Nicholas J. Sarlis
The overwhelming majority of thyroid carcinomas are well-differentiated and belong to one of three distinct histopathologic types: papillary, follicular, and medullary thyroid carcinomas. In this chapter, we review less common types of thyroid tumors, each with unique biologic behavior and treatment correlates (Table 72.1). These tumors should also be taken into consideration in the differential diagnosis of thyroid nodules.
TABLE 72.1. MISCELLANEOUS TUMORS OF THE THYROID GLAND
Mucoepidermoid carcinoma (± sclerosing features peritumoral eosinophilia)
Primary squamous-cell carcinoma
Teratoma (including malignant variant in adults)
Langerhans cell histiocytosis
Metastases from other cancers
ANAPLASTIC THYROID CARCINOMA
Anaplastic thyroid carcinoma (ATC) represents only 1.6% of all thyroid cancers, with an annual incidence of 2 per million (1). Its peak incidence is during the sixth and seventh decades of life, and it has a female:male ratio of 1.5:1. The incidence of ATC has been declining steadily over the past 20 years, for reasons that are unclear (2). Whether this trend will continue in the future remains unknown, depending on the relative impact on ATC incidence of the opposite effects of an aging population versus earlier detection/therapy of PTC (from which many ATCs are thought to originate).
ATC is one of the most aggressive cancers, with rapid growth and tendency for disseminated metastases. Hence, its initial presentation is typically explosive (rapidly enlarging neck mass, with or without tracheal, esophageal, or thoracic inlet compressive symptoms). The average size of the primary tumor at diagnosis is 8 cm (3). Direct invasion of adjacent structures is present in more than 90% of patients at presentation, and 50% of patients have distant metastases at that time. Another 40% will develop them during the course of the disease, with deposits mainly in the lungs, bones, and brain (2,3). All ATCs by convention are assigned as clinical “stage IV” in current staging systems. A few ATCs are found incidentally in thyroidectomy specimens, typically as microscopic foci within a resected PTC.
Fine-needle aspiration biopsy of the primary mass is the method of choice for diagnosis. ATCs can be subdivided into four types, depending on the prevalent morphology of the cells on surgical pathology: spindle (53%), giant-cell (40%), squamoid (2%), and mixed (5%) (3). There is no correlation of the above types with survival (4). At diagnosis, careful staging with appropriate diagnostic imaging studies is needed for definition of the sites of disease, both locoregional and distant. Serum markers used in the evaluation of other types of thyroid cancer [i.e., thyroglobulin (Tg), calcitonin, and carcinoembryonic antigen (CEA)] are typically not useful for diagnosis or follow-up of ATC, because this type of cancer usually does not express or secrete these proteins (3).
Ras oncogene mutations occur infrequently in ATCs, whereas mutations in the tumor suppression gene are commonly found (5). Overexpression of RCAS1 (an antigen that can reduce the vigor of immune responses against tumors) is also present in ATC (6). The molecular phenotype of ATCs is characterized in most cases by complete loss of expression of thyroid-specific molecules, such as Tg, the sodium-iodide symporter (NIS), the thyrotropin receptor (TSH-R), and thyroid transcription factor-1 (TTF-1), and up-regulation of proliferative markers, such as Ki-67 and proliferative cell nuclear antigen (PCNA) (5) (see section Oncogenes in Chapter 70).p53
ATC is an almost universally fatal disease, with median survival from diagnosis ranging from 3 to 7 months (2,3).
Due to the loss of NIS expression, iodine 131 (radioiodine) therapy has no role in management. Similarly, due to the loss of the TSH-R (or downstream effectors), thyroid hormone suppression therapy is inconsequential to final outcome. Usually, a multimodality approach is used, involving tailored combinations of surgery, external beam radiation therapy and chemotherapy (7). ATC management has two goals: prevention of local complications by the primary tumor, such as asphyxiation or erosion of major vessels, and palliation from distant metastatic disease.
The role of primary surgery in ATC remains controversial. At the time of diagnosis, almost all patients have extensive locoregional involvement. Thus, even if thyroidectomy and associated neck dissection are technically feasible, these procedures have a palliative rather than curative intent. In a series of patients who did not initially have distant metastases, those who underwent extensive surgical debulking had an improved 1-year survival versus those who did not (60% vs. 21) (8). Similarly, patients who have undergone surgery with a curative intent (followed by radiotherapy and chemotherapy) had a median survival of 43 months, compared with 3 months in those who had only palliative resection (9). Both studies were small and they may have favored ATC patients with smaller or less aggressive tumors. In fact, a recent retrospective analysis found that neither the extent of the operation nor the achieved completeness of resection had any significant impact on survival; in this series, median survival was 2.3 months for patients with gross residual disease after operation, and 4 months for those with “complete” tumor resection (10), reflecting the impact of rapid development of metastases in both groups. In contradistinction to the above considerations for macroscopic ATCs, in the rare cases of microscopic ATC incidentally discovered in association with a PTC, total thyroidectomy followed by 131I therapy, possibly in addition to external beam radiotherapy, is usually adequate for local disease control.
External electron beam radiotherapy at total doses of 55 to 60 Gy is used for local disease control. Minimally prolonged survival has been reported when the cumulative dose exceeded 45 Gy (11). Hyperfractionated radiotherapy (1–1.5 Gy twice daily up to a total of 30 to 40 Gy over 3 weeks) has also been given in combination with doxorubicin, bleomycin, cisplatin, or 5-fluorouracil (5-FU) (used as radiosensitizers), although toxicity was severe in up to 50% of patients treated with these combinations (12). In small, noncontrolled studies, chemo- and radiotherapy resulted in local control rates as high as 80% (13). Combinations of paclitaxel and external radiotherapy have not proven effective. Newer techniques, such as intensity-modulated radiotherapy (IMRT), may enhance precision of delivery of radiotherapy to the targeted area, while minimizing the side effects. A preliminary feasibility study of IMRT for ATC patients was reported recently (14).
None of the currently available chemotherapeutic regimens has been shown to alter the overall survival of patients with metastatic or residual ATC. Doxorubicin, when used as monotherapy, has disappointing response rates, with no patient having complete response (2). The combination of doxorubicin with cisplatin or bleomycin was not superior to doxorubicin alone in one study (15). More recently, paclitaxel (a microtubule formation inhibitor) has been used in ATC patients with persistent or metastatic disease. Ten of 19 patients had partial responses to paclitaxel. Although this agent resulted in significant slowing of the rate of progression of the disease in the subgroup of “responders,” it did not prevent an eventual fatal outcome in any of the patients (16). Based on the above results with paclitaxel, a combination of paclitaxel (or docetaxel) and carboplatin has been used empirically in large cancer centers in the United States, again with no sustained antitumor responses. A long-lasting complete response was reported in a single patient with ATC during a phase I clinical trial using combretastatin A4-phosphate. This agent is believed to act through a combination of direct cytotoxicity and angiogenesis inhibition (17). Gemcitabine, a deoxycytidine analogue, with or without cis-platinum has been shown to induce apoptosis in cell lines derived from ATC (18), although there is no published clinical experience. Of note, many of the patients with ATC are elderly (>70 years) and typically tolerate chemotherapy or multimodality approaches poorly, due to age-associated comorbidities. The above notwithstanding, a few ATC patients do respond remarkably well to aggressive multimodality therapy; this was evident in the paclitaxel study where one “responder” survived for 15.3 months (16).
Because none of the current therapies substantially improve survival in ATC, novel treatment agents are being actively sought. Gene therapy with functional p53 (with or without chemotherapy) (19), or interleukin-2 (IL-2) combined with herpes simplex virus thymidine kinase (HSV-TK) (20) has shown promising results in preclinical ATC tumor models. Peroxisome proliferator-activated receptor-γ agonists (21) or farnesyl transferase inhibitors (22) are also promising in ATCs, affecting differentiation status and signaling, respectively. The histone deacetylase inhibitor depsipeptide led to a significant increase in the expression of Tg and NIS in cell lines derived from ATC (23). Clinical trials using the above compounds and other biologic modifiers are needed to assess their clinical utility in ATC patients.ras
Until these new agents become clinically available, for patients with ATC, we recommend the following approach: (a) for locoregional disease, surgery (if technically feasible) followed promptly by external beam radiotherapy (with or without chemosensitizers) and then chemotherapy; and (b) for disseminated disease, systemic chemotherapy. Both approaches should be applied in conjunction with frequent and complete restaging with the appropriate diagnostic imaging tests.
Thyroid lymphoma is an uncommon disorder, constituting less than 2% to 3% of all non-Hodgkin's lymphomas (24). Women are most commonly affected, with a peak incidence in the sixth decade of life (24). An association with chronic lymphocytic (Hashimoto's) thyroiditis can be found in 40% to 80% of cases, with the lymphoma typically developing 20 to 30 years after the onset of thyroiditis (25).
The usual presentation is a rapidly enlarging, painless neck mass with prominent obstructive symptoms. Cervical lymphadenopathy is present in 40% to 50% of patients (25). Type B symptoms (fever, night sweats, weight loss) can also occur. Most patients have high serum antithyroid antibody concentrations.
Lymphoma may be suspected on the basis of cytomorphologic criteria alone, but immunophenotype analysis of cytopathology specimens is needed to provide the definitive diagnosis, as well to determine both the lineage and clonality of the cell population with an accuracy rate between 85% and 100% (26). In patients with lymphoma first seen by an endocrinologist or a surgeon, prompt referral to a medical oncologist is needed for optimal management.
Upon diagnosis, clinical staging is important. Staging is performed according to the Ann Arbor classification and includes blood count, liver function tests, serum lactic dehydrogenase and β2-microglobulin measurements, serum protein electrophoresis, chest and abdominopelvic CT scan, as well as biopsies of the bone marrow and other potential sites of lymphomatous spread (24). The main adverse clinical prognostic factors are the presence of mediastinal lymphadenopathy, a low patient performance status, and the presence of type B symptoms, whereas a previous diagnosis of Hashimoto's thyroiditis is a favorable factor (27).
The presence of long-standing Hashimoto's thyroiditis has been associated with a several-fold increase in the relative risk for lifetime development of thyroid lymphoma (24). On a molecular level, Fas and Fas ligand (FasL) mutations have been implicated in the pathogenesis of the thyroiditis, leading to accumulation of apoptosis-resistant lymphoid cells harboring these mutations (28). Clonal expansion/immortalization of such cell populations through cytokine-mediated stimulation is believed to give rise to the lymphoma (29,30).
Thyroid lymphoma is a heterogeneous disease. The lymphoid infiltrates in Hashimoto's thyroiditis bear great resemblance to mucosa-associated lymphoid tissue (MALT). Until the late 1980s, according to earlier classifications of non-Hodgkin's lymphomas (such as the “Working Formulation” system), almost all thyroid lymphomas were considered MALT lymphomas (MALT-L or MALTomas) (31). However, since the mid-1990s, they have been reclassified according to the Revised European-American Classification of Lymphoid Neoplasms (REAL) (32), as well as the World Health Organization (WHO) Classification for Neoplastic Diseases of the Lymphoid Tissues (33). In these classification systems, MALTomas are categorized as marginal zone B-cell lymphoma of MALT-type (MZBL) and are considered “low-grade” lymphomas. Transformation of MZBLs to a large-cell morphologic phenotype can give rise to diffuse large B-cell lymphoma (DLBCL). According to the REAL/WHO classification scheme, the most common thyroid lymphoma subtype is DLBCL, either transformed from MZBL or occurring as such (24,34). DLBCLs are considered “high-grade” lymphomas. Other subtypes include mixed MZBL/ DLBCL, follicular lymphoma, Burkitt's lymphoma, small lymphocytic lymphoma, and Hodgkin's disease (34). Determination of the exact subtype is of paramount importance for prognosis, treatment, and follow-up.de novo
Treatment of thyroid lymphoma is controversial, since the rarity of this condition precludes the conduct of clinical trials comparing the various available therapies. In general, treatment depends on the stage of the lymphoma and its subtype.
Localized (stages I and II) MZBLs can be controlled with regional therapy alone (i.e., radiotherapy) or, more rarely, surgery (35). Although surgery can result in a 95% to 100% survival rate at 5 years (36), the currently preferred treatment is radiotherapy (total dose of 40 Gy to the neck and upper mediastinum), with a similar 5-year survival (27,37), mainly because of the lower risk for local complications with radiotherapy. Disseminated (stages III and IV) thyroid MZBLs can be treated with surgery, followed by chemotherapy with a single agent, usually oral chlorambucil (38). As mentioned above, most thyroid lymphomas belong to the DLBCL subtype. Localized DLBCLs have been treated in the past with an anthracycline-containing regimen, such as CHOP (doxorubicin/ cyclophosphamide/vincristine/prednisone) or CHOP-like combinations, administered along with radiotherapy, with a survival rate of more than 90% at 5 years (39). Disseminated DLBCLs are treated with CHOP or CHOP-like chemotherapy alone (39). New treatments for non-Hodgkin's lymphomas are currently available, including the combination of rituximab (an anti-CD20 monoclonal antibody) and CHOP (the “R-CHOP” scheme) (40), which shows a survival advantage over CHOP-based regimens.
MISCELLANEOUS UNUSUAL THYROID TUMORS
Thyroid Mucoepidermoid Carcinoma
Mucoepidermoid carcinomas are rare tumors, primarily involving the salivary glands, and histologically characterized by a combination of mucin-producing cells and cells with squamous features (41). Occasionally, a sclerosing reaction can be seen within such tumors, along with peritumoral eosophilic infiltrates (41). Mucoepidermoid tumors exhibit a biologic behavior similar to that of papillary carcinomas, with local tissue invasion and lymph node metastasis (41). Primary therapy consists of total thyroidectomy and neck dissection (if there is locoregional dissemination). Postoperative 131I therapy is considered inefficacious. Some patients may benefit from external beam radiotherapy, either postoperatively or as a primary therapy in unresectable tumors (41).
Primary Thyroid Squamous- Cell Carcinoma
This is an extremely rare tumor (42). Its differential diagnosis includes thyroid metastasis from a squamous cell carcinoma in the upper aerodigestive tract. Immunohistochemical study of cytokeratin expression can help in the diagnosis (43). Primary squamous-cell thyroid cancer is considered a lethal tumor, with aggressiveness similar to that of ATC. Complete or partial excision of the tumor with postoperative radiotherapy and chemotherapy [with a -platinum/5-fluorouracil (5-FU) combination] may provide short-term palliation (44).cis
Most teratomas of the thyroid are benign, and occur in neonates and children. Teratomas in adults are extremely rare and, in contrast to such tumors in children, highly malignant (45). Treatment with surgery, radiation, and chemotherapy (-platinum/vincristine/cyclophosphamide actinomycin-D) has been used in these tumors, although most patients survive less than 24 months after diagnosis (46).cis
Mesenchymal Thyroid Tumors
Fewer than 20 cases of this tumor have been reported to date. This mixed lineage carcinoma arises from both epithelial and stromal elements (47). It occurs predominantly in elderly women and is almost uniformly fatal. Treatment is similar to that of ATC, with surgery (whenever feasible), radiotherapy, and -platinum- or ifosfamide-based chemotherapy (48).cis
Most of these rare sarcomas occur in the iodopenic Alpine region of Europe, where they may account for up to 16% of all thyroid cancers in this part of the world (49). In cases occurring outside the Alpine region, thyroid angiosarcoma has been associated with exposure to arsenic, thorium dioxide, polyvinylchloride, and radiation (50). The expression of endothelium-specific markers by the tumor, as well as specific electron microscopic criteria, has been helpful for distinguishing between thyroid angiosarcomas and ATCs with epithelioid differentiation (50), although without any significant impact on prognosis, which is poor. Indeed, most patients have extensive local invasion at the time of diagnosis. Surgery (whenever feasible), radiotherapy, and doxorubicin- or paclitaxel-based chemotherapy can provide palliation (51). Other rare primary thyroid mesenchymal tumors include osteosarcomas, hemangiopericytomas, and fibrosarcomas.
Langerhans Cell Histiocytosis
Langerhans cell histiocytosis is characterized by accumulation or proliferation of a clonal population of histiocytes with a specific immunophenotype, which includes expression of the CD1a antigen (52). Thyroidal histiocystosis is extremely rare, even when there is involvement of multiple other organs by the histiocytic process, with fewer than 40 published cases. It presents as a diffuse or nodular goiter; pain or compressive symptoms are unusual (53). Diagnosis by biopsy can be difficult, and the disorder can be easily confused with other conditions, such as HT, lymphoma, and ATC (53). Treatment of isolated thyroidal LCH involves surgery, with or without postoperative radiotherapy, usually with good response (53). In cases of widespread disease, a variety of chemotherapeutic and immunosuppressive agents have been tried, such as 2′-chlorodeoxyadenosine, cyclosporine, etoposide, azathioprine, and methotrexate (54).
Other Primary Thyroid Tumors
Primary (extramedullary) thyroid plasmacytomas are rare. Progression to multiple myeloma can be found in 17% to 32% of cases (55). Serum protein electrophoresis universally reveals a monoclonal gammopathy (56). Treatment consists of total thyroidectomy with postoperative radiotherapy, with good prognosis in patients in whom there is no progression to myeloma (56).
Thyroid Neuroendocrine Tumors
In addition to C-cell lesions (C-cell hyperplasia, medullary thyroid carcinoma, and mixed C-cell/follicular cell carcinoma), paragangliomas, chemodectomas, and metastases from extrathyroidal neuroendocrine tumors can also occur in the thyroid (57). Thyroid paragangliomas are uncommon and typically present as painless neck masses (57,58). Immunocytochemistry reveals neuroendocrine markers (e.g., chromogranin-A), with concomitant lack of expression of Tg, calcitonin, or CEA (58). The primary therapy is surgery. Most paragangliomas are benign, as evidenced by lack of local invasion or development of metastases, but there is a tendency for local recurrence. A few paragangliomas have a truly malignant phenotype. In locally invasive tumors, postoperative radiation therapy may be beneficial. In metastatic disease, combination chemotherapy (cisplatin/doxorubicin/cyclophosphamide/dacarbazine) has been tried with variable success (59). Of note, a few thyroid paragangliomas secrete catecholamines, and patients with these tumors should be screened with the appropriate biochemical tests (60).
Although the presence of metastases of nonthyroid cancers in the thyroid gland is a common autopsy finding (0.5%–1.5) in patients with a history of disseminated cancer, a thyroid metastasis is an uncommon clinical finding (61). The primary tumors are usually carcinomas of the lung, kidney, breast, and stomach, but metastases of primary carcinomas of the colon, uterus, oral cavity, esophagus, skin (melanoma), neuroendocrine tissue, and unknown origin, as well as sarcomas, are seen rarely (62). If technically feasible, thyroidectomy can be effective for local control. Systemic therapy should always be considered and should include the treatment of choice for the primary tumor. Regional measures, such as resection of additional (extrathyroidal) metastatic deposits and radiotherapy, may also be used for palliation. Survival time after diagnosis of the thyroid metastasis is determined by the biology of the primary disease, but is typically short (6–9 months) (63).
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