WDTC). We identified 11 patients who had undetectable serum Tg and no thyroglobulin antibody (TgAb) in the presence of clinical disease. Three had residual disease after ablation of the thyroid by surgery plus radioiodine and 8 relapsed after a disease-free interval. Histologic review confirmed that 7 of the tumors were papillary carcinomas and 4 were follicular carcinomas. Immunohistochemical staining for Tg was positive in 6 of 7 papillary and in 3 of 4 follicular carcinomas. There were no identifiable histologic or clinical features that could be used to predict further patients who may relapse with absence of this serum marker. Negative serum Tg did not appear to be an adverse prognostic feature. During follow-up, measurement of Tg and TgAb should be supplemented by radioiodine scanning and radiological imaging in patients in whom recurrence is likely or suspected.     

Treatment of papillary microcarcinoma of the thyroid

We retrospectively analyzed the recurrence, distant metastases and mortality of 78 patients with papillary microcarcinoma during a mean period of 6.8 years. None of the 56 patients with unifocal tumors without metastases relapsed, irrespective of the type of treatment (22 submitted to lobectomy, 11 to total thyroidectomy without ablation and 23 with ablation). The same occurred for the 15 cases of multicentric tumors restricted to the thyroid and treated with total thyroidectomy and radioiodine. Of the 7 patients with metastases in the initial presentation and treated with extensive surgery and ablative therapy, cervical recurrence was observed in 1 case. Detectable anti-thyroglobulin antibodies were more common after lobectomy (22.7% vs. 9%) and the specificity of thyroglobulin was compromised by this procedure, but not in patients submitted to total thyroidectomy without ablation. Two cases of definitive hypoparathyroidism were observed in the group submitted to total thyroidectomy (3.5%) and no cases with lobectomy. The present study agrees that lobectomy can be sufficient for the treatment of single microcarcinoma restricted to the thyroid. However, the Tg specificity is compromised. Total thyroidectomy is recommended for multicentric tumors or with lymph nodes metastases, but the routine use of radioiodine is a matter of controversy.     

Pregnancy exacerbated lymph node metastasis of well differentiated thyroid carcinoma: A case report

Introduction:Differentiated thyroid carcinoma is the second most frequently diagnosed cancer during pregnancy, second to breast cancer. Pregnancy can cause an increase in the size of existing thyroid nodules due to the similar structure of placental human chorionic gonadotropin and thyroid stimulating hormone. However, the impact of pregnancy on malignant thyroid tumors is still unclear.Patient concerns:We report a 27-year-old woman with initial thyroid follicular carcinoma was managed with total thyroidectomy and radioiodine therapy. Tumor recurrences with right neck lymph node enlargement were noted during the first and third trimester of pregnancy two years after initial diagnosis.Diagnosis:Right neck lymph node dissection was performed for two episodes of recurrence and the pathology revealed both metastatic papillary thyroid carcinoma, follicular variant but with different pathologic features. And next-generation DNA sequencing of 275 cancer-related genes, which was a commercial set, including common mutations in thyroid cancer revealed only point mutations with unknown clinical correlation.Intervention:For the first recurrence during pregnancy, right neck lymph node dissection was performed at the second trimester of pregnancy. As for the second recurrence in the third trimester of pregnancy, the patient received right neck lymph node dissection with radioiodine therapy one month after uncomplicated delivery.Outcomes:After complete treatment with surgery and radioiodine therapy, the serum thyroglobulin level was 10 ng/ml. During two-year regular follow-ups with serum thyroglobulin and ultrasound, no more recurrence was noted.Conclusion:Pregnancy in differentiated thyroid cancer survivors should be managed and monitored with caution, especially when cancer recurrence is noticed. Further studies are recommended to investigate these previously unreported gene mutations associated with thyroid cancer.     

Familial nonmedullary thyroid cancer.

Familial nonmedullary thyroid cancer (FNMTC) is a syndrome of familial clustering of thyroid cancers of follicular cell origin. It is characterized by multifocality, early onset, more recurrences, and a higher degree of aggressiveness than nonfamilial thyroid cancers of follicular cell origin. An autosomal dominant inheritance pattern with reduced penetrance appears likely in most pedigrees. Although several candidate genes responsible for isolated clinical variants of FNMTC have been identified in single families, the gene(s) responsible for the vast majority of FNMTC cases has yet to be identified. Members of FNMTC cohorts should be followed longitudinally with physical examination and ultrasonography, and aggressively treated when cancer is diagnosed. When cancer is diagnosed, total thyroidectomy should be performed, and most patients should have a prophylactic central neck dissection and a therapeutic lateral functional neck dissection, postoperative radioiodine ablation and thyroid-stimulating hormone (TSH) suppressive therapy. Close follow-up with stimulated thyroglobulin levels, neck ultrasounds, and radioiodine scans are also central to the management strategy.     

Occurrence of symptomatic meningioma as a second neoplasm in patients with differentiated thyroid cancer treated with radioiodine

Occurrence of second tumors has been seen in patients with papillary and follicular thyroid cancer. We studied the occurrence of meningioma as a second neoplasm in patients with differentiated thyroid cancer treated with radioiodine at our institution.     

Gene therapy for thyroid cancer: current status and future prospects.

Despite multimodality treatment for thyroid cancer, including surgical resection, radioiodine therapy, thyrotropin (TSH)-suppressive thyroxine treatment, and chemotherapy/radiotherapy, survival rates have not improved over the last decades. Therefore, development and evaluation of novel treatment strategies, including gene therapy, are urgently needed. A variety of gene therapy approaches have been evaluated for the treatment of follicular cell-derived and medullary thyroid cancer, including corrective gene therapy (p53 restoration, expression of a dominant negative RET mutant), cytoreductive gene therapy (suicide gene/prodrug strategy herpes simplex virus-thymidine kinase [HSV-tk]/ganciclovir, antiangiogenic therapy with endostatin) and immunomodulatory gene therapy (expression of interleukin (IL)-2 and IL-12). Furthermore, cloning of the sodium iodide symporter (NIS) gene has paved the way for the development of a novel cytoreductive gene therapy strategy based on NIS gene transfer followed by the application of radioiodine therapy ((131)I). NIS gene delivery into medullary and follicular cell-derived thyroid cancer cells has been shown to be capable of establishing or restoring radioiodine accumulation and might therefore represent an effective therapy for medullary and dedifferentiated thyroid tumors that lack iodide accumulating activity. The data summarized in this review article clearly demonstrate that the currently available strategies represent potentially curative novel therapeutic approaches for future gene therapy of thyroid cancer. The combination of different therapeutic genes has been demonstrated to be very useful to enhance therapeutic efficacy and seems to have a promising role at least as part of a multimodality approach for advanced thyroid cancer.     

Papillary and follicular thyroid carcinoma

Papillary and follicular carcinomas of the thyroid are differentiated carcinomas developed from the follicular epithelium, that keep some of its morphological and functional characteristics. Their increased incidence is related to an improved screening. Thyroid carcinoma usually presents as a thyroid nodule. Only 5% of nodules are malignant and fine needle biopsy is the most accurate tool for their diagnosis. Initial treatment is standardized and includes a total thyroidectomy with central lymph node dissection in case of papillary carcinoma, that is followed by the administration of a large activity of radioiodine in case of incomplete surgery, distant metastases or high risk factors. Papillary carcinomas of less than 1 cm in diameter, when unifocal and intra-thyroid are treated with surgery only, and radioiodine is not indicated. Thyroxine treatment is given to all patients. The majority of patients are cured, as demonstrated by the work-up performed at 1 year (undetectable serum thyroglobulin following stimulation with recombinant human TSH and normal neck ultrasonography). Subsequent follow-up is yearly with serum Tg and TSH determinations that is maintained within the normal range. In the other patients, other tests may be indicated, starting with the administration of a large activity of radioiodine. In these patients, serum TSH should be decreased to a low level.     

Long-term management of differentiated thyroid cancer

The surveillance and long-term management of patients with differentiated thyroid cancer are highly dependent upon the individual patient's risk for recurrent disease. A 30-year-old woman who presents with a 1-cm intrathyroidal papillary cancer requires minimal surveillance following primary therapy: yearly examinations and thyroglobulin measurements on L-thyroxine suppressive therapy, periodic chest radiographs, and initially, periodic neck ultrasound examinations if the right equipment is available. These should be sufficient to identify the unexpected neck or distant recurrence. A 65-year-old man who presents with a 4-cm follicular cancer invading the thyroid capsule and intrathyroidal blood vessels needs more extensive surveillance. In addition to chest radiographs, neck ultrasound studies, and serum thyroglobulin measurements while the patient is off L-thyroxine therapy, total-body 131I scanning should be done 12 months after remnant ablation, and even if no uptake is demonstrated, 131I scanning should be repeated at 24 or 60 months. Any patient who presents with grossly invasive or metastatic disease should be treated aggressively. If feasible, aggressive surgical treatment of recurrent disease is optimal and may be curative. 131I scanning and treatment may be repeated at 6- to 12-month intervals for slow-growing functional metastases. Rapidly growing metastases should be treated by external beam radiotherapy, which can follow surgical debulking, or be combined with radioiodine or chemotherapy. Unfortunately, chemotherapy is of limited value in late metastatic disease, however, rarely it results in prolonged remission.     

Normal thyroid pathology in patients undergoing thyroidectomy for finding a RETgene germline mutation: a report of three cases and review of the literature.

Genetic screening for germline RET proto-oncogene mutation in hereditary medullary thyroid cancer (MTC) is accurate and allows for preventive total thyroidectomy to be performed early in patients who are gene carriers. We report 3 children who underwent preventive total thyroidectomy based on the finding of a RETgene germline mutation, but who had no evidence of MTC or C-cell hyperplasia on permanent histology, even after calcitonin immunostaining. Review of the English literature of patients undergoing preventive thyroidectomy for a positive RETgene germline mutation, shows that 3.4% of these patients (a total of 209 patients) had normal thyroid glands. Also, 8.6% of patients undergoing preventive total thyroidectomy with prophylactic central neck node dissection had cervical node metastases. We conclude that preventive thyroidectomy in patients screened early for germline RETgene mutation allows for earlier diagnosis and treatment of patients, sometimes even before any hyperplasia or neoplasia can be demonstrated because cervical node metastases can occur early and be demonstrated even with small tumors (< 1 cm), we recommend prophylactic central neck node dissection at the time of preventive thyroidectomy.