Cribriform-morular Variant Of Papillary Thyroid Carcinoma Research Articles

The 2022 WHO Classification of thyroid tumors: novel concepts in nomenclature and grading.

The 5th edition of the Classification of Endocrine and Neuroendocrine Tumors has been released by the World Health Organization (WHO). This timely publication integrates several changes to the nomenclature of non-neoplastic and neoplastic thyroid diseases, as well as novel concepts that are essential for patient management. The heterogeneous group of non-neoplastic and benign neoplastic lesions are now collectively termed "thyroid follicular nodular disease" to better reflect the clonal and non-clonal proliferations which clinically present as multinodular goiter. Thyroid neoplasms originating from follicular-cell derived are distinctly divided into benign, low-risk and malignant neoplasms. The new classification scheme stresses that papillary thyroid carcinoma (PTC) should be subtyped based on histomorphologic features irrespective of tumor size to avoid treating all sub-centimeter/small lesions as low-risk disease. Formerly known as the cribriform-morular variant of PTC is redefined as cribriform-morular thyroid carcinoma since this tumor is now considered as a distinct malignant thyroid neoplasm of uncertain histogenesis. The "differentiated high-grade thyroid carcinoma" is a new diagnostic category including PTCs, follicular thyroid carcinomas and oncocytic carcinomas with high-grade features associated with poorer prognosis similar to the traditionally defined poorly differentiated thyroid carcinoma as per Turin criteria. In addition, squamous cell carcinoma of the thyroid is now considered a morphologic pattern/subtype of anaplastic thyroid carcinoma. In this review, we will highlight the key changes in the newly devised 5th edition of WHO classification scheme of thyroid tumors with reflections on its applicability in patient management and future directions in this field.

Cribriform-Morular Variant of Papillary Thyroid Carcinoma: a Clinical Surprise in a Routine Case

Cribriform morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare variant. It is commonly associated with familial adenomatous polyposis. It is mostly seen in females below 30 years of age. We describe a male patient in his fourth decade of life, who presented with a solitary thyroid nodule and was evaluated and treated. The histopathology of the thyroid nodule was reported as CMV-PTC. In light of this finding, the patient was further investigated and treated for familial adenomatous polyposis (FAP), for which he was asymptomatic. Any patient diagnosed with CMV-PTC must also undergo colonoscopy to rule out FAP and receive appropriate treatment. Clinicians must be aware that this variant can be seen in men too.

Ectopic thyroid with benign and malignant findings: A case series

IntroductionEctopia is the most common sporadically occurring thyroid heterotopy. We present three cases of ectopic thyroid tissue with compression of the upper aerodigestive tract. The first case involved ectopic thyroid tissue in the lingual area of a 60-year-old male with dysphagia, swelling at the base of the tongue, and stomatolalia. The second case was a 66-year-old female with papillary thyroid carcinoma (PTC) in a thyroglossal duct cyst. The third patient was a 50-year-old female with aberrant thyroid tissue in the right submandibular region, with a cribriform-morular variant of PTC (CMV-PTC). MethodsAfter resecting the heterotopic tissue and verifying the presence of PTC, the second and third cases underwent total thyroidectomy, and the third patient also underwent radioactive iodine ablation (RAI). Postoperative athyreosis was compensated by permanent levothyroxine substitution. ResultsThe diagnosis of ectopic thyroid tissue is challenging. Clinical examination together with imaging methods play a key role, especially postoperative histological examination along with scintigraphy and single photon emission computed tomography (SPECT). Ultrasonography should be used to exclude normally localized thyroid tissue and to distinguish other tumorous diseases. In the pre-operative examination, ultrasound-guided fine-needle aspiration biopsy (US-FNAB) often results in technically-difficult sampling and non-diagnostic cytology. ConclusionResection is the most suitable therapy for clinical symptoms of a foreign body in the upper aerodigestive tract and inflammatory complications; total thyroidectomy follows in case of malignant transformation. Thyroid heterotopy is a rare pathological condition, yet it should be taken into consideration during differential diagnosis of tumorous oropharyngeal and neck lesions.

Multifocality in a Patient with Cribriform-Morular Variant of Papillary Thyroid Carcinoma Is an Important Clue for the Diagnosis of Familial Adenomatous Polyposis.

Background: Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare subtype of PTC, which occurrs predominantly in young women. This disease much more frequently presents in patients with familial adenomatous polyposis (FAP). FAP is an autosomal dominant inherited disease, which arises from germline mutations in the adenomatous polyposis coli (APC) gene. To clarify the distinctive clinical features of CMV-PTC, a comparison study was performed between familial types and sporadic types. Methods: Between 2007 and 2018, 15 CMV-PTC patients underwent thyroidectomy in Samsung Medical Center. The clinical features of these patients were retrospectively reviewed. Results: All patients were women with a median age of 26 years (range 17-46 years). The median maximum diameter was 1.0 cm (range 0.4-3.5 cm). All tumors underwent immunostaining and showed nuclear and/or cytoplasmic staining for β-catenin. On ultrasonography, most nodules had benign-looking features (well-defined, hypoechoic, and oval to round shapes without calcification), but a few nodules had capsular invasion and taller than wide shape. On preoperative fine-needle aspiration cytology, five patients (33%) were diagnosed as CMV-PTC, nine (60%) as PTC, but one (7%) as follicular neoplasm or PTC-follicular variant. Six patients (40%) had FAP, and four of them had total colectomy due to FAP. Five of them had a family history of FAP or colon cancer, or thyroid cancer. Germline mutations in the APC gene were found in all six patients with CMV-PTC associated with FAP, and five of them had de novo mutations. All patients with FAP-associated CMV-PTC had multiple tumors. All CMV-PTC patients had excellent response to initial therapy. Conclusions: Because of the association between FAP or colon cancer with multifocal CMV-PTC, we confirm that mutational analysis of the APC gene and colonoscopy should be carried out in these patients when multiple thyroid tumors are found.

A unique case of two somatic APC mutations in an early onset cribriform-morular variant of papillary thyroid carcinoma and overview of the literature

We report a case of a 22-year-old female patient who was diagnosed with a cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC). While at early ages this thyroid cancer variant is highly suggestive for familial adenomatous polyposis (FAP), there was no family history of FAP. In the tumor biallelic, inactivating APC variants were identified. The patient tested negative for germline variants based on analysis of genomic DNA from peripheral blood leukocytes. Somatic mosaicism was excluded by subsequent deep sequencing of leukocyte and normal thyroid DNA using next generation sequencing (NGS). This report presents a rare sporadic case of CMV-PTC, and to the best of our knowledge the first featuring two somatic APC mutations underlying the disease, with an overview of CMV-PTC cases with detected APC and CTNNB1 pathogenic variants from the literature.

Clinicopathologic and molecular features of cribriform morular variant of papillary thyroid carcinoma

Objective: To investigate the clinicopathologic and molecular features of the rare cribriform morular variant of papillary thyroid carcinoma (CMV-PTC). Methods: The clinicopathologic data of 10 patients with CMV-PTC were retrospectively reviewed. Immunohistochemical (IHC) staining was done using LSAB method. DNA sequencing for APC were applied using Sanger method. BRAF V600E mutation was examined using ARMS method. The cytological, morphological, IHC and molecular features were analyzed. Results: All patients were female at an average age of 27 years old. The tumors were mostly located in the right lobe of thyroid. Fine needle aspiration cytology was performed in three patients; two were diagnosed as suspicious for PTC and one as PTC. Nine tumors presented as solitary nodule and two as multiple nodules in both lobes. Infiltration was demonstrated in three cases. The average size was 2.6 cm. The neoplastic cells were arranged in papillary, cribriform, solid and glandular patterns, with rare or without colloid inside the lumen. The number of morula varied, ranging from zero to many. The neoplastic cells were variably enlarged, showing round, oval or spindle shape. Nuclear irregularity was identified as irregular membrane, nuclear grooves or pseudoinclusion, but no typical ground glass feature. Peculiar nuclear clearing could be observed in the morular cells. IHC staining showed the neoplastic cells were negative for thyroglobulin and p63, but positive for TTF1, cytokeratin 19 and estrogen receptor. Diffuse staining with cytokeratin was seen in the neoplastic cells and the morula. Specific cytoplasmic and nuclear staining of β-catenin was seen in the neoplastic cells but not the morula. Ki-67 proliferation index was 1%-30%. No recurrence or metastasis was observed. One patient was demonstrated to harbor both somatic and germline mutations of the APC gene, who was found to have adenomatous polyposis and her mother died of colonic carcinoma. No BRAF V600E mutation was detected. Conclusions: CMV-PTC is rare and shows atypical cytological and clinicopathological features, and it is easily misdiagnosed.TG, TTF1, ER and β-catenin are specific IHC markers for CMV-PTC. The morula is negative for cytokeratin 19, in contrast to squamous metaplasia. Although CMV-PTC has indolent clinical behavior, a definite diagnosis is necessary to rule out the possibility of APC gene mutation and related extra-thyroidal neoplasm, such as FAP and Gardner syndrome.

Cribriform-Morular Variant of Papillary Thyroid Carcinoma: Clinical and Pathological Features of 30 Cases.

Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is rare; it may occur in cases of familial adenomatous polyposis (FAP) or be sporadic. To clarify the clinicopathological features of CMV-PTC, the medical records of these patients were investigated retrospectively. Between 1979 and 2016, a total of 17,062 cases with PTC underwent initial surgery at Ito Hospital. Of these, 30 (0.2%) cases histologically diagnosed with CMV-PTC were reviewed. The patients were all women, with a mean age at the time of surgery of 24years. Seven (23%) cases were thought to have FAP because they had colonic polyposis or a family history of FAP or APC gene mutation. The remaining 23 (77%) were thought to be sporadic. Multiple tumors were detected in 6 cases, with a solitary tumor in 24. One patient had lung metastasis at diagnosis. Eleven patients underwent total thyroidectomy or subtotal thyroidectomy, and 19 underwent lobectomy. Twenty-six (87%) patients underwent neck lymph node dissection. Three patients had tumor metastasis in central lymph nodes, but these were incidentally detected metastatic classical PTC (cPTC) based on histological examination. In this series, there were no cases of LN metastases of CMV-PTC. During a mean follow-up of 15years, one patient had new cPTC in the remnant thyroid after initial surgery, and the other patients showed no signs of recurrence. CMV-PTC occurred in young women, their long-term prognosis was excellent. Total thyroidectomy is recommended for FAP-associated CMV-PTC, but modified neck lymph node dissection is not necessary.

Characteristics of cribriform morular variant of papillary thyroid carcinoma in post-Chernobyl affected region

The aim is to study the characteristics of cribriform morular variant of papillary thyroid carcinoma (CMV-PTC) in patients living in the radiation-affected area of Belarus. The clinical and pathological features of 35 patients with CMV-PTC from Belarus were studied and compared with those of conventional papillary thyroid carcinoma diagnosed in the same period. The patients with CMV-PTC were all females and were younger at presentation (mean age = 24) than those with conventional papillary thyroid carcinoma. Familial adenomatous polyposis (FAP) was identified in 20% of the patients with CMV-PTC. The majority of the CMV-PTCs (29/35; 83%) were staged as pT1 and were less advanced than conventional papillary thyroid carcinoma. There was no evidence of lymph node metastases or distant metastases. CMV-PTCs were positive for β-catenin, APC (adenomatous polyposis coli) and p53 proteins. No psammoma bodies were identified on microscopic examination. Over a median follow-up of 9 years, all the patients were alive, and there was no cancer recurrence or mortality related to the thyroid cancer. To conclude, CMV-PTC in patients in the radiation-affected region behaves in an indolent fashion. They had distinctive features that are different from patients with conventional papillary thyroid carcinoma living in the same region.

Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer.

The aim of this systematic review is to study the features of cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) by analysing the 129 documented cases in the English literature. The disease occurred almost exclusively in women. The median age of presentation for CMV-PTC was 24 years. Slightly over half of the patients with CMV-PTC had familial adenomatous polyposis (FAP). CMV-PTC presented before the colonic manifestations in approximately half of the patients with FAP. Patients with FAP often have multifocal tumours in the thyroid. Microscopic examination of CMV-PTC revealed predominately cribriform and morular pattern of cancer cells with characteristic nuclear features of papillary thyroid carcinoma. Psammoma body is rare. On immunohistochemical studies, β-catenin is diffusely positive in CMV-PTC. The morular cells in CMV-PTC are strongly positive for CD10, bcl-2 and E-cadherin. Pre-operative diagnosis of CMV-PTC by fine-needle aspiration biopsy could be aided by cribriform architecture, epithelial morules and β-catenin immunostaining. Mutations of APC gene are found in the patients with CMV-PTC associated with FAP. In addition, mutations in CTNNB1, RET/PTC rearrangement and PI3K3CA mutations have been reported. BRAF mutation is negative in all CMV-PTC tested. Compared to conventional papillary thyroid carcinoma, CMV-PTC had a lower frequency of lymph node metastases at presentation (12%) and distant metastases (3%) as well as lower recurrence rates (8.5%) and patients' mortality rates (2%). To conclude, patients with CMV-PTC have distinctive clinical, pathological and molecular profiles when compared to conventional papillary thyroid carcinoma.

Familial Adenomatous Polyposis–Associated, Cribriform Morular Variant of Papillary Thyroid Carcinoma Harboring a K-RAS Mutation: Case Presentation and Review of Molecular Mechanisms

The cribriform morular variant of papillary thyroid carcinoma (CMVPTC) is a rare subtype of papillary thyroid cancer that occurs most often in association with the familial adenomatous polyposis (FAP) syndrome. A 18-year-old woman presented with recurrence of PTC in her neck. She had a prior diagnosis of FAP syndrome. Review of her original pathology slides reclassified the case as a CMVPTC. The tumor was examined for the four most common mutations found in PTC: BRAF, RET/PTC, RAS, and PAX/PPARγ. The molecular alterations associated with CMVPTC involve the WNT signaling pathway but are incompletely understood. When CMVPTC is associated with the FAP syndrome, a germline adenomatous polyposis coli (APC) gene mutation is almost always detected. For the initiation of oncogenesis however, one or more additional molecular alterations must occur, such as a new somatic mutation in the APC gene (biallelic inactivation), somatic mutations in the β-catenin (CTNNB1) gene, or gene-gene interaction (epistasis). To date, of the mutations commonly associated with PTC, only RET/PTC mutations have been reported in CMVPTC. We report a FAP-associated CMVPTC tumor with atypically aggressive features harboring a RAS mutation and review the molecular mechanisms associated with this interesting PTC subtype. The literature was reviewed using MEDLINE (included case presentations, original research, and reviews). We report here the first RAS mutation detected in an FAP-associated CMVPTC tumor.

Cribriform Morular Variant of Papillary Thyroid Carcinoma in a Patient with an Incidental Neck Lump: a Case Report and Review of the Literature

The cribriform morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare morphologic entity that is associated with familial adenomatous polyposis (FAP). We report a case of a young lady with an incidentally discovered right-sided neck nodule on ultrasonography with a diagnosis of CMV-PTC confirmed on thyroidectomy and review the literature associated with the clinical presentation, imaging characteristics, pathological findings and the association with FAP.

Cribriform-Morular Variant of Papillary Thyroid Carcinoma Displaying Poorly Differentiated Features

Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) usually occurs in the setting of familial adenomatous polyposis (FAP) although it can rarely arise sporadically. Poorly differentiated thyroid carcinoma (PDTC) is a follicular cell-derived neoplasm with more aggressive behavior than well-differentiated carcinomas such as CMVPTC. We report the case of a 35-year-old woman without FAP history who presented a left neck mass and complained of back pain. Imagiological examinations revealed a nodule in the left lobe of thyroid and multiple nodular lesions in the bone and lungs suggestive of metastases. The patient was submitted to total thyroidectomy and radioactive iodine. The tumor was composed of CMVPTC and PDTC components that shared the same somatic APC gene mutation (p.Cys520Tyr_fsX534). Besides this mutation, no CTNNB1, BRAF, N-RAS, and H-RAS gene mutations were detected in any of the 2 components. To the best of our knowledge, this is the first report of a sporadic CMVPTC with transformation into PDTC. Although the majority of CMVPTCs carry an indolent clinical outcome, the coexistence of poorly differentiated areas may justify the aggressiveness of the CMVPTC reported here.

Unique Growth Pattern in Papillary Carcinoma of the Thyroid Gland Mimicking Adenoid Cystic Carcinoma

We report here three cases of papillary thyroid carcinoma (PTC) with hyaline globules as seen in adenoid cystic carcinoma of the salivary glands. This unique growth pattern was seen in two cases of columnar cell and one case of cribriform morular variant of PTC. Fine-needle aspiration was performed in two cases. By immunohistochemistry, all cases demonstrated expression of TTF-1 and thyroglobulin confirming follicular cell derivation. It is important to be aware of this unusual growth pattern in thyroid carcinomas; immunohistochemistry is warranted for rendering accurate cytopathologic and histopathologic diagnosis.

Familial Adenomatous Polyposis—Rendering a Diagnosis Based on Recognition of an Unusual Primary Thyroid Neoplasm

It has been well established in the literature that the cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) has been observed with higher frequency in familial adenomatous polyposis (FAP) patients. In the usual setting, patients with FAP are identified based on their germline mutations and the diagnosis of thyroid neoplasm is made after the FAP diagnosis. We herein report a case in which the recognition of a CMVPTC led to the initial diagnosis of FAP. The histological and clinical features of CMVPTC are reviewed with emphasis on its relationship to FAP.

Cytologic Characteristics and β-Catenin Immunocytochemistry on Smear Slide of Cribriform-Morular Variant of Papillary Thyroid Carcinoma

Objective: The purpose of this study is to analyze the characteristic cytologic features of the cribriform-morular variant of papillary thyroid carcinoma (CVPTC) and to find out the possibility of a preoperative diagnosis of CVPTC in fine needle aspiration (FNA). Study Design: A retrospective review of cytologic features of 5 patients who were diagnosed with CVPTC after thyroidectomy and underwent preoperative FNA was performed. In addition, β-catenin immunocytochemistry on a smear slide was applied. Results: All cases showed a high cellularity smear, cribriform architecture, ovoid/columnar cells, obvious nucleoli, and nuclear groove. Epithelial morules were observed in 4 (80%) cases. All cases demonstrated a nuclear and cytoplasmic expression in β-catenin immunocytochemistry applied to a smear slide. Conclusion: Preoperative diagnosis of CVPTC can be made by cytologic features of cribriform architecture, epithelial morule, and columnar cells in FNA and β-catenin immunocytochemistry on a smear slide showing a nuclear and cytoplasm expression.

Cribriform‐morular variant of papillary thyroid carcinoma—Cytological and immunocytochemical findings of 18 cases

The purpose of this article was to describe cytologic findings of cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) in detail, to review previously reported cases, and to emphasize the diagnostic significance of this subtype. We examined 19 ultrasound-guided fine needle aspiration (FNA) specimens from 18 CMV-PTC patients. Cytologic features of CMV-PTC were as follows, (1) hypercellularity, (2) papillary arrangement composed of tall columnar cells, (3) cribriform pattern, (4) morules, (5) spindle cells, (6) obscure ground-glass nuclei, (7) peculiar nuclear clearing (PNC), (8) foamy or hemosiderin-laden histiocytes, (9) hyaline materials, (10) absence of colloid in the background. The nuclear and cytoplasmic immunoreactivity of beta-catenin and biotin-positive PNC can indicate CMV-PTC. We believe that cytologic diagnosis of CMV-PTC is possible and it may lead to the early detection of polyposis coli.

The T1799A BRAF mutation is absent in cribriform-morular variant of papillary carcinoma.

Abstract Context.—Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) is one of the rare types of papillary carcinoma. It has been associated with familial adenomatous polyposis, though it can also occur sporadically. The molecular pathogenesis of this tumor is incompletely understood. It appears that there can be molecular contributions from the RET/PTC translocations and from mutations in the APC gene and β-catenin gene, which are both part of the Wnt signaling pathway. However, one of the most common mutations in papillary carcinoma, the BRAF mutation, has not been reported in this variant of papillary carcinoma. Objective.—To investigate the BRAF mutational status in CMVPTC. Design.—Four cases of CMVPTC (1 associated with familial adenomatous polyposis and the others apparently sporadic) were identified from the files of 3 large centers. Deoxyribonucleic acid was extracted and successfully amplified from each case. The polymerase chain reaction products were sequenced and evaluated for ...

The Cytological, Clinical, and Pathological Features of the Cribriform-Morular Variant of Papillary Thyroid Carcinoma and Mutation Analysis of CTNNB1 and BRAF Genes

The cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) is an unusual subtype of papillary thyroid carcinoma. The goal of this study was to determine the clinicopathological features of CMVPTC and whether the tumor can be diagnosed by fine-needle aspiration cytology. We retrospectively analyzed the clinical appearance and pathological findings in five patients with CMVPTC and sequenced exon 3 of CTNNB1 and exon 15 of BRAF in tumor tissue. All patients were young women, 15-34 years of age at the time of the cancer diagnosis. Preoperative cytological examination showed scattered tall columnar cells, fascicular spindle cells, and cribriform and morular patterns in the fine-needle aspirates of the thyroid from the five patients. Grossly, all tumors were well-circumscribed, solid or cystic. Immunohistochemically, most tumor cells showed nuclear expression of thyroid transcription factor-1, estrogen and progesterone receptors, and p53; cytoplasmic expression of cytokeratins 7 and 19, vimentin, and bcl-2; and cytoplasmic and nuclear accumulation of beta-catenin and galectin-3. There was no expression of thyroglobulin, cytokeratin 5/6, or human mesothelial cell-1. However, among these markers, the morular cells showed only positive immunostaining for beta-catenin, galectin-3, p53, and bcl-2. A CTNNB1 mutation was identified in only one case and no BRAF mutation was found in any of the five cases. Taken together, these data suggest that CMVPTC can be diagnosed preoperatively, based on careful cytology examination, and shows unique immunohistochemical findings.

The T1799A BRAF Mutation Is Absent in Cribriform-Morular Variant of Papillary Carcinoma

Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) is one of the rare types of papillary carcinoma. It has been associated with familial adenomatous polyposis, though it can also occur sporadically. The molecular pathogenesis of this tumor is incompletely understood. It appears that there can be molecular contributions from the RET/PTC translocations and from mutations in the APC gene and beta-catenin gene, which are both part of the Wnt signaling pathway. However, one of the most common mutations in papillary carcinoma, the BRAF mutation, has not been reported in this variant of papillary carcinoma. To investigate the BRAF mutational status in CMVPTC. Four cases of CMVPTC (1 associated with familial adenomatous polyposis and the others apparently sporadic) were identified from the files of 3 large centers. Deoxyribonucleic acid was extracted and successfully amplified from each case. The polymerase chain reaction products were sequenced and evaluated for the T1799A BRAF mutation. None of the 4 cases harbored the T1799A BRAF mutation (0/4). Conclusions.-The T1799A BRAF mutation does not appear to play a role in the tumorigenesis of CMVPTC.