Figure 1: CT scan of the neck showing the mass at the level of the thoracic inlet extending to the thyroid and compressing the trachea to the right.
Suryanarayan Mohapatra1* Paul J Davis2 Aleck Hercbergs31Department of Internal Medicine, Fairview Hospital/Cleveland Clinic, Cleveland, USA
2Department of Endocrinology, Albany Medical Center, New York
3Department of Radiation Oncology, Cleveland Clinic, Cleveland, USA
*Corresponding author: Suryanarayan Mohapatra, 18101 Lorain Avenue, Cleveland, Ohio, USA, Tel: +1(216) 339-2732; Fax: +1(216) 476-2944; E-mail: firstname.lastname@example.org
A 55-year-old male with a history of hypothyroidism treated with L-thyroxine (T4 ), 120 mcg daily, was found to have large, fixed left neck mass. There was tracheal compression at the thoracic inlet on CT scan. Biopsy of the lesion revealed anaplastic thyroid carcinoma (ATC). The patient underwent emergent chemoradiation, at the end of which time his T4 dose was reduced to induce a state of subclinical hypothyroidism. The tumor decreased in size, but re-enlarged after 4-5 months and the patient was treated with courses of an experimental drug, combretastatin, and of doxorubicin. Subsequently the patient underwent surgical removal of the residual left neck mass three years later and the excised mass revealed fibrosis and no residual carcinoma. His T4 dose was increased to full replacement level and the patient remained disease-free for 7 years. ATC is an aggressive tumor with a median survival period of 3 months. Surgery, radiation and chemotherapy usually fail to achieve sustained survival. There is no evidence to suggest that TSH suppression prevents disease progression in patients with ATC. Well-standardized primary treatment and long-term management of differentiated thyroid carcinoma (DTC) include lowering or suppression of host thyrotropin (TSH) with exogenous L-thyroxine (T4 ). T4 has been shown to stimulate neo-angiogenesis and proliferation of a variety of human cancer cells in vitro and in certain experimental and retrospective clinical studies; thyroid hormone deprivation may slow tumor growth and apparently enhance response to certain chemotherapeutic agents. The ATC patient reported here exhibited an extraordinary response to conventional radiation therapy and chemotherapy while being maintained in a chemically hypothyroid state.
Hypothyroidism; Survival; Anaplastic Thyroid Carcinoma
ATC: Anaplastic Thyroid Carcinoma; CT: Computed Tomography; DTC: Differentiated thyroid carcinoma; ILK: Integrinlinked kinase; TSH: Thyroid Stimulating Hormone Thyrotropin
Anaplastic thyroid carcinoma (ATC) is a very aggressive undifferentiated tumor. Most patients present with locally advanced, rapidly progressive disease and die with metastases within months of diagnosis . While aggressive endogenous pituitary thyrotropin (TSH) suppression with L-thyroxine (T4 ) may be part of the clinical management of differentiated thyroid cancers there is no evidence that anaplastic thyroid cancer is a TSH-dependent disease. There is evidence, however, that thyroid hormone, chiefly T4 , at physiologic free levels, is a growth factor that induces proliferation of certain tumor cells and of blood vessel cells. Consistent with such observations, recent pre-clinical and clinical studies have provided evidence that a chemically hypothyroid state is associated with better outcome and response rate in certain neoplasms. In the patient reported here, we report an unusually long survival in a patient with ATC with T4 deprivation.
A 55-year-old male was seen in September of 1997 for symptoms of headache, fatigue and hoarseness of voice. He had 4-year history of hypothyroidism and was on replacement T4 , the dose of which was increased two weeks prior to presentation from 100 mcg by mouth daily to 120 mcg, in response to an increase in serum TSH concentration to 16.39 (normal range, 0.32-5.00) µIU/mL. On evaluation, he was found to have a large fixed left neck mass. CT scan showed a 7.5 × 5.0 × 5.0 cm mass at the level of the thoracic inlet extending to the thyroid gland and compressing the trachea to the right (Figure 1), biopsy of the mass revealed anaplastic thyroid carcinoma (Figure 2). Immediately initiated treatment consisted of radiation to the mass of a total dose of 5760 cGy in 36 fractions over 6 weeks (Figure 3), along with cis-platinum chemotherapy. At that point, T4 was reduced to 5 mcg daily with the purpose of inducing a subclinical hypothyroid state. Over the ensuing 24 months, the patient’s serum TSH level fluctuated between 23-58 µIU/mL while he was taking 5 mcg T4 daily. He did well physically, including walking about 3 miles a day. The tumor decreased in size, both clinically and on CT scan over several months, but then re-enlarged and the patient was treated with doxorubicin and an experimental agent, combrestatin, in February and June of 1998, respectively. In May of 2000, he underwent surgery for the residual left neck mass and pathology examination revealed fibrosis with no residual carcinoma (Figure 4). L-thyroxine was subsequently increased to 175 mcg in 2001 and was maintained at this level thereafter (Table 1). The patient remained disease-free for 10 years following the making of the diagnosis. He died of metastatic prostate cancer.
Figure 2: Anaplastic thyroid carcinoma (H&E, original magnification × 40; insert x400).
Figure 3: Radiation Plan: tumor volume and isodoses from the central axis
Figure 4: Fibrotic thyroid with chronic inflammation and scattered acini with Hurtle cell features (H&E, original magnification × 100)
Table 1: Thyroid function tests of the patient
ATC represents <2% of thyroid cancers, but is an aggressive cancer that accounts for 14-39% of deaths from thyroid carcinomas. The median survival time is 3-7 months and prognosis is especially poor when the tumors are large, have distant metastasis, acute obstructive symptoms, and leukocytosis . As per a recent report, the presence of a preexisting tumor, epithelial growth, a squamous cell carcinoma component, no neutrophilic infiltration and lymphocytic infiltration are favorable prognostic factors in anaplastic thyroid carcinoma. In the operable patient, surgery is followed by radiation and chemotherapy . For patients presenting with locally advanced tumor, combined therapy is used. Patients frequently at presentation have widespread local neck invasion and develop metastasis to lungs, pleura, bone and brain.
Drugs used in ATC
Doxorubicin has been used frequently for treatment, but responses are infrequent. Other drugs such as methotrexate, bleomycin and cisplatin have had disappointing outcomes and paclitaxel has been recommended recently. Manumycin is a new drug that is a farnesyl-protein transferase inhibitor and has been shown to inhibit the growth of anaplastic carcinoma in both an in vivo model and in vitro; it has synergistic activity when combined with paclitaxel. Targeted molecular therapy has been investigated in the treatment of ATC and this includes an integrin linked kinase (ILK) inhibitor, since ILK is over expressed in ATC. Currently, the recommended treatment of this aggressive tumor is multi-modality therapy that combines surgery (total thyroidectomy], chemotherapy and radiation. From a prognostic point of view, the patient of less than 60 years of age who has an intrathyroidal tumor has the longest survival. Surgical resection with external beam radiotherapy for ATC is associated with lower cause-specific mortality .
Thyroid hormone: effect on cell surface receptors and growth factors
In dividing endothelial cells, tumor cells, osteoclasts and certain other cells, the plasma membrane bears in large quantities a structural protein, integrin αvβ3, whose extracellular domain contains a specific receptor for thyroid hormone. T4 appears to be the primary ligand for the hormone receptor on the integrin—that is, the receptor has a higher affinity for T4 than 3, 5, 3’-tri-iodo-L-thyronine (T3 ), the principal ligand of nuclear thyroid hormone receptor proteins—and, when activated, induces a mitogen-activated protein kinase (MAPK) cascade that culminates in expression of a number of genes critical to angiogenesis and to tumor cell proliferation and survival pathways [3,4].
This mechanism has been described in a large number of solid tumor cell lines and in myeloma cells [5,6]. Via the receptor on integrin αvβ3, thyroid hormone also modulates activities of the insulin-like growth factor receptor (IGFR) and epidermal growth factor receptor (EGFR) pathways. This effect is noteworthy because these growth factors may be overexpressed in various tumor cell types and are associated with activation of mitogenesis, cell proliferation and resistance to apoptosis. Thyroid hormone is anti-apoptotic in nonmalignant cells and in cancer cells. The action is desirable in non-cancer cells such as neurons and myocardiocytes, but is undesirable in tumor cells where it is a defense mechanism. The hormone may limit chemotherapy-induced apoptosis by shortening intracellular residence time of anticancer drugs that are pro-apoptotic contributing to chemotherapy resistance . In ATC cells, overexpression of EGFR has been reported. Schiff et al.  described the effect of gefitinib on blocking EGFR in ATC cells, inducing apoptosis in vitro and anti-tumor activity in a mouse tumor model. Lower levels of growth factors have been observed in hypothyroid individuals. At a subcellular level, thyroid hormone modulates mitochondrial ATP synthesis, bcl-2 expression and supports maintenance of the mitochondrial membrane potential; leakage or collapse of this membrane potential is associated with apoptosis. Thyroid hormone may also induce angiogenesis and cell migration.
Thyroid hormone actions on solid tumor cells
The effect of thyroid hormone deprivation on different tumor cell types has been investigated. Thyroid hormone effects on such cells include nongenomic actions of T4 on mitogenesis and tumor proliferation via the αvβ3-integrin interaction, as well as anti-apoptotic actions.
Preclinical and experimental data
Pre-clinical data suggest that tumor allo- and xenografts in rodents and in vitro in cell culture systems may undergo accelerated growth/ proliferation following an increase in ambient T4 in physiological free hormone concentrations or T3 at supraphysiological levels. In vitro proliferation of various model tumor types including breast carcinoma, glioma and differentiated thyroid cancer cell lines has been induced by increasing concentrations of thyroid hormone.
In-vivo experimental tumor model systems in rodents have demonstrated significant growth modulation by thyroid deprivation. An increased complete response to chemotherapy and propylthiouracil induced hypothyroidism in mice bearing a mouse mammary carcinoma has been reported. Low thyroid hormone levels improve survival in murine model for ocular melanoma .
Clinical studies and reports of hypothyroidism and cancer (Table 2)
In a clinical study of recurrent high-grade gliomas, patient survival was significantly longer in patients who had propylthiouracil-induced chemical hypothyroidism .
Table 2: Clinical studies and reports
Cristofanilli et al.  reported a reduced risk of primary breast carcinoma in women with primary hypothyroidism, as well as an eightyear delay in age at diagnosis and a less aggressive disease . A similar association has been observed between development of hypothyroidism and improved survival in patients with head and neck cancer.
Anecdotally, spontaneous remission of non-small lung cancer has been reported following recovery from myxedema coma . Accelerated progression of metastatic breast cancer has been reported following increase in dose of T4 supplementation.
ATC and thyroid hormone deprivation: a basis for therapy?
The decision for inducing biochemical hypothyroidism may be more challenging in our patient with ATC, since TSH suppression is standard in thyroid cancer.
TSH suppression has been proven effective in DTC after initial surgery to decrease morbidity and mortality, but this is not the case in ATC. In our patient, however, the tumor had appeared and enlarged extremely rapidly within two weeks of an increase in dosage of T4 replacement in response to a rise in his TSH; this suggests a cause-effect relationship. The patient was therefore advised that lowering his dose of T4 might be therapeutic. A growing body of data supports the lowering of thyroid hormone levels and maintenance of chemical hypothyroidism in individuals with solid tumors. There is also a lack of evidence for the utility of TSH modulation in ATC. As noted above, thyroid hormone is anti-apoptotic in nonmalignant cells and cancer cells and this serves to engage the hormone in cancer cell defense. The hormone may limit chemotherapyinduced apoptosis by shortening intracellular residence time of anticancer drugs that are pro-apoptotic contributing to chemotherapy resistance . We suggest that the novel approach in this patient warrants further investigation and validation. We postulate that our patient’s durable survival is related to reduction in L-thyroxine supplementation and long term maintenance of chemical hypothyroidism in combination with standard chemo and radiation therapy. Medically induced euthyroid hypothyroxinemia has been shown to extend survival in patients with advanced cancers to whom other avenues of treatment are closed, e.g., in 23 end-stage solid tumor patients in whom hypothyroxinemia was induced to prolong life . There have been recent interesting advances showing that tetraiodothyroacetic acid (tetrac), a T4 analog, blocks binding of T4 and T3 by αvβ3 and inhibits angiogenic activity of thyroid hormone . Tetraiodothyroacetic acid (tetrac) and nanoparticulate tetrac arrest growth of renal cell carcinoma xenografts , medullary carcinoma of the thyroid  and a variety of other grafts.
In conclusion, our patient presented initially with a locally advanced anaplastic thyroid tumor for which he received chemotherapy and radiotherapy. In spite of his extremely poor prognosis he stayed diseasefree 7 years following the diagnosis; previous reports state survival of 6 years and 10 years being highest documented. Throughout the survival period, he was chemically hypothyroid. His disease remained under control and he never developed metastases. No additional tissue pathology diagnosis was obtained prior to receiving chemotherapy with an experimental drug combrestatin. We suggest that this unusual outcome of ATC is in part attributable to T4 deprivation complementing multimodality therapy. Further research is warranted to establish the role of subclinical hypothyroidism in the management of anaplastic thyroid cancer.
Hamed Daw, MD; Gaurav KIstangari, MD, MPH; Dima Abdelmannan, MD, MRCP; Sebouh Setrakian, MD.
- Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A (2005) Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 103: 1330-1335. [Ref.]
- Hirokawa M, Sugitani I, Kakudo K, Sakamoto A, Higashiyama T, et al. (2016) Histopathological analysis of anaplastic thyroid carcinoma cases with long-term survival: A report from the Anaplastic Thyroid Carcinoma Research Consortium of Japan. Endocr J. [Ref.]
- Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, et al. (2005) Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 146: 2864-2871. [Ref.]
- Davis PJ, Davis FB, Cody V (2005) Membrane receptors mediating thyroid hormone action. Trends Endocrinol Metab 16: 429-435. [Ref.]
- Cohen K, Ellis M, Khoury S, Davis PJ, Hercbergs A, et al. (2011) Thyroid hormone is a MAPK-dependent growth factor for human myeloma cells acting via αvβ3 integrin. Mol Cancer Res 9: 1385- 1394. [Ref.]
- Cohen K, Flint N, Shalev S, Daniel E, Baharal T, et al. (2014) Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via αvβ3 integrin in myeloma cells. Oncotarget 5: 6312-6322. [Ref.]
- Lin HY, Glinsky GV, Mousa SA, Davis PJ (2015) Thyroid hormone and anti-apoptosis in tumor cells. Oncotarget 6: 14735-14743. [Ref.]
- Schiff BA, McMurphy AB, Jasser SA, Younes MN, Doan D, et al. (2004) Epidermal growth factor receptor (EGFR) is overexpressed in anaplastic thyroid cancer, and the EGFR inhibitor gefitinib inhibits the growth of anaplastic thyroid cancer. Clin Cancer Res 10: 8594-8602. [Ref.]
- Fabian ID, Rosner M, Fabian I, Vishnevskia-Dai V, Zloto O, et al. (2015) Low thyroid hormone levels improve survival in murine model for ocular melanoma. Oncotarget 6: 11038-11046. [Ref.]
- Hercbergs AA, Goyal LK, Suh JH, Lee S, Reddy CA, et al. (2003) Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: A phase I/ II study. Anticancer Res 23: 617-626. [Ref.]
- Cristofanilli M, Yamamura Y, Kau SW, Bevers T, Strom S, et al. (2005) Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer 103: 1122-1128. [Ref.]
- Hercbergs A, Leith JT (1993) Spontaneous remission of metastatic lung cancer following myxedema coma-an apoptosis-related phenomenon? J Natl Cancer Inst 85: 1342-1343. [Ref.]
- Hercbergs A, Johnson RE, Ashur-Fabian O, Garfield DH, Davis PJ (2015) Medically induced euthyroid hypothyroxinemia may extend survival in compassionate need cancer patients: an observational study. Oncologist 20: 72-76. [Ref.]
- Davis PJ, Lin HY, Sudha T, Yalchin M, Tang HY, et al. (2014) Nanotetrac targets integrin αvβ3 on tumor cells to disorder cell defense pathways and block angiogenesis. Onco Targets Ther 7: 1619-1624. [Ref.]
- Yalcin M, Bharali DJ, Lansing L, Dyskin E, Mousa SS, et al. (2009) Tetraidothyroacetic acid (tetrac) and tetrac nanoparticles inhibit growth of human renal cell carcinoma xenografts. Anticancer Res 29: 3825-3831. [Ref.]
- Yalcin M, Dyskin E, Lansing L, Bharali DJ, Mousa SS, et al. (2010) Tetraiodothyroacetic acid (tetrac) and nanoparticulate tetrac arrest growth of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 95: 1972-1980. [Ref.]
Download Provisional PDF Here
Article Type: Case Report
Citation: Mohapatra S, Davis PJ, Hercbergs A (2016) Anaplastic Thyroid Carcinoma - Long Term Survival in a Man with Uncorrected Primary Hypothyroidism: A Case Report with Review of Literature. Int J Endocrinol Metab Disord 2(2): doi http://dx.doi.org/10.16966/2380- 548X.124
Copyright: © 2016 Mohapatra S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.