Hyalinizing Trabecular Tumor
Yuri E. Nikiforov
DEFINITION
Hyalinizing trabecular tumor is a rare noninvasive follicular cellderived thyroid neoplasm with a characteristic trabecular growth pattern and intratrabecular hyalinization. The malignant potential of this tumor is uncertain, but at most is very low. Synonyms include paraganglioma-like adenoma of the thyroid (PLAT), hyalinizing trabecular adenoma, hyalinizing trabecular neoplasm, and hyaline cell tumor of the thyroid with massive accumulation of cytoplasmic microfilaments.
HISTORICAL COMMENTS AND POINTS OF CONTROVERSY
The first detailed description of this tumor in the modern era was provided by Carney and colleagues,1 who reported in 1987 a series of 11 tumors and called them hyalinizing trabecular adenoma. Prior to this publication, this tumor was apparently described and drawn by Rahel Zipkin in 1905 and by Pierre Masson in 1922 and reported in an abstract form by Ward and colleagues in 1982 (as recently reviewed by Carney2). All 11 tumors reported in 1987 were well circumscribed or encapsulated and revealed no invasion, no tumor recurrence, or metastases during a mean follow-up period of 10 years.1 A year later, the same tumor was described as paraganglioma-like adenoma of the thyroid or PLAT by Bronner and colleagues3 in a series of nine cases.
In 1991, a series of nine thyroid tumors with trabecular pattern and hyalinization was reported, and one of those cases had a lymph node metastasis at presentation.4 Although in the latter case only an incisional biopsy of the tumor was available for review, the authors argued that tumors with this appearance may have malignant behavior and should be designated as hyalinizing trabecular tumors. Several subsequent studies have reported occasional cases with similar trabecular appearance and hyalinization but associated with blood vessel or tumor capsule invasion and distant metastases, as well as areas of classic papillary carcinoma merging with this tumor.5,6,7,8,9 Together with the prominent nuclear features of papillary carcinoma typically seen in the tumor cells, these reports argued against the uniformly benign nature of hyalinizing trabecular adenoma. Although no well-documented cases of malignant behavior of tumors with no invasion at presentation have been published so far, many believe that this tumor is likely to represent a peculiar variant of papillary carcinoma.
The tumor relationship to papillary carcinoma was expected to be firmly proven by two simultaneously published reports demonstrating that hyalinizing trabecular tumors frequently harbor RET/PTC rearrangement,10,11 which is a genetic feature of papillary carcinoma. However, these molecular findings did not provide full confirmation of the association and raised a controversy by themselves. In addition to some concerns about the uniformity of the criteria for tumor selection,12 the problem was that these studies did not use a quantitative approach for RET/PTC detection and therefore failed to establish whether the rearrangement in these tumors was clonal, i.e., present in most tumor cells, or nonclonal and occurred only in a small fraction of cells within the nodule. As nonclonal RET/PTC rearrangement is not specific for papillary carcinoma,13,14 the results of these studies cannot be used to confirm that hyalinizing trabecular tumor is a variant of papillary carcinoma. As the controversy persists, the 2004 WHO classification places this tumor in a separate category and designates it as hyalinizing trabecular tumor.15
INCIDENCE AND EPIDEMIOLOGY
Hyalinizing trabecular tumor is a rare type of thyroid tumors. Its exact incidence is not known, although it would be unusual to encounter more than one in-house case of this tumor per year in an average size pathology laboratory. The age of patients at diagnosis ranges between 21 and 81 years, with approximately uniform distribution from the third until the seventh decade and a mean age of 46 to 50 years in the reported series with a substantial number of patients.16,17,18,19 The tumor has a marked female predominance, with a female:male ratio of 5-6:1.
ETIOLOGY
The etiologic factors for hyalinizing trabecular tumor development are not well defined. In the original series of 11 cases, two patients (18%) had a history of radiation exposure.1 However, in a larger series, a history of radiation was found in 5% of patients.16 The tumor frequently arises in thyroid glands affected by chronic lymphocytic thyroiditis or multinodular goiter (Fig. 9.1) and may coexist with a typical follicular adenoma or papillary carcinoma, although whether these associations are coincidental or hyalinizing trabecular tumor shares common causal factors with these conditions remains unclear.
A case of hyalinizing trabecular tumor in a patient with Cowden disease20 and a case of an invasive tumor with similar morphology in a patient with familial polyposis coli7 have been reported. Adenomas with a growth pattern of hyalinizing trabecular tumor were described in individuals with familial oncocytic (oxyphilic) thyroid tumors linked to a locus on chromosome 19p13.2.21 However, concrete evidence for the association between hyalinizing trabecular tumor and familial cancer syndromes is lacking.
PATHOGENESIS AND MOLECULAR GENETICS
DNA Ploidy
Most tumors have a diploid cell population. In one study, flow cytometric analysis of DNA ploidy revealed a diploid pattern in 5/6 (83%) tumors and evidence for aneuploidy in 1 (17%) tumor.1
Cytogenetic Abnormalities
In one reported case,4 the tumor revealed a normal karyotype together with two clones, one with translocation t(2;3)(q21;p27) and another with the same translocation in addition to trisomy 7 and 12.
Somatic Mutations
RET/PTC
Two initial simultaneously published reports found RET/PTC rearrangement in a significant fraction of hyalinizing trabecular tumors.10,11 In a series of 14 tumors reported by Papotti and colleagues,11 29% showed RET expression by immunohistochemistry and 21% revealed RET/PTC1 rearrangement detected by RT-PCR. Cheung and colleagues10 reported a series of eight tumors, including six hyalinizing trabecular adenomas and two hyalinizing trabecular carcinomas diagnosed as such based on the presence of invasion. They found RET expression by immunohistochemistry in six (75%) tumors and detected RET/PTC1 rearrangement by RT-PCR in five of these cases. A subsequent report of a larger series of cases (28 cases) from the first group found RET/PTC1 in 36% of cases and RET/PTC3 in 11%.22 A more recent study revealed no RET/PTC rearrangements in a series of 18 hyalinizing trabecular tumors studied by RT-PCR.19
Although the three positive studies suggested the association between this tumor and RET/PTC, the pathogenetic role of RET/PTC rearrangement remains unclear. This is because all these reports used (1) formalin-fixed and paraffin-embedded tissues to isolate tumor RNA, which is known to provide a suboptimal template for RNA-based studies (see Chapter 20), and (2) highly sensitive detection techniques, that is, 35 to 40 cycles of PCR amplification followed by hybridization with specific probes, which were performed in a qualitative rather than quantitative manner. As a result, these studies were not able to establish what portion of the tumor cells harbored RET/PTC rearrangement. The use of immunohistochemistry with a RET antibody developed in one of the author’s laboratories and not cross-validated for specificity of staining11 or the use of a commercially available RET antibody known for weak and irreproducible staining results10 could not clarify this issue with confidence. RET/PTC are known to occur in a clonal fashion in papillary carcinoma and in a nonclonal fashion, that is, in only a few cells within the tumor mass, in many thyroid lesions.13,14 The lack of understanding of the extent of RET/PTC occurrence in hyalinizing trabecular tumor cells does not allow to establish the link between this tumor and papillary carcinoma or to postulate the pathogenetic role of RET/PTC in the development of hyalinizing trabecular tumors. The conclusive resolution of these issues awaits additional studies that have to be performed using reliable quantitative techniques for the detection of RET/PTC (Chapter 20).
Other Mutations
The prevalence of BRAF and RAS point mutations in these tumors is very low. No BRAF mutation was found in six studies that analyzed 82 hyalinizing trabecular tumors.17,18,19,22,23,24 One study, however, reported the presence of a BRAF V600E mutation in a hyalinizing trabecular tumor developed in black thyroid, although the report did not provide sufficient details of the detection technique and illustrated the tumor quite poorly.25 By contrast, BRAF mutations are found with high prevalence in papillary carcinomas, including papillary carcinomas with a trabecular growth pattern.24
No RAS mutation was found in 31 tumors reported to date.22,26 RAS mutations are common in follicular adenomas, follicular carcinomas, and the follicular variant of papillary carcinoma (30% to 50% incidence). As hyalinizing trabecular tumor is expected to be related to one of these tumor types, the lack of RAS mutations provides evidence for distinct molecular pathways involved in the development of hyalinizing trabecular tumor.
Dysregulation of miRNA
The expression levels of several miRNAs known to be consistently upregulated in papillary thyroid carcinomas were studied in a series of 18 hyalinizing trabecular tumors.19 They included miR-146b, miR-181b, miR-21, miR-221, and miR-222. None of these miRNAs were found to be upregulated in hyalinizing trabecular tumors, in contrast to papillary thyroid carcinoma samples assayed in the same study.19 This provides further evidence suggesting that pathogenesis of hyalinizing trabecular tumor may be different from papillary thyroid carcinoma, at least from its most common variants.
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