Anaplastic thyroid carcinoma with lung metastasis producing CA 19-9 and GM-CSF]

A 68-year-old Japanese woman was admitted to our hospital because of hoarseness, dysphagia and a mass on the right side of her neck. Chest radiographs showed multiple nodular shadows in both lung fields. Detailed investigations resulted in a diagnosis of multiple lung metastasis of anaplastic thyroid carcinoma transformed from papillary adenocarcinoma. Both serum CA 19-9 and GM-CSF levels were elevated, to 70.5 U/ml (normal range: 0-37 U/ml) and 343.4 pg/ml (normal range: 0-8 pg/ml), respectively. Immunostaining disclosed that the primary and metastatic tumors were positive for CA 19-9, but not for GM-CSF antigens. Serum levels of these two parameters slowly decreased after chemo-radiotherapy, suggesting that the tumor may have produced GM-CSF as well as CA 19-9. Recent studies have indicated that the prognosis is poor for non-small cell lung cancers that produce G-CSF or CA 19-9. To our knowledge, this is the first case report of anaplastic thyroid carcinoma characterized by high serum levels of both CA 19-9 and GM-CSF, with metastasis to the lung and other organs.     

Anaplastic thyroid carcinoma in a 49 year-old woman with a long-standing goiter. A case report

A 49 year-old woman with anaplastic thyroid carcinoma came, for the first time, to our clinic with an enlarged supraclavicular lymph node. Ten years earlier she received a diagnosis of benign nodular goiter and has been followed up with ultrasonography, which never demonstrated any enlargement of her thyroid nodule and with fine needle aspiration biopsies (FNAB), that always proved normal. An ultrasonographic control, performed 10 months before diagnosis, showed the onset of a shell calcification all around the thyroid nodule that forbade the performance of FNAB. At initial examination in our endocrinology centre she was found to have an enlarged thyroid nodule (changing from 3.5 cm to 4.5 cm) and a supraclavicular lymph node 3 cm wide. The patient was therefore sent to the surgeon who performed a total thyroidectomy and a lymph node exenteration. The histological examination reported a thyroid anaplastic carcinoma, composed of osteoclast-like cells and large calcifications, which showed signs of local invasion and vessel infiltration; the supraclavicular lymph node proved to be a large metastasis of anaplastic thyroid cancer. Total body CT scan, bone scintigraphy and brain CT scan showed, respectively, lung, bone and brain metastasis. Postoperative chemotherapy was rapidly interrupted for acute toxicity. The patient died for lung, bone and brain metastasis, 2 months after initial examination.     

Anaplastic thyroid cancer with transient thyrotoxicosis: case report and literature review.

A 55-year-old woman with anaplastic thyroid carcinoma presented with hyperthyroidism and neck swelling, hoarseness, and cervical lymphadenopathy. On physical examination, she was found to be clinically hyperthyroid with an enlarged, nontender multinodular goitre. Her serum thyroid hormone levels confirmed hyperthyroidism and technetium-99m pertechnetate scan failed to visualize the thyroid gland. Open biopsy showed an invasion of the thyroid gland by anaplastic thyroid carcinoma. The thyrotoxic phase lasted 60 days with predominantly increased thyroxine level and triiodothyronine/thyroxine (T3/T4) ratio decreased below 15. The thyrotoxic period was followed by subclinical hyperthyroidism and hypothyroidism which continued until she died of lung metastasis.     

Intraocular and orbital metastasis as a rare form of clinical presentation of insular thyroid cancer

Insular carcinoma of thyroid is a rare tumor, which accounts for 4 to 6% of thyroid malignancies. Clinically and morphologically it is considered to be in an intermediate position between well-differentiated carcinoma of the thyroid (papillary or follicular) and undifferentiated or anaplastic carcinoma of the thyroid. Capsular and blood vessel invasion is seen frequently, and metastases to regional lymph nodes, lungs and bones are common. The initial presentation of distant metastasis in patients with thyroid cancer is rare. Thus metastatic thyroid carcinoma rarely involves the orbit. We report a rare case of choroidal metastasis from insular thyroid carcinoma.     

Esophageal carcinosarcoma with granulocyte colony-stimulating factor: a case report

A 62-year-old man was admitted to our hospital for dysphagia, leukocytosis, and pyrexia. The serum level of granulocyte colony-stimulating factor (G-CSF) was high and immunostaining of a biopsy specimen of esophageal tumor using anti-granulocyte-macrophage colony-stimulating factor (anti-GM-CSF) antibody demonstrated GM-CSF expression in the cytoplasm of the tumor cells. After esophagectomy, the leukocyte count and serum G-CSF level normalized. Histologically, this tumor was diagnosed as a carcinosarcoma with two components: squamous cell carcinoma and sarcoma. Tumor cells were also positive for G-CSF receptor, suggesting autocrine growth regulation by G-CSF. Moreover, tumor cells were positive for Ki-67, cyclin D1, p53, and epidermal growth factor receptor (EGFR), which were related to the acquisition of more aggressive tumor behavior. Although G-CSF-producing esophageal carcinosarcoma is very rare, we should consider such disease when a patient has symptoms of leukemia such as leukocytosis and high fever.     

Aggressive metastatic follicular thyroid carcinoma with anaplastic transformation arising from a long-standing goiter in a patient with Pendred's syndrome.

In this article we describe detailed pathological and molecular genetics studies in a consanguineous kindred with Pendred's syndrome. The index patient was a 53-year-old female patient with congenital deafness and goiter. Her parents were first-degree cousins. She had a large goiter (150 g) that had been present since childhood. One of her sisters and a niece are also deaf and have goiter as well. The presence of Pendred's syndrome was confirmed by a positive perchlorate test and the demonstration of a Mondini malformation. Thyroid function tests (under levothyroxine [LT4] therapy) were in the euthyroid range with a thyrotropin [TSH] level of 2.8 microU/mL (0.2-3.2), a serum total thyroxine (T4) of 90 nmol/L (54-142), and a serum total triiodothyronine (T3) of 2.7 nmol/L (0.8-2.4). Total thyroidectomy was performed, and the mass in the right lobe was found to have invaded adjacent tissues. The histopathological findings were consistent with a follicular carcinoma with areas of anaplastic transformation and lung metastasis. The patient was treated twice with 100 mCi 131iodine (3,700 MBq) and received suppressive doses of LT4. Postoperatively, the serum thyroglobulin (Tg) levels remained markedly elevated (2,352 to 41,336 ng/mL). The patient died of a sudden severe episode of hemoptysis. Sequence analysis of the PDS gene performed with DNA from the two relatives with Pendred's syndrome revealed the presence of a deletion of thymidine 279 in exon 3, a point mutation that results in a frameshift and a premature stop codon at codon 96 in the pendrin molecule. We concluded that prolonged TSH stimulation because of iodine deficiency or dyshormonogenesis in combination with mutations of oncogenes and/or tumor suppressor genes, may result in the development of follicular thyroid carcinomas that undergo transformation into anaplastic cancers. It is likely that these pathogenetic mechanisms have been involved in the development of aggressive metastatic thyroid cancer in this unusual patient with Pendred's syndrome.     

A case of lung cancer with hyperthyroidism]

We here report a case of metastasis from lung cancer to the thyroid. On presentation, this patient showed painful anterior cervical swelling and right supraclavicular lymph node swelling. Laboratory data showed primary hyperthyroidism. Although subacute thyroiditis was suspected, echo-guided needle aspiration biopsy and lymph node biopsy revealed poorly differentiated squamous cell carcinoma. As a result, primary lung cancer with thyroid metastasis was diagnosed based on mediastinal enlargement on chest X ray films and normal findings in organs other than the lung and thyroid. Chemotherapy for lung cancer induced a decrease in the size of tumor and the normalization of thyroid function. However, 2 months after the normalization, cervical swelling enlarged and a lung mass in right upper lobe and skin tumor appeared. Despite treatment with chemotherapy, she died. Postmortem revealed that the right upper lung carcinoma was the primary lesion and immunohistochemical staining for surfactant protein was positive in the thyroid, skin tumor and lymph node, which revealed these carcinomas had metastasized from lung cancer. To the best of our knowledge, thyrotoxicosis induced by thyroid metastasis of lung cancer is an uncommon case.     

Three-dimensional structure of the micro-blood vessels in thyroid tumors analyzed by immunohistochemistry coupled with image analysis.

The structure of micro-blood vessels, one of the most important factors influencing the tumor growth and tumor metastasis among histological types of thyroid malignancy, was analyzed immunochemically by staining tissues for platelet endothelial cell adhesion molecule-1 (PECAM-1). Human thyroid tumor tissue obtained at surgery, consisting of 18 cases of papillary carcinoma, 9 cases of follicular carcinoma, and 9 cases of anaplastic carcinoma were fixed in formalin solution, and paraffin sections were made. They were stained for PECAM-1 using the avidin-biotin complex (ABC) technique. The volume of the blood vessels and their three-dimensional (3D) structure were analyzed using an image analyzer. The volume ratios of blood vessels in thyroid tissues were: normal tissues, 1.10%; papillary carcinoma, 3.01%; follicular carcinoma, 8.13%; and anaplastic carcinoma, 0.91%. Ratios in malignant tumors were larger than in normal tissues, except for anaplastic carcinoma. The typical 3D structure of micro-blood vessels was histopathologically varied: branching tree-like blood vessels in papillary carcinomas; vessels of varied diameter surrounding follicle structure in follicular carcinomas; and simple and immature vessels in anaplastic carcinomas. The volume and 3D structure of micro-blood vessels in thyroid malignant tumors differed from those in normal tissues, and varied according to histological classification.     

Expression of the Axl receptor tyrosine kinase in human thyroid carcinoma.

Protein tyrosine kinases (PTKs) play a crucial role in regulating thyroid cell growth and differentiation. The Axl protein is a member of a new family of receptor tyrosine kinases, of which the ligand, Gas6, a protein S-related molecule, recently was proved to be a mitogenic factor for human thyroid cells. To further investigate the involvement of Axl in human thyroid carcinoma, we examined tissues obtained from 81 patients with thyroid carcinomas, 18 with adenomas, and 13 with adenomatous goiters by immunohistochemistry and in situ hybridization. In addition, among the thyroid carcinomas, we compared Axl expression levels with the grade of differentiation and lymph node metastasis of the carcinoma. Axl was expressed faintly in adenomatous goiter and adenomas, but not in normal thyroid tissues. Among the 81 cases of thyroid carcinoma, 70 (86.4%) showed a positive staining for the Axl protein. Immunopositive (+ +) was detected in papillary carcinomas and anaplastic carcinomas. The level of Axl expression, however, had no correlation with the presence of lymph node metastasis in thyroid carcinomas. In situ hybridization also confirmed the presence of axl mRNA in thyroid carcinoma tissues. These findings suggest that Axl expression may be closely involved in human thyroid tumorigenesis.     

Tall cell papillary thyroid carcinoma metastatic to femur: evidence for thyroid hormone synthesis within the femur

A 67-year old man with a 3-month history of left hip pain had a history of Graves disease, treated with 131I 20 years before admission, and papillary thyroid carcinoma, treated with cervical lymphadenopathy 9 years before admission. Removal of a 3.5- x 5-cm mass from the left femur revealed it to be a tall cell variant of papillary thyroid carcinoma. Removal of this mass resulted in his thyrotropin level increasing from 2 (presurgery) to 23 mIU/mL, whereas his thyroxine level simultaneously decreased from 5.79 (presurgery) to 2.29 microg/dL 12 days after surgery despite continuation of levothyroxine of 0.137 mg/day. On histological examination, the tall cell variant in the femur was producing abundant thyroglobulin. This first case of a metastatic papillary thyroid carcinoma in bone producing thyroid hormone to the extent that the patient became hypothyroid after removal of this metastasis illustrates that metastatic thyroid lesion(s) may produce significant amounts of thyroid hormone.     

Neutrophilia associated with anaplastic carcinoma of the thyroid: production of macrophage colony-stimulating factor (M-CSF) and interleukin-6.

Cancers associated with marked neutrophilia are relatively rare. We report here two cases of anaplastic thyroid carcinoma associated with neutrophilia. We measured the concentrations of granulocyte colony-stimulating factor (G-CSF), macrophage CSF (M-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) in sera, pleural effusion, cyst fluid of the thyroid carcinoma region, or culture supernatants of carcinoma cells. Maximum levels of elevated white blood cell counts reached 106.1 x 10(9)/L (neutrophils 103.0 x 10(9)/L) in case 1 and 62.3 x 10(9)/L (neutrophils 57.9 x 10(9)/L) in case 2. Acute-phase reactants were elevated to various degrees, and hypercalcemia was found in both cases. IL-6, G-CSF, and M-CSF seemed to play the principal roles in neutrophilia in case 1, and the elevated levels of IL-6 and M-CSF seemed to mainly contribute to neutrophilia in case 2. Immunohistochemical staining revealed that carcinoma cells themselves produce IL-6 regardless of the types of carcinoma cells. To our knowledge, this is the first report describing the contribution of M-CSF to neutrophilia in patients with thyroid carcinoma.     

Anaplastic thyroid carcinoma with destructive thyrotoxicosis in a patient with preexisting multinodular goiter.

Presentation of anaplastic thyroid carcinoma with thyrotoxicosis is extremely rare and its occurrence in a patient with Wegener's granulomatosis has not been reported previously. We describe an elderly lady with Wegener's granulomatosis who developed a rapidly growing anaplastic thyroid carcinoma in a preexisting multinodular goiter and discuss the mechanism of thyrotoxicosis in this patient.     

An autopsy case of anaplastic thyroid carcinoma that transformed from papillary carcinoma within 5 years from initial diagnosis

An 84-year-old man was admitted to our hospital with right shoulder pain. He had been suffering from well-differentiated papillary thyroid carcinoma since 1994, and had undergone surgery three times, including procedures due to recurrence. Since CT showed a right cervical tumor, recurrence of thyroid carcinoma was diagnosed. He died in September 1999 due to progressive respiratory failure. Autopsy was performed and pathological examination revealed the recurrent tumor and metastatic lesions had totally transformed to anaplastic thyroid carcinoma. Since anaplastic carcinoma is characterized by exceptionally rapid progression with dire prognosis, physicians should be aware of the major risk factors of anaplastic transformation in elderly males aged over 60 years old, with repeated relapses of differentiated carcinoma, and a history of tumor irradiation.     

Riedel's thyroiditis presenting with hypothyroidism and hypoparathyroidism: dramatic response to glucocorticoid and thyroxine therapy

Riedel's thyroiditis is a rare fibro-inflammatory process originating in the thyroid gland with progressive extension and invasion of surrounding tissues. Patients frequently present with a stony hard thyroid mass suggestive of anaplastic carcinoma. We report a striking case of Riedel's thyroiditis associated with hypothyroidism, hypoparathyroidism and bilateral vocal cord paralysis. A dramatic response to high dose prednisone and levothyroxine therapy was seen, with recovery of parathyroid and vocal cord function. Our case suggests that early initiation of combination therapy may be important, particularly in the presence of severe disease.     

黏附分子CD44变异剪接体6在甲状腺肿瘤中的表达及其临床意义

目的探讨CD44变异剪接体6(CD     

黏附分子CD44变异剪接体6在甲状腺肿瘤中的表达及其临床意义

目的　探讨CD44变异剪接体 6(CD44V6 )在甲状腺肿瘤组织的表达情况及其与肿瘤发生、发展、浸润和转移的关系。方法　采用免疫组织化学S P法检测 2 0例癌旁甲状腺组织 ,2 4例甲状腺腺瘤和 64例甲状腺癌的石蜡标本CD44V6 表达水平。结果　CD44V6 在甲状腺腺癌的表达率 ( 92 19%)显著高于甲状腺腺瘤者 ( 5 8 3 3 %,P <0 0 1) ,癌旁甲状腺组织未见表达。甲状腺中不同组织来源的滤泡细胞癌和髓样癌的CD44V6 表达差异具有显著性 ,总阳性率分别为 96 5 5 %及 5 0 0 %(P <0 0 1)。但CD44V6 表达水平在乳头状腺癌和滤泡型腺癌间差别无显著性 (P >0 0 5 )。同时发现 2例未分化癌CD44V6 表达均呈强阳性。CD44V6 的表达水平与甲状腺癌的包膜浸润和淋巴结转移有关 ,CD44V6 表达水平在包膜浸润组和未浸润组之间 ,在淋巴结转移组和非转移组之间差别有显著性 (P <0 0 1)。CD44V6 表达与患者年龄、性别、肿瘤的大小无关 (P >0 0 5 )。结论　CD44V6 的表达与甲状腺肿瘤的分化和浸润、转移显著相关 ,检测CD44V6 有助于甲状腺癌的诊断、判断预后并可能为甲状腺癌的手术和术后综合治疗决策提供新的分子生物学指标。     

Isolated metastasis to small bowel from anaplastic thyroid carcinoma. With a review of extra-abdominal malignancies that spread to the bowel

Symptomatic involvement of the small bowel by isolated metastasis from an extra-abdominal primary malignancy is rare, most commonly resulting from malignant melanoma and lung cancer. A few other extra-abdominal tumors, not including thyroid cancer, have been documented on rare occasions to present with small-bowel involvement as the first evidence of metastasis. We report a case of anaplastic thyroid carcinoma with isolated symptomatic metastasis to the small intestine. We review the literature regarding the frequency and origin of extra-abdominal malignancies developing small-bowel metastases and the spectrum of clinical manifestations resulting from this syndrome.     

Proteomic analysis of human thyroid cell lines reveals reduced nuclear localization of Mn-SOD in poorly differentiated thyroid cancer cells

Differential protein arrays between nuclear extracts of human thyroid cell lines obtained from tumors with different degree of differentiation were exploited to define molecular alterations occurring during thyroid tumor progression. Nuclear extracts from the well differentiated TPC-1 (from papillary carcinoma) and the poorly differentiated ARO (from anaplastic carcinoma) cells showed an overall similar pattern of protein expression as revealed by two-dimensional gel electrophoresis analysis. However, manganese-superoxide dismutase (Mn-SOD) was clearly identified by mass spectrometry procedures as significantly less expressed in ARO compared to TPC-1 cells. A reduced expression of Mn-SOD in the nuclear compartment was confirmed by Western blot and immunofluorescence analysis. A similar expression pattern of nuclear Mn-SOD was detected by immunohistochemistry in human thyroid tumors, with the lowest or absent detection in anaplastic carcinomas. Moreover, the levels of nuclear Mn-SOD in tumor cells were lower than in the normal thyrocytes. These data indicate that an altered nuclear expression of Mn-SOD parallels, together with changes in other elements of the antioxidant protective system, the loss of differentiation occurring during the progression of thyroid tumors.     

Abnormally high expression of proteasome activator-gamma in thyroid neoplasm

PA28-gamma is the activator of 20S proteasome, the ATP-dependent proteolytic system that plays an important role in cell cycle progression in various cell types. In this paper, we show the abnormally high expression of PA28-gamma in various thyroid neoplasms. Thyroid samples were obtained from patients with normal thyroid (4 cases) and with the following diseases: papillary adenocarcinoma (13 cases), multinodular goiter (4 cases), and anaplastic carcinoma (1 case). PA28-gamma expression was estimated by immunohistochemical staining and Western blotting. In all of the papillary adenocarcinoma samples, PA28-gamma was abnormally overexpressed, especially in cancer cells existing at the peripheral region of the cancer mass or in cancer cells invading the capsular region surrounding the cancer mass. In cancer cells of these areas, PA28-gamma was predominantly distributed in nucleus rather than in the cytoplasm of cancer cells. On the other hand, no obvious PA28-gamma expression was observed in the adjacent normal thyroid follicular cells. In multinodular goiter, the expression of PA28-gamma was relatively low compared with papillary adenocarcinoma. In anaplastic carcinoma, PA28-gamma was expressed at the highest level, especially in poorly differentiated regions such as squamous metaplasia of anaplastic cancer tissue. Therefore, the PA28-gamma expression seems to be restricted to thyroid cancer cells, especially in the region where the growth rate of cancer cells is accelerated. This result is further confirmed by the fact that C2, alpha-subunit of 20S proteasome, and proliferating cell nuclear antigen are similarly overexpressed in this region. Thus, PA28-gamma might be involved in the regulatory system for the cell cycle. Moreover, the growth of thyroid cancer cell lines was affected by the proteasome inhibitor, clasto-lactacystin beta-lactone. These results demonstrate that PA28-gamma is overexpressed in thyroid cancer, especially in its growth-accelerated cells.