Thyroid: Oncocytic tumors

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Thyroid: Oncocytic tumors

Written	2003-06	Oluwole Fadare, Giovanni Tallini
		Anatomia Patologica, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy

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Identity

ICD-Topo C739 THYROID GLAND

ICD-Morpho 8290/0 Oncocytic adenoma

Atlas_Id 5068

Phylum Neuro-Endocrine/Endocrine system: Thyroid::Oncocytoic tumor (Hürthle cells adenoma)

Note Oncocytes (from the greek word swell), also known as Hurthle cells, oxyphilic cells or Askanazy cells, are characterized by abundant granular cytoplasm due to aberrant accumulation of mitochondria. The cause for the mitochondria accumulation is unknown. The increased number of mithochondria may be a compensatory to intrinsic defects in the energy production machinery of the cell. Cells that fit this basic description may be identified in a variety of non-neoplastic lesions as well as in the affected tissues of patients with mitochondrial myopaties.
Tumors composed of oncocytes are not restricted to the thyroid gland and may arise in a variety of locations, most commonly in the kidney and salivary gland and may be benign or malignant. By convention, thyroid tumors are designated as oncocytic if at least 75% of their constituent cells can be described as oncocytes. In the context of the traditional classification of differentiated thyroid tumors of follicular cell derivation into follicular and papillary histotypes, the majority of oncocytic neoplasms represent a distinct subtype of thyroid follicular tumors. Papillary carcinomas, as well as a few medullary thyroid carcinomas, may also be oncocytic but for the purpose of this brief review, oncocytic tumors will refer to the follicular cell derived neoplasm that lacks nuclear features of papillary carcinoma.
Thyroid oncocytic tumors are neoplasms composed by a majority of cells with the morphologic features of oncocytes.

Classification

Note
Oncocytic (Hürthle cell, oxyphilic cell, askanazi cell) adenoma: transcapsular and/or vascular invasion absent.

Note Widely invasive oncocytic thyroid carcinoma

Clinics and Pathology

Etiology Unknown. The precise cellular derangements that lead to the abnormal accumulation of mitochondria in oncocytes and tumor development are obscure. Alterations of nuclear genetic material (marked aneuploidy) and of mitochondrial DNA are a feature of thyroid oncocytic tumors.

Epidemiology The mean age at diagnosis was 43 years for adenomas and 52 for oncocytic carcinomas in a recent series. There is a female preponderance in both subgroups, with a female-to-male ratio of 8:1 in adenomas and 2:1 in carcinomas. Thyroid oncocytic tumors represent approximately 5-10% of thyroid neoplasms.

Clinics Most patients with oncocytic neoplasms are euthyroid and present with a thyroid nodule. Secondary syntoms due to compression of the adjacent structures in the neck (e.g. dysphonia, dysphagia) may be present, particularly in patients with malignant tumors.

Pathology Grossly, oncocytic adenomas are encapsulated, solid nodules with a characteristic brown cut surface. Secondary changes, including infarction and hemorrhage are common (particularly after fine needle aspiration), possibly as a result of the low tolerance to ischemia displayed by the oncocytes. Histologically, the follicular growth pattern is most common but cells may also be arranged in trabeculae, solid sheets or papillary formations. The colloid is typically purple (amphophilic) rather than pink on conventional histology sections stained with hematoxylin and eosin. Oncocytes have round uniform nuclei with prominent nucleoli but may display scattered areas of marked nuclear atypia and anisonucleosis. The gross appearance of a minimally invasive oncocytic carcinoma is indistinguishable to that of an adenoma, while widely invasive oncocytic carcinomas are obviously invasive macroscopically and display pervasive vascular invasion with multifocal involvement of the thyroid gland. There are no reliable cytologic features which distinguish oncocytic adenomas from carcinomas and the only criteria for a diagnosis of malignancy is the identification of transcapsular and/or vascular invasion.

Fig 1 : Oncocytic cells showing abundant granular cytoplasm and prominent nucleoli (arrowheads)
Fig 2 : Mitochondria accumulation in oncocytic cells. Some mitochondria have abnormal architecture with electrondense deposits (inset)

Treatment Oncocytic adenomas are treated with a simple lobectomy or nodulectomy, which is curative but should not be enucleated, as an evaluation of their capsule is essential for the pathologist to determine whether the tumor is benign or malignant. Carcinomas are treated with total/subtotal thyroidectomy followed by radioactive iodine therapy. Oncocytic carcinomas tend to have lower iodide uptake compared with non-oncocytic cancers and are often therefore less responsive to radioactive iodide administration.

Prognosis The extent of tumor invasion determines the prognosis in oncocytic carcinomas. Patients with widely invasive tumors (defined as having 2 or more foci of capsular and/or vascular invasion) have a mortality of approximately 50% with median disease specific survival of 7 years. Patients with minimally invasive carcinoma have excellent prognosis with no tumor recurrences or disease related deaths reported in a recent series. Extrathyroidal extension and nodal metastases are adverse predictors of survival after multivariate analysis in widely invasive oncocytic carcinoma.

Cytogenetics

Cytogenetics
Morphological Relatively few cases of oncocytic thyroid tumors have been studied by convential cytogenetic analysis, usually in general reports dealing with chromosomal alterations of thyroid neoplasia. 42-47 chromosomes with structural and numerical changes have been demonstrated in one oncocytic carcinoma.

Cytogenetics Molecular CGH: Chromosomal DNA unbalance and aneuploidy are present in 70-80% of oncocytic thyroid neoplasms. Chromosomal DNA gains (+5, +7, +12, +17 , +19, +20) are more common than losses (-2, -9). Although aneuploidy is a feature of both oncocytic adenomas and carcinomas, sequential acquisition of numerical chromosomal changes (possibly beginning with trisomy 7) appears associated with tumor progression. Carcinomas tend to have more chromosomal gains and losses then adenomas and a statistical association has been demonstrated between the degree of aneuploidy and loss of differentiation, extent of tumor invasion, and recurrence.

Genes involved and Proteins

Note Nuclear genes and proteins: ATP production appears defective in oncocytic thyroid tumors but no specific alterations have been demonstrated in the nuclear genes which code for most of the proteins involved in the mitochondrial oxidative phosphorylation process or which control mtDNA replication. RAS mutations (frequently observed in follicular adenomas and carcinomas) and PAX8/ rearrangement (frequently observed in follicular carcinomas) are uncommon in oncocytic neoplasms. A gene predisposing to the familial development of oncoytic thyroid neoplasms has been mapped at 19p13.2
Mitochondrial DNA (mtDNA) and proteins: The common mitochondrial DNA (mtDNA) deletion is a 4977 bp deletion frequently present in a variety of ageing human tissues. This deletion has been identified in 100% of oncocytic thyroid tumors but only at low level and in 20-30% of the non neoplastic thyroid parenchyma surrounding the tumor. Not only the prevalence but also the amount of the common mtDNA deletion is statistically higher in oncocytic thyroid tumors compared with non oncocytic ones. The proportion of mtDNA harbouring the common deletion appears to be higher in oncocytic carcinomas compared with oncocytic adenomas. Oncoytic tumors (benign or malignant) have a higher prevalence of mutations in the non coding displacaement-loop (D-loop) region of their mtDNA compared with non oncoytic tumors. Although mutations have been identified in the coding portions of the mtDNA, these mutations do not appear different from those observed in thyroid tumors lacking oncocytic features. No specific alterations have been identified in the mtDNA genes coding for the components of the oxidative phosphorylation process.

Bibliography

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Carcangiu ML, Bianchi S, Savino D, Voynick IM, Rosai J

Cancer. 1991 ; 68 (9) : 1944-1953.

PMID 1913544

Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma.

Jenkins RB, Hay ID, Herath JF, Schultz CG, Spurbeck JL, Grant CS, Goellner JR, Dewald GW

Cancer. 1990 ; 66 (6) : 1213-1220.

PMID 2400971

Prognostic factors in patients with Hürthle cell neoplasms of the thyroid.

Lopez-Penabad L, Chiu AC, Hoff AO, Schultz P, Gaztambide S, Ordoñez NG, Sherman SI

Cancer. 2003 ; 97 (5) : 1186-1194.

PMID 12599224

Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hürthle cell tumors.

Máximo V, Soares P, Lima J, Cameselle-Teijeiro J, Sobrinho-Simá M

The American journal of pathology. 2002 ; 160 (5) : 1857-1865.

PMID 12000737

RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.

Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn GW 2nd, Tallini G, Kroll TG, Nikiforov YE

The Journal of clinical endocrinology and metabolism. 2003 ; 88 (5) : 2318-2326.

PMID 12727991

Hürthle cell carcinoma: a critical histopathologic appraisal.

Stojadinovic A, Ghossein RA, Hoos A, Urist MJ, Spiro RH, Shah JP, Brennan MF, Shaha AR, Singh B

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2001 ; 19 (10) : 2616-2625.

PMID 11352953

Frequent chromosomal DNA unbalance in thyroid oncocytic (Hürthle cell) neoplasms detected by comparative genomic hybridization.

Tallini G, Hsueh A, Liu S, Garcia-Rostan G, Speicher MR, Ward DC

Laboratory investigation; a journal of technical methods and pathology. 1999 ; 79 (5) : 547-555.

PMID 10334566

Chromosomal aberrations by comparative genomic hybridization in hürthle cell thyroid carcinomas are associated with tumor recurrence.

Wada N, Duh QY, Miura D, Brunaud L, Wong MG, Clark OH

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PMID 12364440

Citation

This paper should be referenced as such :

Fadare, O ; Tallini, G

Thyroid: Oncocytic tumors

Atlas Genet Cytogenet Oncol Haematol. 2003;7(3):197-200.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/OncocytThyroidID5068.html

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes DPP4 ENO1

External links

arrayMap Topo ( C73) arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]

Disease database Thyroid: Oncocytic tumors

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

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ICD-Topo	C739 THYROID GLAND
ICD-Morpho	8290/0 Oncocytic adenoma
Atlas_Id	5068
Phylum	Neuro-Endocrine/Endocrine system: Thyroid::Oncocytoic tumor (Hürthle cells adenoma)

Note	Oncocytes (from the greek word swell), also known as Hurthle cells, oxyphilic cells or Askanazy cells, are characterized by abundant granular cytoplasm due to aberrant accumulation of mitochondria. The cause for the mitochondria accumulation is unknown. The increased number of mithochondria may be a compensatory to intrinsic defects in the energy production machinery of the cell. Cells that fit this basic description may be identified in a variety of non-neoplastic lesions as well as in the affected tissues of patients with mitochondrial myopaties. Tumors composed of oncocytes are not restricted to the thyroid gland and may arise in a variety of locations, most commonly in the kidney and salivary gland and may be benign or malignant. By convention, thyroid tumors are designated as oncocytic if at least 75% of their constituent cells can be described as oncocytes. In the context of the traditional classification of differentiated thyroid tumors of follicular cell derivation into follicular and papillary histotypes, the majority of oncocytic neoplasms represent a distinct subtype of thyroid follicular tumors. Papillary carcinomas, as well as a few medullary thyroid carcinomas, may also be oncocytic but for the purpose of this brief review, oncocytic tumors will refer to the follicular cell derived neoplasm that lacks nuclear features of papillary carcinoma. Thyroid oncocytic tumors are neoplasms composed by a majority of cells with the morphologic features of oncocytes.

Note	Oncocytic (Hürthle cell, oxyphilic cell, askanazi cell) adenoma: transcapsular and/or vascular invasion absent.


Note	Widely invasive oncocytic thyroid carcinoma

Etiology	Unknown. The precise cellular derangements that lead to the abnormal accumulation of mitochondria in oncocytes and tumor development are obscure. Alterations of nuclear genetic material (marked aneuploidy) and of mitochondrial DNA are a feature of thyroid oncocytic tumors.
Epidemiology	The mean age at diagnosis was 43 years for adenomas and 52 for oncocytic carcinomas in a recent series. There is a female preponderance in both subgroups, with a female-to-male ratio of 8:1 in adenomas and 2:1 in carcinomas. Thyroid oncocytic tumors represent approximately 5-10% of thyroid neoplasms.
Clinics	Most patients with oncocytic neoplasms are euthyroid and present with a thyroid nodule. Secondary syntoms due to compression of the adjacent structures in the neck (e.g. dysphonia, dysphagia) may be present, particularly in patients with malignant tumors.
Pathology	Grossly, oncocytic adenomas are encapsulated, solid nodules with a characteristic brown cut surface. Secondary changes, including infarction and hemorrhage are common (particularly after fine needle aspiration), possibly as a result of the low tolerance to ischemia displayed by the oncocytes. Histologically, the follicular growth pattern is most common but cells may also be arranged in trabeculae, solid sheets or papillary formations. The colloid is typically purple (amphophilic) rather than pink on conventional histology sections stained with hematoxylin and eosin. Oncocytes have round uniform nuclei with prominent nucleoli but may display scattered areas of marked nuclear atypia and anisonucleosis. The gross appearance of a minimally invasive oncocytic carcinoma is indistinguishable to that of an adenoma, while widely invasive oncocytic carcinomas are obviously invasive macroscopically and display pervasive vascular invasion with multifocal involvement of the thyroid gland. There are no reliable cytologic features which distinguish oncocytic adenomas from carcinomas and the only criteria for a diagnosis of malignancy is the identification of transcapsular and/or vascular invasion.


	Fig 1 : Oncocytic cells showing abundant granular cytoplasm and prominent nucleoli (arrowheads) Fig 2 : Mitochondria accumulation in oncocytic cells. Some mitochondria have abnormal architecture with electrondense deposits (inset)

Treatment	Oncocytic adenomas are treated with a simple lobectomy or nodulectomy, which is curative but should not be enucleated, as an evaluation of their capsule is essential for the pathologist to determine whether the tumor is benign or malignant. Carcinomas are treated with total/subtotal thyroidectomy followed by radioactive iodine therapy. Oncocytic carcinomas tend to have lower iodide uptake compared with non-oncocytic cancers and are often therefore less responsive to radioactive iodide administration.
Prognosis	The extent of tumor invasion determines the prognosis in oncocytic carcinomas. Patients with widely invasive tumors (defined as having 2 or more foci of capsular and/or vascular invasion) have a mortality of approximately 50% with median disease specific survival of 7 years. Patients with minimally invasive carcinoma have excellent prognosis with no tumor recurrences or disease related deaths reported in a recent series. Extrathyroidal extension and nodal metastases are adverse predictors of survival after multivariate analysis in widely invasive oncocytic carcinoma.

arrayMap	Topo ( C73) arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]


Disease database	Thyroid: Oncocytic tumors

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed