Immunoreactivity of MIC2 (CD99) in acute myelogenous leukemia and related diseases.

MIC2 is characteristically expressed in lymphoblastic lesions and Ewing's/primitive neuroectodermal tumor sarcomas. Although MIC2 has recently been reported in chloroma and rare terminal deoxynucleotidyl transferase-positive acute myelogenous leukemia (AML), the incidence and the significance of MIC2 (CD99) immunoreactivity in myeloid lesions is not clear. In this study, we evaluated MIC2 positivity in a variety of myeloid diseases and normal marrow to determine its incidence and distribution in myeloid diseases; its correlation with flow cytometric and cytogenetic data in AML; and its association with leukemic transformation, relapse, and chloroma formation. Paraffin sections of 11 chloromas and 94 bone marrow core biopsies from 66 patients were stained with CD99 monoclonal antibody 12E7. Of 94 bone marrow core biopsies, there were 30 AML (fragment antigen binding M0 to M6), 23 remissions, 5 relapses, 12 myeloproliferative disorders, 13 myelodysplastic syndromes, and 11 normal marrows from patients who did not have leukemia. CD99 immunoreactivity was evaluated with light microscopy. MIC2 expression was seen in leukemic blasts in 6 of 11 chloromas (55%) and 13 of 30 AML (43%) but rarely in myeloproliferative disorders, myelodysplastic syndromes, remission, and normal marrow. CD99 tended to be positive in M1-, M3-, and HLA-Dr-negative AML and negative in AML with relapse. MIC2 expression did not correlate with the karyotype independent of French-American-British Cooperative Group classification and the disease remission or occurrence of chloroma in AML. We concluded that MIC2 is commonly expressed in leukemic blasts of AML and is not predictive of leukemic transformation from myeloproliferative disorders and myelodysplastic syndromes or chloroma formation. Caution should be taken when using MIC2 as a marker for Ewing's sarcoma/ primitive neuroectodermal tumor or lymphoblastic lymphoma on paraffin sections of either soft tissue or bone marrow specimens.     

Fine-needle aspiration biopsy of metastatic Ewing's sarcoma with MIC2 (CD99) immunocytochemistry

The use of fine-needle aspiration biopsy (FNAB) has been infrequently described as a diagnostic modality for Ewing's sarcoma (ES) patient follow-up and management. The purpose of this study is to examine the use and accuracy of FNAB combined with MIC2 immunocytochemistry for evaluating metastases in patients with ES. Records from Saint Louis University Health Sciences Center and Indiana University Medical Centers identified patients with known ES who had undergone FNAB for evaluation of potential metastases. Immunocytochemical analysis for MIC2 (CD99) was performed retrospectively on cell blocks and direct aspirate smears. FNABs from nine patients were procured either percutaneously or under radiologic guidance and in all cases a definitive cytologic diagnosis of metastatic ES was rendered. Aspirates were cellular with many single discohesive small round cells and occasional loosely cohesive clusters. The nuclei were round with a fine chromatin pattern and small nucleoli. The cytoplasm was scanty and the nuclear-cytoplasmic ratio was high. Six of six cases showed strongly positive immunocytochemical labeling for MIC2. Immunocytochemistry with MIC2 in FNAB aspirate smears can provide supportive evidence of ES in patients with known disease. Diagn. Cytopathol. 1998;19:382–384. © 1998 Wiley-Liss, Inc.     

CD200 (OX-2 membrane glycoprotein) expression in b cell-derived neoplasms

We studied the expression of CD200, an immunoglobulin superfamily membrane glycoprotein, in a wide range of B cell-derived neoplasms by immunohistochemical staining of paraffin-embedded tissue sections. In addition to chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), CD200 is expressed in other B-cell lymphoproliferative disorders, including hairy cell leukemia. In addition, neoplastic cells in classical Hodgkin lymphoma are immunoreactive for CD200. CD200 was previously reported to be expressed in acute myeloid leukemia, and we find that it is also expressed in B-lymphoblastic leukemia/lymphoma. We conclude that CD200 may be a useful immunophenotypic marker in the evaluation of B cell-derived neoplasms. Furthermore, since an anti-CD200 immunotherapeutic agent is in clinical trials, a number of B cell-derived neoplasms in addition to CLL/SLL may be suitable therapeutic targets.     

CD147 (EMMPRIN) and matrix metalloproteinase-2 expression in uterine endometrioid adenocarcinoma

Low-grade uterine endometrioid adenocarcinomas (EACs) may exhibit a distinct pattern of myometrial invasion characterized by the presence of microcystic, elongated, and fragmented (‘MELF’) glands but the factors influencing this pattern of invasion are not known. Immunohistological expression of CD147 (extracellular inducer of matrix metalloproteinase, EMMPRIN) and matrix metalloproteinase-2 (MMP2) was studied in 22 EAC and the results compared between the ‘conventional’ neoplastic glands, foci of MELF-type invasion, and in the tumor-associated stroma. The conventional tumor areas showed strong membranous expression of CD147, and staining was more consistently present toward the central (luminal) aspect of the larger glands. In contrast, the tumor cells showed only focal expression of MMP2, and in some cases CD147 and MMP2 staining was inversely correlated. The neoplastic epithelium within MELF areas usually was negative for both CD147 and MMP2. However, there was consistent MMP2 expression in the reactive stroma that characteristically surrounds foci of MELF pattern invasion. This micro-anatomical variation in protein expression within EAC suggests a functional alteration in the neoplastic epithelium during the invasive process. It is likely that stromal MMP2 plays a role in potentiating invasion in these tumors but this may be regulated by factors other than CD147.     

Discovered on gastrointestinal stromal tumours 1 (DOG1) expression in non-gastrointestinal stromal tumour (GIST) neoplasms

Hemminger J & Iwenofu O H
(2012) Histopathology  61, 170–177 Discovered on gastrointestinal stromal tumours 1 (DOG1) expression in non‐gastrointestinal stromal tumour (GIST) neoplasms Aims: To further characterize discovered on GIST1 (DOG1) antibody clone K9 expression in a broad range of mesenchymal and epithelial tumours. Methods and results: Formalin‐fixed paraffin‐embedded sections of various tumours were stained with the anti‐DOG1 monoclonal antibody clone K9. The tumours (n = 187) included: gastrointestinal stromal tumours (GISTs) (n = 20); malignant melanoma (n = 19); schwannoma (n = 10); neurofibroma (n = 10); leiomyosarcoma (n = 10); low‐grade fibromyxoid sarcoma (n = 5); angiosarcoma, (n = 10); epithelioid sarcoma (n = 5); clear cell sarcoma (n = 3); synovial sarcoma (n = 10); malignant peripheral nerve sheath tumour (MPNST) (n = 12); alveolar soft part sarcoma (n = 3); chordoma (n = 5); pleomorphic undifferentiated sarcoma (n = 5); perineurioma (n = 4); granular cell tumour (n = 6); acinic cell carcinoma (n = 5); adenocarcinoma, lung (n = 5), colon (n = 10), endometrioid (n = 10), prostate (n = 10) and renal cell (n = 10). Nineteen of 20 GISTs expressed DOG‐1 and 12 of 20 were diffusely positive (≥95%) with moderate to strong intensity. There was focal, predominantly luminal staining of colorectal (three of 10), endometrioid (four of 10) and acinic cell carcinomas (four of five). One case each of spindle cell/desmoplastic melanoma (2+), schwannoma (trace) and MPNST (2+) showed DOG‐1 expression. Conclusions: Our study supports that DOG‐1 is a highly sensitive and specific marker for GISTs and also highlights hitherto unrecognized and unusual patterns of expression in non‐mesenchymal neoplasms.     

Inhibin expression in ovarian-type stroma in mucinous cystic neoplasms of the pancreas.

Mucinous cystic neoplasms (MCNs) of the pancreas are typically found in middle-aged to elderly women and contain ovarian-type stroma in the cyst wall. Whether the resemblance of this stroma to ovarian stroma is only morphologic or has more functional similarity is still unclear. Estrogen receptors (ER) and progesterone receptors (PR) have been shown to be expressed in a wide variety of tissues and tumors, including the ovarian-type stroma of MCN. Inhibin, on the other hand, has been shown to have a more restricted expression, limited to ovarian sex cord-stromal components and placental cells, and has recently been shown to be expressed in pancreatic MCNs. However, it is still unclear whether this expression is limited to MCNs of the pancreas and whether it has any diagnostic role. Seven cases of MCN (4 mucinous cystadenoma, 2 borderline MCN, and 1 mucinous cystadenocarcinoma with microinvasion), 6 cases of intraductal papillary mucinous tumor, 1 of mucinous cystic tumor of uncertain classification, 2 of mucinous noncystic adenocarcinoma, 4 of serous cystadenoma, and 4 solid pseudopapillary neoplasms were selected for this study. Five cases with normal pancreatic tissue were included as controls. Immunohistochemical stains for alpha-inhibin, ER, and PR were performed on a representative section from each case on formalin-fixed, paraffin-embedded tissue sections using a standard indirect immunoperoxidase method. All cases of MCN were in female patients with an average age of 55.3 years, showing ovarian-type stroma and clusters of alpha-inhibin-positive luteinized theca-like cells. In all these cases, moderate to strong PR positivity was also noted in the ovarian-type stroma, including many of the alpha-inhibin-positive luteinized theca-like cells. ER was expressed in 2 cases. The epithelial cells of MCNs were all negative for ER, PR, and alpha-inhibin staining. Of the other tumors, 4 solid pseudopapillary neoplasms showed positivity for only PR in the tumor cells. The remaining tumors were negative for all markers. In conclusion, the finding of alpha-inhibin positivity in MCN with ovarian-type stroma further supports its similarity to true ovarian stromal tissue and may suggest a role of complex hormonal interaction in the pathogenesis. In addition, its limited expression in MCNs of the pancreas may be diagnostically useful in difficult cases.     

p53 expression in neoplasms of the uterine corpus.

It has been recognized that mutations in tumor suppressor genes may have an important oncogenic role. Although abnormalities of the p53 tumor suppressor gene have been reported in tumors from various organ systems, p53 expression has not been studied in neoplasms of the uterine corpus. Using a monoclonal antibody to the p53 product, frozen sections of 56 uterine tumors (40 endometrioid endometrial adenocarcinomas, 7 serous endometrial carcinomas, 4 mixed Müllerian tumors, 2 endometrial stromal sarcomas, 1 leiomyosarcoma, 2 leiomyomas) and 2 normal endometria were stained using the immunoperoxidase technique. Staining was evaluated by light microscopic examination; in carcinomas with strong/diffuse reactivity, evaluation was by digitized image analysis. p53 staining of adenocarcinomas was compared statistically to the histologic type, grade, surgical stage, and clinical follow-up. Specific staining was present in the nucleus of malignant tumor cells only. Benign cells did not stain. Strong/diffuse staining was seen in 14 adenocarcinomas and in 2 mixed Müllerian tumors. Weak/focal staining was observed in 14 adenocarcinomas. Serous carcinomas showed strong positivity more frequently than endometrioid endometrial carcinomas. Staining patterns correlated with histologic grade and stage. Image analysis of immunostained p53 correlated with type of adenocarcinoma, but not with grade or stage in the cases measured. p53 was expressed strongly in tumors of five of eight patients who died of adenocarcinoma but in none of five patients with no evidence of disease and a minimum follow-up of 24 months. In addition, 3 of 12 patients with persistent or recurrent disease showed tumors that strongly expressed p53. It is concluded that abnormal expression of p53 occurs frequently in malignant uterine tumors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms. Frequent expression in renal cell carcinoma and endometrial stromal sarcoma

We tested 505 cases of nonhematopoietic neoplasms by immunohistochemistry using a newly characterized monoclonal antibody (clone 56C6) against the CD10 antigen. CD10 was expressed widely in neoplasms of the genitourinary tract, including 41 (89%) of 46 cases of renal cell carcinoma, 13 (54%) of 24 cases of transitional cell carcinoma, and 11 (61%) of 18 cases of prostatic adenocarcinoma. In addition, 5 (100%) of 5 endometrial stromal sarcomas, 3 (60%) of 5 rhabdomyosarcomas, 7 (50%) of 14 pancreatic adenocarcinomas, 5 (45%) of 11 cases of schwannoma, and 12 (40%) of 30 cases of malignant melanoma also were positive for CD10. Similar to normal tissue, CD10 positivity was restricted to the apical surface of malignant glandular cells of well-differentiated colonic, pancreatic, and prostatic adenocarcinoma, whereas in poorly differentiated adenocarcinoma and other tumors, such as melanoma, transitional cell carcinoma, renal cell carcinoma, and endometrial stromal sarcoma, the CD10 positivity showed diffuse cytoplasmic or membranous/Golgi patterns. The monoclonal antibody clone 56C6 is a reliable marker for CD10 in paraffin immunohistochemistry after heat-induced epitope retrieval. CD10 expression in renal cell carcinoma and endometrial stromal sarcoma may be a useful marker in the differential diagnoses of these tumors because both tumors otherwise lack specific markers.     

CD117在胃肠道间质瘤和其他肿瘤中的表达

CD117是由c—kit基因（4q11-q21）编码的Ⅲ型跨膜酪氨酸激酶受体家族成员,目前CD117已成为诊断胃肠道间质瘤（gastrointestinal stromal tumors,GIST）不可缺少的参考指标。大部分病理医师对CD117的认识是从GIST开始的,可能会认为CD117是GIST的特异标记物。而且,最初认为除GIST外,其他肿瘤尤其是梭形细胞肿瘤很少表达CD117,但随着近年的广泛运用,已发现许多表达CD117的肿瘤。为促进对CD117的了解和在实际工作中的正确使用,有必要就CD117的表达谱等问题作一综述。     

Prevalence of CD99 protein expression in pancreatic endocrine tumours (PETs)

AIMS: To determine the prevalence of CD99 expression in pancreatic endocrine tumours (PETs). We evaluated CD99 expression and analysed Ki67 labelling by immunohistochemistry in PETs. METHODS AND RESULTS: Thirty-eight PETs from 33 patients were analysed. CD99 immunoreactivity was consistently observed in normal islets of the pancreas, regardless of the cell type. Tumours comprising more than 30% CD99+ cells were defined as positively immunoreactive for CD99. CD99 expression was observed in 20 of the 38 PETs examined, but not in any of the pancreatic tumours of other histological subtypes (10 ductal adenocarcinomas, five intraductal papillary-mucinous tumours, and two acinar cell tumours). Loss of CD99 expression was related to markers of worse prognosis for PET, including gross local invasion, metastasis to the lymph nodes or other organs, lymphatic or blood vessel invasion, and neuroendocrine carcinoma (NEC). Thus, CD99 expression may have an efficiency comparable to that of high Ki67 labelling index (5% or more) for prognostication. CONCLUSIONS: CD99 expression was observed frequently and exclusively in PETs, and loss of CD99 expression in PETs was found to be associated with ominous prognostic indicators.     

Glycoprotein CD44 expression in colorectal neoplasms

 CD44 has diverse functions in cell–cell and cell–matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. The immunohistochemical expression of CD44 in a series of 110 colorectal carcinomas and 25 adenomas was examined using the monoclonal mouse anti-human phagocytic glycoprotein-1, CD44 (clone DF 1485) in correlation with the expression of basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, p53, Rb, bcl-2, c-erbB-2, EGFR, proliferation indices (Ki-67, PCNA) and with other conventional clinicopathological variables. In adenomas, low CD44 expression (<10% of neoplastic cells) was present in 16%, moderate (10–50% of neoplastic cells) in 52% and extensive (>50% of neoplastic cells) in 32% of cases. In carcinomas, low CD44 expression was found in 14.5%, moderate in 28.2% and extensive in 57.30%. Although the CD44 expression was higher in carcinomas than in adenomas, we found no statistically significant difference between these two groups. CD44 expression in carcinomas was positively correlated with tumour size (P=0.018), tumour cells cathepsin D (P=0.022), stromal cell cathepsin D (P=0.003) and Rb protein (P=0.021). An inverse correlation was observed between CD44 and the anti-apoptotic protein expression bcl-2 in adenocarcinomas (P=0.039) and in adenomas (P=0.021). These data suggest that CD44 may be involved in the process of invasion and metastasis, probably with the cooperation of cathepsin D. Its expression may be an indicator of poor prognosis in colorectal adenocarcinomas. Received: 28 July 1998 / 8 October 1998     

CD99/MIC-2 surface protein expression in breast carcinomas

AIM: To evaluate the expression of CD99/MIC-2 surface protein in invasive breast carcinomas and demonstrate whether or not there is a relationship with tumour phenotype. METHODS AND RESULTS: Thirty-five invasive breast carcinomas, including five metaplastic carcinomas, were stained with CD99 primary antibodies using standard protocols based on streptavidin-biotin-peroxidase method. Four out of five metaplastic carcinomas expressed CD99/MIC-2 protein, three of them were matrix-producing carcinomas. From the other 30 cases, only an invasive apocrine carcinoma was positive. There was no statistical correlation between CD99 expression and the parameters analysed (histological typing and grading, proliferative index and nodal status). CONCLUSIONS: CD99/MIC-2 is expressed in breast carcinomas, especially in the matrix-producing variant of metaplastic carcinomas, which impairs its use as a marker to differentiate metaplastic carcinomas from primary and metastatic sarcomas of the breast. It seems to have no prognostic implications. However, phenotype similarities with other chondromyxoid tumours that also express the protein, like mesenchymal chondrosarcomas, suggest a relationship between MIC-2 reactivity and morphological differentiation.     

Claudin-5和CD99在胰腺实性-假乳头状肿瘤和神经内分泌肿瘤中的表达及其意义

目的 研究内皮细胞间紧密连接蛋白Claudin-5和细胞间黏附分子CD99在鉴别胰腺实性-假乳头状瘤(SPN)与胰腺神经内分泌性肿瘤(P-NET)中的意义.方法 应用免疫组织化学MaxVision法检测于2003至2012年收集的37例SPN、21例P-NET组织中Claudin-5和CD99的表达情况.结果 37例SPN,Claudin-5在细胞膜表达,阳性率为100％;21例P-NET,Claudin-5均不表达;两者之间差异有统计学意义(P＜0.01).CD99在SPN和P-NET中的表达模式不同,前者呈核旁点状聚集,后者在细胞膜表达,其表达率分别为91.9％(34/37)和61.9％(13/21);两者之间差异有统计学意义(P＜0.01).Claudin-5和CD99在SPN中的表达呈显著正相关(r=0.421,P=0.001).结论 对于大体和镜下特征与P-NET相似的SPN病例,仅依靠形态学诊断十分困难.免疫组织化学联合检测Claudin-5和CD99则对鉴别诊断有重要意义.     

Loss of CD19 expression in B-cell neoplasms

AIMS: To investigate whether an antibody against an intracellular epitope can detect CD19 in routine biopsy specimens and thus to document in detail its expression in human lymphomas. METHOD AND RESULTS: A polyclonal antibody to the C terminus of CD19 was used to immunostain paraffin-embedded samples of normal and neoplastic lymphoid tissues. CD19 was widely expressed in normal B cells and in extramedullary plasma cells. It was found in most B-cell neoplasms, but expression in follicular lymphoma was weak (33/69) or negative (four cases). Similarly, CD19 expression in diffuse large B-cell lymphomas was weak (28/56) or negative (eight cases). In T-cell-rich B-cell lymphomas, CD19 was also weak (4/10) or negative (three cases). CD19 was often absent in post-transplant B lymphoproliferative disease, classical Hodgkin's disease and plasma cell neoplasms. An unexpected finding was the frequent absence of CD19 in the neoplastic cells in lymphocyte predominant Hodgkin's disease. CONCLUSIONS: CD19 can now be detected in routine biopsy specimens. In contrast to the classical pan-B marker CD20, CD19 is not always strongly expressed in B-cell neoplasms. Furthermore, the lymphocytic and histiocytic (L&H) cells of lymphocyte predominant Hodgkin's disease (which express most B-cell-associated markers) commonly lack CD19.     

TCL1 and CLA expression in agranular CD4/CD56 hematodermic neoplasms (blastic NK-cell lymphomas) and leukemia cutis

Agranular CD4/CD56 hematodermic neoplasm (CD4/CD56 HN), also termed blastic natural killer cell lymphoma, is characterized by a peculiar immunophenotype and high skin tropism. The lineage of origin is not known, and a plasmacytoid dendritic cell derivation has been proposed. CD4/CD56 HN generally is diagnosed by using tumor skin biopsy, with the most important differential diagnosis being myelomonocytic leukemia cutis. We evaluated the expression of 2 plasmacytoid dendritic cell antigens, T-cell leukemia 1 (TCL1) and cutaneous lymphocyte-associated antigen (CLA), in 29 cases of CD4/CD56 HN and 18 cases of myelomonocytic leukemia cutis. TCL1 and CLA were expressed in 26 (90%) of 29 CD4/CD56 HN cases vs TCL1 expression in 3 (17%) and CLA expression in 14 (78%) of 18 leukemia cutis cases. Furthermore, CLA antiserum displays a peculiar small-dot staining pattern in CD4/CD56 HN. These results suggest that TCL1 and CLA are good markers for CD4/CD56 HN tumor cells and add support for a plasmacytoid dendritic cell origin. The high skin tropism of CD4/CD56 HN might be related to the skin-homing property of CLA.     

Her-2 expression in cutaneous eccrine and apocrine neoplasms.

Cutaneous eccrine and apocrine glands have many histologic and immunologic similarities to ducts and acini of the breast. Thus, differentiating a primary cutaneous process from a metastatic breast carcinoma can be nearly impossible. In all, 10-34% of breast carcinomas overexpress HER-2 protein, a membrane-associated protein that functions in cell differentiation, adhesion and motility. As expression of this gene in cutaneous neoplasms has not been well characterized, we sought to determine HER-2 expression in a sample of benign and malignant cutaneous eccrine and apocrine neoplasms and to determine if there is value in using this protein expression in differentiating primary cutaneous from metastatic breast lesions. Totally, 85 primary cutaneous neoplasms and 11 cutaneous metastases from HER-2-positive breast carcinomas were retrieved from archived material at our institute. All cases were evaluated for HER-2 protein expression using the Dako Hercept Test kit. Membranous HER-2 staining was noted in three of the 85 cutaneous adnexal neoplasms: one hidrocystoma and two nodular hidradenomas. Seven of the 11 cutaneous metastases from HER-2-positive breast carcinomas maintained moderate-to-strong HER-2 expression. In conclusion, while 10-34% of breast carcinomas overexpress the HER-2 protein, only 3.5% of cutaneous apocrine and eccrine neoplasms in this study stained with the HER-2 antibody. These HER-2-positive cutaneous neoplasms typically do not pose a diagnostic dilemma in the setting of differentiation from breast metastasis. Additionally, although histologically these breast and cutaneous lesions may have morphologic similarities, the relative lack of HER-2 overexpression suggests that they are different nosologically. Finally, this study suggests that HER-2 protein expression can be a useful tool in differentiating a primary cutaneous appendageal neoplasm from HER-2 expressing metastatic breast carcinoma.     

CD34low and SMAhigh represent stromal signature in uterine cervical cancer and are markers for peritumoral stromal remodeling

Peritumoral desmoplastic stromal reaction (DSR) with myofibroblastic phenotype may be of prognostic impact in uterine cervical carcinoma. The present study evaluates the immunostaining (CD34 and smooth muscle actin; SMA) of 97 squamous cell cancers. Staining was scored as low/negative (< 5% stroma positive), moderate (patchy/focal expression, 5%-50%), or high (diffuse expression throughout peritumoral stroma, > 50%) and DSR as negative/weak and moderate/strong. The staining results were correlated to patient survival. Of the cases, 78.3% showed a decreased of CD34 (< 5% stromal positivity) and 71.9% an increased SMA staining with more than 50% SMA positive stromal cells. Tumors representing moderate/strong DSR showed a significant decreased CD34 (P = .001) and an increased but not statistically significant SMA staining (P = 0.345). Cases with low CD34 and high SMA staining showed reduced 5-year overall survival when compared to cases with high CD34 and low SMA positivity (59.9 vs 81.0%; P = 0.025 and 64.6 vs 81.1%; P = 0.243). Peritumoral stromal response in cervical carcinoma is immunohistochemically characterized by CD34^low/SMA^high and associated reduced overall survival.