What is the treatment approach for cribriform thyroid cancer?

Cribriform-Morular Thyroid Carcinoma Treatment

Cribriform-morular thyroid carcinoma should be treated with total thyroidectomy with bilateral central neck dissection, followed by surveillance without radioactive iodine in most cases, given its generally indolent behavior and lack of response to conventional differentiated thyroid cancer therapies.

Understanding Cribriform-Morular Thyroid Carcinoma

Cribriform-morular thyroid carcinoma is a distinct entity that should not be classified as a variant of papillary thyroid cancer, despite historical nomenclature 1. This tumor has unique molecular characteristics:

• Activation of the WNT/β-catenin signaling pathway is the hallmark feature, with nuclear and cytoplasmic β-catenin staining distinguishing it from other thyroid malignancies 1
• Belongs to the non-BRAF-non-RAS molecular subtype, meaning it does not respond to BRAF-targeted therapies used in other thyroid cancers 1
• Strong association with familial adenomatous polyposis (FAP) requires screening for FAP when this diagnosis is made, as patients may have underlying germline APC mutations 1

Surgical Management

Total thyroidectomy with bilateral central neck dissection is the primary treatment for cribriform-morular thyroid carcinoma 1. The surgical approach should consider:

• Multifocal/bilateral disease is common in FAP-associated cases, necessitating complete thyroid removal 1
• Lymph node metastases occur in less than 10% of cases, but central neck dissection is warranted given the potential for nodal involvement 1
• Capsular invasion occurs in approximately 40% and angioinvasion in 30% of cases, though this does not necessarily indicate aggressive behavior 1

Postoperative Management

Radioactive iodine therapy is generally not recommended for cribriform-morular thyroid carcinoma because:

• Tumor cells can be focally positive or negative for thyroglobulin, limiting the utility of RAI therapy 1
• The tumor's unique molecular profile (WNT/β-catenin activation) suggests it will not respond to conventional differentiated thyroid cancer treatments 1
• TSH suppression should maintain TSH in the normal range (0.5-2.0 mIU/L) rather than aggressive suppression, given the generally favorable prognosis 2

Surveillance Strategy

Annual neck ultrasound is the primary surveillance tool after surgery 2. Key monitoring considerations include:

• Serial thyroglobulin measurements have limited utility due to variable thyroglobulin expression in this tumor type 1
• Physical examination focusing on neck lymph nodes should be performed regularly 2
• Screening for FAP-related manifestations including colonoscopy is essential when this diagnosis is made 1

Management of Advanced or Aggressive Disease

Distant metastases occur in only 6% of cases, but when present or when neuroendocrine/poorly differentiated features develop, more aggressive management is needed 1:

• Surgical resection or stereotactic body radiation therapy is preferred for oligometastatic disease over systemic therapy 3
• Lenvatinib (24 mg daily) or sorafenib may be considered for progressive, unresectable disease, though data specific to cribriform-morular carcinoma are limited 4, 3
• Elevated estrogen and progesterone receptor expression suggests potential for hormonal therapy as a therapeutic target in refractory cases 1
• WNT/β-catenin pathway inhibitors represent a rational therapeutic approach for advanced disease, though these should ideally be tested within clinical trials 1

Critical Pitfalls to Avoid

• Do not treat this as standard papillary thyroid cancer with routine RAI ablation, as the molecular profile differs fundamentally 1
• Do not overlook FAP screening in patients diagnosed with cribriform-morular thyroid carcinoma, as this may be the presenting manifestation of an underlying germline syndrome 1
• Do not use BRAF-targeted therapies (such as dabrafenib), as these tumors are BRAF-wild-type 1
• Do not perform aggressive TSH suppression unless there is evidence of persistent structural disease, as the prognosis is generally favorable 2, 1

Prognosis

The overall prognosis is good, with most patients experiencing indolent disease behavior 1. However, neuroendocrine differentiation or poorly differentiated features are associated with aggressive behavior and warrant closer surveillance and consideration of systemic therapy 1.