Controversies in Thyroid Pathology
Moderators: Dr. Thomas Giordano and Dr. Paul Komminoth
Section 2 -
Hyalinizing Trabecular Adenoma/ Tumor of the Thyroid
Mauro Papotti and Marco Volante
Department of Clinical and Biological Sciences
University of Torino and San Luigi Hospital Regione
Gonzole 10 -10043
Orbassano (Torino) - Italy
Hyalinizing trabecular adenoma
(HTA) was first described in 1987 by dr Aidan Carney at Mayo Clinic (Carney et al 1987), who recognized a
trabecular tumor of follicular derivation with peculiar nuclear, architectural and histochemical
features, and termed this lesion hyalinizing trabecular adenoma based on the benign behaviour of the
thirteen cases he originally collected. Several reports followed, defining the typical architecture of
HTA and discussing the differential diagnosis of HTA mainly with medullary carcinoma, primary thyroid
paraganglioma, papillary carcinoma with trabecular architecture and follicular adenomas with HTA-like
patterns (Katoh et al 1989, Chetty et al 1994, Mc Cluggage et al 1996, Schmid et al 1996, Papotti et al
1997, Katoh et al 1999, LaGuette et al 1997, Li et al 1997, Fonseca et al 1997, DeLellis et al 2004).
In most instances, HTA is a well circumscribed
lesion, lacking morphological signs of capsular or vascular invasion. A uniform and diffuse solid and
trabecular architecture is the hallmark of HTA, with markedly hyalinized intratrabecular stroma
containing basal membrane-type material. Hyalinizing trabecular areas, however, may be present within
conventional follicular adenomas and carcinomas, and the recognition of the typical intra-trabecular (as
opposed to inter-trabecular) hyalinization is the keypoint. With regard to nuclear features, clear
nuclei with grooves and pseudoinclusions are typically observed in HTA and the differential diagnosis
from papillary carcinoma may be difficult. Additional features are represented by round paranuclear
cytoplasmic bodies with a light yellow color (so called "yellow bodies") (Rothenberg et al 1999). They
appear as cytoplasmic corpuscles of a few microns having a clear halo. Their colour varies from yellow
to grey to pink. In some cases they are very few and hard to see. They are claimed to be detectable
even in cytological preparations (Rothenberg et al 1999).
The cytological features in fine needle aspriation biopsy material were described by dr Carney again,
in collaboration with dr Goellner at Mayo Clinic ( Goellner & Carney 1989)
In their study and in subsequent publications (Strong et al 1990, Kaleem et al 1997, Papotti et al
1997, Kuma et al 2003, Casey et al 2004a and 2004b), the relevant cytological features included
moderately cellular smears in an hemorrhagic background, containing large irregular tissue fragments and
single cells. The fragments may have a branching profile and abundant stromal tissue, generally
amorphous and hyalinized (pink-appearing in both H&E and Giemsa stains). The cells are medium-sized,
polygonal to spindle-shaped and are arranged in loosely packed aggregates or in cords tightly associated
with the amorphous tissue or even isolated in the background. The cytoplasm may be difficult to
visualize. Nuclei are hyperchromatic and roundish, with irregular borders and nuclear holes &
grooves, as classicallly seen in papillary carcinoma. In cell block preparations, small fragments made
of amorphous connective tissue and cords of medium sized, uniform cells can be observed. No colloid or
necrosis are found in the background, nor are follicles present in the aspirated material.
From a practical point of view, a fine needle aspiration cytological diagnosis of HTA may not be
straightforward. The recognition of a trabecular pattern in a neoplasm of follicular derivation is
sufficient for addressing the patient to the surgeon. Excluding the very rare thyroid paragangliomas
(LaGuette et al 1997) and medullary carcinomas, a trabecular patterned tumor may result in a final
diagnosis of either trabecular adenoma, trabecular/solid/insular (poorly differentiated) carcinoma or of
hyalinizing trabecular adenoma. Rather, the described cytological similarities (nuclear holes and
grooves) with papillary carcinoma, pose major problems of differential diagnosis with the latter, which
is also a much more common occurrence in the thyroid gland.
To exclude two of the major
mimics of HTA, medullary carcinoma and paraganglioma, neuroendocrine markers, such as chromogranin A or
calcitonin - in the case of medullary carcinoma - may be useful, although neuroendocrine differentiation
in HTA, whose meaning is still to be elucidated, has been reported (Shikama et al 2003) and may be a
potential source of confusion. A positive marker of HTA is thyroglobulin, which is diffusely expressed
by tumor cells, as observed in most follicular-derived thyroid tumors (Carney et al 1987). In addition,
a peculiar Ki-67 membrane pattern has been described in HTA (Hirokawa et al 2000a), at least in the
majority of tumors, and a diagnostic impact of such a finding has been suggested by some authors (Casey
et al 2004), but not by others (Boerner et al 2004) even in fine needle aspiration biopsy material.
However, Ki-67 membranous pattern is not restricted to HTA, but reported in other tumors, even as a
diagnostic tool, as in the case of sclerosing hemangioma of the lung (Hattori 2002). Very recently we
found that the immunohistochemical Ki-67 procedure may dramatically affect the occurrence of the
membranous pattern of staining, this feature being restricted to the MIB-1 Ki67 antibody clone used (as
opposed to other Ki67 antibodies), and to the incubation temperature (Leonardo et al 2006). Discrepant
results have been reported concerning the cytokeratin profile in HTA (Hirokawa et al 2000b, Papotti et al
1997, Fonseca et al 1997), thus limiting its diagnostic application. Markers of malignancy described in
follicular neoplasms of the thyroid, namely galectin-3, have been tested in HTA and are positive in
nearly half of the cases (Gaffney et al 2003). Other immunohistochemical markers related to specific
genetic alterations, such as ret protein, have been found to be present in HTA but are of limited
usefulness in the diagnostic practice. The hyaline material present in the neoplastic trabeculae has
been largely investigated and found to contain basal membrane type proteins (Li et al 1997, Papotti et al
The marked cytomorphological similarities of HTA with
papillary carcinoma strongly suggest an association between the two forms (Li et al 1997, LiVolsi 2000,
Lloyd 2002, DeLellis et al 2004). A few molecular investigations have been reported on the genetic
background of HTA, partially supporting this hypothesis. In fact, RET/PTC1 translocation has been found
independently by our and another group, in a percentage varying from 21 to 62% of cases (Cheung et al
2000, Papotti et al 2000). By contrast, BRAF mutations are uncommon (if not absent) in HTA, as well as
N-ras mutations (Salvatore et al 2005, Nakamura et al 2005). Two HTA cases were described in members of
a family affected by oxyphilic thyroid tumors, related to alterations of TCO gene in chromosome 19p13.2
(Harach et al 1999a). Finally a case with HTA features was observed in a patient affected by Cowden
disease (Harach et al 1999b).
Clinical Significance and Prognosis
original publication on HTA included all benign cases (Carney et al 1987). In the series of cases so far
collected by dr Carney and partially published in molecular studies (Gaffney et al 2003, Salvatore et al
2005), none of the cases had morphological signs of malignancy (eg. vascular invasion or capsular
penetration), nor did any of the cases develop a malignant behavior.
The benign nature of HTA has been questioned because of subsequent descriptions of vascular invasion
in aggressive cases of tumors having hyalinizing trabecular patterns (Molberg et al 1994, Sambade et al
1991, Papotti et al 1997, Gonzales-Campora et al 1998). A non committal diagnosis of hyalinizing
trabecular "tumor" (HTT), rather than adenoma, had been therefore favoured by some authors since 1991
(Sambade et al 1991). Indeed the term "adenoma" was replaced by the term "tumor", even in the recent WHO
Classification of Tumors of Endocrine Organs (DeLellis et al 2004).
Comparing the original images and description of HTA with those of published malignant hyalinizing
trabecular carcinomas, a major concern is related to the diagnostic criteria used by the various authors
to label a case as HTA or HTT or hyalinizing trabecular carcinoma. It seems that the group of thyroid
tumors with hyalinised trabecular growth pattern is rather heterogeneous and those cases reported to
follow a malignant course often are characterized by trabecular growth patterns and remarkable
intertrabecular accumulation of hyaline material (rather than intratrabecularly located, as typically
observed in HTA).
More important is, in my opinion, the close genetic relationship to papillary carcinoma, as well as
the expression of markers related to malignancy in follicular-derived thyroid tumors, such as
galectin-3. In this respect, if HTA is related to papillary carcinoma, it is not relevant to identify
the morphological signs of malignancy typical of follicular carcinomas. Nuclear features of papillary
cancer (together with the common genetic background) are in fact sufficient to interpret "HTA" as a
possible variant papillary carcinoma, probably of very low grade in most cases, according to the follow
up data so far available.
TABLE - HISTOPATHOLOGICAL DIFFERENTIAL DIAGNOSIS OF HTA/HTT
|Paraganglioma ||very rare; strikingly similar morphology, expresses neuroendocrine markers|
|Papillary carcinoma ||similar cytological features, but generally papillary or follicular structure; more problematic in case of solid/trabecular variants|
|Medullary carcinoma ||amyloid-like amorphous material and medium sized roundish or elongated cells with eccentric dark nucleus, expresses neuroendocrine markers|
|Trabecular adenoma/carcinoma ||solid nests and cords of uniform cells, generally smaller than HTA, stromal hyaline material, in any case having a inter-trabecular location, no yellow bodies; signs of malignancy in carcinomas|
|Regressive changes in goiter ||abundant dense connective tissue and amorphous/fibrinous material mimicking hyaline material of HTA, but is in any case extra-trabecular; follicular areas|
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- LaGuette J, Matias-Guiu X, Rosai J. Thyroid paraganglioma: a clinicopathologic and immunohistochemical study of three cases. Am J Surg Pathol 1997, 21:748-53.
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- Salvatore G, Chiappetta G, Nikiforov YE, Decaussin-Petrucci M, Fusco A, Carney JA, Santoro M. Molecular profile of hyalinizing trabecular tumours of the thyroid: high prevalence of RET/PTC rearrangements and absence of B-raf and N-ras point mutations. Eur J Cancer 2005, 41:816-21.
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- Shikama Y, Osawa T, Yagihashi N, Kurotaki H, Yagihashi S. Neuroendocrine differentiation in hyalinizing trabecular tumor of the thyroid. Virchows Arch 2003, 443:792-6.
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