This is an uncommon carcinoma of the thyroid accounting for about 10% of all malignant thyroid tumors. In spite of this, it is important for the pathologist to make the diagnosis because of its association with a syndrome known as MEN (multiple neuroendocrine neoplasia syndrome). This association is with types IIa and IIb. About 10-20% of cases are familial and associated with these syndromes. In these cases, mutations have been identified in the ret oncogene on chromosome 10.
These tumors occur in adults in their 6th decade but may occur in the 2-3rd decades in familial cases. Sporadic cases are more common in women while familial cases are autosomal dominant and affect both sexes equally. These tumors are usually firm painless nodules, usually in the lateral two-thirds of the gland, where there is the highest concentration of C cells. They are aggressive and 50% of these tumors may present with lymph node metastases at the time of initial diagnosis. Distant metastases to the liver, lung, or bone may occur in 15-25% of cases. These tumors are derived from the C cells and thus may produce calcitonin as well as other hormones such as ACTH. The stage of the tumor is the most important prognostic factor. In addition, several other factors may affect the prognosis.
Under the microscope, these tumors have a varied appearance with round to oval to spindled cells arranged in vague nests, often with an infiltrative appearance. The nuclei are fairly uniform and show occasional mitoses. Amyloid is characteristically present in the stroma and is derived from precalcitonin. There are several histologic variants which may be difficult to diagnose.
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PATHOGENESIS CHARACTERIZATION Telomerase expression and proliferative activity suggest a stem cell role for thyroid solid cell nests.
Preto A, Cameselle-Teijeiro J, Moldes-Boullosa J, Soares P, Cameselle-Teijeiro JF, Silva P, Reis-Filho JS, Reyes-Santias RM, Alfonsin-Barreiro N, Forteza J, Sobrinho-Simoes M.
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
Mod Pathol. 2004 Jul;17(7):819-26. Abstract quote
Solid cell nests of the human thyroid gland are composed of main cells and C cells. In order to investigate the putative stem cell nature of the role for solid cell nests, we evaluated the histological features, and the immunohistochemical expression of p63, bcl-2, telomerase catalytic subunit, and two proliferative markers (Ki-67 and minichromosome maintenance protein 2), in a series of 24 cases of solid cell nests.
Proliferative indices were determined in (a) solid cell nests, (b) thyroid follicular cells in the vicinity of solid cell nests within a low-power field, and (c) distant thyroid tissue, at a distance of at least three low-power fields from solid cell nests. In 15 cases of solid cell nests (62.5%), mixed follicles were observed; papillary formations were observed in four cases (16.6%), and ciliated cells were observed in the lining of microcysts associated with two cases (8.3%). Salivary gland-type tissue, cartilage islands, adipose and fibrous tissues, and small nerves were also associated with some cases of solid cell nests.
We observed that the main cells of the solid cell nests express consistently telomerase, although at lower levels than p63, and show strong cytoplasmic immunoreactivity for bcl-2, which is associated with an increased differentiation potential. We also observed that despite their relative low proliferative index, main cells of the solid cell nests display higher proliferation than follicular cells in the vicinity and follicular cells in more distant thyroid tissue.
We conclude that main cells of the solid cell nests apparently harbor the minimal properties of a stem cell phenotype (capacity for both self-renewal, conferred by telomerase activity, and differentiation to one or more than one type of specialized cells, given by the high expression of p63 and bcl-2) and may thus represent a pool of stem cells of the adult thyroid.
Germline RET 634 mutation positive MEN 2A-related C-cell hyperplasias have genetic features consistent with intraepithelial neoplasia.
Diaz-Cano SJ, de Miguel M, Blanes A, Tashjian R, Wolfe HJ.
Department of Pathology, Tufts University-New England Medical Center, Boston, Massachusetts 02111, USA.
J Clin Endocrinol Metab 2001 Aug;86(8):3948-57 ABSTRACT QUOTE
C-cell hyperplasias are normally multifocal in multiple endocrine neoplasia type 2A. We compared clonality, microsatellite pattern of tumor suppressor genes, and cellular kinetics of C-cell hyperplasia foci in each thyroid lobe.
We selected 11 females from multiple endocrine neoplasia type 2A kindred treated with thyroidectomy due to hypercalcitoninemia. C-cell hyperplasia foci were microdissected for DNA extraction to analyze the methylation pattern of androgen receptor alleles and microsatellite regions (TP53, RB1, WT1, and NF1). Consecutive sections were selected for MIB-1, pRB1, p53, Mdm-2, and p21WAF1 immunostaining, DNA content analysis, and in situ end labeling. Appropriate tissue controls were run.
Only two patients had medullary thyroid carcinoma foci. Nine informative C-cell hyperplasia patients showed germline point mutation in RET, eight of them with the same androgen receptor allele preferentially methylated in both lobes. C-cell hyperplasia foci showed heterogeneous DNA deletions revealed by loss of heterozygosity of TP53 (12 of 20), RB1 (6 of 14), and WT1 (4 of 20) and hypodiploid G0/G1 cells (14 of 20), low cellular turnover (MIB-1 index 4.5%, in situ end labeling index 0.03%), and significantly high nuclear area to DNA index ratio. MEN 2A (germline point mutation in RET codon 634)
C-cell hyperplasias are monoclonal and genetically heterogeneous and show down-regulated apoptosis, findings consistent with an intraepithelial neoplasia. Concordant X-chromosome inactivation and interstitial gene deletions suggest clone expansions of precursors occurring at a point in embryonic development before divergence of each thyroid lobe and may represent a paradigm for other germline mutations.
Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients.
Niccoli-Sire P, Murat A, Rohmer V, Franc S, Chabrier G, Baldet L, Maes B, Savagner F, Giraud S, Bezieau S, Kottler ML, Morange S, Conte-Devolx B;
The French Calcitonin Tumors Group (GETC). Service d'Endocrinologie, CHU Timone, 13385 Marseilles, France.
J Clin Endocrinol Metab 2001 Aug;86(8):3746-53 Abstract quote
Familial medullary thyroid carcinoma only is related to germline mutations in the protooncogene RET, mainly in exons 10, whereas noncysteine mutations (exons 13-15) are considered infrequent.
We analyzed 148 patients from 47 familial medullary thyroid carcinoma only families, and we found noncysteine RET mutations in 59.5% of these families. Of the index cases with noncysteine mutations, 43.4% presented with a multinodular goiter and high basal calcitonin; they were older at diagnosis than those with mutation in exon 10 and had more multifocal medullary thyroid carcinoma, but no difference in size, bilaterality, presence of C cell hyperplasia, or nodal metastases was found. Gene carriers with noncysteine RET mutations had a lower incidence of medullary thyroid carcinoma (78.2% vs. 94.1%) than those with mutation in exon 10; 20.2% had C cell hyperplasia only, although thyroidectomized at an older age.
In conclusion, familial medullary thyroid carcinoma with noncysteine RET mutations are not infrequent and are overrepresented in presumed sporadic medullary thyroid carcinoma, suggesting that RET analysis should routinely be extended to exons 13, 14, and 15. The phenotype is characterized by a late onset of the disease, suggesting a delayed appearance of C cell disease rather than a less aggressive form. In familial medullary thyroid carcinoma gene carriers, the optimal timing for thyroidectomy remains controversial. Based on these data, we propose that surgery should be performed before elevation of the basal calcitonin level, potentially as soon as the pentagastrin test becomes abnormal.
Genetic testing in medullary thyroid carcinoma syndromes: mutation types and clinical significance.
Heshmati HM, Gharib H, Khosla S, Abu-Lebdeh HS, Lindor NM, Thibodeau SN.
Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic Rochester, MN 55905, USA.
Mayo Clin Proc 1997 May;72(5):430-6 Abstract quote
OBJECTIVE: To determine the types of mutations and the clinical significance of a specific genotype in familial medullary thyroid carcinoma (MTC) syndromes.
DESIGN: We retrospectively and prospectively studied patients with MTC at a tertiary referral center.
MATERIAL AND METHODS: The study cohort consisted of 348 affected patients and at-risk family members of MTC kindreds, including 33 multiple endocrine neoplasia type IIA (MEN IIA) kindreds with 165 members, 13 familial MTC alone (FMTC) kindreds (at least 4 affected members with MTC per kindred, without evidence of pheochromocytoma and hyperparathyroidism) with 108 members, 15 "other hereditary MTC" kindreds (2 or 3 affected members) with 42 members, and 33 individuals with sporadic MTC. An additional 53 subjects from the aforementioned MEN IIA kindreds who were clinically affected but not genetically tested were also included in an analysis of the relationship between genotype and phenotype. The presence of germline mutations in the RET proto-oncogene was studied by DNA sequence analysis of exons 10, 11, and 13.
RESULTS: Germline RET mutations in exons 10 and 11 were identified in 32 of 33 MEN IIA kindreds (97%), 10 of 13 FMTC kindreds (77%), and 10 of 15 "other hereditary MTC" kindreds (67%). No mutations were identified in exon 13. No patient with sporadic MTC had a germline mutation. In MEN IIA, codon 634 was affected in 73% of the kindreds, whereas in FMTC, the main affected codon was codon 618 (54%). In MEN IIA, patients with codon 634 mutations had a higher risk of having C-cell disease, pheochromocytoma, and hyperparathyroidism than did those with other mutations (P < 0.05, P < 0.001, and P < 0.01, respectively).
CONCLUSION: RET analysis is a reliable, practical, and cost-effective test in the screening of at-risk family members of MEN IIA and FMTC kindreds. In addition, RET analysis may be helpful in the follow-up of gene carriers and for the early detection of pheochromocytoma and hyperparathyroidism in patients with codon 634 mutations.
Persistent hypercalcitoninemia in patients with medullary thyroid cancer: a therapeutic approach based on selective venous sampling for calcitonin.
Medina-Franco H, Herrera MF, Lopez G, Tielve-Campillo M, Sierra M, Lozano-Salazar RR, Gonzalez O.
Department of Surgery, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City.
Rev Invest Clin 2001 May-Jun;53(3):212-7 ABSTRACT QUOTE
BACKGROUND: Persistent or recurrent medullary thyroid carcinoma (MTC) can be cured by microdissection of residual metastatic lymph nodes in the neck. Selective venous sampling can be used for localization. The aim of this study is to prospectively analyze our results with a therapeutic approach based on venous sampling, in patients with hyperthyrocalcitoninemia after thyroidectomy for MTC.
METHODS: Selective venous sampling for determination of stimulated calcitonin was obtained in all patients after performing a complete laboratory and imaging workup. Patients with a gradient between the suprahepatic vein and the superior vena cava underwent unilateral or bilateral extensive lymph node dissection. We used the gradient between the right and left jugular veins to decide which side of the neck to operate. Calcitonin levels were obtained after surgery and a pentagastrin test was performed one year later if basal levels remained normal.
RESULTS: Mean age of the five women with a neck gradient in the selective venous sampling who underwent neck exploration was 45 years. In all patients metastatic lymph nodes were found at the site suggested by the study. Mean positive/resected lymph nodes were 5/20. Postoperative basal and stimulated levels of calcitonin became normal in two patients at one year of follow up.
CONCLUSION: Selective venous sampling is useful to localize recurrent MTC.
Radioisotope-guided surgery in patients with pheochromocytoma and recurrent medullary thyroid carcinoma: a comparison of preoperative and intraoperative tumor localization with histopathologic findings.
Adams S, Acker P, Lorenz M, Staib-Sebler E, Hor G.
Department of Nuclear Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main, Germany.
Cancer 2001 Jul 15;92(2):263-70 Abstract quote
BACKGROUND: The objective of this study was to appraise the detection of metastases of medullary thyroid carcinoma (MTC) and pheochromocytoma using radioguided surgery (RGS) and to compare the results with external imaging modalities, surgical palpation, and histopathologic findings.
METHODS: Twenty-five patients with recurrent MTC underwent preoperative scintigraphic imaging with 500 megabecquerels (MBq) of technetium 99m(V)-dimercaptosuccinic acid [(99m)Tc(V)-DMSA] and 222 MBq of indium 111 ((111)In)-pentetreotide. The radiopharmaceutical that showed the greatest preoperative tumor uptake was selected for intraoperative RGS. Surgery was performed 24 hours after the administration of (111)In-pentetreotide or 4 hours after the injection of (99m)Tc(V)-DMSA. Furthermore, three male patients underwent surgery who suffered from recurrent pheochromocytoma (injection of 180 MBq iodine 123-labeled metaiodobenzylguanidine [(123)I-MIBG] 4--5 hours before surgery).
RESULTS: Overall, lesion detection sensitivities in patients with MTC for computed tomography, (111)In-pentetreotide, and (99m)Tc(V)-DMSA were 32%, 34%, and 65%, respectively. Surgical palpation identified lymph node metastases of recurrent MTC with a sensitivity of 65%, whereas RGS localized 64 malignant lesions (sensitivity, 97%). Altogether, 71 lesions could be excised, 5 of which were adjudged false positive with respect to MTC metastases. Both surgical palpation and RGS localized all paravertebral subdiaphragmatic lesions (size > or = 2 cm) of recurrent pheochromocytoma seen in the preoperative MIBG scan.
CONCLUSIONS: RGS was capable of localizing more and smaller metastases of MTC compared with conventional imaging modalities and surgical palpation. However, the relatively high radioligand accumulation in the kidneys ((111)In-pentetreotide) and the dense hepatic and biliary signals using MIBG limited their use for intraoperative detection of tumors in the area of the adrenal gland.
HISTOPATHOLOGY CHARACTERIZATION Papillary Follicular Encapsulated Small cell Giant cell Clear cell Oncocytic Squamous VARIANTS Medullary thyroid microcarcinoma
Medullary thyroid microcarcinoma (micro-MTC), characterized by a tumor size of <10 mm in diameter
Increasingly observed entity among patients without RET proto-oncogene germline mutations
Inherited Medullary Microcarcinoma of the Thyroid
A Study of 11 Cases
Jo Ellen Krueger, M.D.; Anirban Maitra, M.D.; Jorge Albores-Saavedra, M.D.
From the Division of Anatomic Pathology, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, U.S.A.
Am J Surg Pathol 2000;24:853-858 Abstract quote
The authors report 11 patients with genetically determined medullary microcarcinomas.
Nine patients were either children or adolescents and two patients were young adults. The youngest patient was 7 years old and the oldest was 34 years of age (mean age, 15.4 yrs). The preoperative diagnosis was based on family history and elevated serum calcitonin levels. In addition, six patients had RET protooncogene mutations in exons 10, 11, and 16. Two patients who had the RET protooncogene mutations did not have serum calcitonin measurements. Nine patients had bilateral medullary microcarcinomas (<1.0 cm), whereas the two patients with unilateral tumors demonstrated multifocal disease. The principle microscopic differences between these genetically determined medullary microcarcinomas and larger sporadic (>1 cm) medullary carcinomas were the low incidence of stromal desmoplasia and amyloid deposition, the high incidence of C-cell hyperplasia, and the low incidence of lymph node metastases. Only one patient, a 34-year-old man, presented with lymph node metastases. All patients remain disease free 11 to 70 months after diagnosis.
This small series of thyroid microcarcinomas illustrates the impact molecular diagnostics is having on the management and prognosis of genetically determined medullary carcinoma.
Sporadic Versus Familial Medullary Thyroid Microcarcinoma A Histopathologic Study of 50 Consecutive Patients
Klaus Kaserer, M.D.; Christian Scheuba, M.D.; Nikolaus Neuhold, M.D.; Andreas Weinhäusel, Ph.D.; Oskar A. Haas, M.D.; Heinrich Vierhapper, M.D.; Bruno Niederle, M.D.
From the Department of Clinical Pathology (K.K.), the Division of General Surgery, Department of Surgery (C.S., B.N.), the Division of Endocrinology and Metabolism, Department of Internal Medicine III (H.V.), University of Vienna, Medical School, Vienna, Austria; the Department of Surgical Pathology (N.N.), Kaiserin Elisabeth Hospital, Vienna, Austria; and St. Anna Children's Hospital (A.W., O.A.H.), Vienna, Austria.
Am J Surg Pathol 2001;25:1245-1251 Abstract quote
By means of calcitonin screening programs, sporadic and hereditary medullary thyroid carcinoma (MTC) can be detected at an early stage.
We investigated the histopathologic findings of 16 familial (mean age 32 ± 21 years, female/male ratio 1.6:1) and 34 sporadic (mean age 58 ± 15 years; female/male ratio 2.4:1) MTCs with stage T1 comparatively.
Patients with hereditary tumors were younger. Hereditary tumors were more often found multifocal (13 of 16 vs 3 of 34; p <0.001), bilateral (11 of 16 vs 3 of 34; p <0.001), displaying desmoplastic stroma (14 of 16 vs 19 of 34; p = 0.02), and accompanied by C cell hyperplasia (16 of 16 vs 24 of 34; p = 0.01), but all of these factors were present in some sporadic patients. Only tumors with desmoplastic stroma showed lymph node metastasis, which was observed in eight of the 50 patients. After surgery all patients showed permanent normalization of calcitonin levels.
We conclude that 1) morphologic parameters considered to indicate familial MTC risk are of no value in the individual patient, 2) many sporadic MTCs develop on the background of CCH, 3) tumors with desmoplastic stroma are more likely to develop lymph node metastasis, and 4) early detection of MTC permits curative surgery in the majority of patients.
Immunohistochemical detection of somatostatin receptor types 1-5 in medullary carcinoma of the thyroid.
Papotti M, Kumar U, Volante M, Pecchioni C, Patel YC.
Department of Biomedical Sciences and Oncology, University of Turin, Italy.
Clin Endocrinol (Oxf) 2001 May;54(5):641-9 Abstract quote
BACKGROUND: We have analysed the distribution of the five somatostatin receptors (sst1-5) by immunohistochemistry in a large retrospective series of 51 medullary carcinoma of the thyroid (MCT) specimens and correlated the pattern of sst expression with expression of somatostatin (SRIF) peptide, tumour pathology and clinical outcome.
MEASUREMENTS: Immunohistochemistry was performed with rabbit polyclonal antipeptide antibodies directed against the extracellular domains or cytoplasmic tail of human (h) sst1-5. SRIF immunoreactivity was investigated in parallel paraffin sections.
RESULTS: Eighty-five percent of the tumours were positive for one or more sst, localized to both tumour cells as well as surrounding peritumoural structures, especially blood vessels. Forty-nine percent of the tumours were positive for sst1, 43% for sst2, 47% for sst3, 4% for sst4, and 57% for sst5. Fifty-one percent of tumours expressed one or two sst subtypes; 33% were positive for three or more sst isoforms. All five sst receptors were detected in only two cases. Tumours expressing octreotide sensitive subtypes (sst2,3,5) accounted for 75% of the series. 50% of the tumours co-expressed SRIF suggesting tumour cell regulation by endogenous SRIF via paracrine/autocrine circuits. There was no correlation between sst1-5 expression and age, sex, tumour size or stage, histological type or clinical outcome. Simultaneous analysis of primary tumour and lymph node metastases revealed a similar pattern of sst immunoreactivity indicating that sst expression is not modified in the course of disease progression.
CONCLUSIONS: With the exception of sst4, medullary carcinoma of the thyroid display a rich but heterogeneous expression of sst subtypes. Immunohistochemical typing of sst receptor expression using specific antireceptor antibodies represents an ideal approach for characterizing sst subtype expression in medullary carcinoma of the thyroid for optimizing receptor targeted diagnosis and therapy with somatostatin analogs.
TTF-1 Thyroid transcription factor-1, but not p53, is helpful in distinguishing moderately differentiated neuroendocrine carcinoma of the larynx from medullary carcinoma of the thyroid.
Hirsch MS, Faquin WC, Krane JF.
1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Mod Pathol. 2004 Jun;17(6):631-6. Abstract quote
Moderately differentiated neuroendocrine carcinoma/atypical carcinoid tumor is the most common nonsquamous malignancy in the larynx; however, due to morphologic overlap and calcitonin immunoreactivity, it can be difficult to distinguish from thyroid medullary carcinoma. Currently, low serum calcitonin is the most reliable means for distinguishing primary laryngeal moderately differentiated neuroendocrine carcinoma from metastatic medullary carcinoma. Thyroid transcription factor-1 (TTF-1) is positive in at least 80% of medullary carcinomas, but has not been evaluated in laryngeal moderately differentiated neuroendocrine carcinomas. Additionally, it has been suggested that p53 is positive in laryngeal moderately differentiated neuroendocrine carcinomas and negative in other neuroendocrine tumors, but this has not been validated.
The purpose of this study was to determine if the immunohistochemical markers TTF-1 and p53 could be used to discriminate between laryngeal moderately differentiated neuroendocrine carcinomas and thyroid medullary carcinomas. Eight laryngeal moderately differentiated neuroendocrine carcinomas and 10 thyroid medullary carcinomas were identified from the archival files of the BWH and MGH Pathology Departments. Hematoxylin and eosin slides were reviewed, and immunohistochemistry was performed using antibodies to calcitonin, TTF-1, and p53. Calcitonin immunohistochemistry demonstrated immunoreactivity in 100% of laryngeal moderately differentiated neuroendocrine carcinomas (N=8) and 100% of thyroid medullary carcinomas (N=10). There was weak, focal immunoreactivity with TTF-1 in one of eight (13%) laryngeal moderately differentiated neuroendocrine carcinomas, whereas nine of ten (90%) medullary carcinomas were positive for TTF-1, with strong diffuse staining in seven of these cases (78%). p53 was positive in three of six (50%) laryngeal moderately differentiated neuroendocrine carcinomas, and three of ten (30%) medullary carcinomas.
Our data demonstrate that immunoreactivity for TTF-1, but not calcitonin or p53, may be helpful in distinguishing laryngeal moderately differentiated neuroendocrine carcinoma and thyroid medullary carcinoma. In particular, diffuse and/or strong TTF-1 immunoreactivity favors a diagnosis of primary thyroid medullary carcinoma over laryngeal moderately differentiated neuroendocrine carcinoma.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
The pathologist must distinguish routine changes within the tumor which occasionally may mimic other tumors.
Mucin may be present in 40% of tumors and occasional tumors may contain melanin.
Finally, familial cases may be associated with C-cell hyperplasia and careful examination and quantification of these cells must be performed.
May be seen in familial cases of medullary carcinoma as well as hyperparathyroidism, Hashimoto's thyroiditis, and chronic hypercalcemia.
In familial cases, these cells are usually obvious on routine staining and are distinguished by larger size and nuclear atypia. In sporadic or secondary cases, these cells are subtle and immunostains for calcitonin may be needed. Current definitions include the following:
>50 cells per low power field
>50 cells per 3 low power fields
C-cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients.
Guyetant S, Josselin N, Savagner F, Rohmer V, Michalak S, Saint-Andre JP.
Department of Pathology, Centre Hospitalier Universitaire, Angers, France.
Mod Pathol. 2003 Aug;16(8):756-63. Abstract quote
Routine calcitonin (CT) assay programs and genetic testing for RET proto-oncogene mutations have consistently modified the management and understanding of C-cell proliferative disorders.
We report a series of 66 consecutive patients with C-cell hyperplasia (CCH) or medullary thyroid carcinoma (MTC) observed in our institution within an 8-year time period. All the patients had a preoperative basal CT assay and an RET proto-oncogene sequencing. Seventeen patients (F-M ratio: 8:9, mean age: 29.7 y) had a multiple endocrine neoplasia Type 2: 3 children <10 years of age had CCH only, and 14 patients had an MTC, with neoplastic CCH in 10/14 cases. Twenty-seven patients (F-M ratio: 18:9, mean age: 56.6 y) had a sporadic MTC, with physiological CCH in 8 and neoplastic CCH in 3 cases. Twenty-two men (mean age: 46.2 y) had CCH only (physiological CCH in 17 men and neoplastic CCH in 5).
We conclude that (1) clinical and pathological characteristics (familial MTC, tumor multifocality, neoplastic CCH) usually associated with hereditary MTC may be misleading and that on the contrary, RET sequencing gives no false positive result; (2) sporadic neoplastic CCH accompanies (and probably precedes) a number of sporadic MTC; and (3) women presenting with a sporadic elevated basal CT have a 100% risk of having an MTC (15/15), but this risk is 3-fold less in men (31%), who will most often have CCH only (69%).
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTOR OUTCOME Confined to the thyroid Favorable <40 yrs of age Favorable Female Favorable Associated with MEN IIa Favorable Encapsulated tumors Favorable Uniform cytology and abundant amyloid Favorable Associated with MEN IIb Unfavorable Small cell pattern Unfavorable Necrosis within tumor Unfavorable High mitotic activity Unfavorable
Molecular genotyping of medullary thyroid carcinoma can predict tumor recurrence.
Sheikh HA, Tometsko M, Niehouse L, Aldeeb D, Swalsky P, Finkelstein S, Barnes EL, Hunt JL.
Am J Surg Pathol. 2004 Jan; 28(1): 101-6 Abstract quote.
SUMMARY: Medullary thyroid carcinoma can have an aggressive behavior, and little is known about the molecular basis for clinical outcome. Defining risk of recurrent or metastatic disease is difficult, and it has been limited to clinical and pathologic features, such as advanced age, cervical lymph node metastases, and stage at presentation.
Using microdissection and genotyping, we studied 11 cases of medullary carcinoma for allelic losses in a panel of known tumor suppressor genes. The tumor suppressor genes with the most frequent allelic losses were NF2, l-myc, and p53 (75%, 44%, and 44%, respectively). The average frequency of allelic loss across all tumors was 44% and was higher in tumors that recurred. A combination of previously described high-risk variables (increased patient age and cervical lymph node metastases) with the frequency of allelic loss yielded a high-risk group, in which 6 of 6 patients recurred, and a low-risk group, in which 0 of 5 patients recurred (P = 0.004).
Frequency of allelic loss in tumor suppressor genes may provide a useful adjunctive prognostic test in medullary thyroid carcinoma.
Out Medullary thyroid cancer: multivariate analysis of prognostic factors influencing survival.
Hyer SL, Vini L, A'Hern R, Harmer C.
Thyroid Unit, Royal Marsden NHS Trust, UK.
Eur J Surg Oncol 2000 Nov;26(7):686-90 Abstract quote
AIMS: The aims of this study were to assess the long-term results of treatment of medullary thyroid carcinoma (MTC) and to define prognostic factors.
METHODS: Retrospective analysis of all patients diagnosed with MTC between 1949 and 1998 and treated in our unit was carried out.
RESULTS: One hundred and sixty-two patients (87 females, 75 males) were identified; 52 patients (32%) had familial disease. Median follow-up was 9 years (2-20 years). The majority of patients (90%) presented with a thyroid mass or enlarged neck nodes. Total/subtotal thyroidectomy was performed in 129/18 patients respectively; 45 patients also underwent neck dissection while 52 had simple nodal excision. External beam radiotherapy (RT) was given to 76 patients with advanced disease at presentation. Overall survival was 72% at 5 years and 56% at 10 years; case-specific survival was very similar. In multivariate analysis the factors which were significant predictors of survival were age at diagnosis, extent of nodal disease, extent of surgery and metastases at presentation. RT significantly reduced local relapse in patients with ipsilateral nodal disease.
CONCLUSIONS: MTC may be associated with prolonged survival; the best prognosis occurs in young patients undergoing total thyroidectomy and neck dissection. External beam RT significantly reduces local relapse in patients with limited nodal disease.
Long term prognosis of medullary thyroid carcinoma in 39 patients.
Voutilainen PE, Multanen M, Haapiainen RK, Haglund CH, Sane T, Sivula AH.
Department of Surgery, Helsinki University Central Hospital, Finland.
Ann Chir Gynaecol 2000;89(4):292-7 Abstract quote
BACKGROUND AND AIMS: Thyroidectomy and radical cervical lymph node dissection have been suggested as primary and secondary operations aimed at achieving biochemical cure in cases of medullary thyroid carcinoma (MTC). The purpose of this study was to find out behaviour of MTC in long-term follow-up, and to estimate possible difference in biological virulence between sporadic MTC and MTC in MEN2A.
MATERIAL AND METHODS: From 1967 through 1994, 39 patients with MTC, including 9 patients with hereditary disease, were operated on at the Second Department of Surgery, Helsinki University Central Hospital. Enlarged lymph nodes were dissected selectively. The main outcome measure was carcinoma-specific survival.
RESULTS: In sporadic MTC, ten-year carcinoma-specific survival was 57.9% (95% CI 39.1%-76.7%) and ten-year survival after reoperation due to lymphatic node recurrence was 51.4% (CI 18.7%-84.2%). The presence of distant metastases at diagnosis (p = 0.0001) and extrathyroidal growth of the primary tumor (p = 0.0008) were independent predictors of carcinoma-specific survival in the Cox model. The risk ratio of sporadic MTC to MTC in MEN2A was 5.40 (CI 0.67-43.2) after adjusting the survival time for the size of the primary tumor.
CONCLUSION: Distant metastases and the local extrathyroidal extent of the primary tumor have a significant effect on the prognosis of MTC, lymphatic node metastases and other clinical factors being less important. The biological virulence of sporadic MTC may be clinically significantly higher than that of MTC in MEN2A.
Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma.
Franc S, Niccoli-Sire P, Cohen R, Bardet S, Maes B, Murat A, Krivitzky A, Modigliani E;
French Medullary Study Group (GETC). Department of Endocrinology, Avicenne Hospital AP-HP, University of Paris, Bobigny, France.
Clin Endocrinol (Oxf) 2001 Sep;55(3):403-9 Abstract quote
BACKGROUND: Medullary thyroid carcinoma is a rare tumour derived from the thyroid parafollicular calcitonin-secreting cells. Calcitonin is a very specific marker of this cancer that allows preoperative diagnosis. Serum calcitonin assay is particularly useful to define the postoperative state of patients (cured, apparently cured, not cured) and, because of its great sensitivity, it has a major place in the postoperative follow-up.
OBJECTIVE: To identify, among patients thyroidectomized for medullary thyroid carcinoma (MTC), the characteristics of authentic recurrent MTC [re-elevation of stimulated serum calcitonin (CT) level measured by a sensitive immunoradiometric assay, after postoperative normalization].
PATIENTS AND METHODS: We first collected, through the national registry of the French Calcitonin Tumour Study Group (GETC), patients who had undergone a total thyroidectomy with or without lymph node surgery and who were not cured at the last follow-up visit. Among 453 such patients included in the database, 15 patients met the criteria for authentic recurrence as defined in previous studies: they had been first considered as cured during the 6 months following the initial surgical procedure (basal and pentagastrin-stimulated serum calcitonin level 2 ng/l) immediate postoperative CT, confirming the initial postoperative cure. The characteristics (age, nature of disease, stage at surgery and type of node dissection) of these 15 patients were studied.
RESULTS: According to the Tumour Node Metastasis classification, nine patients were T1 and, among them, five patients had had complete lymph node surgery without any evidence of nodal metastases (N0). The recurrence was 3.2 +/- 2.2 years (range: 0.7-7.5) after the initial surgery.
CONCLUSIONS: 3.3% of patients not cured at the last visit had a recurrent MTC. This recurrence occurred whatever the stage, and even if the primary surgery for MTC was a priori complete. These results emphasize the need for a regular biochemical follow-up because recurrence may appear many years after the initial surgery.
Occult micro medullary thyroid carcinoma: therapeutic strategy and follow-up.
Peix JL, Braun P, Saadat M, Berger N, El Khazen M, Mancini F.
Department of Surgery, Hopital de l'Antiquaille, 69321 Lyon Cedex 05, France
World J Surg 2000 Nov;24(11):1373-6 Abstract quote
Twenty micro medullary thyroid carcinomas (MTCs) were found in histologic specimens of 19 patients in our department from 1990 to 1998.
There were 14 women and 5 men, with a median age of 63 years. The indication for surgery was goiter in 12 patients and a solitary nodule in 7 patients (three differentiated cancers). Altogether, 18 patients had unifocal micro-MTCs with a median diameter of 3.6 mm. One patient had a bilateral MTC (3 and 5 mm, respectively). Surgical procedures consisted of 9 total thyroidectomies and 10 lobectomies or subtotal thyroidectomies. Of these 10 patients, 4 underwent reoperation (totalization). One was operated on 48 months after a positive pentagastrin test: There was no thyroid residual tumor but three lymph node micrometastases. Among the six patients in whom thyroid tissue was left, a 91-year-old woman died of unrelated cause and the five others remain disease-free without biologic abnormalities at follow-ups of 18 to 70 months. Considering the aggressiveness of MTCs, total thyroidectomy with central compartment dissection is theoretically indicated. However, among the nine total thyroidectomies and four secondary totalizations associated with at least central compartment dissection, no other thyroid lesion was observed and only one case of lymph node microinvasion was found.
Because of the morbidity associated with reoperation and neck dissection, we propose that it is indicated only for microcarcinomas > 5 mm in diameter, in cases of an abnormal response to pentagastrin, or when it is difficult to ensure prolonged follow-up of the patient.
Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome?
Hansen HS, Torring H, Godballe C, Jager AC, Nielsen FC.
Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
Cancer 2000 Aug 15;89(4):863-7 Abstract quote
BACKGROUND: The results and consequences of genetic testing in a family with familial medullary thyroid carcinoma (FMTC) are described.
METHODS: In the screening of relatives, serum calcitonin is replaced by RET mutation analysis that was performed in families suspected of hereditary medullary thyroid carcinoma (MTC). In 4 of 10 families, mutation in exon 10 was found in codon 611.
RESULTS: One hundred fifty persons belonging to 30 families were tested, of which 10 families were carriers of RET mutation in exon 10. In 1 of these families with MTC only, 2 brothers were gene carriers of a RET codon 611 mutation and lived without any sign of MTC. One is aged 79 years, and the other died at the age of 71 of other causes.
CONCLUSIONS: The results indicate that the gene carrier in families with MTC without other endocrine tumors (FMTC) exhibits a highly variable disease course. A 611 codon mutation is most often a rather mild and slow progression form of MTC. Because 2 gene carriers were still alive at age 70 years without showing any sign of the disease, it is tempting to ask if all gene carriers with a 611 codon mutation without other endocrine tumors should be operated on, and if so, at what age? In the authors' opinion, more information is needed to be able to answer these questions. The current guidelines for treatment of patients with hereditary MTC are discussed.
Prophylactic thyroidectomy in the treatment of thyroid medullary carcinoma. Age for surgery?
Hassett S, Costigan C, McDermott M, Fitzgerald RJ.
Department of Paediatric Surgery, Our Lady's Hospital for Sick Children, Dublin, Ireland.
Eur J Pediatr Surg 2000 Oct;10(5):334-6 Abstract quote
Since the association of RET proto-oncogene mutations and medullary thyroid carcinoma in children there has been much discussion regarding timing of surgery.
Our study group was formed from a brother and sister (8 and 5) and 3 brothers (9, 13, 16) selected on the basis of a positive family history for thyroid medullary carcinoma. Histological examinations of the thyroidectomy specimens showed that the 8- and 9-year old had microinvasive carcinoma and the remaining three had C-cell hyperplasia.
Our recommendation is for prophylactic thyroidectomy for children with RET proto oncogene mutations at an early age, clearly before age 5.
Surgical treatment of postoperative, incidentally diagnosed small sporadic C-cell carcinomas of the thyroid.
Cupisti K, Simon D, Wolf A, Gerharz CD, Goretzki PE, Dotzenrath C, Witte J, Roher HD.
Klinik fur Allgemein und Unfallchirurgie, Heinrich-Heine-Universitat Dusseldorf, Germany.
Langenbecks Arch Surg 2000 Dec;385(8):526-30 Abstract quote
BACKGROUND AND AIMS: The surgical strategy in small sporadic C-cell carcinomas of the thyroid that are incidentally diagnosed after goiter resection for benign disease is controversial. It remains unclear whether a completion thyroidectomy should be performed in every case.
PATIENTS AND METHODS: We present nine patients who were operated on between October 1992 and October 1997 in whom an unexpected, small sporadic C-cell carcinoma (seven with pT1, two with pT2) was found in the postoperative histology.
RESULTS: All patients were calcitonin negative and there were no signs of the disease being inherited (no familial history, negative RET proto-oncogene). No patient underwent a completion thyroidectomy. All patients had a follow-up with pentagastrin-stimulated calcitonin and carcinoembryonic antigen (CEA) 3 months, 6 months and annually after the operation. No patient became calcitonin positive or showed any other signs of tumor recurrence after a follow-up period of 2-7 years.
CONCLUSION: A completion thyroidectomy is not necessary in small sporadic C-cell carcinoma that is incidentally diagnosed after resection for benign disease if there is no sign of familial cancer and if calcitonin is negative. A close follow-up is necessary.
Update on the MEN 2A c804 RET mutation: is prophylactic thyroidectomy indicated?
Frohnauer MK, Decker RA.
Department of Endocrinology, Maine Medical Center, Portland, ME, USA.
Surgery 2000 Dec;128(6):1052-7;discussion 1057-8 Abstract quote
BACKGROUND: Mutations of the RET proto-oncogene co-segregate with multiple endocrine neoplasia type 2A. A rare sequence abnormality at codon 804 (c804) has been reported in 6 kindreds and linked to mild C-cell disease, which raises the question of the appropriateness of thyroidectomy in childhood. The purpose of this study was to (1) report the clinical correlates of 5 additional c804 kindreds, and (2) clarify therapeutic options in children.
METHODS: Thirty-eight members from five c804 kindreds underwent genetic analysis. Biochemical, operative, and pathology reports were reviewed.
RESULTS: Twenty-three gene carriers were identified, of whom 14 had thyroidectomy. Medullary thyroid carcinoma was found in 7 patients (aged 5-56 years), C-cell hyperplasia in 6 patients (aged 13-40 years), and normal histology in a single patient (aged 27 years). One patient with medullary thyroid carcinoma died of metastases (aged 12 years). Nine of the 23 gene carriers delayed operation, 4 of whom had calcitonin testing. Three of the 4 patients had abnormal calcitonin levels and a single patient was negative (aged 40 years). Of the remaining 9 patients, 2 await thyroidectomy, and 3 have refused evaluation.
CONCLUSIONS: Penetrance of the c804 mutation is highly variable. Medullary thyroid carcinoma associated with this genotype has aggressive potential. Prophylactic thyroidectomy in childhood is a viable approach.
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