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.     

Biotin-rich intranuclear inclusions in morule-lacking adenocarcinoma of the gallbladder: a new category of “neoplastic/non-morular” lesions

Biotin-rich intranuclear inclusions, also called optically clear nuclei, are observed in various neoplastic and non-neoplastic lesions, including pregnancy-related endometrium and benign and malignant neoplasms with morular structures. A recent study reported that lesions with biotin-rich intranuclear inclusions can be classified as (non-neoplastic) pregnancy-related endometrial and as (neoplastic) morular category. In the present report, we describe two cases of well-differentiated adenocarcinoma of the gallbladder in which biotin-rich intranuclear inclusions were found without morular structures. Immunohistochemically, as reported previously, the intranuclear inclusions were positive for biotin and two biotin-binding enzymes (pyruvic acid carboxylase and propionyl CoA carboxylase). Intranuclear expression of -catenin was also observed in neoplastic cells with and without intranuclear inclusion. We also detected a frame shift mutation of APC gene in one case but no mutation of -catenin gene in both cases. Although intranuclear expression of -catenin by mutation of APC gene might contribute to carcinogenesis in our cases, the relationships among intranuclear expressions of -catenin, biotin, biotin-binding enzymes and intranuclear inclusions remain unclear. Our cases are the first neoplastic lesions with biotin-rich intranuclear inclusions that lacked morular structures. We propose a new neoplastic/non-morular category for lesions with biotin-rich intranuclear inclusions.     

Comparative analysis of biotin intranuclear inclusions of gestational endometrium using the APAAP, ABC and the PAP immunodetection systems.

AIMS/BACKGROUND: Intranuclear inclusions have been observed in gestational endometrial glands. Although resembling Herpes simplex virus infected cells, these nuclei have been shown to contain endogenous biotin. Hence, immunohistochemical systems using the avidin-biotin complex will result in cross reaction and false positivity. This study investigates a series of 10 gestational endometria (formalin fixed and paraffin wax embedded) with intranuclear inclusions using three different immunodetection systems with primary anti-biotin. RESULTS: Both the alkaline phosphatase anti-alkaline phosphatase (APAAP) and peroxidase anti-peroxidase (PAP) systems confirmed that the intranuclear inclusions were endogenous biotin. The streptavidin biotin complex (StreptABC) system produced a positive reaction in both test sections and controls (omitting primary anti-biotin) in the presence of prior blocking with free avidin and biotin. In addition, aberrant immunoreactivity was observed in adjacent nuclei/cytoplasm of endometrial glands and decidualised stroma in the negative control of the PAP system. This was subsequently eliminated using microwave pretreatment prior to immunohistochemistry. CONCLUSION: The use of either the APAAP or PAP immunodetection systems (the latter with microwave pretreatment) is recommended for any immunohistochemical or non-isotopic in situ hybridisation investigation undertaken on gestational endometria.     

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.     

Shadow cell differentiation from squamoid morule in endometrial adenoacanthoma

Shadow cell differentiation (SCD), commonly found in cutaneous pilomatricoma (PMX), has been said to be extremely rare in extracutaneous tumors and its morphogenesis has not been clarified yet. In the present study, 25 cases of endometrial adenoacanthoma were examined with special reference to SCD and with immunohistochemistry for beta-catenin and CD10. Shadow cell nests (SCNs) were observed in 2 out of 5 cases of adenocarcinoma with squamoid morules and all of 4 cases of adenocarcinoma with squamous differentiation and morules, but not in any cases of adenocarcinoma with squamous differentiation. SCNs were just adjacent to morules with or without a mutual transition. Immunohistochemical examination revealed nuclear accumulation of beta-catenin and expression of CD10 in the squamoid morules around SCNs. These results indicate that SCNs are derived from squamoid morules in endometrial adenoacanthoma, and established a link between matrical basaloid cells in PMX and squamoid morules in endometrial adenoacanthoma, as common original tissues, showing nuclear accumulation of beta-catenin and expression of CD10, of SCNs. It seems that SCD is not so uncommon as previously estimated in endometrial adenoacanthoma.     

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.     

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.     

Morule with biotin-containing intranuclear inclusions in thyroid carcinoma

One thousand and sixty cases of thyroid carcinoma were reviewed to compare morules with squamous metaplasia clinicopathologically and immunohistochemically. Morules and squamous metaplasia were found in five (0.47%) and 32 cases (3.0%) respectively. The five patients with morules were all female (age 20–36 years) including four with papillary carcinoma and one with follicular carcinoma. The 32 patients with squamous metaplasia consisted of 30 females and 2 males (age 14–78 years), all of whom had papillary carcinoma except for one follicular carcinoma. The morules demonstrated characteristic 'optically clear nuclei' (OCN), which ultrastructurally showed filamentous structures in the nuclei. The OCN were immunohistochemically demonstrated to contain intranuclear biotin. Furthermore, the morule often accompanied with the OCN was positive for Ulex Europaeus agglutinin I (UEA-I) but negative for bovine muzzle epidermal keratin (EK). On the contrary, squamous metaplasia unaccompanied with the OCN was negative for UEA-I, but positive for EK. Follow-up information revealed that one of the five patients with morules had died of the disease, one was alive with pulmonary metastasis, and three were disease-free. Eight of 32 patients with squamous metaplasia had died of the disease; of the others who were alive, four patients have had recurrence.     

Thyroid adenomatous nodule with bizarre nuclei: a case report and mutation analysis of the p53 gene

We present a rare case of adenomatous nodule with bizarre nuclei. The patient was incidentally found to have a nodule in the left lobe of the thyroid gland by ultrasonographic examination. Papillary thyroid carcinoma was suspected by fine needle aspiration cytology, and hemithyroidectomy was performed. The demarcated 1.5-cm nodule had a multinodular appearance with various features, including micro- and macrofollicular components, cystic degeneration, a hyalinized area, and a papillary structure. Hyperchromatic bizarre nuclei with cytoplasmic inclusions were restrictively observed in the microfollicular area. The bizarre nuclei demonstrated diffuse p53 protein immmunoreactivity, but no mutation in exons 5-9 of the p53 gene was detected. The bizarre nuclei were reactive for anti-5-methyl-2'-deoxycytidine antibody, indicating the enclosure of presumably inactive methylated DNA. The intranuclear cytoplasmic inclusions (ICIs) were proven to contain vimentin and beta-catenin by immunohistochemistry. In this case, a degenerative process is involved in the formation of bizarre nuclei because of the compression by surrounding micronodules, unidentifiable mitotic figures, and a quite low proliferative activity. This case suggests that bizarre nuclei and ICIs, which might be identical to those of papillary carcinomas, can be seen in benign thyroid lesions, and overdiagnosis should be avoided regardless of immunohistochemical overexpression of p53.     

Cytological features of atypical polypoid adenomyoma of the endometrium: A case report with literature review

Atypical polypoid adenomyoma (APA) is a rare mixed epithelial and mesenchymal tumor characterized histopathologically by the presence of disorganized hyperplastic glands with cytological atypia embedded in intersecting fascicles of fibromuscular stromal cells. Herein, we report the first documented endometrial cytological case of APA. A 35‐year‐old Japanese female presented with irregular menstrual cycles and then was found to have polypoid lesions of the endometrium. Cytological examination of the endometrium and endometrial curettage were performed. The Papanicolaou smear revealed the presence of abundant clusters of crowded glandular cells in a clean background. These clusters exhibited irregular branching and dilatation, and these glandular cells had mild to moderately enlarged round to oval nuclei. Within the dilated glands, metaplastic squamous cells (squamous morules) were observed. The most striking feature was the presence of short fascicles of the spindle cells without atypia around the dilated atypical glandular cell clusters with squamous morules. Histopathological and immunohistochemical examinations revealed a diagnosis of APA. Our report demonstrates that the characteristic cytological feature suggestive of APA is the presence of short fascicles of the spindle cells without atypia surrounding dilated atypical glandular cell clusters with squamous morules in a clean background, and their appearance can allow cytologists/cytopathologists to consider APA in differential diagnosis in the endometrial cytological specimens. Diagn. Cytopathol. 2017;45:345–349. © 2016 Wiley Periodicals, Inc.     

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.     

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.     

Navigating through perplex morphologic changes after exogenous hormone usage

Clinical application of exogenous hormone as a method of contraception and/or treatment of various gynecologic disorders is exceedingly common. Unfortunately, the concurrent use of these agents also complicates the interpretation of pathology specimens. Various studies have shown that morphologic changes induced by hormonal therapies are present in both non-neoplastic and neoplastic tissues within the women's reproductive tract. It is important to understand the exogenous hormone induced morphologic changes, as it helps the pathologists make the accurate diagnosis, and in turn, guide clinicians to make optimal clinical decisions. In this review, we summarize the morphologic changes in both neoplastic and non-neoplastic endometrial, cervical, and myometrial surgical specimens after hormonal therapies, particularly after progestin treatment. In the endometrium, particularly in the scenario of progestin-treated atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN), there is notoriously poor interobserver agreement and difficulty in assessing for the residual disease. We summarize current literature and propose our recommended approach in assessing these challenging endometrial biopsies, including a diagnostic algorism, the use of PAX-2, PTEN, beta-catenin immunohistochemistry panel, as well as consistency in diagnostic wording of the report. In the cervix, progestin makes dysplastic lesions appear metaplastic, thus high-grade squamous dysplastic lesions may be easily missed. Within the myometrium, lesions such as adenomyosis may show various degree of decidualization, while smooth muscle neoplasms may show apoplectic changes, and stromal lesions including endometrial stromal sarcoma may show more eosinophilic cytoplasm. All such changes may pose more or less diagnostic challenges in our daily practice. However, most are readily recognizable when we understand particular hormone related scenarios.     

Universal Markers of Thyroid Malignancies: Galectin-3, HBME-1, and Cytokeratin-19

Difficulties in diagnosis of thyroid lesions, even with histologic analysis, are well known. This study has been carried on to evaluate the role of immunohistochemical markers including galectin-3, Hector Battifora mesothelial cell-1 (HBME-1), and cytokeratin-19 in the diagnosis and differential diagnosis of benign and malignant thyroid lesions. The expressions of galectin-3, HBME-1, and cytokeratin-19 were tested in formalin-fixed, paraffin-embedded tissues from 458 surgically resected thyroid lesions including non-neoplastic and neoplastic lesions. Immunostaining with standard avidin–biotin complex technique was performed by using monoclonal antibodies. In malignant neoplastic thyroid lesions, galectin-3, HBME-1, and cytokeratin-19 were diffusely expressed in general. Diffuse expression rates of these three markers were 72.3% (47/65), 70.7% (46/65), and 76.9% (50/65), respectively. The use of galectin-3, HBME-1, and cytokeratin-19 may provide significant contributions in the differential diagnosis of malignant thyroid tumors. Although focal galectin-3, HBME-1, and cytokeratin-19 expression may be encountered in benign lesions, diffuse positive reactions for these three markers are characteristic of malignant lesions. It has concluded that cytokeratin-19 alone and its combinations with other markers were more sensitive in accurate diagnosis of papillary carcinoma than the other combinations; meanwhile, there were similar results for follicular carcinomas with HBME-1 alone and its combinations.     

Concomitant progressive multifocal leucoencephalopathy and primary central nervous system lymphoma expressing JC virus oncogenic protein, large T antigen.

This report describes the concomitant occurrence of the JC virus (JCV) induced demyelinating disease progressive multifocal leucoencephalopathy (PML) and a primary central nervous system lymphoma (PCNS-L) in a patient with AIDS. Postmortem neuropathological examination revealed characteristic features of PML including multiple lesions of demyelination, enlarged oligodendrocytes with hyperchromatic nuclei (many containing eosinophilic intranuclear inclusions), and enlarged astrocytes with bizarre hyperchromatic nuclei. Immunohistochemical analysis demonstrated the expression of the JCV capsid protein VP-1 in the nuclei of infected oligodendrocytes and astrocytes. The PCNS-L lesion located in the basal ganglia was highly cellular, distributed perivascularly, and consisted of large atypical plasmacytoid lymphocytes. Immunohistochemical examination of this neoplasm identified it to be of B cell origin. Moreover, expression of the JCV oncogenic protein, T antigen, was detected in the nuclei of the neoplastic lymphocytes. This study provides the first evidence for a possible association between JCV and PCNS-L.     

Immunohistochemical analysis of steroid receptors, proliferation markers, apoptosis related molecules, and gelatinases in non-neoplastic and neoplastic endometrium

Endometrioid endometrial carcinoma developed from endometrial hyperplasia is associated with anomalies of proliferation, apoptosis, and matrix metalloproteinase (MMP) expression. Our study was designed to investigate steroid receptor (ER, PR) expression and its correlation with proliferative activity (PCNA), apoptosis (Fas, FasL, Bcl-2, Bax, and p53), gelatinases (MMP-2 and MMP-9) and their tissue specific inhibitor (TIMP-1 and TIMP-2) immunoexpression in endometrial carcinogenesis. A total of 38 cases were investigated, 10 non-neoplastic, 11 hyperplastic, and 17 carcinomatous endometria. Immunolabeling showed a higher expression of steroid receptors in hyperplasia and carcinoma than in non-neoplastic endometria and an ER/PR imbalance in carcinoma. The epithelial component of endometrial carcinomas had the highest proliferative index. Bcl-2 had a stronger expression in hyperplasia and carcinoma compared to non-neoplastic endometria and stromal tissue. The Bcl-2/Bax ratio was lower in endometrial carcinoma. Fas and FasL expression was stronger in hyperplasia and furthermore in carcinoma. p53 expression was progressively stronger along the sequence non-neoplastic endometrial to hyperplasia-carcinoma. Both types of investigated MMPs showed an increased expression in neoplastic endometria reaching a maximum level in carcinomas. MMP-9 immunostaining could be correlated to myometrial invasion. TIMP-1 decreased and TIMP-2 increased in expression from non-neoplastic endometria to hyperplastic and carcinomatous endometrial, respectively. Our study demonstrates that coordinated anomalies of steroid receptors, apoptosis and invasiveness factors are already present in hyperplasia as cumulative steps along the way to malignant transformation and that a complex MMP-2, MMP-9, TIMP-2/TIMP-1 imbalance seems to be responsible for the endometrial proliferation.     

Frequent beta-catenin mutations in juvenile nasopharyngeal angiofibromas

Juvenile nasopharyngeal angiofibromas (JNAs) are locally aggressive vascular tumors occurring predominantly in adolescent males. The pathogenesis of JNAs is unknown. Recently, JNAs have been reported to occur at increased frequency among patients with familial adenomatous polyposis, suggesting that alterations of the adenomatous polyposis coli (APC)/beta-catenin pathway might also be involved in the pathogenesis of sporadic JNAs. We analyzed somatic beta-catenin and APC gene mutations in 16 sporadic JNAs from nonfamilial adenomatous polyposis patients using immunohistochemistry for beta-catenin, and direct DNA sequencing for exon 3 of the beta-catenin gene and the mutation cluster region of the APC gene. Nuclear accumulation of beta-catenin was diffusely present in the stromal cells but not in the endothelial cells of all 16 JNAs. Activating beta-catenin gene mutations were present in 75% (12 of 16) of JNAs. Six JNA patients also had recurrent tumors after surgery, and in all cases the beta-catenin gene status of the recurrent JNA was identical to the initial tumor. No mutations in the mutation cluster region of the APC gene were detected in the four JNAs without beta-catenin mutations. The high frequency of beta-catenin mutations in sporadic JNAs and the presence of identical beta-catenin gene mutations in recurrent tumors indicates that activating beta-catenin gene mutations are important in the pathogenesis of JNAs. The immunohistochemical localization of beta-catenin only to the nuclei of stromal cells further suggests that the stromal cells, rather than endothelial cells, are the neoplastic cells of JNAs.     

Skin and superficial soft tissue neoplasms with multinucleated giant cells: Clinical,histologic, phenotypic,and molecular differentiating features

Multinucleated giant cells (MGC) are commonly seen in an array of neoplastic and non-neoplastic conditions, to include: granulomatous dermatitis, fibrohistiocytic lesions such as xanthogranulomas, and soft tissue tumors such as giant cell tumors of soft tissue. In addition, multinucleated giant cells are infrequently seen in melanoma, squamous cell carcinoma, and atypical fibroxanthoma. There are many different types of MGCs and their presence, cytologic, and immunohistochemical features within these pathologic entities vary. Thus, correct identification of the different types of MGCs can aid the practicing pathologist in making the correct diagnosis of the overall pathologic disease. The biologic diversity and variation of MGCs is currently best exemplified in cytologic appearance and immunohistochemical profiles. However, much remains unknown about the origination and evolution. In this review, we i) reflect on the various types of MGCs and the current understanding of their divergent development, ii) describe the histologic, immunohistochemical, and molecular (if previously reported) differentiating features of common skin and superficial soft tissue neoplasms that may present with multinucleated giant cells.