Challenges in Diagnosing Cribriform Morular Thyroid Carcinoma

Abstract

Cribriform morular thyroid carcinoma (CMTC) is a rare thyroid malignancy strongly associated with familial adenomatous polyposis (FAP). About 50% of CMTC cases are associated with FAP, including a subset in which CMTC is the presenting symptom in previously undiagnosed FAP. We present a case of a young woman with thyroid nodules monitored for several years due to low suspicion ultrasound features. After development of macrocalcifications in 1 nodule, she had a fine needle aspiration (FNA). The cytology was concerning for papillary thyroid carcinoma. She underwent total thyroidectomy with final pathology of CMTC. Given the strong association between CMTC and FAP, the patient completed endoscopy, colonoscopy, and genetic testing, which led to a diagnosis of FAP. The diagnosis of CMTC can be difficult because nodules are often small without concerning ultrasound features, not meeting recommendations for FNA. Due to an increased risk of CMTC in individuals with FAP, current criteria may be inadequate in identifying nodules warranting thyroid FNA. Continued ultrasound surveillance should be considered for nodules with low suspicion ultrasound features in this population.

Introduction

Cribriform morular thyroid carcinoma (CMTC) is a rare thyroid malignancy with incidence ranging from 0.16% to 0.30%, most often diagnosed in women in the third decade of life [1-3]. Previously, CMTC was categorized as cribriform-morular variant of papillary thyroid carcinoma until the World Health Organization reclassified it in 2022 as its own entity because of differences in pathology between CMTC and papillary thyroid carcinoma (PTC). CMTC on pathology is defined by nuclear and cytoplasmic β-catenin expression and expression of thyroid transcription factor-1 (TTF-1) in areas of cribriform pattern [4].

Nearly 50% to 60% of CMTC cases occur in individuals with familial adenomatous polyposis (FAP), an autosomal dominant condition where a germline mutation in the adenomatous polyposis coli gene results in hundreds of adenomas in the large intestine. Sporadic CMTC accounts for the other 50% of cases [5]. The prevalence of thyroid cancer for individuals with FAP varies, from 1% to 2% to up to 12% [3, 6]. Guidelines from the American College of Gastroenterology and the American Society of Colon and Rectal Surgeons recommend annual thyroid ultrasound screening for individuals with FAP [7, 8]. However, current thyroid nodule guidelines do not recommend different thresholds for fine needle aspiration (FNA) in patients with FAP [9].

We present a case of CMTC diagnosed on FNA of a thyroid imaging reporting and data system (TI-RADS) 3 nodule with mildly suspicious ultrasound features that led to a subsequent diagnosis of FAP in a young woman. Initial diagnosis of CMTC was delayed because of low suspicion ultrasound features, which is common with CMTC, and suggests current ultrasound guidelines may not be appropriate for patients with FAP.

Case Presentation

A 27-year-old female with no significant medical history presented to primary care after noticing a growth on the left side of her neck. She was asymptomatic without dysphagia or hoarseness. She also denied recent changes in weight, compressive symptoms, or gastrointestinal symptoms. Family history was notable for a mother with Hashimoto thyroiditis but otherwise no family history of any other thyroid disease or gastrointestinal disease.

Diagnostic Assessment

She was euthyroid with a TSH level of 3.57 µIU/mL (3.57 mIU/L) (normal reference range: 0.4-5.0 µIU/mL; 0.4-5.0 mIU/L). A thyroid ultrasound showed a 1.0 × 0.8 × 0.9 cm right superior pole solid, hypoechoic, smooth margin TI-RADS 4 nodule and a 3.4 × 2.0 × 2.3 cm left mid-pole mixed solid cystic, hyperechoic, smooth margin TI-RADS 2 nodule (Fig. 1A and 1B). Repeat ultrasound in 1 year was recommended because the nodules did not meet American College of Radiology criteria for biopsy (FNA recommended for TI-RADS 4 nodules >1.5 cm, no FNA recommended for TI-RADS 2 nodules) [10].

Figure 1.

Initial thyroid ultrasound with left nodule in (A) transverse and (B) sagittal views. Subsequent thyroid ultrasound 2.5 years later with left nodule in (C) transverse and (D) sagittal views, now with new possible macrocalcifications (white arrows), leading to a TI-RADS 3 classification.

The patient had a follow-up ultrasound 2.5 years later, delayed because of the COVID-19 pandemic. The right TI-RADS 4 nodule was stable, whereas the left nodule showed new macrocalcifications without significant changes in size, now a TI-RADS 3 classification (Fig. 1C and 1D). This met criteria for FNA (TI-RADS 3 nodule >2.5 cm), which was performed. Cytology demonstrated atypical follicular cells in crowded sheets and papillary structures with the cells composed of nuclear pallor, nucleoli, nuclear contour irregularities, nuclear grooves, and frequent pseudo-inclusions. This was concerning for papillary thyroid carcinoma, Bethesda 6 (Fig. 2).

Figure 2.

Alcohol fixed and Papanicolaou (PAP)-stained cytology specimen. High-power field shows atypical follicular cells in crowded sheets with enlarged nuclei, chromatin margination, nuclear contour irregularities, and nuclear pseudo-inclusions. Examples of (A) nuclear pseudo-inclusion, (B) irregular nuclear contour with a nuclear groove, and (C) chromatin clearing and margination are labeled (black arrows).

Treatment

Given the presence of bilateral nodules, the patient underwent total thyroidectomy. Surgical pathology showed multifocal T2N0a CMTC with no evidence of malignancy in regional lymph nodes. Staining was positive for TTF-1, β-catenin, and paired-box gene 8 (PAX8) and negative for thyroglobulin (Tg) (Fig. 3). She started levothyroxine 112 mcg daily postoperatively to achieve a goal TSH level of <2.0 µIU/mL (2.0 mIU/L). Due to presence of bilateral, multifocal disease, she was referred to nuclear medicine, where they chose 115 mCi iodine-131 (I-131) following recombinant-TSH stimulation with an undetectable stimulated Tg <0.1 ng/mL (<0.1 μg/L) (reference range: 0.0-35.0 ng/mL; 0.0-35.0 μg/L), negative Tg antibodies, and uptake in the central neck only.

Figure 3.

Surgical pathology. (A) Positive TTF-1 staining and (B) positive β-catenin staining consistent with cribriform morular thyroid carcinoma.

Outcome and Follow-up

Despite no family history of colon cancer or FAP, because of the strong association between CMTC and FAP, we referred her to genetic counseling and gastroenterology for screening. Colonoscopy described multiple tubular adenoma polyps in her colon. Genetic testing confirmed pathologic variant in adenomatous polyposis coli. She ultimately underwent total proctocolectomy with permanent end ileostomy as recommended for patients with FAP for colon cancer prevention. It is not known whether any family members have been screened for FAP.

Discussion

CMTC is a rare form of thyroid cancer that is strongly associated with FAP. Current understanding of CMTC is based on case reports or case series. Therefore, overall recommendations are limited.

Approximately 40% to 50% of CMTC occurs in individuals with FAP with the remainder occurring as sporadic disease [5, 11, 12]. In 40% of FAP-associated CMTC cases, a diagnosis of CMTC precedes the diagnosis of FAP [13]. Therefore, timely diagnosis of CMTC can be important for discovery of FAP. However, this can be challenging as CMTC often lacks suspicious ultrasound features that would prompt FNA, as was the case for our patient. CMTC often appears as a solid, hypoechoic nodule without microcalcifications. Based on TI-RADS criteria, this corresponds to a TI-RADS 4 nodule with size threshold for biopsy being 1.5 cm and malignancy risk of 5% to 20% [10]. For American Thyroid Association (ATA) guidelines, this would be considered an intermediate risk pattern with cancer risk 10% to 20% and biopsy recommendation at 1 cm or greater [9].

Ultrasound features of CMTC are similar to those of follicular thyroid carcinoma (FTC), which are often iso- or hyperechoic, round with smooth margins, and noncalcified [9]. One study found that ultrasound features of CMTC and FTC are more similar than PTC in being round (50% for CMTC, 54% for FTC, 8% for PTC), having smooth margins (100% for CMTC, 100% for FTC, 36% for PTC), and with low incidence of microcalcifications (4.2% for CMTC, 4.0% for FTC, 51% for PTC) (P < .001) [14].

Herraiz et al (2007) assessed the prevalence of thyroid cancer in 51 patients with FAP at a single tertiary institution and found 6 with thyroid cancer, all of whom were female and 5 of whom had CMTC. Initial ultrasound findings identified multiple benign-appearing nodules that proved malignant on surgical pathology, suggesting ultrasound appearance is not a reliable predictor of malignancy for CMTC [6].

In case series, at least 80% of FAP-associated CMTC present as multifocal disease [12, 13]. Multifocality can be a clue to association with FAP. Compared to classic variant PTC, CMTC is associated with a lower incidence of lymph node metastases and distant metastases [1]. Our patient had benign features initially on ultrasound and did not undergo FNA until the development of macrocalcifications more than 2 years later. Like other individuals with CMTC and FAP, she had multifocal disease and was without metastases.

Microscopically, CMTC is typically encapsulated and distinct in its cribriform and morular growth patterns; however, follicular, trabecular, papillary, and solid growth patterns are also present. Cribriform areas are characterized by cellular foci forming lumen-like structures without intervening stroma, and the morular areas are characterized by squamoid whorls of ovoid cells, without keratinization. Cytologically, the cells demonstrate features similar to papillary thyroid carcinoma, including nuclear pallor, irregular nuclear contours, nuclear grooves, and pseudo-nuclear inclusions. By immunohistochemical studies, CMTC is positive for TTF-1 and demonstrates the aberrant nuclear β-catenin staining characteristic of its pathogenic WNT/β-catenin pathway activation [1, 15].

Although our patient did not have known FAP during initial ultrasound, and thus was not believed to be a high-risk patient, this case and our review of the literature illustrate the challenges in evaluation for thyroid cancer in patients with established FAP. Nodules harboring CMTC are often small, multifocal, and without suspicious ultrasound features. They do not often meet the recommended threshold for FNA, and thus diagnosis of thyroid cancer may be delayed.

For our patient, ATA risk stratification for recurrence is believed to be low risk because of resection of all macroscopic tumor and no local or distant metastases [9]. About 8.5% of individuals with CMTC will develop recurrence compared to 16.1% for classic-variant PTC, varying from 9.1% for follicular variant PTC to 27.3% for tall cell variant [1].

The ATA does not specify guidelines regarding surgical or radioactive iodine treatment for CMTC or TSH goal after thyroidectomy. In case reports and case series, management often follows management of classic PTC [1, 5]. This could be due to CMTC being rare, leading to few total cases, and its prior classification as a variant of PTC. ATA guidelines do recommend gastroenterology screening and genetic counseling for FAP after an initial diagnosis of CMTC [9]. For those with both CMTC and FAP, total thyroidectomy is recommended [1]. It is not known whether radioactive iodine adjuvant therapy is beneficial because of uncertainty regarding follicular cell differentiation [16]. In the literature, many patients with CMTC receive radioactive iodine adjuvant therapy due to modeling treatment after that of PTC [1, 5, 6, 16]. Our patient received 115 mCi I-131 as determined with nuclear medicine, although the authors may have instead recommended 75 mCi based on ATA guidelines.

In summary, our patient had delays in CMTC diagnosis and thereby delay in diagnosis of FAP because of her initial ultrasound exhibiting low suspicion features. Her clinical course was additionally challenging as she lacked symptoms of FAP and had no family history of thyroid or gastrointestinal malignancy. Although she had no indications to prompt screening for FAP until her CMTC diagnosis, the importance of recognizing this association is key to obtaining genetic testing and appropriate tumor surveillance for FAP and colon cancer. This is particularly true as TI-RADS does not consider family history when determining criteria for biopsy of thyroid nodules. CMTC often presents as a low suspicion thyroid nodule on ultrasound. In patients with FAP, given higher risk of CMTC, ongoing ultrasound monitoring of thyroid nodules that do not meet FNA criteria would be appropriate. Although current guidelines recommend no ultrasound follow-up for low suspicion TI-RADS 2 nodules and follow-up of moderate suspicion TI-RADS 3 nodules only if >1.5 cm [10], the increased risk of malignancy for patients with FAP and the low suspicion appearance of CMTC on ultrasound may warrant ultrasound follow-up for smaller nodules. This would not be applicable to our patient, as she had not yet been diagnosed with FAP when her nodule was identified, but her case does illustrate the low suspicion character of CMTC on ultrasound and supports this consideration.

Further research is needed to create clear guidelines on screening, diagnosis, and management of CMTC for this unique patient population, particularly with regard to surgical management, subsequent TSH goal, and indications for radioactive iodine adjuvant therapy.

Learning Points

• CMTC is a rare form of thyroid cancer with a strong association with FAP, with thyroid carcinoma being the initial diagnosis in 40% to 60% of FAP-associated CMTC.

• CMTC may present with low suspicion ultrasound findings, leading to delays in diagnosis.

• Consideration should be made to continue ultrasound surveillance of thyroid nodules with low suspicion ultrasound features in individuals with FAP.

Contributors

All authors contributed equally to the conception, design, and preparation of the manuscript. T.T. was involved in the diagnosis and management of the patient and manuscript submission. J.Q. performed a detailed literature review and wrote the initial draft of the manuscript. M.R. and M.E. both provided expert opinion on appropriate patient management for this case. R.O. was involved in the preparation of histology images and discussion of histopathology. All authors reviewed and approved the final manuscript.

Funding

No public or commercial funding.

Disclosures

T.T. is a consultant for Abbvie. All other authors have no disclosures to declare.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.