© Borgis - Postępy Nauk Medycznych 1/2015, s. 38-46
*Barbara Jarząb, Jolanta Krajewska, Jan Włoch, Zbigniew Wygoda
Genetyka kliniczna raka rdzeniastego tarczycy
Clinical genetic of medullary thyroid carcinoma
Nuclear Medicine and Endocrine Oncology Department, M. Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch
Head of Department: prof. Barbara Jarząb, MD, PhD
Streszczenie
Rak rdzeniasty tarczycy (RRT) jest neuroendokrynnym nowotworem złośliwym, wywodzącym się z okołopęcherzykowych komórek C. Komórki te pochodzą z grzebienia nerwowego, w czasie rozwoju płodowego migrują z V kieszonki skrzelowej do tarczycy, gdzie produkują kalcytoninę. Kalcytonina jest hormonem peptydowym, ułatwiającym przejście wapnia z krwi do kości.
Rak rdzeniasty tarczycy występuje w postaci sporadycznej oraz dziedzicznej, której wystąpienie związane jest z obecnością mutacji germinalnych protoonkogenu RET. Dziedzicznemu RRT mogą nie towarzyszyć żadne inne objawy i mówi się wówczas o rodzinnym raku rdzeniastym tarczycy (ang. familial medullary thyroid carcinoma, FMTC). Częściej jednak dziedziczny RRT jest objawem zespołu wielogruczołowego typu 2 (ang. multiple endocrine neoplasia type 2, MEN 2).
Zespół wielogruczołowy typu 2A (MEN 2A), zwany również zespołem Sipple’a, charakteryzuje się skojarzeniem RRT z guzami chromochłonnymi nadnerczy (u około 50% chorych) i gruczolakami lub hiperplazją przytarczyc (u około 15-25% chorych). Rozpoznanie zespołu MEN 2B jest daleko bardziej jednoznaczne, tak ze względu na obraz kliniczny jak i charakterystyczne mutacje. W tym zespole RRT rozwija się najszybciej, jeszcze u małych dzieci i towarzyszą mu nerwiaki błon śluzowych oraz przerost zwojów przywspółczulnych śluzówki jelita grubego. Guzy chromochłonne nadnerczy występują później i ujawniają się u około połowy chorych, natomiast nadczynność przytarczyc nie występuje.
W artykule przedstawiono aktualny stan wiedzy na temat molekularnego podłoża dziedzicznej postaci RRT oraz zależność między lokalizacją mutacji punktowej RET i obrazem klinicznym choroby. Omówiono również postępowanie diagnostyczne i lecznicze w dziedzicznej postaci RRT oraz postępowanie w razie wykrycia nosicielstwa mutacji protoonkogenu RET. Jednocześnie w podsumowaniu podano krótkie wskazówki dotyczące postępowania w przypadku wykrycia dziedzicznej postaci RRT.
Summary
Medullary thyroid carcinoma (MTC) is a neuroendocrine malignant neoplasm, developing from the parafollicular thyroid cells. These cells, arising from the neural crest, migrate from the fifth branchial cleft into thyroid gland during the embryogenesis. They secrete calcitonin, a peptide hormone, facilitating calcium transition from blood to bones.
MTC occurs in the sporadic and hereditary form, which presence is related to the RET protooncogene germline mutations. Hereditary form of MTC can be divided into familial medullary thyroid carcinoma (FMTC) without any other endocrinopathies and as a part of multiple endocrine neoplasia type 2 (MEN 2).
Multiple endocrine neoplasia type 2a (MEN 2a), named also as Sipple syndrome, is characterized by the presence of MTC, pheochromocytoma (in about 50% of patients) and parathyroid adenomas or hyperplasia (15-25% of patients). The diagnosis of MEN 2b syndrome is more unequivocal because of its characteristic clinical status and a typical RET mutation. In this syndrome, MTC develops the most quickly, even in young children. A characteristic symptom is the presence of mucosal neuromas and neurogangliomatosis of the distal intestinal tract. Pheochromocytoma develops later, in about half of patients. Parathyroid adenomas are absent.
In this chapter the actual state of knowledge concerning the molecular basis of MTC hereditary form, its relation to localization of RET mutations and clinical disease status are presented. Diagnostic and therapeutic procedures in hereditary MTC and the way of proceeding in a presence of germline RET mutation are discussed Short guidelines about management in hereditary MTC are also given.
INTRODUCTION
Medullary thyroid carcinoma (MTC) is a neuroendocrine malignant neoplasm, arising from the parafollicular thyroid cells. According to the world literature its discovery is associated with the name of Hazard (1). However, it is worthy to emphasize that the first information concerning this type of cancer was published earlier, in the Polish oncological journal „Nowotwory” by professor Laskowski who named it „carcinoma hyalinicum”.
C-cells arise from the neural crest and migrate from the fifth brachial cleft into thyroid gland during the embryogenesis. They secrete calcitonin, a peptide hormone, facilitating calcium transition from blood to bones.
MTC is usually localized in the middle-upper part of lateral thyroid lobes, where accumulation of parafollicular cells is the greatest. Histologically, neoplastic C-cells are usually disposed in small groups or nests, separated by thin fibro-vascular layers or rarely they form trabecular, insular or solid structures. C-cell hyperplasia may be seen in surrounding thyroid tissue. A typical feature, however not always observed, is the presence of amyloid in the background. MTC cells show a positive reaction for calcitonin. Thus, regardless of classical histopathological examination, immunohistochemistry with the use of anticalcitonin antibodies is obligatory to state MTC diagnosis. MTC in more than 90% of cases causes significant increase of serum calcitonin level (Ct). Therefore, its assessment in patients suspicious for cancer significantly facilitates the diagnosis.
MTC spreads via lymphatic and blood vessels. Lymph node metastases, involving central neck compartment at the beginning and later lateral neck lymph nodes, present at diagnosis in 50-75% of cases, are often bilateral with extracapsular invasion. However, neck ultrasound (US) may fail to identify nodal metastases, mostly with reference to central neck compartment. The degree of lymph node involvement usually correlates to the primary tumor diameter. Distant metastases, via blood route, are usually localized in the liver, lung and bones.
In cases of locally advanced MTC a thyroid tumor may infiltrate adjacent tissues such as blood vessels, nerves, neck muscles, trachea and esophagus.
The first MTC symptom, observed in most patients is a nodule of thyroid gland, gradually increasing, showing different dynamics of growth, mostly indolent and generally painless. Few to several percent of subjects sometimes demonstrate chronic diarrhea, the first sign of advanced disease, which is related to excessive secretion of biologically active biogenic amines and peptides by the tumor. Dyspnea, obstacles feeling when swallowing or even dysphagia occur in patients with locally advanced disease. Cough, liver enlargement, bone pain (both spontaneous and palpable) and rapid weight loss may accompany disseminated MTC.
The percentage of MTC patents showing genetic predisposition is relatively high 20-25%, whereas in selected populations, intensively screened, even up to 30% (2, 3).
HEREDITARY MEDULLARY THYROID CANCER
Hereditary MTC may occur as an isolated disease – familiar medullary thyroid carcinoma (FMTC) or it constitutes a part of multiple endocrine neoplasia type 2 (MEN 2) syndrome (tab. 1).
MEN 2a is also known as Sipple syndrome in which MTC, affecting nearly 100% of patients, is accompanied by pheochromocytoma (~ 50% of all cases) and/or parathyroid hyperplasia (~ 15-25% of all cases). MTC usually constitutes the first symptom of Sipple syndrome and occurs within the first two decades of life, whereas pheochromocytoma is usually diagnosed later and rarely is the first sign of the disease. Primary hyperthyroidism appears as the last one, so its prevalence varies depending on the age of the investigated population.
Table 1. Hereditary medullary thyroid carcinoma: clinical manifestations.
| Symptome | FMTC | MEN 2A | MEN 2B |
| Medullary thyroid cancer | > 95% | > 95% | > 95% |
| Pheochromocytoma | – | ~ 50% | ~ 50% |
| Primary hyperparathyroidism | – | 15-60% | – |
| Typical appearance: elongated face with a big jaw, mucous neuro-matosis, colon hyperganglionosis causing symptoms similar to Hirschprung’s disease | – | – | 100% |
In a non classical form of MEN 2a syndrome cutaneous lichen amyloidosis (CLA) or Hirschsprung’s disease rarely may also occur (2).
Pheochromocytoma is characterized by an episodic high blood pressure (paroxysmal hypertension) with concomitant tachycardia sometimes accompanied by pallor and/or excessive perspiration. Unrecognized/untreated pheochromocytoma may lead to sudden death and in fact it is much more life threatening than MTC itself, especially taking into consideration its relatively low aggressive course in patients with MEN 2a syndrome.
Primary hyperparathyroidism results in hypercalcemia secondary to excessive PTH secretion. PTH increases bone resorption, therefore osteoporosis belongs to early symptoms of the disease in contrary to brown bone tumors observed much later. Among typical features of advanced primary hyperparathyroidism are renal stones, peptic ulcer disease, pancreatitis, gastrointestinal disturbances, cardiovascular and psychiatric disorders. Untreated hyperparathyroidism may lead to hypercalcemic crisis.
Because MTC represents the most frequent initial diagnosis, the differentiation between FMTC and a classical MEN 2a syndrome requires a long follow-up as pheochromocytoma may occur after years and never affects all members of a family. According to the literature the diagnosis of truly FMTC is unequivocal when at least four family members are diagnosed with MTC only. If the number of patients is lower than 4, unclassified hereditary MTC is diagnosed, as even DNA tests do not allow to distinguish unequivocally between FMTC and MEN 2a syndrome (see below).
The diagnosis of MEN 2b syndrome is much more unequivocal because of its characteristic clinical appearance as well as a typical RET mutation. In MEN 2b syndrome MTC develops much earlier than in FMTC or MEN 2a syndrome, even in small children. Pheochromocytoma occurs later and affects ~ 50% of patients, while primary hyperparathyroidism is not a part of this syndrome. Phenotype features of MEN 2b syndrome such as: elongated face with a big jaw and very prominent lips are so characteristic that an experienced clinician may state the diagnosis during the first patient’s visit. Neuromatosis of tongue margins and oral mucosa constitute a very typical feature that is seen during physical examination. Some patients also present marfanoid habitus.
Hereditary nature of some MTC cases has been known since the 60-ties of XXth century. At this time, to early diagnose MTC in family members serum calcitonin concentration in pentagastrin stimulation test used to be measured (4). Such tests were carried out in all family members up to the age of 14. To avoid false positive results (pentagastrin may stimulate an increase in serum calcitonin level even in healthy subjects, mostly in young male patients) the value above 100 pg/ml were considered as diagnostic. This assessment of serum calcitonin concentration sometimes made possible to properly characterize a genetic predisposition in family members and therefore facilitated to investigate a linkage between the incidence of MTC and genetic markers of the disease.
THE RET PROTOONCOGENE AND MTC
A gene responsible for hereditary MTC was localized in a centromeric region of chromosome 10 in 1987. It was identified as the RET protooncogene and simultaneously its mutations, responsible for FMTC, MEN 2a and MEN 2b syndromes, were described in 1993 (5-7).
The RET protooncogene encodes a membranous receptor tyrosine kinase. Its extracellular part includes a ligand binding site, cadherin like domain and cysteine rich domain (fig. 1).
Fig. 1. The scheme of a structure of RET receptor tyrosine kinase with localization of codons undergoing activating mutations.
A short transmembrane domain, fixes the protein within the cell membrane. The third, an intracellular part contains closely located two tyrosine kinase domains. The structure of RET protein strictly corresponds with a structure of other growth factor receptors (such as EGF), which are in fact receptor tyrosine kinases. A ligand responsible for a growth signal transduction by the RET protein is a small neuropeptide, glial cell-derived neurotrophic factor (GDNF). This peptide does not directly bind to the RET protein but to other membrane protein known as α GDNF receptor (currently GFRα-1) acting as RET co-receptor (fig. 2). The consequence of receptor activation is its autophosphorylation leading to downstream induction of MAP kinases and transcription of genes involved in cell proliferation.
Fig. 2. Physiological activation of the RET tyrosine kinase.
The RET protooncogene mutations, responsible for MTC development, are activating mutations resulting in overactive RET protein (2). The RET protooncogene consist of 21 exons. However, mutations occur only in a few of them and most are point mutations (fig. 1 shows their localization with reference to encoded protein). They mainly concern cysteine rich domain of the receptor extracellular part, close to the cell membrane. RET codon 634, localized in exon 11 is mostly (75-80% of all hereditary MTC cases) subject to mutations (tab. 2). More than 90% of them result from replacement of amino acid cysteine with arginine, tyrosine or tryptophan (8, 9).
Table 2. The localization of the RET protooncogene mutation responsible for hereditary MTC (10, 11).
| Codon/Exon | Syndrome | Incidence % (13) | Incidence (39) |
| 609/10 | MEN 2A/FMTC
MEN 2A/ Hirschsprung’s disease | 0-1 | 0% |
| 611/10 | MEN 2A/FMTC | 2-3 | 2.5% |
| 618/10 | FMTC/MEN 2A
MEN 2A/
Hirschsprung’s disease |
3-5
| 12% |
| 620/10 | FMTC/MEN 2A
MEN 2A/
Hirschsprung’s disease | 6-8 | 3% |
| 630/11 | MEN 2A/FMTC | 0-1 | 0% |
| 634/11 | MEN 2A
MEN 2A/CLA | 75-85 | 42% |
| 635/11 | MEN 2A | rarely | not
investigated |
| 637/11 | MEN 2A | rarely | not
investigated |
| 768/13 | FMTC | 0-1 | 1% |
| 790/13 | FMTC/MEN 2A | 0-1 | 2.5% |
| 791/13 | FMTC | 0-1 | 16% |
| 804/13 | MEN 2A/FMTC | 0-1 | 8% |
| 883/15 | MEN 2B | rarely | rarely |
| 891/15 | FMTC | rarely | not
investigated |
| 918/16 | MEN 2B | 3-5 | 12% |
| 922/16 | MEN 2B | rarely | not
investigated |
The classical MEN 2a syndrome is the most likely when RET codon 634 mutations are present, whereas other mutations are related to significantly lower probability of pheochromocytoma development and most often cause FMTC without other endocrinopathies (tab. 2).
Mutations in codon 918 of the RET protooncogene (exon 16) concern the tyrosine kinase domain. Because other proteins are phosphorylated, phenotypes of MEN 2a and MEN 2b syndromes are different. RET overactivation is observed also in peripheral nerves (neurinomas of tongue and mucous of oral cavity, colon hyperganglionosis). MTC occurs earlier and is characterized by the more aggressive course. However, there is no parathyroid hyperplasia (12, 13).
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Piśmiennictwo
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