Use of immunohistochemistry in the diagnosis of miscellaneous and metastatic tumors of the uterine corpus and cervix

Uncommon tumors in the uterus present diagnostic challenges. In some cases, the tumor subtype is usually seen outside the gynecologic tract and the possibility of a uterine primary is not considered. In other cases, histologic overlap with more common uterine tumors leads to potential misdiagnosis. Finally, metastatic carcinoma may involve the uterus and cervix. Rarely, symptoms related to the uterine metastasis may precede diagnosis of an extrauterine primary. Without the proper clinical context, the possibility of a missed diagnosis is increased. One must first be aware of these possibilities, but immunoperoxidase studies are often necessary to confirm the diagnosis. In this review, unusual and metastatic tumors involving the uterine corpus and cervix and immunoperoxidase studies used to diagnosis such tumors are discussed.     

Prognostic value of podoplanin expression in intratumoral stroma and neoplastic cells of uterine cervical carcinomas

OBJECTIVE:

To investigate the clinicopathological significance of podoplanin expression in the intratumoral stroma and neoplastic cells of early stage uterine cervical cancer.

MATERIALS AND METHODS:

A total of 143 patients with clinical stage I and IIA uterine cervical carcinomas underwent surgery between 2000 and 2007. Clinicopathological data and slides associated with these cases were retrospectively reviewed. Immunodetection of podoplanin expression in histologic sections of tissue microarray blocks was performed using the monoclonal antibody D2‐40.

RESULTS:

Expression of podoplanin was detected in neoplastic cells in 31/143 (21.6%) cases, with 29/31 (93.5%) of these cases diagnosed as squamous carcinoma. For all of the cases examined, the strongest signal for podoplanin expression was observed at the proliferating edge of the tumor nests. The rate of positive podoplanin expression for node‐positive cases was lower than that of node‐negative (18.9% vs. 22.6%, respectively). Furthermore, the rate of positive podoplanin expression in fatal cases was 10.5% vs. 21.6%, respectively. In 27/143 (18.8%) cases, podoplanin expression was detected in fibroblasts of the intratumoral stroma, and this expression did not correlate with patient age, clinical stage, tumor size, histologic type, depth of infiltration, or vascular involvement. Moreover, expression of podoplanin in intratumoral stroma fibroblasts was only negatively associated with nodal metastasis. A greater number of fatal cases was observed among negative intratumoral stroma fibroblasts (15.5% vs. 3.7%, respectively), although this difference was not significant.

CONCLUSIONS:

These preliminary results suggest that podoplanin may have a role in host‐tumor interactions and, as a result, may represent a favorable prognostic factor for squamous cervical carcinomas.     

CD117阴性胃肠道间质瘤的临床病理及免疫组织化学研究

目的 探讨免疫组织化学在形态学典型、免疫组织化学CD117阴性胃肠道间质瘤(GIST)诊断中的意义.方法 对10例CD117阴性、形态学典型的GIST进行c-kit基因第9、11、13、17号外显子及血小板源性生长因子受体α(PDGFRA)基因第12和18号外显子的基因检测,同时所有病例均进行CD117、CD34、平滑肌肌动蛋白(SMA)、结蛋白、S-100蛋白、WT-1、DOG-1 的免疫组织化学染色(EnVision法).结果 10例中8例完成c-kit及PDGFRA基因的检测,仅1例有c-kit基因第9号外显子突变,余未发现基因突变.10例CD117阴性的病例9例CD34阳性,2例SMA局灶阳性.结蛋白和S-100蛋白均阴性.DOG1弥漫阳性者5例,1例弥漫弱阳性,2例局灶阳性,2例阴性.4例WT-1弥漫阳性,2例局灶阳性,1例有散在肿瘤细胞阳性,3例阴性.结论 对胃肠道及胃肠道外形态学典型、但CD117阴性的GIST病例,联合应用多种免疫组织化学标记有助于诊断.DOG-1和WT-1可作为补充加入到CD117阴性GIST的诊断中.

Abstract：

Objective To study the immunophenotype and c-kit or platelet derived growth factor receptor alpha(PDGFRA)gene mutations in CD117-negative gastrointestinal stromal tumors(GISTs).Methods Ten cases of GISTs with typical histologic features but no CD117 expression were retrieved from the archival of Department of Pathology,Peking Union Medical College Hospital,China.The Cages were further evaluated for the presence of c-kit exons 9.11, 13 and 17 mutations and PDGFRA exons 12 and 18mutations.DNA was extracted from the paraffin-embedded tuinor tissue.The PCR products were sequenced directly for the mutations.An immunohistochemical study for CD117,CD34,smooth muscle actin,desmin,S-100 protein.WT-1 and DOC-1 Was also performed.Results Eight of the 10 Cases had the mutation tests completed.C-kit mumfion in exon 9 Wag detected in only one case.Amongst the 10 cases studied, CD34Wag expressed in 9 cases. Smooth muscle actin was focally positive in 2 cases.None of them expressed desmin or S-100 protein.DOG-1 and WT-1 were diffusely positive in 5 and 4 Cages.respectively.In addition.DOG1 Was diffusely but weakly positive in 1 case and focally expressed in 2 cages.Three cases were focally positive for WT-1.Conclusion Pathologic diagnosis of CD117-negative GISTs can be facilitated with the application of a panel of immunohistochemical markers.including DOG-1 and WT-1.     

小胃肠间质瘤的临床病理学特征

目的探讨小胃肠间质瘤(small gastrointestinal stromal tumors,sGIST)的临床病理学特征。方法回顾性分析21例sGIST的临床病理学及免疫表型特征,对比分析非sGIST,并进行随访。结果 21例sGIST中女性7例,男性14例,中位年龄63岁,直径0.5~1.5 cm,主要发生于胃,全部为梭形细胞型,其中9例同时伴有胃肠道恶性肿瘤。与非sGIST相比,sGIST很少出现肿瘤内出血、坏死、黏膜侵犯、溃疡及核分裂,复发风险明显低于非sGIST;免疫组化标记p53、Ki-67及肿瘤内微血管密度(microvascular density,MVD)明显低于非sGIST,差异有统计学意义(P0.05)。结论 sGIST可与胃肠道恶性肿瘤同时伴发,免疫组化标记p53、Ki-67及MVD均低于非sGIST,其预后较好。     

灯盏花素注射液对骨髓间充质干细胞的诱导分化

目的探索灯盏花素注射液体外诱导大鼠骨髓间充质细胞(BMSCs)分化为神经元和胶质细胞的可行性。方法贴壁法分离纯化SD大鼠骨髓间充质细胞。第4代细胞行表型鉴定后,用灯盏花素注射液诱导,每6h倒置相差显微镜观察形态变化,免疫细胞化学染色鉴定诱导后细胞的神经元特异性稀醇化酶(NSE)、神经胶质纤维酸性蛋白(GFAP)的表达情况,四甲基偶氮唑盐(MTT)检测不同浓度灯盏花素注射液诱导后细胞的活力,流式细胞术及RT-PCR检测诱导前后细胞中NSE、GFAP mRNA的表达变化。结果BMSCs表型鉴定为CD44+、CD54+、CD34-,诱导18h后BMSCs胞体开始收缩,有突起伸出,24h后突起增多形成网络结构。免疫细胞化学染色,NSE阳性表达率为(48.7±3.4)%,GFAP阳性表达为(56.8±4.2)%,流式细胞仪检测诱导24h后的细胞NSE及GFAP蛋白表达量均较未诱导组升高,RT-PCR检测诱导后细胞表达NSE、GFAP mRNA,未诱导的细胞则不表达。结论灯盏花素注射液可诱导大鼠骨髓间充质细胞在体外分化为神经元和神经胶质细胞。     

小肠间质瘤的免疫组织化学特征其意义

目的探讨小肠间质瘤的临床病理诊断及免疫组织化学特征。方法收集我校附属医院临床病理科6年来对外科手术切除的小肠肿瘤标本,光镜观察、免疫组织化学方法检测Vimentin、desmin、S-100、actin、CD117、CD34和SMA的表达。结果13例肿瘤中良性3例,潜在恶性4例,恶性6例;其中黏膜下生长3例,浆膜下生长5例,肠系膜处生长2例,肌壁内生长3例,常见症状是上腹部肿块和上消化道出血,免疫表形特征为:CD11713例(100%)胞质阳性表达;CD3410例阳性(76.9%)表达,S-100蛋白2例(15.4%)呈局灶表达,10例SMA阴性表达。结论小肠间质瘤发生率较高,多为恶性,有必要和肠的雪旺细胞瘤、平滑肌瘤相区别,CD117、CD34可作为诊断小肠间质瘤免疫标记物,而肿瘤大小、有无出血和坏死、核分裂像等均可作为良恶之判断的参照指标。     

Prostatic stromal sarcoma with rhabdoid features

Rhabdoid tumors have been reported in many different anatomic sites as an aggressive tumor and usually present with a rhabdoid tumor component (a composite tumor) rather than a pure rhabdoid tumor. Rhabdoid tumor in the prostate has been described only once in the prostatic region as a possible epithelial origin. Rhabdoid features in prostatic stromal sarcomas (PSSs) have never been described in the literature. Here, we report a case of a PSS with rhabdoid features. A 31-year-old man presented with a 4-month history of voiding difficulty and anal pain. Computed tomography of the abdomen revealed an ovoid mass in the prostate invading rectum and urinary bladder. A needle biopsy was diagnosed as an unclassified spindle cell sarcoma, and 2 cycles of adriamycin-based neoadjuvant chemotherapy were given, followed by radical prostatectomy. The prostatectomy specimen revealed a high-grade sarcoma with fascicles of highly cellular spindle cells and numerous mitoses with hemorrhage and necrosis. In areas, the tumor also contained sheets of loosely cohesive epithelioid cells with rhabdoid tumor component. Both spindle and rhabdoid tumor cells were positive for vimentin, CD34, and progesterone receptor and negative for desmin and cytokeratin immunostainings. The rhabdoid tumor cells retained INI1 expression. The tumor recurred in the bladder, and the patient died of sepsis. To the best of our knowledge, this is the first case of PSS with rhabdoid features. The tumor showed an aggressive clinical behavior with a short-term survival (7 months after diagnosis).     

脂肪基质干细胞的研究进展

脂肪基质干细胞是存在于脂肪组织中的一群能多向分化的细胞。它们具有与骨髓间充质干细胞相似的特性,在不同的诱导条件下能向不同组织细胞分化。脂肪基质干细胞也具有一定的免疫负调节作用,能用于造血干细胞移植后的造血支持。     

Juvenile nasopharyngeal angiofibroma: an immunohistochemical characterisation of the stromal cell

AIMS: Juvenile nasopharyngeal angiofibroma (JNA) is a rare tumour occurring almost exclusively in young adult males. Although histologically benign, it can be locally aggressive with a significant recurrence rate. The finding of activating beta-catenin gene mutations in the stromal cells indicates these are the neoplastic cells and supports the association of JNA and familial adenomatous polyposis (FAP). Previous immunohistochemical studies have demonstrated a null or focal myoepithelial immunophenotype in the stromal cells. Recently, expression of several growth factors and oncoproteins including CD117 (c-kit) in the stromal cells has been demonstrated. Our objective is to evaluate the immunohistochemical phenotype of the stromal cell of JNA, particularly within the proliferative zone of the tumour, by application of antibodies against MNF116, CAM5.2, S-100, CD31, CD34, CD99, CD68, vimentin, EMA, SMA, desmin, calponin, Bcl-2 and (CD117) c-kit in a series of 54 cases. METHODS: A routine immunohistochemical protocol was applied to representative paraffin sections of 54 JNAs collected from the Port Moresby General Hospital, Papua New Guinea, and Princess Alexandra and Royal Brisbane Hospitals, Queensland, Australia. Immunoexpression of each antigen was assessed in the stromal cells and the vessels. RESULTS: The majority of stromal cells in more than half of the cases demonstrated no staining with any of the 14 antibodies other than vimentin. Of 54 cases, 22 contained a microvascular component (usually peripherally located and indicating the active growth front of the tumour) in which the stromal cells demonstrated a hybrid immunophenotype with both smooth muscle and endothelial differentiation. c-kit was negative in all cases. CONCLUSIONS: The majority of stromal cells have an undifferentiated immunophenotype with no evidence of epithelial, myoid, endothelial or other lineage specific differentiation. In the microvascular component the stromal cells appear able to show smooth muscle or endothelial differentiation. No c-kit expression was identified.     

Multinucleated stromal giant cells of testis

 

Aims:

This study documents the frequency of multinucleated stromal giant cells within the interstitium of the testis and looks for possible aetiological reasons for this occurrence.  

Materials and methods:

We examined sections of testes from 150 unselected autopsy cases finding stromal giant cells in 43%. An aetiological association between the occurrence of multinucleated stromal giant cells in this site and hormonal or other pathogenetic influences could not be established.  

Conclusions:

In many instances, this occurrence appears to be an age related phenomenon.     

Paracrine effects of uterine leucocytes on gene expression of human uterine stromal fibroblasts

The endometrium contains a distinct population of immune cellsthat undergo cyclic changes during the menstrual cycle and implantation.The majority of these leucocytes are uterine NK (uNK) cells,however how these cells interact with uterine stromal fibroblastsremains unclear. We therefore investigated the paracrine effectof medium conditioned by uterine decidual leucocytes (whichare enriched for uNK cells) on the gene expression profile ofendometrial stromal fibroblasts in vitro using a cDNA microarray.Our results, verified by real-time PCR, ELISA and FACS analysis,reveal that soluble factors from uterine leucocytes substantiallyalter endometrial stromal fibroblast gene expression. The largestgroup of up-regulated genes found was chemokines and cytokines.These include IL-8, CCL8 and CXCL1, which have also been shownto be stimulated by contact of stromal fibroblasts with trophoblast,suggesting that uNK cells work synergistically to support trophoblastmigration during implantation. The decidual leucocytes alsoup-regulated IL-15 and IL-15R in stromal fibroblasts which couldproduce a niche for uNK cells allowing proliferation withinand recruitment into the uterus, as seen in bone marrow. Overallthis study demonstrates, for the first time, the paracrine communicationbetween uterine leucocytes and uterine stromal fibroblasts,and adds to the understanding of how the uterine immune systemcontributes to the changes seen within the cycling endometrium.     

Pathologic and molecular features of uterine carcinosarcomas

Uterine carcinosarcomas (UCSs), formerly known as malignant mixed müllerian tumors, are uncommon neoplasias that account for <5% of uterine malignancies. Traditionally, UCSs have been considered a subtype of sarcoma and the staging system and adjuvant oncological treatments used have been similar to those used for high-grade uterine sarcomas. However, there is now enough clinical, pathologic, and biological evidence to consider UCSs more closely related to high-grade endometrial carcinomas. Thus, these tumors should be staged based on the surgicopathologic staging system used for endometrial carcinomas. Morphologically, UCSs are heterogeneous biphasic tumors composed of an admixture of malignant (endometrioid and nonendometrioid) epithelial and (homologous and heterologous) mesenchymal elements in different proportions. UCSs predominantly metastasize as carcinomas and they are associated with a poor prognosis. Although stage is a consistent prognostic factor, the significance of several histopathological features, such as myometrial invasion, lymphovascular space involvement, type of carcinomatous component, extent of the sarcomatous component, and the presence of heterologous elements, remains controversial and probably differs among different stages. Although the diagnosis of UCS is not difficult in most cases, the differential diagnosis may include entities such as undifferentiated or dedifferentiated carcinoma, endometrioid adenocarcinoma with spindle cell elements, sarcomatous overgrowth in a low-grade müllerian adenosarcoma, and pure malignant mesenchymal tumors. Genetic and molecular studies have confirmed the clonal origin of most UCSs and have shown these tumors to be similar to those observed in high-grade/nonendometrioid carcinomas, with p53 mutations being the most common molecular alteration. Finally, from a biological standpoint, the process by which epithelial malignant cells of UCS transdifferentiate to malignant mesenchymal cells could be considered a true example of epithelial mesenchymal transition in human neoplasias.     

Value of immunohistochemistry in uterine pathology: Common and rare diagnostic dilemmas

Although the majority of diagnoses in gynecological pathology are established on the examination of routine hematoxylin- and eosin-stained sections, additional tests are occasionally required to render an accurate diagnosis. Immunohistochemistry is one such ancillary stain widely used to provide additional diagnostic information in problematic cases.     

Immunohistochemical analysis of carcinomatous and sarcomatous components in the uterine carcinosarcoma: a case report

Uterine carcinosarcoma (malignant mixed Mullerian tumor) is an uncommon female genital tract neoplasm characterized by an admixture of epithelial and stromal malignant cells. We report a case of 50-year-old peri-menopausal woman diagnosed to have early-stage (IB due to FIGO) uterine carcinosarcoma of the homologous type with superficial (3mm) myo-invasion. The patient showed no clinical symptoms of the disease and had no family history of female genital tract malignancies. Positive immunostaining for steroid receptors (estrogen-alpha and progesterone receptors), cytokeratin, and EGFR was detected only in the carcinomatous area, whereas beta-catenin, BCL-2, COX-2, p16(INK4a), PTEN, RB-1, and vimentin were immunoreactive in both components. Androgen receptor, CD10, desmin, HER-2/neu, and P53 were found to be negative either in the carcinomatous or in the sarcomatous area. Tumor proliferative activity was higher in the carcinomatous (25%) than in the sarcomatous (2%) component. Based on these findings, immunohistochemical evaluation of multiple receptor status in the carcinomatous and sarcomatous areas of carcinosarcoma may provide a clue to the pathogenesis and hormonal receptor status of this uncommon uterine malignancy.     

Angiosarcoma of the uterus: report of 2 new cases with deviant clinicopathologic features and review of the literature

A few cases of uterine angiosarcoma have been detailed in the literature: 2 new cases are herein described featuring some unusual clinical or phenotypic differences compared with previously published cases, such as occurrence in premenopausal age or a poorly differentiated histology. The patients were 35 and 81 years old, and both presented with extrauterine spread and evidence of distant metastases. Grossly, they were fleshy, hemorrhagic, and necrotic. Microscopically, they were made up of poorly differentiated, epithelioid, or spindle cells. In one case, the neoplastic growth deceitfully recalled a poorly differentiated leiomyosarcoma showing focal rudimentary endothelial differentiation. The other index case was characterized by a more pronounced vascular pattern, the neoplasm was composed of spindle cells arranged in loose channels. A diffuse immunopositivity for CD31, CD34, and factor VIII–related antigen was detected. Tumor cells were negative for other tested antigens including keratins, desmin, actins, and H-caldesmon. One patient died shortly during the follow-up, whereas the other is alive with evidence of disseminated disease. Occurrence in childbearing age or a deviant histologic pattern, as documented in this report, may be added to the clinicopathologic spectrum of uterine angiosarcoma.     

CD117阴性胃肠道间质瘤的临床病理及免疫组织化学研究

目的 探讨免疫组织化学在形态学典型、免疫组织化学CD117阴性胃肠道间质瘤(GIST)诊断中的意义.方法 对10例CD117阴性、形态学典型的GIST进行c-kit基因第9、11、13、17号外显子及血小板源性生长因子受体α(PDGFRA)基因第12和18号外显子的基因检测,同时所有病例均进行CD117、CD34、平滑肌肌动蛋白(SMA)、结蛋白、S-100蛋白、WT-1、DOG-1 的免疫组织化学染色(EnVision法).结果 10例中8例完成c-kit及PDGFRA基因的检测,仅1例有c-kit基因第9号外显子突变,余未发现基因突变.10例CD117阴性的病例9例CD34阳性,2例SMA局灶阳性.结蛋白和S-100蛋白均阴性.DOG1弥漫阳性者5例,1例弥漫弱阳性,2例局灶阳性,2例阴性.4例WT-1弥漫阳性,2例局灶阳性,1例有散在肿瘤细胞阳性,3例阴性.结论 对胃肠道及胃肠道外形态学典型、但CD117阴性的GIST病例,联合应用多种免疫组织化学标记有助于诊断.DOG-1和WT-1可作为补充加入到CD117阴性GIST的诊断中.     

Aspiration biopsy cytology of metastatic endometrial stromal sarcoma and extragenital mixed mesodermal tumor

Aspiration biopsy from metastatic tumors in two cases of endometrial stromal sarcoma and one case of endometrial adenosarcoma revealed malignant endometrial stromal cells with ill-defined cytoplasm and round or oval hyperchromatic nuclei showing irregular chromatin clumping and conspicuous nucleoli. They were seen mainly in clusters. Aspirate from a metastatic tumor of a mixed mesodermal tumor arising from the omentum showed similar malignant endometrial stroma cells, irregular tight clusters of malignant glandular cells having scanty but well-defined cytoplasm and vesicular nuclei with conspicuous nucleoli, and fragments of atypical smooth muscle tissue. The diagnostic malignant endometrial stromal cells in those reported cases did not display any distinctive cellular features permitting their cytologic identification. They were difficult to differentiate from those of other types of sarcoma. In a clinical setting, with a known primary endometrial stromal sarcoma or mixed mesodermal tumor, however, a cytodiagnosis of its metastases may be suggested when malignant endometrial stromal-cell-like cells are seen in aspirated material, oviating an open-tissue biopsy.     

Low-grade periductal stromal sarcoma of the breast with myxoid features: Immunohistochemistry

A 52-year-old woman was admitted with a painful right breast tumor measuring more than 20 cm in largest diameter, which ulcerated the overlying skin. The lesion had appeared 4 years previously but the patient hesitated to seek medical care due to 'fear of cancer'. Microscopically, the tumor was composed of spindle cells that formed cuffs around multiple open tubules and ducts set in an abundant, myxoid stroma. The spindle cells had significant atypia with nuclear pleomorphism, occasional cytoplasmic vacuolation and moderate mitotic activity. The ducts and lobules surrounded by the proliferating tumor cells had minimal distortion, with a pericanalicular growth pattern devoid of the phyllodes pattern. The tumor had a multinodular growth pattern with coalesced and individual tumor nodules, the latter being found mostly at the periphery of the lesion. On immunohistochemistry the tumor cells were positive for smooth muscle actin, CD34, and vimentin, and focally positive for CD10. A diagnosis of low-grade periductal stromal sarcoma (PDSS) with myxoid features was established. PDSS is a distinct low-grade breast sarcoma, the appropriate diagnosis of which requires extensive tumor sampling and additional broad immunohistochemistry. PDSS should not be confused with other spindle cell breast tumors because they require different treatment.     

Endometrial stromal sarcoma of the uterus with rhabdoid features

A case of endometrial stromal sarcoma of the uterus with rhabdoid features, occurring in a 57 year old woman is reported. Electron microscopy and immunohistochemistry revealed that the rhabdoid cells contained intermediate filaments which were positive for vimentin, cytokeratin, alpha-smooth muscle actin, and muscle specific actin, but not for myoglobin and desmin. This indicated that the tumor in this case differed somewhat from the three rhabdoid tumors and an endometrial stromal sarcoma with rhabdoid differentiation previously reported and that, therefore, these tumors were heterogeneous.     

子宫内膜间质肉瘤与转移复发瘤的形态特点

目的探讨子宫内膜间质肉瘤(ESS)和转移复发瘤组织形态与免疫组织化学染色特点,及其肿瘤分化特点和鉴别诊断。方法观察15例子宫原发ESS及4例转移复发瘤的组织形态,并用免疫组织化学EnVisonTM二步法检测CD10、平滑肌肌动蛋白(SMA)、雌激素受体(ER)、孕激素受体(PR)、AE1/3及α-抑制素的表达,以10例富于细胞平滑肌瘤作对照。结果15例患者发病年龄22～75岁(平均45岁)。组织学分型:7例经典型,3例平滑肌分化型,2例纤维黏液型,3例分化差型,细胞异型明显。4例复发转移瘤中3例组织形态与原发瘤不同。免疫组织化学染色阳性结果:在14例ESS及4例复发转移瘤中CD1015/18、SMA5/18、ER7/18、PR10/18;AE1/3和α-抑制素仅在腺样分化区阳性。平滑肌瘤对照组CD10为1/10、SMA为10/10,表达差异均有统计学意义(P<0.05)。结论ESS多向分化的特点使其呈现多样的组织形态,且转移复发瘤形态可与原发瘤不同。CD10与SMA联合应用有助于ESS的诊断和鉴别诊断。