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.     

Oncofetal expression of blood group-related antigen on morules in thyroid carcinoma

Morule formation In associatlon wtth characteristic biotln-rich 'optically clear nuclei' were found In 7 of 2514 cases of thyrold carclnoma. The seven patients were all young females aged from 20 to 36 years who were suffering from efther papillary carclnoma (SIX cases) or follicular carcinoma (one case). The ABH (O) blood group (BG) types were A In three, AB In two and H(O) in two patients. lmmunohlstochemical study revealed that ABH(O) and Lewis BG antigens were expressed more specifically on morules than on ordinary neoplastic cells of paplllary or follicular carcinoma. Lewis BG antigens tested in the present study were as follows: CA50, CA19–9, stagespecific embryonic antigen 1 (SSEA-l), and slalyl SSEA-1. Ulex europaeus agglutinin I (UEA-I) histochemistry showed a posftive reaction on all the morules of blood groups A and H(0) patients, but yielded completely negative results on the morules of type AB patients. Sequential digestion by neuraminldase and α-galactosidase unmasked the reactivity for UEA-I even on the morules of type AB patients. The consistent reactivity for UEA-I on the morules seemed to be related to specific expression of BG antigens, which were characterized as oncofetal expression. It is suggested that the morules in thyroid carcinoma might be a kind of fetal component Induced by the differentiation of the neoplastic cells to the stage of immature embryonic cells.     

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.     

Keratin subsets in papillary and follicular thyroid lesions

 Previous studies indicate that keratins 7, 8 and 18 are present in all thyroid papillary and follicular lesions, but the distribution of other keratins has been incompletely characterized. The profile of individual keratin (K) polypeptides was evaluated immunohistochemically in over 200 non-neoplastic and neoplastic thyroid papillary and follicular lesions. Monoclonal antibodies to K19, K17, K16, K5/6 and K10 were applied in paraffin sections of formaldehyde-fixed tissue. K19 was present variably, often only focally in goitres, and was present only sporadically in papillary hyperplasia. However, K19 was strongly and uniformly expressed in virtually all papillary carcinomas, indicating differential diagnostic usefulness in differentiating papillary hyperplasia and papillary carcinoma. About half of the follicular carcinomas (defined as tumours strictly excluding the follicular variant of papillary carcinoma) were also strongly K19-positive, suggesting that K19 patterns are not reliable in differentiating papillary and follicular carcinoma. K17 and K5/6 were present in cysts and squamous metaplasia of goitres, and focally in papillary but only exceptionally in follicular carcinoma in areas of squamous differentiation and tumour cells in desmoplastic stroma. K16 in turn was present only focally in well-developed squamous metaplasia in goitres but was not found in differentiated thyroid carcinomas. K10, a high-molecular-weight keratin typical of epidermal differentiation, was identified neither in non-neoplastic nor in neoplastic differentiated thyroid lesions, including squamous metaplasia. These results indicate that papillary carcinomas differ from other differentiated thyroid tumours in their varying, usually focal, expression of stratified epithelial keratins that are partly but not exclusively related to squamous differentiation in such lesions. However, papillary carcinomas do not express truly epidermally restricted keratins; their previously described reactivity with polyclonal ”epidermal keratin” antibodies most probably results from the reactivity of such antibodies with K19. Received: 14 April 1997 / Accepted: 28 May 1997     

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.     

Squamous differentiation in thyroid carcinoma. With special reference to histogenesis of squamous cell carcinoma of the thyroid

Squamous differentiation of thyroid carcinoma was studied clinicopathologically and immunohistochemically in 29 autopsy cases. Tumor cell nests with squamous differentiation (CNSD), which histologically resembled squamous cell carcinoma, were found in 6 cases (20.7%). All of these 6 cases with CNSD had areas of undifferentiated carcinoma, representing 31.6% of 19 cases with undifferentiated carcinoma, and all but one case also showed coexisting papillary carcinoma. The CNSD were histologically associated with undifferentiated carcinoma in 5 cases, and with papillary carcinoma in one case; the CNSD were occasionally intermingled with these types of carcinoma, and there were findings suggesting a histological transition between the CNSD and undifferentiated carcinoma or papillary carcinoma. Immunohistochemistry revealed that all the CNSD were reactive with antibodies for keratin and vimentin, whereas thyroglobulin and desmin were not expressed. It was concluded that the CNSD examined here were most probably due to extensive squamous differentiation (squamous metaplasia) in undifferentiated carcinoma and papillary carcinoma. In addition, the present results may explain the fact that cases diagnosed solely as squamous cell carcinoma sometimes show a prognosis similar to that of undifferentiated carcinoma, and may well represent extensive squamous differentiation in such tumors rather than true squamous cell carcinoma of the thyroid.     

Squamous Differentiation in Thyroid Carcinoma With Special Reference to Histogenesis of Squamous Cell Carcinoma of the Thyroid

Squamous differentiation of thyroid carcinoma was studied clinicopathologically and immunohistochemically in 29 autopsy cases. Tumor cell nests with squamous differentiation (CNSD), which histologically resembled squamous cell carcinoma, were found in 6 cases (20.7%). All of these 6 cases with CNSD had areas of undifferentiated carcinoma, representing 31.6% of 19 cases with undifferentiated carcinoma, and all but one case also showed coexisting papillary carcinoma. The CNSD were histologically associated with undifferentiated carcinoma in 5 cases, and with papillary carcinoma in one case; the CNSD were occasionally intermingled with these types of carcinoma, and there were findings suggesting a histological transition between the CNSD and undifferentiated carcinoma or papillary carcinoma. Immunohistochemistry revealed that all the CNSD were reactive with antibodies for keratin and vimentin, whereas thyroglobulin and desmin were not expressed. It was concluded that the CNSD examined here were most probably due to extensive squamous differentiation (squamous metaplasia) in undifferentiated carcinoma and papillary carcinoma. In addition, the present results may explain the fact that cases diagnosed solely as squamous cell carcinoma sometimes show a prognosis similar to that of undifferentiated carcinoma, and may well represent extensive squamous differentiation in such tumors rather than true squamous cell carcinoma of the thyroid. Acta Pathol Jpn 39: 306 312, 1989.     

Clinicopathologic features of cutaneous squamous cell carcinomas of the head and neck in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

The clinicopathologic features of 32 cutaneous squamous cell carcinomas of the head and neck in 12 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma were examined to determine the frequency of clinically aggressive and histologically poorly differentiated carcinomas in this group of patients. Two thirds of the neoplasms were multiple and 56% were high grade (grade 3 or 4). One of the 12 patients had recurrent carcinoma, two patients had recurrent and metastatic disease, and two patients had metastatic tumor without recurrence. Two patients died of tumor, one patient is alive with extensive recurrent and metastatic disease, and one patient died of an uncertain type of carcinoma. An additional patient with squamous cell carcinoma of the face died of cutaneous squamous cell carcinoma that arose on the chest. This study shows that cutaneous squamous cell carcinomas of the head and neck in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma are often high grade and have the potential for recurrence and metastasis.     

Frequency of medullary thyroid carcinoma in an endemic goiter area

A series of 41 poorly differentiated follicular carcinomas of the thyroid gland without histopathological features of medullary or papillary carcinoma and 9 cases of undifferentiated thyroid carcinoma of the small cell type (diagnosed between 1967 and 1983) were investigated immunohistochemically. Two poorly differentiated follicular carcinomas showed a considerable number of calcitonin-positive cells in addition to the weakly thyroglobulin-positive tumor cells. One of these cases revealed several areas with calcitonin-positive tumor cells with additional squamous metaplasia with keratinization. No medullary carcinomas could be demonstrated among the 9 cases previously diagnosed as undifferentiated thyroid carcinomas of the small cell type. From the epidemiological point of view the application of immunohistochemistry does not significantly increase the proportion of medullary carcinomas detected in our endemic goiter area. The incidence of medullary carcinoma remains surprisingly low when compared with nonendemic areas.     

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.     

Classification of follicular cell tumors of the thyroid gland: Analysis involving Japanese patients from one institute

Prognostic analyses of thyroid carcinomas of follicular cell origin were carried out on patients treated at Kuma Hospital, Kobe, Japan. A new histopathological classification based on the prognostic evidence is proposed in this study, and it is applicable to the patients treated curatively. Major histological types of papillary carcinoma, follicular carcinoma and poorly differentiated carcinoma were combined into one single entity of follicular cell adenocarcinoma because (i) they have the same cell origin (follicular cell); (ii) clear-cut separation of papillary and follicular carcinoma is not always possible, and 10 year cause-specific survival was essentially similar when the patients were treated curatively; and (iii) poorly differentiated carcinoma usually has a background of either papillary or follicular carcinoma. This adenocarcinoma together with undifferentiated carcinoma was stratified into four prognostic groups using pure morphological criteria of the degree of cellular differentiation and histological grade. They are termed well-differentiated adenocarcinoma, moderately differentiated adenocarcinoma, poorly differentiated carcinoma and undifferentiated carcinoma of the thyroid. The 10 year disease-free survival rates were 86.3–93.1%, 65.4–78.7%, and 43.0–53.8%, and 0%, respectively. The 10 year cause-specific survival rates were 97.2–100%, 91.5–97.4%, and 71.2–80.0%, and 0%, respectively.     

Atypical Adenoma of the Thyroid: A Clinicopathologic and Flow Cytometric DNA Study in Comparison with Other Follicular Neoplasms

A clinicopathologic and DNA flow cytometric study was performed on seven patients (three males, four females) with atypical adenoma of the thyroid gland, using formalin-fixed paraffin-embedded tissues. The results were compared with those of 30 follicular adenomas and 13 follicular carcinomas. The patients ranged in age from 32 to 74 years (mean: 55.8 years), and the mean follow-up period was 11.0 years. All patients except two who died of other diseases were free of thyroid disease after initial surgery. It showed that there was no evidence of clinical cancer in this follow-up study of patients operated on for atypical adenomas. Four of the atypical adenomas were diploid, two were aneuploid, and one was tetraploid. Twenty-seven of the 30 follicular adenomas were diploid. Three patients with aneuploid follicular adenoma were free of disease. Of the 13 follicular carcinomas with a mean follow up period of 6.9 years, five were diploid, seven were aneuploid, and one was tetraploid. Two patients with aneuploid follicular carcinoma and one with diploid carcinoma developed lung metastases, and one patient each with diploid and aneuploid follicular carcinoma died of disease. There was no significant correlation between histologic features, ploidy status and prognosis among follicular carcinomas. The results of this study suggest that DNA flow cytometric analysis is not a useful tool for predicting the clinical behavior of follicular neoplasms. Acta Pathol Jpn 42: 632–638, 1992.     

Immunophenotypic heterogeneity of hyalinizing trabecular tumours of the thyroid

 

Aims:

We studied 12 cases of hyalinizing trabecular tumour of the thyroid gland (HTT) with the aim of reviewing the cytological, histological and immunophenotypic features and of investigating the relationships of HTT with other thyroid neoplasms.  

Methods and results:

Eleven patients were female and one male, aged 8–74 years (median 58). Ten cases had a benign behaviour, while two cases were locally aggressive. Of the latter, one developed distant metastases and the other is a recent case. All patients are alive 6–311 months after diagnosis. Cytologically, HTT was characterized by hypercellular smears with aggregates of roundish cells having features of papillary carcinoma (nuclear grooves, vacuoles) and fragments of fibrous tissue. Histologically, prominent nesting, trabecular growth patterns and a hyaline stroma (partly positive for laminin and collagen type IV) were found. One case was associated with a papillary microcarcinoma. Two additional cases had extensive areas of papillary carcinoma. In one of these, hyalinized papillary stalks were observed. All tumours contained thyroglobulin but not calcitonin. High molecular weight cytokeratin (a marker of papillary carcinoma) was focally positive in 4/12 cases only and thyroperoxidase (a marker of follicular adenomas, but not of papillary carcinoma) was found in 3/12 cases.  

Conclusions:

The immunophenotypic profile and the morphological features suggest that HTTs are an heterogeneous group of tumours, some of them probably representing variants of papillary carcinoma with hyalinized stroma.     

Diffuse sclerosing variant of papillary thyroid carcinoma: A clinicopathologic and immunophenotypic analysis of 22 cases

Background: The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is an uncommon tumor making up about 2% of all papillary thyroid carcinomas. Previous studies have not comprehensively evaluated these tumors in a large series of patients. Design: Twenty-two cases of DSV-PTC diagnosed between 1970 and 2000 were identified in the files of the AFIP. Histologic and immunohistochemical features were evaluated and patient follow-up was obtained. Results: The tumors affected 14 females and 8 males, aged 6 to 49 yr (mean, 18 yr), with males presenting at a mean older age than females (24 vs 14 yr). Symptoms included an enlarging mass in the thyroid, present for a mean of 9.5 mo. While a dominant tumor was identified in a single lobe, bilateral disease was common (n=16). The dominant mass ranged in size from 1.7 to 5.8 cm in diameter (mean, 3.8 cm). Histologically, all cases demonstrated a papillary carcinoma (conventional, solid, or follicular pattern) diffusely involving the gland. Extrathyroidal extension, lymphocytic thyroiditis, squamous metaplasia, increased fibrosis/sclerosis, and psammoma bodies were present to a variable degree. Both the papillary carcinoma and squamous metaplasia cells were strongly immunoreactive with CK19, thyroglobulin, and TTF-1. An increased number of S-100 protein immunoreactive dendritic cells were recognized. p53 was increased (>15%) in the tumor cells in 12 patients, while Ki-67 was increased in the tumor cells in two patients. Perithyroidal and cervical lymph node metastasis occurred in 18 (82%) patients. All metastases demonstrated histologic features similar to the primary. Complete resection (thyroidectomy in 18 patients) with lymph node dissection, yielded a 95% 5-yr survival without evidence of disease. One patient died of disease after a malignant transformation of the squamous metaplasia into squamous cell carcinoma. Conclusions: The recognition of DSV-PTC can be made with the following features: classic to solid foci of PTC, lymphocytic thyroiditis, squamous metaplasia, increased fibrosis, and innumerable psammoma bodies. DSV-PTC is more biologically aggressive than conventional PTC, but the patients’ survival is not significantly different. This diagnosis should lead the clinician to aggressively manage these patients (thyroidectomy and lymph node dissection) in an effort to achieve an excellent long-term clinical outcome.     

Reappraisal of synchronous and multifocal mucinous lesions of the female genital tract: a close association with gastric metaplasia

Aims:  To describe the gastric phenotype of synchronous mucinous metaplasia and neoplasms of the female genital tract (SMMN–FGT).
Methods and results:  Six patients (mean age 57 years, range 39–83 years) were diagnosed with SMMN–FGT. All six patients had mucinous metaplasia of endometrium, which showed features of lobular endocervical glandular hyperplasia (LEGH)/pyloric gland metaplasia (PGM) in five and was associated with mucinous adenocarcinoma in three. Five patients had mucinous metaplasia of the fallopian tubes, of which three showed borderline features. Two patients had mucinous borderline tumour of the ovary. Five patients had cervical lesions including LEGH/PGM associated with either adenocarcinoma in situ or minimal deviation adenocarcinoma of the cervix. All mucinous lesions were positive for HIK1083 and/or MUC6. One patient with minimal deviation adenocarcinoma involving the vagina died of her disease, whereas five patients, including three with microinvasion and three with positive peritoneal cytology or mucinous ascites, were alive without recurrence after a mean follow-up of 46 months (range 13–102 months).
Conclusions:  There is a close association between SMMN–FGT and LEGH/PGM. Microinvasion and positive peritoneal cytology may not have an influence on outcome.     

Primary mucoepidermoid carcinoma and sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid gland: a report of nine cases.

Mucoepidermoid carcinoma is a rare primary thyroid tumor with indolent biologic potential. Two types of tumors have been described under this category: mucoepidermoid carcinoma (MEC) and sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE). The MEC shows both squamous and glandular differentiation in a background of a noninflamed gland, whereas SMECE is characterized by extensive sclerosis, squamous and glandular differentiation, a concomitant inflammatory infiltrate rich in eosinophils, and a background of lymphocytic thyroiditis. We present nine cases of these entities: five MEC and four SMECE. All tumors occurred in women (age 27 to 73 years). Five tumors showed extrathyroidal invasion and multiple lymph node metastases. One case of MEC showed a concomitant tall cell variant of papillary carcinoma with vascular invasion, and two cases showed intimately associated areas of usual papillary carcinoma. One of the latter cases also showed areas of transformation to anaplastic carcinoma. In all cases of SMECE and in only one case of MEC, the uninvolved thyroid tissue showed lymphocytic thyroiditis. Follow-up information was available in four of the nine cases (3 months to 7 years). Two patients with SMECE are alive with no evidence of disease. One patient with MEC and tall cell variant of papillary carcinoma died of disease after 3 months, and the patient with anaplastic carcinoma died after 5 months with lung metastasis. Both MEC and SMECE were positive for cytokeratin and negative for calcitonin. All cases of MEC were positive for thyroglobulin, whereas all cases of SMECE were negative. The immunohistochemical findings suggest that both MEC and SMECE have different histogenesis.     

p53 immunoreactivity in endometrial metaplasia with dysfunctional uterine bleeding

AIM: Overexpression of p53 has been reported in endometrial carcinomas, especially in uterine papillary serous carcinoma (UPSC), to correlate with worse prognosis. Endometrial metaplasia is commonly encountered in patients with dysfunctional uterine bleeding (DUB) and may on occasion be difficult to distinguish from atypical endometrial hyperplasia or carcinoma on biopsies. The present study was initiated in the belief that metaplastic tissue might not show overexpression of p53 and would thus help to distinguish it from carcinomas of non-endometrioid histology. METHODS AND RESULTS: Paraffin-embedded tissue of endometrial biopsies with papillary metaplasia (22 cases), tubal metaplasia (five cases) and eosinophilic meta-plasia (seven cases) from patients with DUB were immunostained for p53 immunoreactivity. No evidence of hyperplasia was noted in any of the cases selected for the study. Twenty-eight cases of UPSC were included for comparison. Our study showed p53 overexpression in 25 of 28 (89%) UPSC. Weak and heterogeneous p53 immunoreactivity was present in 10 of 22 (45%) papillary metaplasias, four of five (80%) tubal metaplasias and four of seven (57%) eosinophilic metaplasias. Follow-up of 16-45 (median 32) months was unremarkable except for one patient with eosinophilic metaplasia who had simple endometrial hyperplasia in subsequent biopsy. CONCLUSIONS: The presence of weak and heterogeneous p53 immunoreactivity in metaplastic endometrium is unexpected and might be a consequence of DNA damage. Intense, diffuse and homogeneous p53 staining favours carcinoma.     

Morules and morule-like features associated with carcinomas in various organs: report with immunohistochemical and molecular studies

BACKGROUND: Morules have been reported in pulmonary blastoma (PB), well differentiated fetal adenocarcinoma of the lung (WDFA), and uterine endometrioid carcinoma (EC), and rarely in other carcinomas. beta Catenin gene mutation has been associated with morule formation. AIMS: To compare and clarify the cellular characteristics of morules in carcinomas in various organs and show that morules are distinct from epithelial cellular nodules. METHODS: Twenty tumours were studied: two PBs, three WDFAs, three papillary lung adenocarcinomas, 11 ECs, and one papillary thyroid carcinoma. Numerous epithelial cell, oncofetal, and neuropeptide antibodies were used for immunohistochemistry. beta Catenin gene mutation was investigated. RESULTS: Morules in PBs and ECs were uniform cell clusters distinct from squamous differentiation. All were immunonegative for epithelial cell and oncofetal antigens, but those in ECs were positive for neurone specific enolase gamma (NSEgamma). Synaptophysin, encephalin, and somatostatin were sporadically immunopositive in PB morules. Morules were not seen in the other carcinomas and WDFAs, although morule-like features closely resembling morules histopathologically were seen. These were positive for epithelial cell and oncofetal antigens, and showed squamous differentiation. Their nuclei were more atypical and slightly larger than those in morules. Morule-like features were seen in WDFAs. beta Catenin gene mutation was demonstrated in one EC and PB, and in two WDFAs. CONCLUSION: Morules were non-epithelial cell clusters showing neuronal differentiation. There were two types: endometrioid type, expressing NSEgamma, and blastoma type, expressing neuropeptides. In contrast, similar morule-like features were epithelial nodules. Although the number of cases was small, the presence of morules showed no clear prognostic correlations.     

DNA Copy Number Changes in Thyroid Carcinoma

The genetic changes leading to thyroid cancer are poorly characterized. We studied DNA copy number changes by comparative genomic hybridization (CGH) in 69 primary thyroid carcinomas. In papillary carcinoma, DNA copy number changes were rare (3 of 26, 12%). The changes were all gains, and they were associated with old age (P = 0.01) and the presence of cervical lymph node metastases at presentation (P = 0.08). DNA copy number changes were much more frequent in follicular carcinoma (16 of 20, 80%) than in papillary carcinoma (P < 0.0001), and follicular carcinomas had more often deletions (13/20 versus 0/26, P < 0.0001). Loss of chromosome 22 was common in follicular carcinoma (n = 7, 35%), it was more often seen in widely invasive than in minimally invasive follicular carcinoma (54% versus 0%, P = 0.04), and it was associated with old age at presentation (P = 0.01). In three of the four patients with follicular carcinoma who died of cancer, the tumor had loss of chromosome 22. DNA copy number changes were found in 5 (50%) of the 10 medullary carcinomas studied. Four of these five carcinomas had deletions, and in two of them there was deletion of chromosome 22. Eleven (85%) of the thirteen anaplastic carcinomas investigated had DNA copy number changes, of which five had deletions, and one had deletion of chromosome 22. The most common gains in anaplastic carcinoma were in chromosomes 7p (p22-pter, 31%), 8q (q22-qter, 23%), and 9q (q34-qter, 23%). We conclude that DNA copy number changes are frequent in follicular, medullary, and anaplastic thyroid carcinoma but rare in papillary carcinoma when studied by CGH. Loss of chromosome 22 is particularly common in follicular carcinoma, and it is associated with the widely invasive type.