cribriform-morular variant of papillary thyroid carcinoma

FIGURE 3. Immunostaining for beta-catenin. The cribriform-morular variant in case 2 shows aberrant nuclear and cytoplasmic staininginside and outside the morule, which is delineated by arrows (left). The adjacent normal thyroid shows membranous staining only(right). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]ing more aggressive variants of thyroid carcinomas,such as poorly differentiated thyroid carcinoma.The cribriform-morular variant often showspseudostratified nuclei, leading to an erroneous diagnosisof columnar cell carcinoma, a potentiallyaggressive variant of PTC. The reverse is alsotrue, in the sense that hyalinized areas, a frequentoccurrence in the cribriform-morular variant, canpoint toward a diagnosis of hyalinizing trabeculartumor, a neoplasm with excellent prognosis (evenbetter than the cribriform-morular variant) if strictlydefined.The diagnosis of thyroid cancer can predatethe symptoms of colorectal polyposis by 4 to 12years in up to 30% of patients in some series. 8,10In one study of seven patients with the cribriformmorularvariant of PTC, two patients were foundto have polyposis; both tested positively for germlineadenomatous polyposis coli (APC) gene mutation,and both underwent subsequent colectomy. 2Because of the potential of detecting FAP early inpatients diagnosed with the cribriform-morularvariant, we strongly encouraged our first patientto undergo screening colonoscopy. Fortunately,colonoscopy ruled out the presence of colonicpolyposis. If screening can detect FAP, it is possibleto reduce the development of an individual’srisk of colorectal cancer.Immunohistochemically, these tumors stainpositively for estrogen and progesterone receptorsthat may correlate with the female predominancein the cribriform-morular variant. The tumorsalso stain well for thyroglobulin, cytokeratins AE1/AE3 and cytokeratin 7, and have also been shownto stain positively for cytokeratin 34betaE12,neuron-specific enolase, vimentin, bcl-2, and retinoblastomaprotein. 1,4,11 The tumor in our patientwith FAP stained for thyroglobulin and cytokeratin7 and was negative for cytokeratin 20, indicatingits lineage from the thyroid follicular epithelium.In PTC associated with FAP, genetic alterationsinclude germline APC mutations, 12 somaticmutations, 13 or loss of heterozygosity of the APCgene. 9,12,14 In addition to loss of function of theAPC gene, genetic alterations in FAP-associatedthyroid cancer involve gain of function of the retproto-oncogene (ret/PTC). 15 In fact, two smallseries have shown a 80% to 100% frequency ofret/PTC rearrangement and activation of theret/PTC1 and ret/PTC3 isoforms in these patients. 7,15As seen in our first patient, the cribriformmorularvariant may be encountered in patientswith non-FAP. First described in 1999, the sporadiccribriform-morular variant of PTC tends tobe well circumscribed and solitary and also occursin women younger than 30. 16 Immunohistochemically,these tumors stain positively for thyroglobulin,as with our first patient, and for cytokeratins,vimentin, estrogen, and progesterone receptors,bcl2, and retinoblastoma protein. 16 In onestudy of seven patients diagnosed with the cribriform-morularvariant, four patients had no evidenceof polyposis or APC gene mutation. 2 However,a somatic APC mutation was found in a474 Cribriform-Morular Variant of Papillary Cancer HEAD & NECK—DOI 10.1002/hed May 2006