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This is a poorly defined category of thyroid carcinomas which are so poorly differentiated, they do not fit into any other histologic categories. The large cell histologic variant is the most common type.


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SYNONYMS Undifferentiated carcinoma, dedifferentiated carcinoma, sarcomatoid carcinoma
INCIDENCE 10% of all thyroid malignancies


Prior radiation exposure  
Iodine deficiency Goiter may be found in 80% of affected patients


BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment.

Begum S, Rosenbaum E, Henrique R, Cohen Y, Sidransky D, Westra WH.

1Department of Pathology, Head and Neck Surgery (Division of Head and Neck Cancer Research), The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Mod Pathol. 2004 Nov;17(11):1359-63. Abstract quote  

Anaplastic thyroid carcinoma is a highly aggressive neoplasm. Affected patients typically present with advanced disease where there is little hope for cure using conventional therapeutic modalities. Understanding the genetic alterations underlying the development of anaplastic thyroid carcinoma, such as mutational activation of BRAF, could help clarify its relationship with well-differentiated forms of thyroid carcinoma (ie follicular and papillary carcinoma) and could help select patients most likely to benefit from novel therapeutic strategies targeting BRAF.

We tested 16 anaplastic thyroid carcinomas for the thymine (T) --> adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector((R)) assay). Seven of these anaplastic thyroid carcinomas arose in association with a well-differentiated thyroid carcinoma, and these were also evaluated. The 1796T --> A mutation was detected in eight (50%) of the anaplastic thyroid carcinomas, in four of five (80%) associated papillary thyroid carcinomas, and in zero of two (0%) associated follicular carcinomas. In all seven cases where anaplastic thyroid carcinoma arose in association with a well-differentiated thyroid carcinoma, BRAF status in the two components was concordant. Like papillary thyroid carcinoma, a significant percentage of anaplastic thyroid carcinomas also harbor BRAF mutations.

Indeed, when papillary thyroid carcinoma and anaplastic thyroid carcinoma occur together, they consistently share the same BRAF profile, supporting the notion that many anaplastic thyroid carcinomas actually represent progressive malignant degeneration of a pre-existing well-differentiated thyroid carcinoma.

The high frequency of BRAF mutations in a tumor that is generally regarded as uniformly fatal justifies evaluation of the potential benefits of anti-BRAF therapy for patients with anaplastic thyroid carcinoma.

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

Hunt JL, Tometsko M, LiVolsi VA, Swalsky P, Finkelstein SD, Barnes EL.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Am J Surg Pathol. 2003 Dec;27(12):1559-64. Abstract quote  

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 (Hurthle 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.

Expression of Epstein-Barr virus in thyroid carcinoma correlates with tumor progression.

Shimakage M, Kawahara K, Sasagawa T, Inoue H, Yutsudo M, Yoshida A, Yanoma S.

Clinical Research Institute and Department of Pathology, Osaka National Hospital, Japan.

Hum Pathol. 2003 Nov;34(11):1170-7. Abstract quote  

There have been few studies regarding cancer progression from differentiated thyroid carcinoma to the undifferentiated one. To examine the possible involvement of Epstein-Barr virus (EBV) in this progression, 10 papillary carcinomas and 11 undifferentiated carcinomas were subjected to mRNA in situ hybridization, indirect immunofluorescence staining, polymerase chain reaction (PCR), and reverse-transcriptase PCR. mRNA in situ hybridization using a BamHIW probe revealed signals in all of the examined samples, although the signal strength was weaker in the papillary carcinomas than in the undifferentiated carcinomas. EBV nuclear antigen-2 (EBNA2) in situ hybridization produced almost the same results; however, the signals were detected less frequently in the papillary carcinomas. Indirect immunofluorescence using anti-EBNA2, anti-latent membrane protein-1 (LMP1), and anti-BZLF1 antibodies also showed positive results with high frequency and with more prominent fluorescence in undifferentiated carcinomas than in papillary carcinomas.

An examination of thyroid carcinoma cell lines also confirmed these findings. EBV infected all of the thyroid carcinomas irrespective of the degree of pathological differentiation. The expression of EBV, especially of EBNA2 and LMP1 (both of which are oncogene products of EBV), was stronger in the undifferentiated carcinomas than in the papillary carcinomas.

These results suggest that increased expression of EBV may be involved in the progression of thyroid papillary carcinoma to undifferentiated carcinoma.


General Large bulky tumors with extensive intrathyroidal and extrathyroidal extension



Poorly differentiated malignancy with varying combinations of giant cells, spindle cells, squamous cells, and fibrosis

Mitotic figures abundant with necrosis and vascular invasion

The periphery may show a goiter or a well differentiated thyroid carcinoma such as a papillary carcinoma

Poorly Differentiated Thyroid Carcinoma: The Turin Proposal for the Use of Uniform Diagnostic Criteria and an Algorithmic Diagnostic Approach.

*Department of Clinical and Biological Sciences at San Luigi Hospital †Department of Pathology Istituto Nazionale Tumori ‡Department of Pathology, Pittsburgh School of Medicine, Pittsburgh §Department of Pathology, Kyorin University School of Medicine, Tokyo ∥Department of Pathology, Wakayama Medical University, Wakayama City ¶University of Yamanashi Interdisciplinary Graduate School of Medicine and Engineering, Yamanashi, Japan ♯Departments of Laboratory Medicine and Pathology and Statistics, Mayo Clinic, Rochester, MN **Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA ††Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal ‡‡Department of Biomedical Sciences and Human Oncology, University of Turin, Orbassano, Turin §§Centro Diagnostico Italiano, Milan, Italy

Am J Surg Pathol. 2007 Aug;31(8):1256-1264. Abstract quote

Poorly differentiated (PD) thyroid carcinomas lie both morphologically and behaviorally between well-differentiated and undifferentiated (anaplastic) carcinomas. Following the original description of this entity, different diagnostic criteria have been employed, resulting in wide discrepancies and confusion among pathologists and clinicians worldwide.

To compare lesions occurring in different geographic areas and the diagnostic criteria applied in those countries, we designed a study with a panel of internationally recognized thyroid pathologists to develop consensus diagnostic criteria for PD carcinomas. Eighty-three cases were collected from Europe, Japan, and the United States, and circulated among 12 thyroid pathologists. Diagnoses were made without any knowledge of the clinical parameters, which were subsequently used for survival analysis.

A consensus meeting was then held in Turin, Italy, where an agreement was reached concerning the diagnostic criteria for PD carcinoma. These include (1) presence of a solid/trabecular/insular pattern of growth, (2) absence of the conventional nuclear features of papillary carcinoma, and (3) presence of at least one of the following features: convoluted nuclei; mitotic activity >/=3x10 HPF; and tumor necrosis. An algorithmic approach was devised for practical use in the diagnosis of this tumor.

Glandular patterns in a thyroid carcinoma with insular and anaplastic features: A case with possible implications for the classification of thyroid carcinomas.

Fadare O, Sinard JH.

Department of Pathology, Yale University School of Medicine, New Haven, CT.


Ann Diagn Pathol 2002 Dec;6(6):389-98 Abstract quote

We describe the case of a 33-year-old woman with a thyroid carcinoma showing poorly differentiated (insular), anaplastic, and glandular features, the latter with extensive clear cell changes.

Grossly, the well-circumscribed tumor nodule measured 3.6 cm in maximum dimension and was confined to the thyroid. Microscopically, the majority of the tumor was composed of well-defined "insular" nests showing microfollicular formation, high mitotic activity, and areas of necrosis. Other regions, as well as the intervening stroma of the insular nests, were characterized by highly atypical and pleomorphic stromal cells, extensive necrosis, and malignant cartilaginous nodules. Approximately 30% of the tumor was composed of diffuse glandular formations, each of which were lined by elongated, simple columnar cells with basally situated, mildly pleomorphic nuclei, clear supranuclear, periodic acid-Schiff + (and diastase sensitive) cytoplasm, empty lumens, and no myoepithelia or basement membranes.

Immunohistochemically, the glandular elements displayed diffuse and strong positivity for thyroid transcription factor-1, bcl-2, and CAM 5.2, sparse positivity for thyroglobulin and Ki67, and diffuse but weak positivity for p53. Calcitonin was negative throughout the tumor. Karyotypic analysis of a primary culture showed a complex hypertriploid karyotype including structural abnormalities of chromosomes X, 1, 4, 6, 9, 13, and 14 in the majority of cells examined. This composite of histologic findings, especially the glandular patterns, is unusual and their prognostic significance is unclear. The patient is alive with no evidence of tumor recurrence or metastasis at 5 months follow-up.

Overall, the morphologic and immunohistochemical properties of the glandular component suggests that they are less differentiated than well-differentiated carcinomas and are probably more differentiated than the insular component. This case supports the theory that the various primary carcinomas of the thyroid may represent points along a spectrum rather than distinct entities.

Insular and anaplastic carcinoma of the thyroid: a 45-year comparative study at a single institution and a review of the significance of p53 and p21.

Lam KY, Lo CY, Chan KW, Wan KY.

Department of Pathology, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong.

Ann Surg 2000 Mar;231(3):329-38 Abstract quote

OBJECTIVE: To analyze the clinicopathologic features of a large cohort of patients with insular or anaplastic carcinomas treated at a single institution.

SUMMARY BACKGROUND DATA: Insular and anaplastic carcinomas of the thyroid, although uncommon, have more aggressive clinical behavior than well-differentiated carcinomas of the thyroid. In the literature, the incidence and features of these carcinomas have not been fully characterized.

METHODS: The authors reclassified 740 primary thyroid carcinomas diagnosed and treated between January 1, 1954, and December 30, 1998, to select those with features that met the histologic criteria of insular or anaplastic carcinoma. The clinicopathologic features of these carcinomas were studied and compared. The expression of p53 and p21 in these tumors was analyzed by immunohistochemistry.

RESULTS: Twenty-two patients (5 men, 17 women) with insular carcinoma and 38 patients (7 men, 31 women) with anaplastic carcinoma were found. Patients with insular carcinomas were younger (mean age 45 vs. 70 years) and had smaller tumors than those with anaplastic carcinomas (mean diameter 5 vs. 8 cm). Insular carcinomas were commonly mislabeled as other histologic subtypes, whereas anaplastic carcinomas might be overdiagnosed on pathologic examination. A history of longstanding goiter (>10 years) was noted in 27% of patients with insular carcinoma and 24% of patients with anaplastic carcinomas. Concomitant well-differentiated carcinomas of the thyroid were noted in 59% of patients with insular carcinoma and 39% of patients with anaplastic carcinoma. In anaplastic carcinomas, 13% of patients had concomitant insular carcinoma. Calcification or bone was noted in the stroma of 23% of patients with insular carcinomas and 47% of those with anaplastic carcinomas. The 10-year survival rates for patients with insular carcinoma and anaplastic carcinoma were 42% and 3%, respectively. Distant metastases were seen in 32% of patients with insular carcinoma and in 47% of patients with anaplastic carcinomas. In both types of carcinomas, metastatic tumors were often seen in bone and lung. Distant metastases were noted in a variety of organs in anaplastic carcinomas. In insular carcinoma, neither p53 nor p21 expression was present. In anaplastic carcinoma, p53 and p21 expression was identified in 69% and 3%, respectively. Concomitant expression of p53 and p21 was noted in one tumor.

CONCLUSIONS: Insular carcinoma and anaplastic carcinoma had distinctive clinicopathologic features, and recognition of these histologic variants is important for better management of these tumors in the future. p53 overexpression might have a role in dedifferentiation from insular carcinoma to anaplastic carcinoma.

Poorly differentiated ("insular") carcinoma of the thyroid gland: an aggressive subset of differentiated thyroid neoplasms.

Flynn SD, Forman BH, Stewart AF, Kinder BK.

Department of Pathology, Internal Medicine, Yale University School of Medicine, New Haven, Conn. 06510.

Surgery 1988 Dec;104(6):963-70 Abstract quote

Four patients with a histologically distinctive thyroid carcinoma--which recently has been referred to as poorly differentiated ("insular") carcinoma--are reported. This study confirms the previous conclusions that patients with this neoplasm often experience an aggressive clinical course, with focal recurrences and distant metastases common, which results in death in the majority of patients. Such aggressive behavior may occur even when the insular component accounts for only a small percentage of an otherwise well-differentiated carcinoma, as seen in one of our patients.

After subtotal or total thyroidectomy, three of the four patients have experienced local recurrence (1) and metastases to lung (3), mediastinum (1), and bone (1). All three of these patients died within 2 years of the diagnosis of insular carcinoma. The remaining patient is alive without evidence of disease 1 year after total thyroidectomy. Histologically, this neoplasm is characterized by well-defined nests (insulae) that are composed of relatively small, uniform cells and sometimes associated with small, thyroglobulin-containing follicles. Tumor necrosis is often present. Insular carcinoma may comprise the entire neoplasm (2 patients) or be associated with well-differentiated follicular (1 patient) or papillary (1 patient) carcinoma.

The rapid and often fatal course associated with insular carcinoma warrants aggressive treatment at the time of initial diagnosis, including total thyroidectomy and node dissection (if involved), as well as possible iodine-131, external beam irradiation and chemotherapy.

LARGE CELL 3-5% of all thyroid tumors
Lymphoepithelioma-like anaplastic thyroid carcinoma: Report of a case not related to Epstein-Barr virus

Ann Diagn Pathol 2001;5:21-24 (Abstract quote)

Case Report:
A 68-year-old man developed a rapidly growing thyroid tumor that extended into the retropharyngeal, prevertebral, and perilaryngeal spaces, and eventually invaded the esophagus. The patient was treated with radiotherapy, obtaining a good but incomplete response. The neoplasia was composed of syncytial sheaths of epithelial cells with large vesicular nuclei, prominent nucleoli, and high mitotic activity. There was abundant lymphoid infiltrate surrounding and invading the cell sheaths. The overall picture was of a lymphoepithelioma, but no evidence of Epstein-Barr virus infection was detected by studies of immunohistochemistry and polymerase chain reaction.

We believe this case represents a morphologic variant of anaplastic carcinoma that should be separated from carcinoma showing thymus-like differentiation, a tumor that also resembles lymphoepithelioma but has an indolent course.

Mucinous carcinoma (poorly differentiated carcinoma with extensive extracellular mucin deposition) of the thyroid: A case report with immunohistochemical studies.

Kondo T, Kato K, Nakazawa T, Miyata K, Murata S, Katoh R.
Hum Pathol. 2005 Jun;36(6):698-701. Abstract quote  

Summary We report on a case of mucinous carcinoma of the thyroid in an 82-year-old Japanese woman. The 3 x 2 x 2-cm thyroid tumor located in the patient's right lateral lobe was soft and yellowish gray on the cut section.

Microscopically, the tumor was composed entirely of strands or solid clusters accompanied by extensive extracellular mucin. Extracellular mucin was positive with Alcian blue stain and negative with periodic acid-Schiff stain. Immunohistochemically, the tumor cells were positive for thyroglobulin, thyroid-specific transcription factor 1, and low-molecular-weight cytokeratin but negative for carcinoembryonic antigen, calcitonin, and high-molecular-weight cytokeratin. The MIB-1 labeling index was rather high (11%), and immunoexpression of p53 was detectable in the nuclei of carcinoma cells.

From these findings, we classified the present tumor as a mucinous carcinoma of the thyroid (poorly differentiated thyroid carcinoma producing massive extracellular mucin). The patient died of multiple metastases 4 years after the initial operation.

Am J Clin Pathol 1996;105:388

Associated with dense fibrosis and calcifications
May be associated with poor outcome


Special stains  
Immunoperoxidase CK+
Thyroglobulin usually negative


Prognostic Factors  
Survival Poor, median less than 6 months following diagnosis

Thyroid carcinomas with distant metastases: a review of 111 cases with emphasis on the prognostic significance of an insular component.

Decaussin M, Bernard MH, Adeleine P, Treilleux I, Peix JL, Pugeat M, Tourniaire J, Berger N.

Department of Pathology, Hopital de l'Antiquaille, Lyon, France.


Am J Surg Pathol 2002 Aug;26(8):1007-15 Abstract quote

Distant metastases (DM) are rare in well-differentiated thyroid carcinomas and correlate with a poor survival. Among the histologic subtypes, insular carcinoma has an intermediate prognosis that lies between well and undifferentiated carcinomas.

To assess the characteristics that could predict a worse prognosis, we reviewed the initial thyroid cancer slides from patients with DM. We achieved a comparative statistical analysis with a control group without DM. Among 1230 differentiated carcinomas treated from 1960 to 1999, 9% developed DM. In this group the mean age was 53 years, with a 73% rate of death. The histologic slides were available in 80 cases. The primary thyroid tumors were classified as papillary (51 cases), follicular (25), and pure insular carcinomas (4). Extrathyroidal extension was present in 47% of papillary carcinomas. The mean tumor size was above 5 cm for all the histologic subtypes, and at least a vascular invasion was found in 69%. Fifty-four percent of these tumors had an insular component compared with only 6.5% in the control group. The statistical analysis confirmed by univariate and multivariate logistic regression that the risk of DM was highly elevated in the presence of insular carcinoma.

Our study indicates that elevated age, large tumor size, vascular invasion, and extrathyroidal extension are important prognostic factors in well-differentiated carcinomas. We also demonstrate that the presence of an insular component in an otherwise differentiated carcinoma is a strong independent poor prognostic factor.

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Last Updated August 7, 2007

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