Bladder carcinoma with shadow cell differentiation: a case report with immunohistochemical analyses

A peculiar case of bladder carcinoma showing shadow cell differentiation (SCD) in a 72-year-old man is presented. The tumor histologically revealed high grade urothelial carcinoma (UC) and partially contained squamous component with a transition to shadow cell nests, similar to those seen in cutaneous pilomatricoma (PMX). Immunohistochemically, the modes of cell death in the component of SCD were identical to those in PMX. The present case as well as 10 cases of cutaneous PMX showed nuclear expression of beta-catenin, whereas 10 cases of bladder UC with squamous differentiation revealed membranous localization without nuclear expression. These results suggest that nuclear accumulation of beta-catenin may play an important role for SCD in the present case. SCD in extracutaneous tumor is extremely rare and, in the literature, the present case is the second one as for bladder carcinoma.     

Morules in endometrial carcinoma and benign endometrial lesions differ from squamous differentiation tissue and are not infected with human papillomavirus

BACKGROUND: Squamous differentiation/squamous metaplasia is often associated with endometrial adenocarcinoma and benign lesions, such as endometrial hyperplasia and chronic endometritis. Morules have distinct histological characteristics, and are referred to as squamous metaplasia or squamoid metaplasia. AIM: To focus on the histological characteristics of morules and clarify the difference between morules and squamous differentiation. MATERIALS/METHODS: Twenty endometrioid carcinomas with morules or squamous differentiation, five adenosquamous carcinomas, and eight non-carcinomatous endometrial lesions with morules were investigated. Numerous antibodies for epithelial membrane antigen (EMA), involucrin, cytokeratins, neuropeptides, and oncofetal antigens were used for immunohistochemistry. In situ hybridisation and polymerase chain reaction were used to detect human papillomavirus (HPV). RESULTS: The morules observed were uniform cell clusters, with no squamous differentiation. They were immunonegative for epithelial antigens including involucrin, EMA, and cytokeratins, but were positive for neurone specific enolase. A few morules were immunopositive for acetylcholine esterase, and one case was positive for somatostatin; neither oncofetal nor proliferative cell markers, including blood group A, B, and AB, or other neuropeptides were demonstrated in the morules. HPV DNA was not found in either the morules in the carcinomas or in the benign lesions. However, true squamous differentiation tissue in four endometrioid carcinomas and two adenosquamous carcinomas was HPV positive using in situ hybridisation. CONCLUSION: Morules are histologically distinct from squamous metaplasia/squamous differentiation tissue. Morules are thought to be neuroectodermal-like cell clusters, and are not infected with HPV. In contrast, some of the true squamous differentiation tissue was associated with HPV infection.     

Frequent nuclear beta-catenin accumulation and associated mutations in endometrioid-type endometrial and ovarian carcinomas with squamous differentiation

Focal squamous differentiation is a common feature of endometrioid endometrial and ovarian carcinomas (E-Em and E-Ova Cas). A close association between mutated beta-catenin accumulation and alteration in cellular morphology has recently been demonstrated in murine L cell lines. To clarify the possible role of beta-catenin abnormalities and changes in tumour morphology, 60 grade (G) 1 or G2 E-Em Cas with areas of squamous differentiation (SqD), including morules and squamous metaplastic (SqM) foci, as well as 32 G1 or G2 tumours without such lesions, were investigated and the results compared with findings for c-jun and wnt-1 expression. Twenty-three E-Ova Cas, with and without SqD lesions, were also examined. In E-Em Cas, frequent nuclear beta-catenin accumulation was observed in 22 (84.6%) of 26 tumours with morules and 15 (45.5%) of 33 with SqM foci, in contrast to 4 (12.5%) of 32 without such lesions. Similar findings were also noted for mutations in exon 3 of the beta-catenin gene, involving codons 32, 33, 34, 37, 41, and 45, the single nucleotide substitutions being identical between SqD and the surrounding carcinoma tissue in most informative cases. The mutations were positively related to nuclear immunopositivity, but inversely to membrane expression, while there was no association with the status of c-jun or wnt-1. These E-Ova Cas, nuclear beta-catenin accumulation and mutations were limited to tumours with SqD features, independent of c-jun and wnt-1 status. These data indicate that beta-catenin abnormalities are relatively common in E-Em and E-Ova Cas with SqD features, implying a role in the squamous differentiation of tumour cells, not necessarily related to c-jun and/or wnt-1 status.     

Immunohistochemical analysis of morules in colonic neoplasms: morules are morphologically and qualitatively different from squamous metaplasia.

Morules develop in several neoplasms and have been considered as a type of squamous metaplasia despite the absence of keratinization and intercellular bridges. The objective of this study was to clarify the pathological significance of morules and to distinguish morules from squamous metaplasia in colonic neoplasms. Ten cases of morule-associated colonic neoplasms (4 adenocarcinomas, 1 adenoma with carcinoma in situ, and 5 adenomas), and 3 cases of squamous metaplasia in colonic adenocarcinoma were examined morphologically and immunohistochemically. Morules were well-defined structures composed of small, oval to short-spindled cells with bland nuclei, and frequently associated with intranuclear inclusions that were positive for biotin and biotin-binding enzymes (pyruvic acid carboxylase and propionyl CoA carboxylase). On immunohistochemical examination, morules characteristically showed nuclear overexpression of beta-catenin, cyclin D1 and p63, low Ki-67 labeling index (<1%), cytoplasmic overexpression of CD10, and no expression of cytokeratin 20. These molecules were useful for the differentiation of morules. Furthermore, p63 and 34betaE12 positivities in morules suggested that they have a basal/stem cell phenotype. Thus, morules were morphologically and qualitatively different from squamous metaplasia. We consider that morules in colonic neoplasms are cell clusters with a basal/stem cell phenotype, and have less proliferative and less invasive potential than other cancer cells.     

Aberrant intranuclear localization of biotin, biotin-binding enzymes, and beta-catenin in pregnancy-related endometrium and morule-associated neoplastic lesions.

Biotin-rich intranuclear inclusions, also known as optically clear nuclei, have been observed in various neoplastic and non-neoplastic lesions. They look like nuclei of herpesvirus-infected cells and cause a false-positive immunohistochemical result by avidin-biotin-complex (ABC) method. In the literature, all types of neoplastic lesions with intranuclear inclusions, with one exception, have been characteristically associated with squamoid structures known as morules. By contrast, all reported non-neoplastic lesions with such inclusions lacked morules and were confined to pregnancy-related endometrium. In the present study, adding unreported types of morule-associated neoplastic lesions, we investigated the distribution of biotin, biotin-binding enzymes, and beta-catenin in these lesions by immunohistochemical staining. We detected the intranuclear localization of biotin and of two mitochondrial biotin-binding enzymes (pyruvic acid carboxylase and propionyl CoA carboxylase) in all lesions examined, regardless of whether they were neoplastic or non-neoplastic and irrespective of the presence or absence of morules. The intranuclear localization of beta-catenin was detected in all neoplastic lesions with morules and in ovarian endometrioid adenocarcinoma without morules, but not in non-neoplastic endometrial lesions. These results suggest the following conclusions: (1) lesions with biotin-rich intranuclear inclusions can be classified as non-neoplastic/pregnancy-related endometrial and as neoplastic/pregnancy-unrelated or morular category; (2) the intranuclear biotin in both types of lesion is found in conjunction with biotin-binding enzymes. However, the role of beta-catenin in morule-associated neoplastic lesions, the relationship between beta-catenin and biotin/biotin-binding enzymes, and the mechanism of migration of biotin and biotin-binding enzymes from the cytoplasm to the nucleus remain unclear.     

Aberrant Cdx2 expression in endometrial lesions with squamous differentiation: important role of Cdx2 in squamous morula formation

Only a few reports have described Cdx2 expression in endometrial lesions of the uterus. Our aim was to determine whether Cdx2 expression is related to squamous differentiation in endometrial lesions. Furthermore, we examined whether there is any correlation between Cdx2 and beta-catenin, a well-known marker of aberrant nuclear accumulation in endometrial squamous foci secondary to mutation. We performed immunohistochemical analysis of 225 cases (29 normal endometrium, 28 nonproliferative conditions, 21 polyps, 46 hyperplasias, and 101 endometrioid carcinomas) that included 72 cases (4 polyps, 16 hyperplasias, and 52 carcinomas) showing morular or keratinizing squamous differentiation (SD(+)). Normal endometrium and nonproliferative conditions showed no staining for Cdx2. Whereas there was a low rate of Cdx2 positivity in SD(-) polyps (5.9%) and hyperplasias (10%), all SD(+) lesions expressed Cdx2 (P < .001). Thirty-eight (73%) of the SD(+) carcinomas were positive for Cdx2, whereas only 6 SD(-) cases (14.0%) were positive (P < .001). Furthermore, the larger the number of squamous foci, the greater the number of Cdx2-positive cells that was found. The labeling indices of Cdx2 were significantly higher in morular components than in keratinizing or glandular ones (P < .001). There was a strong correlation of the labeling indices of Cdx2 and beta-catenin in squamous foci of hyperplasias and carcinomas. Using immunofluorescence, we confirmed the coexpression of the 2 markers. The Cdx2 protein is expressed frequently in endometrial lesions with squamous differentiation, especially morular-type differentiation, and correlates strongly with nuclear beta-catenin expression. These facts suggest that Cdx2 plays an important role in squamous morula formation.     

Morules in cribriform-morular variant of papillary thyroid carcinoma: Immunohistochemical characteristics and distinction from squamous metaplasia

Morules are a diagnostic clue to the cribriform-morular variant (C-MV) of papillary thyroid carcinoma, and are superficially similar to squamous metaplasia. In order to clarify the histogenesis of morules and differentiate them from squamous metaplasia, we immunohistochemically compared the morules in five cases of C-MV with squamous metaplasia in six cases of diffuse sclerosing variant (DSV) of papillary thyroid carcinoma. The squamous metaplastic cells were immunopositive for low- and high-molecular-weight cytokeratin, whereas the morular cells were negative or focally positive. Vimentin-positive cells were observed focally in the morules and squamous metaplasia, except for one case of CMV that showed intense positivity. The morular cells showed weak cytoplasmic positivity for beta-catenin, and the cell membrane was not highlighted. Some nuclei of the morular cells were also positive for this antibody. Beta-catenin was intensively positive along the cell membrane of the metaplastic cells, and did not react against the nuclei or cytoplasm. Bcl-2 was positive in the morular cells, but negative in the metaplastic cells. S-100 protein-positive dendritic cells were observed in the metaplastic nests, but not in the morules. We argue that morules appear in connection with nuclear and cytoplasmic aberrant localization of beta-catenin, and are not an early form of squamous metaplasia.     

Biotin-rich, optically clear nuclei express estrogen receptor-beta: tumors with morules may develop under the influence of estrogen and aberrant beta-catenin expression

Recent studies have indicated that aberrant beta-catenin expression may be a common denominator for the morular formation of tumors from various anatomic sites. The evidence for the influence of female sex hormones in the formation of morules has been circumstantial, most previous studies having failed to demonstrate female sex hormone receptors in the morular cells. We investigated a possible role of estrogen receptor (ER)-beta in the occurrence of tumors that form morules with biotin-rich optically clear nuclei (BROCN)(BROCN-family tumors) and its possible relationship with aberrant nuclear/cytoplasmic (N/C) beta-catenin expression. We immunostained 14 BROCN-family tumors, including 6 low-grade adenocarcinomas of the fetal lung type, 3 papillary thyroid carcinomas of cribriform-morular variant (CMV), 2 ovarian endometrioid tumors, 2 colonic adenocarcinomas, and 1 gallbladder adenoma, as well as 4 cases of endometrial tissue with BROCN during gestation, for ERbeta, ERalpha, progesterone receptor (PgR), beta-catenin, and, on a subset of cases, c-Fos and MIB-1 as well. BROCN in all 18 cases expressed ERbeta but not ERalpha or PgR. In the BROCN-family tumors, the morular cells and budding glandular cells expressed ERbeta in the cytoplasm and BROCN, which overlapped with the N/C expression pattern of beta-catenin. Beta-catenin showed only membranous expression in the endometrial glands during gestation. In CMV and ovarian endometrioid tumors, nuclear expression of ERalpha and PgR were observed in association with N/C beta-catenin expression only in the glandular component. C-Fos was also constantly and strongly expressed in BROCN in all cases examined. The MIB-1 labeling index was low in the morular area, ranging from 1% to 3%. The present study indicates that N/C co-localization of ERbeta and beta-catenin is a feature common to the morules with BROCN that appear in the BROCN-family tumors from various anatomic sites. Whether the estrogen-signaling pathway and the Wnt-signaling pathway have crosstalk, cooperating in the development of the BROCN-family tumors, awaits further study.     

Squamous differentiation in carcinoma of the endometrium: a critical appraisal of adenoacanthoma and adenosquamous carcinoma

Although squamous differentiation within endometrial carcinomas has long been recognized by pathologists, its biologic significance has been the subject of continued debate. While some authors have found a worsened prognosis for women who have tumors with squamous elements, others have reported the prognosis to be better than conventional endometrial adenocarcinomas. Persisting confusion and disagreement about the use of the terms adenoacanthoma and adenosquamous carcinoma have complicated the issue. In this article we review the literature on the pathogenesis of squamous differentiation in the endometrium and discuss the histologic features, prevalence, and biologic behavior of adenocarcinoma with squamous differentiation. We conclude that keratin is a constituent of normal and neoplastic endometrial epithelial cells, and that overt squamous differentiation occurs by a mechanism that is currently unknown. Squamous differentiation is present in about 25% of endometrial adenocarcinomas, a frequency that appears to have been constant for the past 50 years. The squamous component of endometrial carcinomas may histologically appear benign, malignant, or indeterminant, and in the majority of instances closely parallels the differentiation of the glandular component. Endometrial adenocarcinomas with malignant-appearing squamous elements usually have poorly differentiated glandular components and have a prognosis identical to that of poorly differentiated adenocarcinoma without squamous differentiation. Endometrial adenocarcinomas with benign-appearing squamous elements are usually associated with well-differentiated glandular components and have a prognosis identical to that of typical well-differentiated adenocarcinoma. Some endometrial adenocarcinomas contain foci of squamous differentiation that appear neither clearly benign nor malignant. These often are associated with moderately differentiated glandular components; the prognosis for these women is not yet clearly defined. At the present time we are unable to attribute any prognostic significance to the presence of squamous differentiation in endometrial carcinomas. Because of the confusion and semantic arguments that revolve about the use of the terms adenoacanthoma and adenosquamous carcinomas, we recommend that those terms be abandoned and be replaced by the single term adenocarcinoma with squamous differentiation. As for any other endometrial tumor, the pathologist should provide information on histological grade, depth of myometrial invasion, and presence of vascular involvement or spread to the cervix in order to guide the gynecologist in determining appropriate therapy.     

Morules with optically clear nuclei in ovarian borderline endometrioid tumor

Optically clear nuclei (OCN) have been observed in morules of some neoplasms and in some conditions unrelated to the development of the morules. We first report a case of ovarian borderline endometrioid tumor (BET) showing the morules associated with OCN. The patient was a 47-year-old premenopausal woman with a left ovarian cystic tumor, atypical endometrial hyperplasia, and elevated serum levels of FSH, LH, estradiol, and CA 125. The resected ovarian tumor measured 6 cm in diameter, and showed a papillary growth. Histologically, the ovarian tumor was consistent with BET, and the morules with OCN were scattered. Immunohistochemically, OCN were proven to be rich in biotin. An aberrant nuclear expression of beta-catenin was observed in both the tumor cells and the morular cells. Our case may suggest the possibility that the appearance of OCN with or without morules in ovarian tumors is related to endometrioid differentiation of the tumor cells, and should be recognized as a diagnostic clue of ovarian endometrioid tumors. Although female sex hormones have been reported to play a role in the occurrence of OCN, the participation of beta-catenin mutation has also been suggested.     

TWO AUTOPSY CASES OF PRIMARY ADENOACANTHOMA OF THE STOMACH

The incidence of primay adenoacanthoma of the stomach is extremely low. In the Sasebo City Hospital, there were only two autopsy cases of adenoacanthoma among 46 cases of gastric cancer during the past four years. The first case was a 45 year-old male with adenoacanthoma. The second case was a49 year-old female with metachronous triple cancers; adenoacanthoma of the stomach, squamous cell carcinoma of the uterus and squamous cell carcinoma of the tongue. Histological examination showed muconodular adenocarcinoma of the stomach at the time of first operation and adenoacanthoma at the time of autopsy. These two cases suggest that adenoacanthomas of the stomach may originate from squamous metaplasia or squamous differentiation of a preexisting glandular carcinoma.     

Aberrant nuclear localization and gene mutation of beta-catenin in low-grade adenocarcinoma of fetal lung type: up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors that form morules.

The salient histopathologic features of low-grade adenocarcinoma of the fetal lung type (L-FLAC)/well-differentiated fetal adenocarcinoma (WDFA) include complex glandular structures and morules with biotin-rich optically clear nuclei. Interestingly, these characteristic features are shared by the cribriform-morular variant of papillary thyroid carcinoma, whose morphology is identical to that of familial adenomatous polyposis (FAP)-associated thyroid carcinoma. Furthermore, the single reported case of lung cancer associated with FAP was L-FLAC/WDFA. These observations lead us to hypothesize that up-regulation of the Wnt signaling pathway underlies the development of L-FLAC/WDFA. To verify this hypothesis, 11 cases of L-FLAC/WDFA, including the one FAP-associated case, eight cases of high-grade adenocarcinoma of the fetal lung type (H-FLAC), 24 cases of conventional pulmonary adenocarcinoma (CAC), and 13 fetal lungs were immunostained for beta-catenin. All cases of L-FLAC/WDFA showed predominantly aberrant nuclear/cytoplasmic expression, especially in budding glands and morules, whereas six of eight cases (75%) of H-FLAC and all but one case (96%) of CAC showed predominantly membranous expression. Fetal lungs showed nuclear/cytoplasmic expression restricted to the distal branching airway epithelium. Mutational analysis of exon 3 of the beta-catenin gene in five sporadic cases of L-FLAC/WDFA showed a point mutation at codon 34 and codon 37 in two cases, respectively. The present study indicates that up-regulating disturbances in the Wnt signaling pathway, including mutation of the beta-catenin gene, underlie tumorigenesis of L-FLAC/WDFA. The expression pattern of beta-catenin in L-FLAC/WDFA resembles that of the developing fetal lung airway. With the expression pattern of beta-catenin as a marker, most cases of H-FLAC as well as CAC appear to have different oncogenic pathways from cases of L-FLAC/WDFA. The present study together with other available data also suggests that abnormal up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors with morular formation from a variety of anatomic sites.     

Loss of E-cadherin and cytoplasmic-nuclear expression of beta-catenin are the most useful immunoprofiles in the diagnosis of solid-pseudopapillary neoplasm of the pancreas

Solid-pseudopapillary neoplasm of the pancreas occurs preferentially in young women and has a favorable prognosis. Differentiation of solid-pseudopapillary neoplasm from pancreatic endocrine neoplasm or adenocarcinoma can be difficult in the small biopsy specimen because they share common morphological features and immunoprofiles. Alterations of adenomatous polyposis coli (APC)/beta-catenin pathway have been identified as a genetic event contributing to the development of solid-pseudopapillary neoplasm. In the present study, to establish the diagnostic utility of beta-catenin and E-cadherin as markers for solid-pseudopapillary neoplasm, we performed immunohistochemical staining in 4 core biopsy specimens diagnosed as solid-pseudopapillary neoplasm and in tissue microarray blocks that contained histologically confirmed samples of 302 cases of adenocarcinoma, 56 cases of pancreatic endocrine neoplasm, and 50 cases of solid-pseudopapillary neoplasm. We compared the immunohistochemical results for beta-catenin and E-cadherin with those for known markers. Of the solid-pseudopapillary neoplasm cases, 51 (94.4%) were positive for nuclear beta-catenin, 45 (83.3%) were positive for CD10, 30 (55.5%) were positive for CD56, 15 (27.8%) were positive for synaptophysin, 3 (5.6%) were positive for cytokeratin (CK), and none was positive for E-cadherin and chromogranin. Of the adenocarcinoma cases, all were positive for CK, 300 (99.3%) were positive for E-cadherin, 30 (9.9%) were positive for CD10, 2 (0.7%) were positive for synaptophysin, 1 (0.3%) was positive for CD56, and none was positive for chromogranin and nuclear expression of beta-catenin. Of the pancreatic endocrine neoplasm cases, 54 (96.4%) were positive for synaptophysin and E-cadherin, 50 (89.3%) were positive for chromogranin, 26 (46.4%) were positive for CK, 15 (26.8%) were positive for CD56, 6 (10.7%) were positive for CD10, and none was positive for nuclear expression of beta-catenin. In conclusion, nuclear expression of beta-catenin and loss of E-cadherin can be used in the definite diagnosis of solid-pseudopapillary neoplasm on small biopsy specimens. CD10 immunopositivity should be carefully interpreted in the diagnosis of solid-pseudopapillary neoplasm because pancreatic adenocarcinoma or pancreatic endocrine neoplasm can also stain for CD10.     

Significance of aberrant (cytoplasmic/nuclear) expression of beta-catenin in pancreatoblastoma

This study concerns the significance of aberrant (nuclear/cytoplasmic) expression of beta-catenin in pancreatoblastoma (PBL). On immunohistochemistry, all seven PBLs examined showed nuclear/cytoplasmic expression of beta-catenin, predominantly in the squamoid corpuscles (SCs). In areas with acinar/ductular differentiation, few tumour cells displayed nuclear/cytoplasmic expression of beta-catenin and more than half of the tumour cells showed membranous expression. Two out of five (40%) tumours examined showed missense mutations in codons 33 and 37 of exon 3 of the beta-catenin gene. No mutation of the adenomatous polyposis coli (APC) gene was detected in two of the remaining three tumours. Amplifiable DNA for APC analysis was not obtained from the one other tumour. Immunoreactivity for cyclin D1, one of the nuclear targets of beta-catenin, was found predominantly in the SCs of the seven tumours. In contrast, the Ki-67 labelling index was 2-4% (median 3%) in the SCs and 8-18% (median 12%) in the other areas, indicating a negative correlation with nuclear cyclin D1 reactivity. These results imply that in PBLs, nuclear/cytoplasmic accumulation of beta-catenin and overexpression of its target gene cyclin D1 are not associated with the induction of tumour cell proliferation. Nuclear/cytoplasmic accumulation of beta-catenin may be related to the morphogenesis of the SCs that are considered most characteristic for PBL.     

Immunohistochemical detection of p53 homolog p63 in solid cell nests, papillary thyroid carcinoma, and hashimoto's thyroiditis: A stem cell hypothesis of papillary carcinoma oncogenesis

Most models suggest that the cell of origin of papillary carcinoma is the mature thyroid follicular epithelial cell. In a recent study, p63 was detected in papillary carcinoma, Hashimoto's thyroiditis, and in squamoid aggregates and solid cell nests (SCNs), embryonic remnants found sporadically in the fully developed thyroid. In the present study, the relationship between solid cell nests and papillary carcinoma was investigated further. Four-micrometer sections from 88 routinely fixed and processed archival thyroidectomy specimens were pretreated with citric acid pH 6.0 for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained with a streptavidin-biotin kit and diaminobenzidine as chromogen and were counterstained with hematoxylin. Squamoid aggregates or SCNs were noted in 21 specimens. Several morphologic variants of SCNs were found, all of which displayed p63 positivity. These included undifferentiated SCNs and those displaying commitment toward squamoid and ciliated glandular differentiation. Small, morphologically inconspicuous aggregates of p63-positive cells were commonly found in Hashimoto's thyroiditis. Commitment of p63-positive undifferentiated cells toward thyroid follicular epithelial differentiation was occasionally noted. One SCN variant, also associated with Hashimoto's thyroiditis, was a floretlike arrangement of p63-positive cells with fusiform nuclei. p63 staining was strong and uniform in some SCNs, but in other SCNs it was compartmentalized and homologous to stem cell-staining patterns in normal squamous or bronchial epithelia. Stem cell-like staining, associated with compartmentalized p63 staining or p63-positive undifferentiated cells, was noted in 7 of 27 papillary carcinomas. p63 immunostaining is a highly sensitive means of detecting SCNs. p63 expression patterns in SCNs and a subset of papillary carcinomas are closely homologous to stem cell-associated p63 staining patterns that have been described elsewhere in squamous and bronchial epithelia. We propose a stem-cell-associated model of papillary carcinoma oncogenesis that suggests that (1) p63-positive embryonal remnants rather than mature follicular cells are the cells of origin of a subset of papillary carcinomas; (2) these p63-positive cells are pluripotent and may stay undifferentiated or undergo benign squamoid or glandular maturation, may undergo thyroid follicular epithelial differentiation, may undergo oncogenic change leading to papillary carcinoma, or may trigger an immune reaction, resulting in lymphoid infiltration and Hashimoto's thyroiditis; and (3) Hashimoto's thyroiditis and papillary carcinoma may therefore be linked etiologically, because both disorders may be initiated by the same population of pluripotent p63-positive embryonal stem cell remnants.