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CRIBRIFORM-MORULAR VARIANT OF PAPILLARY THYROID CARCINOMA. A PROTOTYPE OF CLINICAL, PATHOLOGICAL AND GENETIC CORRELATION
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Dr. José Cameselle-Teijeiro
Department of Pathology, Clinical Universitary Hospital, 15706 Santiago de Compostela, Spain
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Editorial 2009
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José Cameselle-Teijeiro1, Ihab Abdulkader1, Paula Soares2, Alfredo Romero-Rojas3,
Rosa M. Reyes-Santías1, Manuel Sobrinho-Simões2.
1Department of Pathology, Clinical University Hospital, Galician Health Service,
University of Santiago de Compostela, Galicia, Spain; 2IPATIMUP (Institute of Molecular
Pathology and Immunology, University of Porto), Porto, Portugal; 3Department of
Pathology, Instituto Nacional de Cancerología, Bogotá, Colombia.
Concise Review invited by Clara Alvarez. Reviewing Editor: Clara Alvarez
The authors declare no conflict of interest related to this work.
Correspondence to:
Dr. José Cameselle-Teijeiro
Department of Pathology
Clinical Universitary Hospital
15706 Santiago de Compostela
Spain
E-mail: josemanuel.cameselle@usc.es
ABSTRACT
The cribriform-morular variant of papillary thyroid carcinoma is an unusual neoplasm
developing in patients with familial adenomatous polyposis but also occurring as a sporadic tumor.
Histologically this variant is characterized by a combination of cribriform, follicular, papillary,
trabecular, solid and spindle cell growth patterns with morular areas. Its peculiar morphological
features are related with the permanent activation of the WNT pathway, with nuclear and cytoplasmic
accumulation of beta-catenin. In addition to the genetic alterations in the APC/beta-catenin pathway,
RET/PTC-1 and RET-PTC-3 rearrangements have been found in this variant, supporting this tumor
as being a subtype of papillary thyroid carcinoma. Because this follicular cell derived carcinoma can
develop before familial adenomatous polyposis becomes clinically manifest, the recognition of its
particular histological features should alert to the possibility of FAP whenever such a tumor is found.
In this article we describe the main clinical, pathological, immunohistochemical and molecular
characteristics of the cribriform-morular variant of papillary thyroid carcinoma, including the genotypephenotype
correlations.
While pathological findings remain as the “gold standard” for tumor diagnosis, discoveries
made in the field of molecular pathology have served to support the great value of the histological
evaluation as well as opening possibilities for new therapies. Thyroid cancer is particularly interesting
for pathologists given that each histological tumor type (and subtype) strongly correlates with its own
particular molecular alterations, biological behavior (e. g. routes of metastatization), and clinical
aggressiveness (1, 2). The genotype-phenotype correlation in medullary carcinoma of the thyroid is
well recognized (1). In this paper, upon reviewing the principal features of the cribriform-morular
variant (CMV) of papillary thyroid carcinoma (PTC), we portray a clear example of association
between morphological, immunohistochemical, molecular and clinical findings.
The CMV of PTC was first recognized in 1994 by Harach et al (3) as a peculiar form of thyroid
carcinoma developing in patients with familial adenomatous polyposis (FAP). Five years later,
Cameselle-Teijeiro and Chan (4) reported the sporadic counterpart of this tumor as a peculiar subtype
of papillary carcinoma. This is a rare tumor representing approximately 0.1%-0.2% of all PTC (4),
with a prevalence of up to 12% in patients with FAP who have about 160 times higher risk of
developing thyroid carcinoma than healthy people (5). The presentation of this tumor was over 10
times more frequent than that expected for sporadic papillary thyroid microcarcinoma (6). The CMV of
PTC has a striking female predominance (female/male ratio ≈ 17:1); one still ignores the genetic
and/or epigenetic and/or environmental reason(s) for this gender difference. The mean age at
diagnosis was about 28 years (range 12 to 53 yrs), sometimes preceding the diagnosis of FAP (7).
The term cribriform-morular variant is now generally used to describe this tumor type when it occurs
as a sporadic tumor (often solitary) as well as in the setting of FAP (often multicentric).
The CMV has a very unusual histology, characterized by a combination of cribriform, follicular,
papillary, trabecular, solid and spindle cell growth patterns with morular (squamoid) areas (3, 4, 8, 9)
(Figure 1). Characteristically, the luminal spaces are devoid of colloid, and morules with peculiar
nuclear clearing caused by biotin accumulation are scattered in the tumor. The neoplastic cells are
columnar with chromatin rich nuclei usually showing nuclear grooves, sometimes a clear appearance
and, very occasionally, with intranuclear cytoplasmic pseudoinclusions. Immunohistochemically, most
tumor cells are positive for the thyroid transcription factor-1, cytokeratins 7 and 19, vimentin, estrogen and progesterone receptors, bcl-2, E-cadherin and galectin-3. Thyroglobulin may be positive focally or
totally negative and there is no immunoreaction for calcitonin or cytokeratin 20 (3, 4, 8-10). Strong
cytoplasmic and nuclear immunoreactivity for β-catenin is very characteristic (7) (Figure 2). A single
case that was partially positive for chromogranin and synaptophysin but negative for thyroglobulin and
calcitonin has been reported (7). The CMV of PTC could be diagnosed preoperatively after cytology
examination because its tall columnar cells, fascicular spindle cells, and cribriform and morular
patterns can be found in the fine-needle aspirates (10). Since this neoplasm can develop before FAP
becomes clinically manifest, the recognition of the peculiar cytological and/or histological features of
the CMV of PTC should alert to the possibility of FAP whenever such a tumor is found, especially in
young patients (3, 4, 6-10).
Figure 1. Microscopic appearance of the cribriform-morular variant of papillary thyroid carcinoma
(CMV of PTC). A combination of cribriform, follicular, papillary, solid and spindle cell patterns with
morules can be seen (x200).
FAP is an autosomal dominantly inherited cancer-predisposition syndrome characterized by
the progressive development of multiple colorectal adenomatous polyps and an increased incidence
of colorectal carcinoma. It is often accompanied by various benign and malignant manifestations,
including epidermoid cysts, dental abnormalities, gastric and duodenal tumors, osteomas,
hepatoblastomas, desmoid tumors, osseous tumors, congenital hypertrophy of the retinal pigmented
epithelium (CHRPE), adrenocortical neoplasms, brain tumors, and, of course, thyroid tumors (11).
Figure 2. Immunohistochemical stain for β-catenin in a case of the CMV of PTC. Strong cytoplasmic
and nuclear expression of β-catenin appears in tumor cells. Less intense positivity is seen in one
morule (arrows). Normal follicular cells (inset) in the same case show a normal pattern of reactivity for
β-catenin with no nuclear staining (x400).
FAP is caused by germline mutation of the adenomatous polyposis coli (APC) gene, a tumor
suppressor gene mapped to 5q21 (11). APC forms a complex with glycogen synthase kinase-3β
(GSK-3β), β-catenin, and Axin, and is involved in the WNT transduction signalling pathway,
sequestering β-catenin and targeting it for degradation (12, 13) (Figure 3). The binding of β-catenin by APC requires phosphorylation of β-catenin by GSK-3β on specific serine and threonine residues, and
aminoacids adjacent to them, all of which are encoded by exon 3 of the β-catenin gene (CTNNB1).
GSK-3β binds to and phosphorylates several proteins in this pathway and is instrumental to the downregulation
of β-catenin. Unphosphorylated β-catenin accumulates in the cytoplasm, and translocates
to the nucleus. In the cell nucleus, β-catenin forms a complex with the T-cell factor/lymphoid enhancer
factor family of transcriptional activators, that results in the activation of development-related genes.
Figure 3. Schematic representation of WNT pathway in normal cells (A and B) as well as in tumor
cells of the CMV of PTC with APC gene mutations (C) or CTNNB1 gene mutations (D).
Mutations in the APC gene characteristically lead to a truncated APC protein that lacks the
capacity to degrade β-catenin. Alternatively, mutations in exon 3 of the CTNNB1 gene, which prevent
phosphorylation of serine and threonine residues, result in activation of this WNT pathway because of
the increased cytoplasmic β-catenin. The peculiar morphological features of the CMV of PTC are
associated with the permanent activation of the WNT pathway, and consequently, with the aberrant
nuclear and cytoplasmic immunoexpression of β-catenin (7, 9, 10, 15) (Figure 2). It has been shown
that germline mutation of the APC gene, somatic APC gene mutation, and/or somatic mutation of the
β-catenin gene (CTNNB1) lead to this permanent activation of the WNT pathway, explaining the
uniform morphology of the CMV of PTC (7). In fact, the aberrant nuclear translocation of β-catenin as
well as the presence of morular structures are characteristic features of a peculiar group of tumors of
various organs, all of them sharing alterations in the APC/β-catenin pathway (15, 16).
Regarding the genotype-phenotype correlations in patients with FAP and CMV of PTC, it has
been reported that more than 85% of germline mutations of the APC gene were in exon 15 in the
same genomic area associated with congenital hypertrophy of the retinal pigmented epithelium
(CHRPE) (codons 463 to 1387) (17); interestingly, more than 90% of these germline mutations were
outside the mutation cluster region (MCR) (codons 1286 to 1513), currently considered the hot spot
mutation area. The majority of these mutations occurred before codon 1220 and outside the MCR
(17-24). The mutation at codon 1061 has been found to be a hot spot for both thyroid carcinoma and
hepatoblastoma (17). The difference in the incidence of germline mutations before and after codon
1220 between PTC and non PTC FAP patients was significant (P< 0.05) for both patients and
kindreds (P= 0.005 and P= 0.049, respectively); so that, in patients with PTC, restriction of the
mutational analysis of the APC gene to the MCR will detect germline and/or somatic mutations in
<20% cases (6, 17). Cetta et al (17) recommended intensive screening for thyroid nodules after the
age of 15 years if a single patient or entire kindred have ocular patches (CHRPE) and/or mutations in
the 5’-portion of exon 15. The mean size of the thyroid tumors in patients with FAP was 1.3 cm (0.9
cm-3.5 cm), and the majority (75%) were multifocal and bilateral (6). In patients with germline APC
mutation and multiple thyroid tumors, each thyroid tumor in the same patient usually showed a somatic APC mutation that was different from the germline APC mutation as well as from the other
somatic APC mutations (18, 23). Due to these different somatic mutations, this multicentricity of
thyroid carcinoma formation is analogous to the multiplicity of colorectal tumor formation (23). A
possible pathogenetic role of the common p.Thr1493Thr variant of the APC gene in CMV of PTC has
recently been reported (7, 24).
For some cases of the sporadic form of CMV of PTC with somatic APC mutation, a dominant
negative effect of the APC1309 mutation has been proposed as the second hit (Knudson two-hits
hypothesis) to explain the development of the tumor (8). Mutations in exon 3 of the CTNNB1 gene
with aberrant nuclear expression of β-catenin have also been reported by Xu et al (9) in sporadic
cases of the CMV of PTC.
In addition to genetic alterations in the WNT pathway, RET/PTC-1 and RET-PTC-3
rearrangements have been found in this variant, supporting the concept that this tumor may be
considered a subtype of PTC (7, 20, 25). No BRAF mutations have been found to date (7, 10, 26).
The CMV of PTC generally involves encapsulated or locally advanced tumors without distant
spread, and usual treatment consists of total/near total thyroidectomy with or without radioiodine
therapy (27). Although this tumor type is generally associated with a good prognosis, 6 out of 126
reported cases (5%) died of the neoplasia (7). More recently, an especially aggressive (poorly
differentiated) case of familial CMV of PTC, showing neuroendocrine differentiation has been reported
(7).
Acknowledgement
This work was supported by grant PI060209 from Institute de Salud Carlos III (Ministry of Health and
Consumer Affairs), Madrid, Spain.
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Address:
CRIBRIFORM-MORULAR VARIANT OF PAPILLARY THYROID CARCINOMA. A PROTOTYPE OF CLINICAL, PATHOLOGICAL AND GENETIC CORRELATION |
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Title: Hot Thyroidology; Abbreviated key title: Hot Thyroidol.; Online ISSN: 2075-2202
Legal Note: © All rights reserved European Thyroid Association 2009
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