Takako Kiyokawa

The Jikei University School of Medicine, Tokyo, Tokyo-to, Japan

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Publications (18)42.75 Total impact

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    ABSTRACT: The aim of this study was to determine the impact of prognostic factors in primary fallopian tube carcinoma (PFTC). All cases of PFTC diagnosed between 1990 and 2010 were retrieved from the files of 6 academic centers. The cases were staged according to a modification of the International Federation of Obstetrics and Gynecology staging system proposed by Alvarado-Cabrero et al (Gynecol Oncol 1999; 72: 367-379). One hundred twenty-seven PFTC cases were identified. The mean age of the patients was 64.2 years. Stage distribution was as follows: 72 (57%), stage I; 19 (15%), stage II; 28 (22%), stage III; and 8 (6.2%), stage IV. Depth of infiltration of the tubal wall was an independent prognostic factor in stage I cases (P < .001). Carcinomas located in the fimbriated end even without invasion had a worse prognosis than did carcinomas involving the tubal portion of the organ. The presence of vascular space invasion correlated with the depth of tubal wall invasion (P = .001) and the presence of lymph node metastases (P = .003). Tumor grade significantly correlated with survival (P < .0001), but histologic type was of marginal significance and only if it was grouped as nonserous/non-clear cell vs serous/clear cell (P = .04). The depth of invasion of the tubal wall and the presence of carcinoma in the fimbriated end even without invasion are important prognostic indicators. The modified International Federation of Obstetrics and Gynecology staging system should be used on a routine basis in all carcinomas of the fallopian tube.
    Annals of diagnostic pathology 11/2012;
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    ABSTRACT: Choriocarcinoma is a highly malignant tumor of trophoblastic origin. Most cases occur in association with preceding gestational events. However, on very rare occasions, nongestational choriocarcinoma arises from germ cell or trophoblastic differentiation in different types of carcinoma. This article reports the case of a 58-year-old woman with primary nongestational choriocarcinoma of the uterus that developed 19 years after her final pregnancy and 4 years after menopause. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. Histopathological examination showed choriocarcinoma of the uterus without components of other germ cell tumors. Karyotype analysis of the tumor cells demonstrated XX. We confirmed its nongestational origin by DNA polymorphism analysis at 15 short tandem repeat loci. After surgery, the patient was given four courses of combination chemotherapy. She is still alive and there has been no evidence of recurrence 3 years after surgery.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 05/2012; 31(4):364-8. · 2.07 Impact Factor
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    ABSTRACT: CD147 is a membrane glycoprotein that is expressed in various cancer cells and is involved in tumor invasion and metastasis by inducing stromal fibroblastic cells to produce matrix metalloproteinases. This study was carried out to evaluate the correlation between CD147 expression and various clinicopathologic parameters, including histological grade and prognosis in a small sample set of human ovarian cancer patients. Paraffin-embedded surgical tissue samples from 25 patients with ovarian serous and endometrioid adenocarcinoma were stained with anti-CD147 antibody (monoclonal antibody 12C3: MoAb 12C3) for immunohistochemical analysis. CD147 protein was expressed in 84.0% (21 of 25 cases) of cancerous lesions, but not in normal lesions. CD147 expression by ovarian cancer cells was inversely correlated with overall survival. There was no correlation between CD147 expression and histological grade. These results suggest that measurement of CD147 expression may enhance the understanding of the pathophysiology of epithelial ovarian cancer.
    Journal of Obstetrics and Gynaecology Research 05/2012; 38(9):1211-9. · 0.84 Impact Factor
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    ABSTRACT: To clarify the preoperative differential diagnosis and management of minimal deviation adenocarcinoma (MDA) and lobular endocervical glandular hyperplasia (LEGH), a multicenter study was performed. A total of 112 patients who underwent conization or a hysterectomy for suspected MDA were collected from 24 hospitals. The pathological diagnosis in each case was determined by a central pathological review board. The diagnostic significance of clinicopathologic findings including results of magnetic resonance imaging (MRI), Papanicolaou (Pap) smears, and testing for gastric mucin was analyzed. The central pathological review identified 37 cases of Nabothian cyst or tunnel cluster, 54 cases of LEGH, 6 cases of MDA, 11 cases of adenocarcinoma, and 4 cases of benign disease. Lobular endocervical glandular hyperplasia was often associated with adenocarcinoma in situ, MDA, and mucinous adenocarcinoma. Three MDA patients had a recurrence, whereas none of LEGH patients had a recurrence irrespective of the type of surgery. On MRI, LEGH appeared as a characteristic multicystic lesion with an inner solid component, whereas MDA showed a predominantly solid pattern. A Pap smear or gastric mucin alone had limited diagnostic power. However, a combination of these findings is useful; that is, a cystic structure with inner solid components on MRI associated with mild glandular atypia and gastric mucin strongly suggested LEGH (24/26, 92%). A solid structure with atypical glandular cells was indicative of MDA or adenocarcinoma (5/5, 100%). The combination of MRI, Pap smears, and gastric mucin will improve the accuracy of the preoperative diagnosis of MDA and LEGH. Patients suspected of having LEGH may need to be treated with less aggressive methods.
    International Journal of Gynecological Cancer 06/2011; 21(7):1287-96. · 1.94 Impact Factor
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    ABSTRACT: A subset of endocervical-type mucinous adenocarcinomas (ACs) of the uterine cervix exhibit a gastric phenotype and morphology, as reported in cases of minimal deviation AC in which the presence of human papillomavirus (HPV) has been rarely detected. To investigate the HPV-independent pathway of carcinogenesis in cases of gastric-type AC, we investigated the common high-risk HPV (hr-HPV) status in 52 nonsquamous cell carcinomas, using a PCR-based typing method and immunohistochemistry of p16INK4a (a cyclin-dependent kinase inhibitor that is overexpressed in both cancerous and precancerous cervical tissue, making it an ideal biomarker for cervical cancer cases). Using novel morphological criteria, seven of 52 (13.5%) carcinomas were designated as gastric-type ACs, all of which were negative for both hr-HPV DNA and p16INK4a. Nongastric-type ACs were frequently positive for both hr-HPV DNA (90%, 28/31) and p16INK4a (94%, 29/31) with adenosquamous and neuroendocrine carcinomas demonstrating the presence of hr-HPV DNA in 86% (6/7) and 83% (5/6) of cases, respectively. In these two types of carcinoma, 86% (6/7) and 100% (6/6) were positive for p16INK4a, respectively. Our data suggests that gastric-type AC appears to represent an oncogenic hr-HPV-independent neoplasm and therefore is a potential pitfall of HPV DNA testing and vaccination.
    American Journal Of Pathology 11/2010; 177(5):2169-75. · 4.52 Impact Factor
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    ABSTRACT: We report a mitochondrial (MT) scoring system related to response to platinum treatment in ovarian cancer (OC). Ultra-thin sections of surgical specimens of primary tumors prepared from 41 OC patients were examined by electron microscopy. The ovarian carcinoma cell line 2008 and its platinum-resistant variant C13 were used as controls. Seven independent MT features, including MT diameter, pattern of cresta structure, electron density, MT distribution, pattern of distribution, ovoid ratio and MT architecture, were examined. Each of the seven parameters was assigned a point score of 0-2 and was summed up with a total score of 14. Clinical response and in vitro sensitivity to platinum, taxane, irinotecan and doxorubicin were evaluated. Clinical information was available for 37 of the 41 cases. Twenty-four cases were stage III and, histologically, 16 serous, 6 endometrioid and 6 clear cell carcinoma were included. All of the patients underwent surgery followed by 6 cycles of taxane and platinum chemotherapy. Fifteen patients exhibited a response, while 22 were resistant to treatment. The total MT score was 5.13±1.13 (mean ± SE) in the 15 responsive cases and 11.41±0.43 in the 22 resistant cases (P<0.001). Receptor operative characteristic (ROC) analysis revealed that the resistant total 'cut-off' score was ≥10 points (P<0.05; AUC=0.86) with 95.5% sensitivity and 80.0% specificity. The MT scoring system correlated well with response to drugs, with the exception of doxorubicin. The progression-free survival (PFS) curves showed an absolute difference in the 6-month PFS of 10% (83 vs. 73%) and in the 12-month PFS of 21% (80 vs. 59%), in favor of patients with low MT scores. This MT scoring system correlates very closely with clinical response as well as cellular sensitivity to chemotherapy, resulting in an association with PFS.
    Experimental and therapeutic medicine 01/2010; 1(5):783-788. · 0.34 Impact Factor
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    ABSTRACT: Ovarian stromal hyperthecosis is characterized by diffuse distribution of luteinized stromal cells accompanied by varying degrees of stromal hyperplasia. We report a case of ovarian stromal hyperthecosis with particular regard to magnetic resonance (MR)-pathologic correlation. At initial MR imaging, the central areas of the bilateral ovarian masses showed hypointensity on T1-weighted images and hyperintensity on T2-weighted images, while the peripheries of the bilateral masses showed isointensity to myometrium on T1-weighted images and heterogeneous signal intensities on T2-weighted images. At 15 days after the initial MR imaging examination, a second MR imaging demonstrated shrinkage of the bilateral ovarian masses. Change in the peripheries to predominantly isointensity to myometrium on the T2-weighted images was also observed. The patient underwent bilateral oophorectomy. Microscopic examination revealed scattered nests of lutein cells on a background of densely proliferated ovarian stroma with minimal collagen production in both ovaries. Edema was occasionally seen in the outer portion but was marked in the central zone of the ovaries, particularly on the left. The final pathologic diagnosis was stromal hyperthecosis. With regard to MR-pathologic correlation, the MR findings in the peripheries of the bilateral masses (isointensity relative to myometrium on both T1- and T2-weighted imaging) showed the characteristics of stromal hyperthecosis.
    Acta Radiologica 10/2009; 50(8):954-7. · 1.33 Impact Factor
  • Histopathology 10/2009; 55(3):362-4. · 2.86 Impact Factor
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    ABSTRACT: Apart from typical yolk sac tumors, ovarian tumors with elevated alfa-fetoprotein (AFP) are uncommon and the differential diagnosis needs to consider the hepatoid pattern of a yolk sac tumor, hepatocellular carcinoma metastatic to the ovary, hepatoid carcinoma, and other epithelial ovarian tumors. We report here an AFP-producing ovarian tumor with uncertain pathological diagnosis, which was extremely responsive to chemotherapy. A 59-year-old Japanese woman presented with lower abdominal distension and was found to have a left ovarian mass on pelvic examination and magnetic resonance imaging (MRI) scan. Laboratory tests showed serum AFP, 73 687 ng/ml; carbohydrate antigen 125 (CA125), 1599 U/ml; and carcinoembryonic antigen (CEA), 13.9 ng/ml. Total hysterectomy with bilateral salpingo-oophorectomy, partial omentectomy, and low anterior resection of the rectum was performed, without any residual macroscopic tumor. Microscopically, the tumor was characterized by a hepatoid carcinomatous component composed of solid sheets of large eosinophilic cells with pleomorphic nuclei. The pathological stage was pT2N0M0. Tumor cells were diffusely immunoreactive for AFP and cytokeratin (CAM5.2), but monoclonal CEA and CA19-9 were focally positive in the cytoplasm, while CA125 was negative. The patient was treated postoperatively with three cycles of chemotherapy consisting of bleomycin, etoposide, and cisplatin; with this regimen, serum AFP decreased to 16 ng/ml from 12 600 ng/ml just before the initiation of chemotherapy. The patient received secondary cytoreductive surgery of systemic lymphadenectomy, which revealed no evidence of residual tumor.
    International Journal of Clinical Oncology 03/2009; 14(1):70-3. · 1.73 Impact Factor
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    ABSTRACT: To describe the gastric phenotype of synchronous mucinous metaplasia and neoplasms of the female genital tract (SMMN-FGT). 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). There is a close association between SMMN-FGT and LEGH/PGM. Microinvasion and positive peritoneal cytology may not have an influence on outcome.
    Histopathology 02/2009; 54(2):184-91. · 2.86 Impact Factor
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    ABSTRACT: We developed mitochondrial (MT) scoring system based on MT ultrastructural findings in association with response to chemotherapy in ovarian cancer (OC). Ultrathin sections of MT prepared from 28 OC patients before chemotherapy were examined by electron microscopy. Platinum-sensitive ovarian carcinoma cell line 2008 and its resistant variant C13 were used as control cells. Seven independent MT features including, diameter, pattern of cresta structure, electron density, distribution-density and -pattern, ratio of minimal/maximal diameter and MT architecture were examined and were assigned a score between 0 and 2. Twenty-eight cases were primary advanced OC, including 4 recurrent cases. Nine cases were chemosensitive while 19 were resistant. Univariate and multivariate analysis in each factor showed good correlation to chemosensitivity for 2 factors of electron density, distribution pattern. Total score of these 2 factors in 9 sensitive cells was 1.44+/-0.41 (M +/- SE) and was 3.58+/-0.18 in 19 resistant cells (P<0.001). Receptor operative characteristics (ROC) analysis revealed that total 'cut-off' score was 3 point (P<0.05; AUC=0.84). In conclusion, this MT scoring system was excellently correlated to response regardless of histopathologic findings and this strongly suggests that the system is deemed to be of great value as biomarker for the chemosensitivity in OC.
    Oncology Reports 01/2009; 21(1):199-204. · 2.30 Impact Factor
  • Histopathology 10/2008; 53(4):487-90. · 2.86 Impact Factor
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    ABSTRACT: Ovarian mucinous borderline tumor of müllerian type (MMBT) and mixed epithelial borderline tumor of müllerian type (MEBT) are uncommon subtypes of ovarian surface epithelial tumors. Both are often associated with endometriosis, but their histogenesis is still debated. We have noticed occasional foci of subepithelial cuboidal cells resembling uterine cervical reserve cells (RCs) in MMBTs/MEBTs, which have not been documented in the literature to the best of our knowledge. This study was carried out to identify the presence of RC-like cells (RCLCs) in MMBTs/MEBTs and their immunohistochemical features in comparison to those of cervical RCs. We analyzed 10 consecutive cases of RC-like MMBTs/MEBTs, 6 of which were associated with endometriosis. Immunohistochemistry was performed for p63, cytokeratin 34BE12, cytokeratin 17 (CK17), and low-molecular cytokeratin CAM5.2. In 9 of 10 cases, RCLCs were appreciated in hematoxylin-eosin stain, although their amount in the tumor varied from case to case. Immunohistochemically, RCLCs were positive for p63 in 9 cases. They were positive for both 34BE12 and CK17 and were very weakly positive or negative for CAM5.2 in 8 cases. This immunohistochemical profile is similar to that seen in the cervical RCs. Reserve cell-like cells were also found in the foci of endometriosis coexisting with MMBTs/MEBTs in 1 of 5 cases examined. We draw attention to the existence of the RCLCs in MMBTs/MEBTs and in endometriosis. Their similarity to the cervical RCs may indicate their potential role as precursor cell that may subsequently differentiate into different müllerian cell types, thus merit further study.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 05/2008; 27(2):199-206. · 2.07 Impact Factor
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    ABSTRACT: Ovarian small cell carcinoma of hypercalcemic type is a rare neoplasm that typically occurs in young females. We describe three cases of ovarian small cell carcinoma of hypercalcemic type occurring in patients aged 24, 37, and 25 years. The first patient had stage IIc disease and had primary surgery with a left salpingo-oophorectomy and omentectomy, followed by chemotherapy with cisplatin and etoposide. Upon a second relapse, pelvic lymphadenectomy was performed, followed by chemotherapy with docetaxel. She is alive for 4 years without any recurrence after the initial treatment. In vitro drug-sensitivity assay revealed the tumor cells were sensitive to taxane and resistant to irinotecan. The second patient had stage III disease and had primary debulking surgery with bilateral salpingo-oophorectomy, simple hysterectomy, omentectomy, low-anterior resection, and lymphadenectomy, followed by chemotherapy with paclitaxel and carboplatin. Four months after the initial treatment she relapsed and died. The tumor cells were sensitive to platinum, taxane, and doxorubicin, but resistant to irinotecan. The third patient had stage III disease and had right salpingo-oophorectomy, omentectomy, and lymphadenectomy, followed by chemotherapy with cisplatin, cyclophosphamide, and doxorubicin. She relapsed 4 months after completing the chemotherapy and died 5 months after secondary debulking surgery. The tumor cells were sensitive to platinum, taxane, and doxorubicin, but resistant to irinotecan. The drug-sensitivity assays suggested that a non-irinotecan, taxane-containing combination might have been suitable as first-line chemotherapy for these patients. However, an effect of such a regimen was seen in only one patient with early-stage disease, and this questions the validity of chemosensitivity testing.
    International Journal of Clinical Oncology 05/2008; 13(2):161-5. · 1.73 Impact Factor
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    ABSTRACT: Multiagent chemotherapy for small cell carcinoma of the ovary (SCCO) may contribute to the prolonged survival of young women who are suffering from this disease, even in the advanced stage with remaining tumor, although the rarity of SCCO complicates the generalization of chemotherapy agents and operation methods for this disease. A 24-year-old patient with SCCO FIGO stage IIC is alive after recurrences and chemotherapy including cisplatin + etoposide after the first operation and docetaxel for the second recurrence. She is now doing well with no evidence of disease more than 4 years after the first operation and 2 years after docetaxel treatment. This may be the first report describing the use of docetaxel that may be included in multiagent chemotherapy.
    International Journal of Gynecological Cancer 01/2006; 16(5):1944-6. · 1.94 Impact Factor
  • Y Mikami, T Kiyokawa, T Moriya, H Sasano
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    ABSTRACT: To define the phenotypic alteration of the stromal component in association with destructive invasion which is a crucial feature in distinguishing minimal deviation adenocarcinoma (MDA) from benign endocervical glandular lesions. We studied endocervical glandular hyperplasias including non-specific-type (NEGH) (n = 3) and lobular-type (LEGH) (n = 8), and minimal deviation adenocarcinoma (MDA) (n = 11), well-differentiated endocervical adenocarcinoma of usual-type (WDA) (n = 11), and adenocarcinoma in situ (AIS) (n = 6) of the cervix, by double immunostaining for oestrogen receptor (ER) and alpha-smooth muscle actin (alpha-SMA) using peroxidase- and alkaline phosphatase-polymer methods, respectively. Glands in NEGH invariably showed nuclear staining for ER, with surrounding ER+/alpha-SMA- stromal cells, whereas LEGH also harboured ER+/alpha-SMA- spindle cells, but lacked nuclear staining for ER in constituent glands. In contrast, both WDA and MDA displayed accompanying stroma rich in alpha-SMA+ spindle cells in close vicinity to the infiltrating neoplastic glands, with only occasional weakly ER+ stromal cells. WDA tended to contain more alpha-SMA+ cells. The distribution of alpha-SMA+ cells was periglandular (6/11), patchy (6/11), and/or diffuse (4/11) in WDA, whereas in MDA it was periglandular (11/11) and/or patchy (8/11). AIS was surrounded by ER+/alpha-SMA- stromal cells. All cases of WDA, MDA, and AIS lacked nuclear staining for ER. Both MDA and WDA can be distinguished from LEGH and NEGH by identifying surrounding alpha-SMA+ stromal cells and the absence or decreased number of ER+ cells, possibly as a result of the desmoplastic reaction with myofibroblasts replacing pre-existing ER+ stromal cells. In particular, the periglandular distribution of these alpha-SMA+ stromal cells can be a clue suggesting destructive stromal invasion in cases of MDA, although occasional glands may lack these cells.
    Histopathology 03/2005; 46(2):130-6. · 2.86 Impact Factor
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    ABSTRACT: Gastrointestinal phenotype in cervical adenocarcinomas was examined by immunohistochemistry and correlated with morphologic features. Antibody panels included anti-MUC2, MUC6, CD10, chromogranin A (CGA) and HIK1083. In addition, expression of p16INK4, a cyclin-dependent kinase inhibitor which is expressed in a variety of high-risk HPV-related conditions, was studied. A total of 94 invasive adenocarcinomas including 20 minimal deviation adenocarcinomas (MDAs) and 72 adenocarcinomas in situ (AIS) were examined. MDAs were most frequently positive for HIK1083 and/or MUC6, two representative gastric markers, with a rate of 95%, followed by intestinal-type adenocarcinomas (IAs) with a rate of 85% whereas only 27% of 56 usual endocervical-type adenocarcinomas (UEAs) were positive. MUC2, a goblet cell marker, was positive in 85% and 25% of IAs and MDAs, respectively, while in only 14% of UEAs. CD10 was positive in 15% of IAs, indicating incomplete intestinal differentiation without a brush border in most of the cases. CGA-positive cells were frequently seen in MDAs and IAs with rates of 60% and 62%, respectively. Nuclear and cytoplasmic p16INK4 positivity was identified in 93% of UEAs, whereas 30% of MDAs were positive for p16INK4. Results in AISs were comparable to their invasive counterparts, but morphologically usual-type AISs identified in eight cases of MDA were frequently positive for HIK1083 (75%) and MUC6 (63%), and p16INK4. Of note was the existence of lobular endocervical glandular hyperplasia (LEGH) with atypical features including cytologic abnormalities, and/or papillary projection, which were identified in this study in pure form (n=3) or in association with MDAs (n=6), but not in cases of other types of adenocarcinomas. These observations indicate that gastrointestinal phenotype is frequently expressed in MDAs and IAs, and there seems to be a possible link between MDA, and LEGH and morphologically usual-type AIS with gastric immunophenotype in histogenesis. Frequent absence of p16INK4 expression in MDAs suggests a possibility that high-risk HPV does not play a crucial role in development of MDAs, in contrast to the majority of endocervical adenocarcinomas. p16INK4 immunohistochemistry appears to be a promising diagnostic tool, but pathologists should be aware of frequent negative staining in MDAs, which can be a source of erroneous diagnosis.
    Modern Pathology 09/2004; 17(8):962-72. · 5.25 Impact Factor
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    ABSTRACT: CD10 has been demonstrated to be positive in endometrial stromal sarcoma (ESS) and thus is useful in establishing the diagnosis, but its expression in malignant müllerian mixed tumor (MMMT) and müllerian adenosarcoma remains to be clarified. In this study, 12 cases of MMMT (9 uterine, 2 tubal, and 1 metastatic), 6 cases of müllerian adenosarcoma (three corporeal, two cervical, and one tubal), and 7 cases of primary uterine sarcomas had their tissues examined immunohistochemically for expression of CD10, desmin, myoglobin, alpha-smooth muscle actin (SMA), and cytokeratin. Of the primary uterine sarcomas, two were primary rhabdomyosarcomas (one cervical and one corporeal), two were ESSs, two were high-grade leiomyosarcomas, and one was a high-grade endometrial sarcoma. Sarcomatous components in all cases of MMMT and müllerian adenosarcoma, as well as all uterine sarcomas, were positive for CD10, showing moderate to marked staining intensity with varying distribution except in one MMMT, which showed weak and very focal staining. In four MMMTs, three adenosarcomas, and one rhabdomyosarcoma, myoglobin- and/or desmin-positive rhabdomyoblastic cells were positive for CD10. The immunoreactivity for CD10 showed the same distribution for alpha-SMA and myoglobin in three and two MMMTs, respectively. In five cases of MMMT, carcinomatous components were focally positive for CD10, and in two cases small populations of round or short spindle cells in sarcomatous components were positive for CD10, alpha-SMA, and cytokeratin (CAM5.2). These results indicate that CD10 expression is not restricted to ESS but can be positive in MMMT and müllerian adenosarcoma as well as in a variety of uterine tumors including high-grade leiomyosarcoma and rhabdomyosarcoma. CD10 expression might be one of the characteristics of müllerian system-derived neoplastic mesenchymal cells.
    Modern Pathology 10/2002; 15(9):923-30. · 5.25 Impact Factor