Mixed Medullary and Follicular Carcinoma of the Thyroid
1999; Elsevier BV; Volume: 155; Issue: 5 Linguagem: Inglês
10.1016/s0002-9440(10)65453-3
ISSN1525-2191
Autores Tópico(s)BRCA gene mutations in cancer
ResumoThe recognition of the pathological features of medullary thyroid carcinoma (MTC) by Horn1Horn RC Carcinoma of the thyroid. Description of a distinctive morphological variant and report of 7 cases.Cancer. 1951; 4: 697-707Crossref Scopus (59) Google Scholar and Hazzard et al2Hazard JB Hawk WA Crile Jr, G Medullary (solid) carcinoma of the thyroid: a clinicopathologic entity.J Clin Endocrinol Metab. 1959; 19: 152-161Crossref PubMed Scopus (544) Google Scholar in the 1950s and the demonstration that it derived from the calcitonin-producing parafollicular cells3Williams ED Histogenesis of medullary carcinoma of the thyroid.J Clin Pathol. 1966; 19: 114-118Crossref PubMed Scopus (287) Google Scholar, 4Bussolati G Foster GV Clark MB Pearse AG Immunofluorescent localization of calcitonin in medullary (C cell) thyroid carcinoma using antibody to the pure porcine hormone.Virchows Arch B Cell Pathol. 1969; 2: 234-238PubMed Google Scholar allowed the distinction of such a tumor type from the more common follicular cell tumors. Five typical pathological features are usually present in MTCs: 1. amyloid-rich stroma; 2) trabecular and nesting arrangement; 3) scarce atypia and nuclear uniformity; 4) neurosecretory granules; and 5. calcitonin and CEA immunostaining. However, MTC has a great ability to show unusual features that may mimic other tumors5Albores-Saavedra J LiVolsi VA Williams ED Medullary carcinoma.Semin Diagn Pathol. 1985; 2: 137-146PubMed Google Scholar: acini; tubules (follicles)6Harach HR Williams ED Glandular (tubular, and follicular) variants of medullary carcinoma of the thyroid.Histopathology. 1983; 7: 83-89Crossref PubMed Scopus (75) Google Scholar. papillae7Kakudo K Miyauchi A Yakai SI C-cell carcinoma of the thyroid: papillary type.Acta Pathol Jpn. 1979; 29: 653-659PubMed Google Scholar; small,8Eusebi V Damiani S Riva C Lloyd RV Capella C Calcitonin free oat cell carcinoma of the thyroid gland.Virchows Arch. 1990; 417: 267-271Crossref Scopus (51) Google Scholar giant,9Mendelsohn G Bigner SH Eggleston JC Baylin SB Wells SA Anaplastic variants of medullary thyroid carcinoma.Am J Surg Pathol. 1980; 4: 333-341Crossref PubMed Scopus (84) Google Scholar clear,10Landon G Ordoñez NG Clear cell variant of medullary carcinoma of the thyroid.Hum Pathol. 1985; 16: 844-847Abstract Full Text PDF PubMed Scopus (48) Google Scholar or oxyphilic11Harach HR Bergholm U Medullary (C-cell) carcinoma of the thyroid with features of follicular oxyphilic cell tumors.Histopathology. 1988; 13: 645-656Crossref PubMed Scopus (32) Google Scholar, 12Dominguez-Malagon H Delgado-Chavez R Torrez-Najera M Gould E Albores Saavedra J Oxyphil and squamous variants of medullary thyroid carcinoma.Cancer. 1989; 63: 1183-1191Crossref PubMed Scopus (53) Google Scholar cells; squamous differentiation12Dominguez-Malagon H Delgado-Chavez R Torrez-Najera M Gould E Albores Saavedra J Oxyphil and squamous variants of medullary thyroid carcinoma.Cancer. 1989; 63: 1183-1191Crossref PubMed Scopus (53) Google Scholar; and mucin secretion.13Martin-Lacave I Gonzalez-Cámpora R Moreno-Fernandez A Sanchez-Gallego F Montero C Galera-Davidson H Mucosubstances in medullary carcinoma of the thyroid.Histopathology. 1988; 13: 55-66Crossref PubMed Scopus (8) Google Scholar MTC may also resemble vascular tumors.14Papotti M Sapino A Abbona GC Palestini N Bussolati G Pseudosarcomatous features in medullary carcinomas of the thyroid. Report of two cases.Int J Surg Pathol. 1995; 3: 29-34Google Scholar The occurrence of pseudoacinar, follicular, or papillary growth patterns in MTC was particularly controversial. Although in some cases they have an artifactual origin,5Albores-Saavedra J LiVolsi VA Williams ED Medullary carcinoma.Semin Diagn Pathol. 1985; 2: 137-146PubMed Google Scholar it is now well accepted that MTC, like carcinoids and many other neuroendocrine carcinomas, may display glandular features. In fact, elegant electron-microscopic studies showed the presence of microvilli on the surface of MTC cells lining glands or papillae.15Sobrinho-Simoes M Johannessen JV Surface features in human thyroid disorders. A scanning electron microscopic study of ninety-five cases.J Submicrosc Cytol. 1982; 14: 187-202PubMed Google Scholar, 16Sobrinho-Simoes M Sambade C Nesland JM Holm R Damjanov I Lectin histochemistry and ultrastructure of medullary carcinoma of the thyroid gland.Arch Pathol Lab Med. 1990; 114: 369-375PubMed Google Scholar These structures should not be considered of follicular origin unless thyroglobulin expression is convincingly demonstrated. In the early 1980s, several authors started describing tumors that combined features of MCT and follicular cell carcinomas. Since then, individual cases and short series of tumors have appeared in the literature.17Hales M Rosenau W Okerlund MD Galante M Carcinoma of the thyroid with a mixed medullary and follicular pattern: morphological, immunohistochemical and clinical laboratory studies.Cancer. 1982; 50: 1352-1359Crossref PubMed Scopus (104) Google Scholar, 18Pfaltz M Hedinger CE Mühlethaler JP Mixed medullary and follicular carcinomas of the thyroid.Virchows Arch A. 1983; 400: 53-59Crossref Scopus (69) Google Scholar, 19Ljungberg O Bondeson L Bondeson AG Differentiated thyroid carcinoma, intermediate type: a new tumor entity with features of follicular and parafollicular carcinoma.Hum Pathol. 1984; 15: 21-28Abstract Full Text PDF Scopus (107) Google Scholar, 20Ljungberg O Ericson UB Bondesson L Thorell JA A compound follicular-parafollicular cell carcinoma of the thyroid: a new tumor entity?.Cancer. 1983; 52: 1053-1061Crossref PubMed Scopus (99) Google Scholar, 21Tanda F Massarelli G Mingioni V Bosincu L Moroni RV Cossu Mixed follicular-parafollicular carcinoma of the thyroid: a light, electron microscopic and histoimmunologic study.Surg Pathol. 1990; 3: 65-74Google Scholar, 22Mizukami Y Nonomura A Michigishi T Noguchi M Ishizaki T Mixed medullary-follicular carcinoma of the thyroid gland: a clinicopathologic variant of medullary thyroid carcinoma.Mod Pathol. 1996; 9: 631-635PubMed Google Scholar, 23Papotti M Negro F Carney JA Bussolati G Lloyd RV Mixed medullary-follicular carcinoma of the thyroid. A morphological, immunohistochemical and in situ hybridization analysis of 11 cases.Virchows Arch. 1997; 430: 397-405Crossref PubMed Scopus (64) Google Scholar, 24Mizukami Y Michigishi T Nonomura A Nakamura S Noguchi M Hashimoto T Itoh N Mixed medullary-follicular carcinoma of the thyroid occurring in familial form.Histopathology. 1993; 22: 284-287Crossref PubMed Scopus (30) Google Scholar During this period, it has become clear that mixed medullary and follicular carcinoma is a rather controversial neoplasm. Some authors have voiced reservations about its consideration as a real entity,25LiVolsi VA Mixed thyroid carcinoma: a real entity?.Lab Invest. 1987; 57: 237-238PubMed Google Scholar its histogenesis, and its diagnostic criteria.26Sobrinho-Simoês M Mixed medullary and follicular carcinoma of the thyroid.Histopathology. 1993; 23: 287-289Crossref PubMed Scopus (25) Google Scholar In 1988, in the second edition of the WHO booklet Histological Typing of Thyroid Tumours, mixed medullary-follicular carcinomas were defined as tumors showing the morphological features of both a MTC with immunoreactivity for calcitonin and a follicular carcinoma with immunoreactivity for thyroglobulin.27Hedinger C Williams E Sobin L Histological typing of thyroid tumours.World Health Organization International Histological Classification of Tumors. 2nd ed. Springer Verlag, Berlin1988Google Scholar By following these strict criteria, true mixed medullary and follicular carcinomas are rare. They should be distinguished from MTCs with follicles6Harach HR Williams ED Glandular (tubular, and follicular) variants of medullary carcinoma of the thyroid.Histopathology. 1983; 7: 83-89Crossref PubMed Scopus (75) Google Scholar or papillae7Kakudo K Miyauchi A Yakai SI C-cell carcinoma of the thyroid: papillary type.Acta Pathol Jpn. 1979; 29: 653-659PubMed Google Scholar as well as from MTCs with entrapped normal follicles at their infiltrating edges. They should also be separated from follicular cell tumors with trabecular, solid, or insular patterns, such as hyalinizing trabecular adenomas or carcinomas,28Carney JA Ryan J Goêllner JR Hyalinizing trabecular adenoma of the thyroid gland.Am J Surg Pathol. 1987; 11: 583-591Crossref PubMed Scopus (195) Google Scholar, 29Sambade C Franssila KO Cameselle-Teijeiro J Nesland JM Sobrinho-Simoês M Hyalinizing trabecular adenoma. A misnomer for a peculiar tumor of the thyroid gland.Endocr Pathol. 1991; 2: 83-91Crossref Scopus (61) Google Scholar, 30Molberg K Albores-Saavedra J Hyalinizing trabecular carcinoma of the thyroid gland.Hum Pathol. 1994; 25: 192-197Abstract Full Text PDF PubMed Scopus (78) Google Scholar and poorly differentiated follicular carcinomas31Carcangiu ML Zampi G Rosai J Poorly differentiated (“insular”) thyroid carcinoma. A reinterpretation of Langhans' “wuchernde Struma.”.Am J Surg Pathol. 1984; 8: 655-668Crossref PubMed Scopus (432) Google Scholar; they may resemble MTC and may even contain a minor population of neuroendocrine cells. For many years, immunohistochemistry was almost the exclusive tool for the study of mixed medullary and follicular carcinomas. As mentioned above, staining for both calcitonin and thyroglobulin was required to establish the diagnosis. However, this finding was considered to be necessary but not exclusive for this type of tumor. Occasional immunostaining for thyroglobulin in otherwise typical MTCs was initially explained by osmosis, passive absorption, or transfer of thyroglobulin from entrapped normal follicular cells to neoplastic cells.32De Lellis RA Moore FM Wolfe HJ Thyroglobulin immunoreactivity in human medullary carcinoma.Lab Invest. 1983; 48: 20AGoogle Scholar A similar phenomenon is frequently seen in thyroid metastases of carcinomas from other organs.33Rosai J Carcangiu ML DeLellis RA Tumors of the thyroid gland.in: Atlas of Tumor Pathology, series 3. vol 5. Armed Forces Institute of Pathology, Washington DC1992Google Scholar Soon immunostaining for both thyroglobulin and calcitonin was demonstrated in lymph node metastases of some MTCs.34Fenoglio-Preiser CM Mixed medullary-follicular thyroid carcinoma.Am J Surg Pathol. 1986; 10: 362-363Crossref PubMed Google Scholar Still, in these cases, draining of thyroglobulin from damaged follicular thyroid tissue infiltrated by the tumor into regional lymph nodes was an alternative explanation.35Gebel F Ramelli F Bürgi U Ingold S Rtuder H Winand R The site of leakage of intrafollicular thyroglobulin into the blood stream in simple human goiter.J Clin Endocrinol Metab. 1983; 57: 915-919Crossref PubMed Scopus (29) Google Scholar The later demonstration of colocalization of both hormones in distant metastases made osmosis or passive absorption very unlikely. It is worth mentioning that several authors recommended caution in the interpretation of thyroglobulin immunostaining, because of the lack of absolute specificity of some polyclonal and monoclonal antibodies that could recognize epitopes on several other molecules, such as mucins.36De Micco CM Chapel F Dor AM Garcia S Ruf J Carayon P Henry JF Lebreuil G Thyroglobulin in medullary thyroid carcinoma: immunohistochemical study with polyclonal and monoclonal antibodies.Hum Pathol. 1993; 24: 256-262Abstract Full Text PDF PubMed Scopus (25) Google Scholar In 1987, Holm et al reported a series of classical MTCs that showed thyroglobulin immunoreactivity.37Holm R Sobrinho-Simoês M Nesland JM Sambade C Johannessen JV Medullary thyroid carcinoma with thyroglobulin immunoreactivity. A special entity?.Lab Invest. 1987; 57: 258-268PubMed Google Scholar These authors claimed that thyroglobulin-positive MTC was an unusual variant of MTC, which carried a better prognosis than its thyroglobulin-negative counterpart. The existence of thyroglobulin immunoreactive MTC explained the reports of incorporation of radioactive iodine in rare cases of MTC. In fact, MTC is a tumor known to be capable of producing a great variety of hormonal and nonhormonal substances, such as histaminase, somatostatin,38Mato E Matias-Guiu X Chico A Webb SM Cabezas R Berna L DeLeiva A Somatostatin and somatostatin receptor subtype gene expression in medullary thyroid carcinoma.J Clin Endocrinol Metab. 1998; 83: 2417-2420PubMed Google Scholar cathecolamines, or ACTH. The existence of these tumors raised three important questions: Why could a typical MTC not produce thyroglobulin ectopically? Should an otherwise typical, thyroglobulin immunoreactive MTC be considered as a true mixed medullary and follicular carcinoma? Should the patients be treated with 131I? It soon became obvious that in daily practice, there were tumors that combined some features of medullary and follicular cell carcinomas, without fulfilling the strict criteria of the WHO. The spectrum of these tumors included MTC with thyroglobulin immunoreactive cells at one extreme39Sobrinho-Simôes M Thyroid oncology: the end of the dogmas.Endocr Pathol. 1991; 2: 117-119Crossref Scopus (8) Google Scholar and carcinomas of follicular cell origin with neuroendocrine cells at the other. In fact, it was shown that coexpression of follicular and parafollicular markers was particularly common in hyalinizing trabecular tumors as well as in papillary, mucoepidermoid, mucinous, and poorly differentiated carcinomas.19Ljungberg O Bondeson L Bondeson AG Differentiated thyroid carcinoma, intermediate type: a new tumor entity with features of follicular and parafollicular carcinoma.Hum Pathol. 1984; 15: 21-28Abstract Full Text PDF Scopus (107) Google Scholar, 39Sobrinho-Simôes M Thyroid oncology: the end of the dogmas.Endocr Pathol. 1991; 2: 117-119Crossref Scopus (8) Google Scholar, 40Calmettes C Caillou B Moukhtar MS Milhaud G Gerard-Marchant R Calcitonin and carcinoembryonic antigen in poorly differentiated follicular carcinoma.Cancer. 1982; 49: 2342-2348Crossref PubMed Scopus (25) Google Scholar Furthermore, even tumors fulfilling the WHO criteria showed a great variation in microscopic appearance, particularly in the follicular component, which was reported to exhibit areas of oxyphilic,23Papotti M Negro F Carney JA Bussolati G Lloyd RV Mixed medullary-follicular carcinoma of the thyroid. A morphological, immunohistochemical and in situ hybridization analysis of 11 cases.Virchows Arch. 1997; 430: 397-405Crossref PubMed Scopus (64) Google Scholar poorly differentiated,21Tanda F Massarelli G Mingioni V Bosincu L Moroni RV Cossu Mixed follicular-parafollicular carcinoma of the thyroid: a light, electron microscopic and histoimmunologic study.Surg Pathol. 1990; 3: 65-74Google Scholar and even anaplastic carcinoma.41Parker LN Hollin J Wu SY Rypins EB Juler GL Carcinoma of the thyroid with a mixed medullary, papillary, follicular and undifferentiated pattern.Arch Intern Med. 1985; 145: 1507-1509Crossref PubMed Scopus (37) Google Scholar The pathological scenario of mixed medullary and follicular thyroid carcinoma was further complicated by the description of cases of MTC that contained intimately admixed populations of cells with the features of papillary carcinoma as well as thyroglobulin immunoreactivity.42Albores-Saavedra J Gorraez de la Mora T De la Torre-Rendon F Gould E Mixed medullary-papillary carcinoma of the thyroid. A previous unrecognized variant of thyroid carcinoma.Hum Pathol. 1990; 21: 1151-1155Abstract Full Text PDF PubMed Scopus (72) Google Scholar, 43Matias-Guiu X Caixas A Costa I Cabezas R Prat J Compound medullary-papillary carcinoma of the thyroid: true mixed tumour.Histopathology. 1994; 25: 183-185Crossref PubMed Scopus (33) Google Scholar, 44Lax SF Beham A Kronberger SD Langsteger W Denk H Coexistence of papillary and medullary carcinoma of the thyroid gland-mixed or collision tumour? Clinicopathological analysis of three cases.Virchows Arch. 1994; 424: 441-447Crossref PubMed Scopus (56) Google Scholar The areas of MTC, which predominated in the vast majority of the reported cases, were thyroglobulin negative but immunoreacted for calcitonin and CEA. Admixtures of both components were also identified in lymph node metastases. Moreover, distinction between a true mixed medullary and follicular carcinoma and a tumor resulting from the collision of two different medullary and follicular cell carcinomas was not always easy. In some cases, the distribution of the two neoplastic components in the thyroid gland allowed their classification as obvious collision tumors.45Gero MJ Lipper S Chernys AE Silver L Medullary and papillary carcinoma occurring as a collision tumor: report of a case.Clin Nucl Med. 1989; 14: 171-174Crossref PubMed Scopus (17) Google Scholar In other cases, the extension of the neoplastic growth of the two components complicated the pathological interpretation. In fact, examples of concurrent (independent), medullary and papillary or follicular carcinomas in the same thyroid gland or even localized in the same thyroid lobe have been reported.46Gonzalez-Campora R Lopez-Garrido J Martin-Lacave I Miralles-Sanchez EJ Villar JL Concurrence of a symptomatic encapsulated follicular carcinoma, an occult papillary carcinoma and a medullary carcinoma in the same patient.Histopathology. 1992; 21: 380-382Crossref PubMed Scopus (36) Google Scholar, 47Kobayashi K Teramoto S Maeta H Ishiguro S Mori T Horie Y Simultaneous occurrence of medullary carcinoma and papillary carcinoma of the thyroid.J Surg Oncol. 1995; 59: 276-279Crossref PubMed Scopus (20) Google Scholar, 48Lamberg BA Reissel P Stenman S Koivuniemi A Ekbolm M Makinen J Franssila K Concurrent medullary and papillary thyroid carcinoma in the same thyroid lobe and in siblings.Acta Med Scand. 1981; 209: 421-424Crossref PubMed Scopus (34) Google Scholar After a careful review of the literature available, I have formed the impression that the term “mixed medullary and follicular thyroid carcinoma” has been used to designate a heterogeneous group of neoplasms. I believe that some of the reported cases represent MTCs with follicles, MTCs with thyroglobulin expression, collision tumors, and even poorly differentiated carcinomas containing neuroendocrine cells. Obviously, many other reported tumors are convincing examples of true mixed medullary and follicular carcinomas, but exhibiting a great variability in the morphological appearance of the follicular component. In this regard, I think that the hypothesis proposed by Volante et al in this issue of The American Journal of Pathology49Volante M Papotti M Roth J Saremaslani P Speel EJM Lloyd RV Carnei AJ Heitz PhU Bussolati G Komminoth P Mixed medullary-follicular thyroid carcinma: molecular evidence for a dual origin of tumor components.Am J Pathol. 1999; 155: 1499-1509Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar agrees with such a point of view. The “hostage hypothesis” would explain perfectly the histological variability of the follicular cell component of true mixed medullary and follicular thyroid carcinomas; MTC would contain a hyperplastic (polyclonal) follicular proliferation in some cases, but a fully developed neoplastic (monoclonal) component in others. The neoplastic proliferation would be able to acquire either a follicular or a papillary phenotype in different cases. Once it was clear that immunohistochemistry was not going to answer all of the questions raised by the existence of mixed medullary and follicular carcinomas, several authors began to apply molecular pathology techniques. Noel et al first demonstrated by Northern blot and in situ hybridization the presence of calcitonin and thyroglobulin mRNAs in tumor cells of two cases.50Noel M Delehaye MCh Segond N Lasmoles F Caillou B Gardet P Fragu Ph Moukhtar MS Study of calcitonin and thyroglobulin gene expression in human mixed follicular and medullary carcinoma.Thyroid. 1991; 1: 249-256Crossref PubMed Scopus (31) Google Scholar Papotti et al studied 11 cases by combined immunohistochemistry and in situ hybridization.23Papotti M Negro F Carney JA Bussolati G Lloyd RV Mixed medullary-follicular carcinoma of the thyroid. A morphological, immunohistochemical and in situ hybridization analysis of 11 cases.Virchows Arch. 1997; 430: 397-405Crossref PubMed Scopus (64) Google Scholar They detected separated thyroglobulin and calcitonin gene expression in the vast majority of the tumors, although concurrent expression of the two genes was seen occasionally in cells of two neoplasms. Although these molecular studies clearly rendered interesting results, they did not provide conclusive evidence of the histogenesis of this tumor type. Several methods can be used to assess the independent or common origin of two different components of a neoplasm. They have been applied to a great variety of tumors showing divergent differentiation (carcinosarcomas of different organs, malignant mixed müllerian tumors),51Thompson L Chang B Barsky SH Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis.Am J Surg Pathol. 1996; 20: 277-285Crossref PubMed Scopus (319) Google Scholar, 52Kounelis S Jones MW Papadaki H Bakker A Swalsky P Finkelstein SD Carcinosarcomas (malignant mixed mullerian tumors) of the female genital tract: comparative molecular analysis of epithelial and mesenchymal components.Hum Pathol. 1998; 29: 82-87Abstract Full Text PDF PubMed Scopus (162) Google Scholar as well as to establish the independent or metastatic origin of simultaneously occurring tumors (synchronous mucinous tumors of the appendix and the ovaries, simultaneous endometrioid adenocarcinomas of the uterus and the ovaries).53Cuatrecasas M Matias-Guiu X Prat J Synchronous mucinous tumors of the appendix and the ovary associated with pseudomyxoma peritonei. A clinicopathologic study of six cases with comparative analysis of c-Ki-ras mutations.Am J Surg Pathol. 1996; 20: 739-746Crossref PubMed Scopus (98) Google Scholar, 54Fujita M Enomoto T Wada H Inoue M Okudaira Y Shroyer KR Application of clonal analysis. Differential diagnosis for synchronous primary ovarian and endometrial cancers and metastatic cancer.Am J Clin Pathol. 1996; 105: 305-359PubMed Google Scholar, 55Emmert-Burck MR Chuaqui R Zhuang Z Nogales F Liotta LA Merino MJ Molecular analysis of synchronous uterine and ovarian endometrioid tumors.Int J Gynecol Pathol. 1997; 16: 143-148Crossref PubMed Scopus (52) Google Scholar They include loss of heterozygosity (LOH), gene mutation, and clonal X-inactivation analyses. The most reliable of them are those addressing the molecular alterations that occur in the early stages of tumor development. Although LOH may indicate inactivation of tumor suppressor genes involved in the early steps of tumorigenesis, there is evidence suggesting that LOH may also reflect the existence of the genetic instability that occurs at more advanced steps.56Lerngauer Ch Kinzler KW Vogelstein B Genetic instabilities in human cancers.Nature. 1998; 396: 643-649Crossref PubMed Scopus (3405) Google Scholar Several studies have shown different patterns of LOH at different areas of the same tumor as a result of tumor heterogeneity.57Boni R Matt D Voetmeyer A Burg G Zhuang Z Chromosomal allele loss in primary cutaneous melanoma is heterogeneous and correlates with progression.J Invest Dermatol. 1998; 110: 215-217Crossref PubMed Scopus (45) Google Scholar, 58Blaker H Graf M Rieker RJ Otto HF Comparison of losses of heterozygosity and replication errors in primary colorectal carcinomas and corresponding liver metastases.J Pathol. 1999; 188: 258-262Crossref PubMed Scopus (36) Google Scholar Although these data suggest that LOH analysis is not the best way to assess monoclonality in neoplasias, it can provide interesting information. In other words, different LOH patterns do not necessarily indicate a different origin for two tumor components; but the concordance in LOH pattern in two different cell populations is highly suggestive of a common clonal origin.59Matias-Guiu X Garcia A Curell R Prat J Renal cell carcinoma metastatic to the thyroid gland. A comparative molecular study between the primary and the metastatic tumor.Endocr Pathol. 1998; 9: 255-260Crossref PubMed Scopus (6) Google Scholar, 60Pilotti S Manenti G De Georgio L Rilke F Chiarle R Pierotti MA Identification of the same HRAS1 mutation in a primary minimally invasive follicular carcinoma of the thyroid gland and its bone metastasis developed 15 years later.Diagn Mol Pathol. 1995; 4: 73-74Crossref PubMed Scopus (11) Google Scholar Mutation analysis of genes involved in early steps of tumorigenesis is a good method for assessing the common origin of two different tumor components. In fact, a few years ago we used such an approach to study a series of synchronous mucinous tumors of the appendix and the ovaries.53Cuatrecasas M Matias-Guiu X Prat J Synchronous mucinous tumors of the appendix and the ovary associated with pseudomyxoma peritonei. A clinicopathologic study of six cases with comparative analysis of c-Ki-ras mutations.Am J Surg Pathol. 1996; 20: 739-746Crossref PubMed Scopus (98) Google Scholar By using a very sensitive RFLP-polymerase chain reaction method, we found a concordant k-RAS mutation pattern in both the appendiceal and the ovarian tumors in each case, suggesting that they had a common clonal origin, giving support to the currently well-accepted idea that the ovarian neoplasms were metastases from the primary appendiceal tumors. Similar approaches have been used in different tumor settings.60Pilotti S Manenti G De Georgio L Rilke F Chiarle R Pierotti MA Identification of the same HRAS1 mutation in a primary minimally invasive follicular carcinoma of the thyroid gland and its bone metastasis developed 15 years later.Diagn Mol Pathol. 1995; 4: 73-74Crossref PubMed Scopus (11) Google Scholar The only objection against this method is that a common carcinogenic agent theoretically could be capable of inducing the same genetic alteration in two different tumors developed as a result of a field effect. However, comparative analysis of simultaneous colonic adenomas and carcinomas (which are supposed to be the result of common carcinogenic agents) has shown different k-RAS mutation patterns in these synchronous lesions.61Terunuma H Hayakashi T Tsuneyoshi T Fujita M Kino I Baba S Mutational heterogeneity among individual tumors in a case of multiple primary malignancy of the colon.Jpn J Clin Oncol. 1993; 23: 350-355PubMed Google Scholar Although Volante et al49Volante M Papotti M Roth J Saremaslani P Speel EJM Lloyd RV Carnei AJ Heitz PhU Bussolati G Komminoth P Mixed medullary-follicular thyroid carcinma: molecular evidence for a dual origin of tumor components.Am J Pathol. 1999; 155: 1499-1509Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar could have chosen k-RAS for the assessment of clonality in mixed medullary and follicular carcinomas (k-RAS mutations are early events in follicular cell tumorigenesis,62Capella G Matias-Guiu X Ampudia X Prat J Perucho M Ras oncogene mutations in thyroid tumors: a PCR-RFLP analysis from paraffin-embedded tissues.Diagn Mol Pathol. 1996; 5: 45-52Crossref PubMed Scopus (56) Google Scholar while very infrequent in MTC), they decided to study RET and gsp gene mutations. The RET proto-oncogene (rearranged during transfection) is located on chromosome 10q11.2, contains 21 exons spread over a genomic region of approximately 60 kb, and encodes a cell-surface receptor with tyrosine kinase activity.63Matias-Guiu X RET protooncogene analysis in the diagnosis of medullary thyroid carcinoma and multiple endocrine neoplasia type II.Adv Anat Pathol. 1998; 5: 196-201Crossref PubMed Scopus (7) Google Scholar RET mRNA is expressed in some tissues and tumors presumably developed from migratory cells of the embryonal neural crest, such as parathyroid cells, thyroid C-cells, and adrenal medullary cells.64Matias-Guiu X Colomer A Mato E Cuatrecasas M Komminoth P Prat J Wolfe H Expression of the ret proto-oncogene in pheochromocytoma. An in situ and Northern blot study.J Pathol. 1995; 176: 63-68Crossref PubMed Scopus (10) Google Scholar Germline missense point mutations of RET are responsible for familial MTC and MEN type II.65Mulligan LM Kwork JB Healey CS Eldson MJ Eng C Gardner E Love DR Mole SE Moore JK Papi L Ponder MA Telenius H Tunnacliffe A Ponder BAJ Germ-line mutations of the ret proto-oncogene in multiple endocrine neoplasia type 2A.Nature. 1993; 363: 458-460Crossref PubMed Scopus (1746) Google Scholar, 66Donis-Keller H Dou S Chi D Carlson KM Toshima K Lairmore TC Howe JR Moley JF Goodfellow P Wells Jr, SA Mutations in the ret proto-oncogene are associated with MEN 2A and familial medullary thyroid carcinoma.Hum Mol Genet. 1993; 2: 851-856Crossref PubMed Scopus (1176) Google Scholar, 67Komminoth P Kunz EK Matias-Guiu X Hiort O Christiansen G Colomer A Roth J Heitz PhU Analysis of ret proto-oncogene point mutations allows for the discrimination of sporadic and inherited medullary thyroid carcinoma.Cancer. 1995; 76: 479-489Crossref PubMed Scopus (136) Google Scholar However, somatic point mutations in exons 15 and 16, and less frequently in exons 11 and 13, are common genetic alterations of sporadic MTCs.68Marsh DJ Learoyd DL Andrew SD Krishnan L Pojer R Richardson AL et al.Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma.Clin Endocrinol (Oxf). 1996; 44: 249-257Crossref PubMed Scopus (186) Google Scholar, 69Romei C Elisei R Pinchera A Ceccherini I Molinaro E Mancusi F Martino E Romeo G Pacini F Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence.J Clin Endocrinol Metab. 1996; 81: 1619-1622Crossref PubMed S
Referência(s)