Pediatric medullary carcinoma of the thyroid with point mutation of RET proto-oncogene associated with multiple endocrine neoplasia and initially diagnosed by fine-needle aspiration biopsy. (Case Report).
Abstract: A 7-year-old girl presented with a thyroid mass, elevated serum levels of calcitonin calcitonin /cal·ci·to·nin/ (-to´nin) a polypeptide hormone secreted by C cells of the thyroid gland, and sometimes of the thymus and parathyroids, which lowers calcium and phosphate concentration in plasma and inhibits bone resorption. and carcinoembryonic antigen, as well as multiple mucosal nodules in the upper lip and tongue. Cytologic material obtained by fine-needle aspiration biopsy from the thyroid mass was diagnosed as medullary carcinoma and confirmed by immunohistochemical studies in the cell-block sections. Subsequent histopathologic examination showed involvement of both thyroid lobes by medullary carcinoma, and electron microscopic studies further confirmed the diagnosis. Molecular studies showed a point mutation in amino acid 918 in exon 16 of the RET proto-oncogene. Biopsies from the upper lip and tongue showed mucosal neuromas. Fine-needle aspiration biopsy is frequently used in the initial evaluation of thyroid nodules. This case illustrates the value of fine-needle aspiration biopsy as a safe and accurate diagnostic modality in the workup of pediatric pediatric /pe·di·at·ric/ (pe?de-at´rik) pertaining to the health of children.
Of or relating to pediatrics. thyroid nodules. Fine-needle aspiration biopsy should always be considered for the investigation of thyroid nodules in pediatric patients.
Key Words: medullary carcinoma, multiple endocrine neoplasia Multiple endocrine neoplasia
Abnormal tissue growth on one or more of the endocrine (hormone-secreting) glands.
Mentioned in: Follicle-Stimulating Hormone Test
multiple endocrine neoplasia See MEN. , RET proto-oncogene, pediatric neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. , point mutation, thyroid neoplasms
Medullary carcinoma of the thyroid (MCT) is an uncommon malignant neoplasm arising from the parafollicular cells that produce calcitonin and carcinoembryonic antigen (CEA). It accounts for up to 10% of thyroid malignancies. (1) It may occur sporadically (70-80% of cases) or as a familial form (20% of cases) associated with multiple endocrine neoplasia (MEN) type 2. Sporadic MCT occurs primarily in middle-aged adults (aged 36 to 51 years) as unilateral enlargement of the gland. The familial form is seen in a younger population (aged 15 to 20 years); it is often multicentric, involving both lobes, and coexists with T-cell hyperplasia. (1) The combination of elevated serum calcitonin level plus a thyroid nodule is virtually pathognomonic pathognomonic /pa·thog·no·mon·ic/ (path?ug-no-mon´ik) specifically distinctive or characteristic of a disease or pathologic condition; denoting a sign or symptom on which a diagnosis can be made. of MCT. (2) The biologic behavior of MCT is ranked between the well-differentiated thyroid neoplasms and aggressive anaplastic an·a·plas·tic
1. Relating to the surgical restoration of a lost or absent part.
2. Of, relating to, or characterized by cells that have become less differentiated.
1. carcinoma. The treatment approach is also more aggressive, with radical neck dissection Radical Neck Dissection Definition
Radical neck dissection is an operation used to remove cancerous tissue in the head and neck.
Purpose recommended in all cases.
MCT is also disproportionately important because of its strong association with other neuroendocrine tumors and familial occurrence. Recently, molecular studies have demonstrated that patients with MEN 2A, MEN 2B, and familial MCT have specific sequence changes within the coding region of the RET proto-oncogene. (3) It has been recommended that thyroidectomy Thyroidectomy Definition
Thyroidectomy is a surgical procedure in which all or part of the thyroid gland is removed. The thyroid gland is located in the forward part of the neck (anterior) just under the skin and in front of the Adam's apple. be performed as early as possible in children with the clinical manifestations of MEN 2B, such as the mucosal neuroma neuroma /neu·ro·ma/ (ndbobr-ro´mah) a tumor growing from a nerve or made up largely of nerve cells and nerve fibers.neurom´atous
acoustic neuroma syndrome. Analysis of RET proto-oncogene mutation at codon 918 should be performed in all children born to parents with MEN 2B, as well as in children with ambiguous clinical features suggestive of MEN 2B. (4)
In pediatric patients, a thyroid nodule should always arouse suspicion of carcinoma, and the mass must be promptly investigated. Although the risk of relapse exists for young patients with thyroid carcinomas, the prognosis is very good when the disease is diagnosed early and properly treated. (5) Fine-needle aspiration biopsy (FNAB) has become a mandatory diagnostic tool in the preoperative diagnosis of thyroid nodules. (2) This safe, economic, and highly accurate technique has not been used as widely in children as it has been in adults.
Almost all cases of MCT in childhood are familial. Two of the inherited syndromes associated with MCT, namely MEN 2A and familial MCT, were found to have mutations in the extracellular domain of the RET protein. The third and most severe inherited syndrome, MEN 2B, was found to have the characteristic M918T mutation in the intracellular domain of the RET tyrosine kinase. (6,7) The substitution of methionine in the tyrosine kinase catalytic core is thought to alter the substrate specificity of this kinase both quantitatively and qualitatively. This mutation has been found in 30 to 40% of sporadic cases of MCT. (8) It has not been found in MEN 2A or familial MCT.
Familial and multifocal multifocal /mul·ti·fo·cal/ (mul?te-fo´k'l) arising from or pertaining to many foci.
Relating to or arising from many foci. MCT are more aggressive tumors with early metastasis, particularly in young patients with MEN 2B. In sporadic cases, RET mutations are generally seen only in tumor DNA, although a de novo germ-line mutation will be present in all tissues. In hereditary cases, the RET mutations are always present in tumor and in constitutive DNA. Both sporadic and familial cases are more prevalent in females and are associated with elevated serum levels of calcitonin. (4)
This case illustrates the value of FNAB as a safe and rapid diagnostic tool in the initial outpatient evaluation of pediatric thyroid nodules. Two cases similar to ours were reported in adults with MCT diagnosed by FNAB of thyroid gland or node metastases. Tissues evaluated for DNA studies confirmed the mutation, which led to the final diagnosis of MEN type 2. (9,10) In one of these cases, MCT and MEN type 2 went undiagnosed for years, in spite of the fully developed clinical phenotype, until a thyroid FNAB and DNA studies revealed the diagnosis. (10)
The early detection of the RET proto-oncogene mutation in children with MEN type 2 has become a crucial diagnostic tool to guide preventive thyroidectomy. (11) According to a consensus statement from an international group, RET testing should replace evaluation of calcitonin level to diagnose the MEN type 2 carrier state. (12)
The cytologic findings of MCT mirror the histologic findings. (1,2) Amyloid, demonstrated by Congo red stain, is present in 60 to 80% of the reported cases. (2) The amyloid is found more often on EM and is seen as webs of nonbranching fibrils (as in our case). (1)
The differential diagnosis of MCT on morphologic grounds includes papillary carcinoma of the thyroid (PCT), anaplastic carcinoma (AC), and small cell carcinoma small cell carcinoma
See oat cell carcinoma.
small cell carcinoma Small cell undifferentiated carcinoma, undifferentiated carcinoma A highly aggressive malignancy, usually of lung, which arises in proximal bronchi . Among the benign lesions in the differential diagnosis are hyalinizing trabecular adenoma, follicular Hurthle cell neoplasms, hyperplastic nodules, and granulation tissue. (2,13) Pseudopapillae may be seen in MCT, but the tumor rarely has true papillae with fibrous cores, as seen in PCT. (2) In addition, both neoplasms may contain intranuclear in·tra·nu·cle·ar
Situated or occurring within the nucleus of an atom or cell. pseudo-inclusions. (1,2,14) The spindle cells in MCT may be mimicked by fibroblasts from stroma stroma /stro·ma/ (stro´mah) pl. stro´mata [Gr.] the matrix or supporting tissue of an organ.stro´malstromat´ic
n. pl. stro·ma·ta
1. , as well as granulation tissue and cellular repair in old hemorrhagic goiter goiter: see thyroid gland. . (13) Small cell MCT represents the poorly differentiated end of the spectrum of neuroendocrine carcinomas and can be identical to small cell carcinomas of the lung. Immunohistochemical testing of calcitonin level should be performed every time diagnostic doubts arise. (1,2)
Fine-needle aspiration biopsy of the thyroid can be an important diagnostic tool for thyroid nodules in pediatric patients. Vital information for the diagnosis, prognosis, and epidemiology of tumors can be gained from DNA studies of pathology specimens.
Accepted May 6, 2002.
(1.) Rosai J, Carcangiu ML, DeLcllis RA. Medullary carcinoma: Tumors of the thyroid gland, in Rosai J, DeLellis RA (eds): Atlas of Tumor Pathology: Thinors of the Thyroid Gland. Washington, DC, Armed Forces Institute of Pathology Armed Forces Institute of Pathology A section of the US military which provides consultations, reference atlases and educational programs for pathologists , 1994, 3rd series, fascicle fascicle /fas·ci·cle/ (fas´i-k'l)
1. a small bundle or cluster, especially of nerve, tendon, or muscle fibers.
2. a tract, bundle, or group of nerve fibers that are more or less associated functionally. 5, pp 207-241.
(2.) DeMay RM. Thyroid, in The Art and Science of Cyropothology: Vol 2. Aspiration Cytology. Chicago, American Society of Clinical Pathologists Press, 1996, pp 703-766.
(3.) Ferraris AM, Mangerini R, Gaetani GF, Romei C, Pinchera A, Pacini F. Polyclonal origin of medullary carcinoma of the thyroid in multiple endocrine neoplasia type 2. Hum Genet 1997;99:202-205.
(4.) Evans DB, Burgess MA, Goepfert H, Gagel RF. Medullary medullary /med·ul·lary/ (med´ah-lar?e)
1. pertaining to a medulla.
2. pertaining to bone marrow.
3. pertaining to the spinal cord. thyroid carcinoma. Curr Ther Endocrinol Metab 1997;6:127-132.
(5.) Fassina AS, Rupolo M, Pelizzo MR, Casara D. Thyroid cancer in children and adolescents. Tumor 1994;80:257-262.
(6.) Takahashi M. Oncogenic oncogenic /on·co·gen·ic/ (-jen´ik) giving rise to tumors or causing tumor formation; said especially of tumor-inducing viruses.
on·co·gen·ic or on·cog·e·nous
adj. activation of the RET protooncogene in thyroid cancer. Grit Rev Oncog 1995;6:35-46.
(7.) Hofstra RM, Landsvater RM, Ceceherini I, Stulp RP, Stelwagen T, Luo Y, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994;367:375-376.
(8.) Blaugrund JE, Johns MM Jr, Eby YJ, Ball DW, Baylin SB, Hruban RH, et al. RET proto-oncogene mutations in inherited and sporadic medullary thyroid cancer Medullary thyroid cancer (MTC)
A slow-growing tumor associated with MEN.
Mentioned in: Multiple Endocrine Neoplasia Syndromes . Hum Mol Genet 1994;3:1895-1897.
(9.) Russo D, Arturi F, Chiefari E, Meringolo D, Bianchi D, Bellanova B, et al. A case of metastatic medullary thyroid carcinoma: Early identification before surgery of an RET proto-oncogene somatic mutation in fine-needle aspirate as·pi·rate
To take in or remove by aspiration.
A substance removed by aspiration.
The removal by suction of a fluid from a body cavity using a needle. specimens. J Clin Endocrinol Metab 1997;82:3378-3332.
(10.) Ohyama T, Sato M, Murao K, Kittaka K, Namihira H, Matsuhara S, et al. A case of multiple endocrine neoplasia type 2B undiagnosed for many years despite its typical phenotype. Endocrine 2001;15:143-146.
(11.) Sanso GE, Domene HM, Garcia R, Pusiol E, De M, Roque M, et al. Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: Presence of C-cell malignant disease in asymptomatic carriers. Cancer 2002;94:323-330.
(12.) Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-5671.
(13.) Kaur A, Jayaram G. Thyroid tumors: Cytomorphology of medullary, clinically anaplastic, and miscellaneous thyroid neoplasms. Diagn Cytopathol 1990;6:383-389.
(14.) Uribe M, Fenoglio-Preiser CM, Grimes M, Feind C. Medullary carcinoma of the thyroid gland: Clinical,' pathological, and immunohisto-chemical features with review of the literature. Am J Surg Pathol 1985;9:577-594.
RELATED ARTICLE: Case Report
A 7-year-old white girl enjoyed general good health with steady growth and development, except for an intermittent, pruritic, circular rash about her face and trunk, which had been present for several years. Her mother had recently noticed a slow-growing mass in the patient's anterior neck. There was also a persistent swelling of the upper lip and tongue.
Physical examination revealed a normal prepubertal prepubertal /pre·pu·ber·tal/ (-pu´ber-tal) before puberty; pertaining to the period of accelerated growth preceding gonadal maturity. female with a thyroid mass left of midline, prominent upper lip (Fig. 1), and multiple submucosal submucosal /sub·mu·co·sal/ (-mu-ko´sal)
1. pertaining to the submucosa.
2. beneath a mucous membrane. nodules at the tip of her tongue. There was a circular, red skin rash distributed diffusely throughout the trunk. Family history was unremarkable. On admission, basal serum calcitonin level was 6,192 pg/mL (normal, 0-100 pg/mL) and serum CEA level was 36.2 ng/mL (normal, 0-10 ng/mL). Thyroid indices, including levels of triiodothyronine triiodothyronine /tri·io·do·thy·ro·nine/ (tri?i-o?do-thi´ro-nen) one of the thyroid hormones, an organic iodine-containing compound liberated from thyroglobulin by hydrolysis. It has several times the biological activity of thyroxine. (T3) resin uptake, total thyroxine ([T.sub.4]), free [T.sub.4], and thyroid-stimulating hormone (TSH), were normal. Thyroid autoantibody autoantibody /au·to·an·ti·body/ (-an´ti-bod?e) an antibody formed in response to, and reacting against, an antigenic constituent of one's own tissues.
n. test and biochemical screening for pheochromocytoma Pheochromocytoma Definition
Pheochromocytoma is a tumor of special cells (called chromaffin cells), most often found in the middle of the adrenal gland. (vanillylmandelic acid, plasma metanephrine, and plasma free-catecholamine levels) showed no evidence of disease. Ultrasound examination of the neck revealed a 2.4-cm well-defined mass arising within the left thyroid lobe, and an additional 0.7-cm well-defined, solid mass in the center of the right lobe.
FNAB of the left thyroid mass showed hypercellular aspirates composed of loose clusters and scattered, single spindle cells with relatively uniform central nuclei, speckled chromatin pattern, occasional conspicuous nucleoli nucleoli
plural form of nucleolus. , and wispy cytoplasm (Fig. 2). Occasional polygonal cells were noted in the background. Colloid colloid (kŏl`oid) [Gr.,=gluelike], a mixture in which one substance is divided into minute particles (called colloidal particles) and dispersed throughout a second substance. , amyloid, mitotic figures, and necrosis were all absent. Immunohistochemical tests performed on cell-block sections were strongly positive for calcitonin and chromogranin. The diagnosis of MCT was rendered based upon the morphology and immunohistochemical findings.
The patient underwent total thyroidectomy and bilateral neck dissection. The thyroid gland in the surgical specimen weighed 27.4 g. The right lobe had a well-demarcated, whitish tan, firm nodule that measured 0.7 X 0.4 )< 0.4 cm. The left lobe contained a similar firm nodule measuring 2.3 X 2.2 X 1.5 cm. The neck dissection specimen yielded 102 lymph nodes, all of which were negative for cancer. Microscopically, the tumor consisted of nests of neoplastic cells separated by thin strands of eosinophilic eosinophilic /eo·sin·o·phil·ic/ (-fil´ik)
1. readily stainable with eosin.
2. pertaining to eosinophils.
3. pertaining to or characterized by eosinophilia. stroma, with a predominant pattern of spindle cells with mild to moderate nuclear pleomorphism pleomorphism /pleo·mor·phism/ (-mor´fizm) the occurrence of various distinct forms by a single organism or within a species.pleomor´phicpleomor´phous
1. and a trabecular pattern at the periphery. Mitoses were rare. Neither calcification nor amyloid was detected with hematoxylin and eosin staining. Congo red stain was negative for amyloid. Electron microscopy (EM), however, revealed a disordered meshwork of fibrils characterizing intracy-toplasmic amyloid; EM also showed numerous intracy-toplasmic, round, neurosecretory neurosecretory
pertaining to or emanating from the secretory activities of nerve cells.
the form in which neurosecretions are passed along axons to release them into the blood. granules (150-300 nm in diameter) in the tumor cel ls. Repeated immunohisto-chemical studies of both nodules confirmed MCT. Biopsies from the nodules on both the upper lip and the tongue showed submucosal neuromas. One intrathymic parathyroid parathyroid /par·a·thy·roid/ (-thi´roid)
1. situated beside the thyroid gland.
2. see under gland.
1. gland was histologically normal. Biopsies of the upper lip and the tongue revealed submucosal neuromas. DNA was isolated from a small fragment of tumor carved out from a paraffin block from the surgical specimen. Polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is (PCR) amplification of exon 16 of the RET proto-oncogene demonstrated loss of a normally present FokI restriction site. Electrophoretic separation of the digested PCR products in an agarose gel resulted in 3 bands, 2 of which had the expected sizes of the restricted normal allele, while 1 band represented the unrestricted, mutant allele (Fig. 3).
Postoperatively, the serum CEA and calcitonin levels returned to normal range. The skin rash, for which no etiology could be found, was never biopsied and persisted after surgery, but subsequently vanished. The dermatology consultation diagnosed an erythema multi-forme/marginatum type of lesion with pruritic scales. At last follow-up, 30 months after surgery, there was no evidence of recurrence of the thyroid tumor and no record of a skin rash. The patient's mother and father were evaluated for possible DNA mutations, and none were detected.
* Fine-needle aspiration is important in the diagnosis of thyroid tumors in children.
* Molecular studies are fundamental in medullary carcinomas of the thyroid.
* Medullary carcinomas of the thyroid, particularly in children, can be a component of one of the multiple endocrine neoplasia syndromes Multiple Endocrine Neoplasia Syndromes Definition
The multiple endocrine neoplasia (MEN) syndromes are three related disorders affecting the thyroid and other hormonal (endocrine) glands of the body. .
From the Departments of Pathology and Preventive Medicine, University of Mississippi Medical Center University of Mississippi Medical Center (UMC) is the health sciences campus of the University of Mississippi (Ole Miss). Located in Jackson, Mississippi (USA), it houses the Schools of Medicine, Dentistry, Nursing, Health Related Professions, and Graduate Studies in the Health , Jackson, MS.
Reprint requests to Luciano B. Lemos, MD, Department of' Pathology, Lyndon B. Johnson General Hospital, 5656 Kelley Street, Houston, TX 77026. Email: email@example.com
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