cribriform-morular variant of papillary thyroid carcinoma

CASE REPORTDennis H. Kraus, MD, Section EditorCLINICAL CURIOSITY: CRIBRIFORM-MORULAR VARIANTOF PAPILLARY THYROID CARCINOMAKimberly M. Dalal, MD, 1 Dimitrios Moraitis, MD, 1 Carlos Iwamoto, MD, 2 Ashok R. Shaha, MD, 1Snehal G. Patel, MD, 1 Ronald A. Ghossein, MD 21 Division of Head and Neck Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center,1275 York Avenue, New York, New York 10021. E-mail: shahaa@mskcc.org2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New YorkAccepted 20 October 2005Published online 13 February 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20383Abstract: Background. There is an increasing awareness ofthe association of papillary thyroid carcinoma and familial adenomatouspolyposis (FAP). Although the incidence is rare, mosttend to occur in women. Several authors have described a distinctivehistologic variant of papillary thyroid carcinoma, thecribriform-morular variant, which is associated with FAP but alsomay be encountered in patients with non-FAP. This diagnosismay precede the symptoms of colorectal polyposis.Methods. A healthy 36-year-old woman was seen with a leftthyroid nodule, and a 34-year-old woman with FAP was seenwith a right thyroid nodule; both masses were suspicious forpapillary thyroid carcinoma. Both patients underwent total thyroidectomy.Results. Pathologic examination of both specimens revealedpapillary thyroid carcinoma, cribriform-morular variant. The firstpatient subsequently underwent colonoscopy, which was negativefor polyposis.Conclusions. Patients diagnosed with the cribriform-morularvariant of papillary thyroid cancer should be screened for thepresence of FAP. VC 2006 Wiley Periodicals, Inc. Head Neck28: 471–476, 2006Keywords: papillary thyroid cancer; familial adenomatouspolyposis; cribriform-morular variantCorrespondence to: A. R. ShahaPresented at the Eastern Section Meeting, Triological Society, Washington,DC, January 28–30, 2005.VC2006 Wiley Periodicals, Inc.There is a growing awareness of the association ofpapillary thyroid carcinoma (PTC) and familial adenomatouspolyposis (FAP). Although the incidenceof PTC in FAP is only 1% to 2%, most tend to occurin women. 1,2 Several authors have described a distinctivehistologic variant of PTC, the cribriformmorularvariant, which includes intermingledcribriform, follicular, papillary, trabecular, andmorular architecture. 1,3 Immunohistochemically,these tumors stain positively for thyroglobulin,estrogen, and progesterone receptors. 1,4 This variantof papillary carcinoma is extremely unusualand occurs predominantly in patients with FAP.However, the cribriform-morular variant may alsobe encountered in patients with non-FAP. At times,this diagnosis may predate the symptoms of colorectalpolyposis. The purpose of this report is to providean example of each of these clinical situationsand to discuss the therapeutic decisions involved.CASE REPORTPatient 1. A healthy 36-year-old woman was seenwith a left thyroid mass detected by her gynecolo-Cribriform-Morular Variant of Papillary Cancer HEAD & NECK—DOI 10.1002/hed May 2006 471

gist. Her family history was notable for memberswith both hyperthyroidism and hypothyroidism; amaternal grandmother had colonic polyps at theage of 70.On physical examination, she had a 2 3 2 cm,firm, mobile nodule of the left thyroid lobe. No palpablecervical or supraclavicular lymphadenopathywas found. Ultrasound demonstrated a 2.1-cmmass in the left thyroid lobe as well as a 5-mmnodule in the isthmus. A thyroid scan revealed acold left thyroid nodule. A fine-needle aspiration(FNA) biopsy specimen demonstrated cells suspiciousfor follicular neoplasia. Thyroid functiontests were normal. On review of her disease by ourinstitution, concern was raised for a PTC. Thepatient underwent a total thyroidectomy. Postoperatively,colonoscopy revealed a normal colonwithout polyposis.The final pathology report revealed a 2.05-cmPTC of the left thyroid lobe. The tumor was well differentiatedand did not have capsular or vascularinvasion, extrathyroidal extension, or multicentricity.Of note, the tumor was a ‘cribriform-morularvariant’ of PTC and demonstrated intermingled cribriform,follicular, papillary, trabecular, and morulararchitecture (Figure 1). The remainder of thethyroid had nodular hyperplasia. Immunohistochemically,the tumor stained positively for thyroglobulinand cytokeratin 7 and was negative for cytokeratin20, estrogen receptor, and progesteronereceptor. No nuclear staining with beta-cateninwas found.Patient 2. A 34-year-old woman with a history ofFAP was found to have an enlarged thyroid glandon routine physical examination. In 1992, thepatient had undergone a proctocolectomy and excisionof an abdominal wall desmoid tumor; desmoidsoccur in up to 10% of FAP patients and area manifestation of Gardner’s syndrome. 5 The desmoidwas also treated with adjuvant radiation. In1998, the desmoid tumor recurred in the pelvisand was treated with chemotherapy. In 1999, thepatient was diagnosed with duodenal tubularadenomas. Her paternal grandmother was the indexcase of FAP.Physical examination revealed a 2-cm, smoothdominant nodule of the right thyroid lobe andvague nodularity of the left thyroid lobe. Examinationof the larynx revealed normal mobile vocalcords. Ultrasound demonstrated three nodules inthe right lobe and two smaller nodules in the leftFIGURE 1. The variegated histologic appearance of the cribriform-morular variant. This sporadic case (patient 1) displays cribriform(upper left), papillary (upper right), and hyalinized areas (lower left). Interspersed islands of squamoid and spindle cells (mainly spindlecells in this case) known as morules were also seen (delineated by the arrows; lower right). [Color figure can be viewed in the onlineissue, which is available at www.interscience.wiley.com.]472 Cribriform-Morular Variant of Papillary Cancer HEAD & NECK—DOI 10.1002/hed May 2006

lobe. The most suspicious nodule was located inthe middle of the right thyroid lobe, had coarse,punctuate calcifications, and measured 1.6 cm indiameter. FNA cytology under ultrasonographicguidance strongly suggested PTC. The patientunderwent a total thyroidectomy and had anuneventful postoperative recovery.The final pathology revealed a 2.3-cm PTClocated in the right thyroid lobe. The tumor wasdescribed as containing the ‘cribriform-morularvariant’ of PTC (Figure 2). Although the tumorwas well encapsulated and had no extrathyroidalextension, there was evidence of focal capsuleinvasion. No vascular invasion was identified. Ofinterest, the papillary carcinoma was multifocalwith three additional foci of the ‘cribriform-morularvariant’ ranging from 0.17 to 0.8 cm, located inboth thyroid lobes. The tumor was positive for thyroglobulinand cytokeratin 7 and was negative forcytokeratin 20. The tumor also showed diffuseaberrant nuclear staining for beta-catenin, whereasthe adjacent normal thyroid showed a membranousstaining pattern (Figure 3). In addition, there wasstrong and diffuse nuclear positivity for both estrogenand progesterone receptors.DISCUSSIONIn 1968, the relationship between FAP and thyroidcarcinoma was first suggested. 6 Although theincidence of PTC in patients with FAP is rare at1% to 2%, the relative risk for thyroid carcinomain patients with FAP younger than 35 years of ageis estimated at 160 times that of the general population.2The cribriform-morular variant of papillarycancer of the thyroid is often associated with FAP,as was seen in our second patient. Clinically, thisentity has a female predominance, is multifocal,and tends to occur in patients under the age of30. 1,2,4,7–9 Histologically, this variant has beendescribed as having distinct features, includingan intricate blending of cribriform, trabecular,solid, follicular, morular, and papillary architecture.1,3,8 The uncharacteristic cribriform growthpattern can mislead the pathologist into diagnos-FIGURE 2. Histopathologic features of the cribriform-morular variant (CMV) in case 2. The tumor typically shows mixed architecturalfeatures with cribriform structures (upper left) and an intricate blending of empty follicles and papillae (upper right). Island of squamoidand spindle cells (morule delineated by arrows) shows the typical biotin-rich homogeneous nuclear inclusion also known as peculiarnuclear clearing (lower left). The nuclei are often pseudostratified and resemble those seen in papillary carcinoma, columnar cell variant,leading to the misdiagnosis of the latter variant that can be much more aggressive than CMV (lower right). [Color figure can beviewed in the online issue, which is available at www.interscience.wiley.com.]Cribriform-Morular Variant of Papillary Cancer HEAD & NECK—DOI 10.1002/hed May 2006 473

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

patient without a germline APC mutation. 17 Thesepatients with the sporadic cribriform-morular varianthave an excellent prognosis, with one reportdescribing no recurrence of tumor up to 13 yearsafter diagnosis. 16Mutant beta-catenin contributes to the developmentof the cribriform-morular variant of PTCin both FAP and sporadic forms. 11 APC forms amacromolecular complex with beta-catenin and isinvolved in the Wnt transduction signaling pathway,sequestering beta-catenin and targeting itfor degradation. 18,19 Mutations in the APC genelead to a truncated APC protein that lacks theability to degrade beta-catenin, leading to increasedcytoplasmic beta-catenin levels. 20 Cytoplasmicand nuclear immunolocalization of beta-cateninin FAP-associated cribriform-morular variant ofPTC suggests an abnormality in the Wnt transductionsignaling pathway. 21 Xu et al 11 demonstratedsomatic mutations in the beta-catenin geneCTNNB1 in patients with either FAP-associatedor sporadic cribriform-morular variant of PTC.Cytoplasmic and nuclear immunolocalization ofbeta-catenin was noted in both sets of patients,suggesting that the aberrant nuclear accumulationof mutant beta-catenin can occur independentlyfrom APC mutations and may contribute tothe genesis of these tumors. 11 Beta-catenin alsoseems to be responsible for the peculiar morphology(i.e., cribriform growth and morules) seen inthese tumors. Indeed, beta-catenin accumulationhas also been found in ex-trathyroidal neoplasmsdisplaying morules and intricate glandular growthpatterns, such as fetal lung adenocarcinoma andendometrioid-type adenocarcinoma of the endometrium.22Also, supporting a role in the morphogenesis ofthe cribriform-morular variant is the fact thatbeta-catenin nuclear/cytoplasmic accumulationis critical in the epithelial budding, branching,and hair follicle formation in embryogenesis. Thecribriform pattern may, therefore, recapitulatethe epithelial budding seen in embryos, and themorules may recapitulate the hair formation seenin embryogenesis. 22In our patient with FAP, we found aberrantaccumulation of beta-catenin in the tumor nuclei,in agreement with previous reports. However,the tumor in our sporadic case did not show betacateninnuclear or cytoplasmic staining, and therewas no estrogen or progesterone immunoreactivity.These findings suggest alternative pathways(other than beta-catenin) may be responsible forthe formation of these neoplasms.Because of their multicentricity and bilaterality,total thyroidectomy is the treatment of choice forthe cribriform-morular variant of PTC. 1 Althoughthe tumor in our patient with non-FAP did notreveal multicentricity, the tumor of the patientwith FAP did demonstrate multicentricity, supportingthe argument for total thyroidectomy inthese patients. These tumors may metastasize toregional lymph nodes. Long-term prognosis isexcellent for patients with FAP-associated cribriform-morularvariant, with 5-year and 20-yearsurvival rates of 90% and 77%, respectively. 1CONCLUSIONSThe cribriform-morular variant of papillary thyroidcancer may be associated with familial adenomatouspolyposis. Patients with FAP in whomthere is a concern for PTC should undergo totalthyroidectomy. Although rare, when the cribriform-morularvariant is diagnosed, patients shouldundergo screening colonoscopy to rule out thepresence of colonic polyposis. The prognosis of thisvariant of PTC is similar to that of the classicaltype. This distinct histologic finding should alertphysicians to screen such patients and their familymembers for FAP, thereby facilitating early diagnosisof FAP.REFERENCES1. Perrier ND, van Heerden JA, Goellner JR, et al. Thyroidcancer in patients with familial adenomatous polyposis.World J Surg 1998;22:738–742.2. Tomoda C, Miyauchi A, Uruno T, et al. Cribriform-morularvariant of papillary thyroid carcinoma: clue to earlydetection of familial adenomatous polyposis-associatedcolon cancer. World J Surg 2004;28:886–839.3. Harach HR, Williams GT, Williams ED. Familial adenomatouspolyposis associated thyroid carcinoma: a distincttype of follicular cell neoplasm. Histopathology 1994;25:549–561.4. Ng SB, Sittampalam K, Goh YH, Eu KW. Cribriformmorularvariant of papillary carcinoma: the sporadic counterpartof familial adenomatous polyposis-associated thyroidcarcinoma. A case report with clinical and moleculargenetic correlation. Pathology 2003;35:42–46.5. Clark SK, Phillips RK. Desmoids in familial adenomatouspolyposis. Br J Surg 1996;83:1494–1504.6. Camiel MR, Mule JE, Alexander LL, Benninghoff DL.Association of thyroid carcinoma with Gardner’s syndromein siblings. N Engl J Med 1968;278:1056–1058.7. Cetta F, Chiappetta G, Melillo RM, et al. The ret/ptc1oncogene is activated in familial adenomatous polyposisassociatedthyroid papillary carcinomas. J Clin EndocrinolMetab 1998;83:1003–1006.8. Cetta F, Pelizzo MR, Curia MC, Barbarisi A. Geneticsand clinicopathological findings in thyroid carcinomas associatedwith familial adenomatous polyposis. 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