College of American Pathologists
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  Anatomic Abstracts





January 2009

Michael Cibull, MD
Melissa Kesler, MD

Link between tumor-infiltrating lymphocytes and prognosis
Mature and immature extracranial teratomas in children
Immunophenotyping of serous carcinoma of the female genital tract
ZEB1 expression in type I versus type II endometrial cancers
Prognostic factors for lymph node metastases in prostatic cancer

Link between tumor-infiltrating lymphocytes and prognosis Link between tumor-infiltrating lymphocytes and prognosis

Tumor-infiltrating lymphocytes have been correlated with a better prognosis for some tumors, such as medullary carcinoma of the breast. However, a recent study of invasive micropapillary carcinoma of the breast found tumor-infiltrating lymphocytes to be associated with increased lymph node metastasis and a poorer prognosis. The authors conducted a study to explore possible mechanisms underlying this difference in immune responsiveness and tumor behavior. They compared 28 cases of invasive micropapillary carcinoma with prominent lymphocyte infiltration with 29 cases of medullary carcinoma. In both tumors, the majority of tumor-infiltrating lymphocytes were T lymphocytes (ρ<.01), and CD8+ T lymphocytes were predominant (ρ<.01). Functional differences in CD8+ cytotoxic T lymphocytes were identified in the two types of tumor. While lymphocytes infiltrated the stroma and epithelial components of medullary carcinoma, the tumor-infiltrating lymphocytes of invasive micropapillary carcinoma were almost exclusively confined to the stroma. Tumor-infiltrating lymphocytes of medullary carcinoma showed stronger expression of FasL than those in invasive micropapillary carcinoma (ρ<.01), and medullary carcinoma cells exhibited stronger expression of Fas than did invasive micropapillary carcinoma cells (ρ<.01). In the subgroups of tumors with strong (++/+++) Fas expression, double immunohistochemistry revealed that most of the tumor-infiltrating lymphocytes in medullary carcinoma, particularly those infiltrating the tumor nests, were CD8+ cytotoxic T lymphocytes, but this was not the case in invasive micropapillary carcinoma. Furthermore, upregulated expression of perforin, granzyme B, and FasL by cytotoxic T lymphocytes was greater in medullary carcinoma than in invasive micropapillary carcinoma (ρ<.01, respectively). The results suggest that immunity provided by tumor-infiltrating lymphocytes varies by tumor type. The relative lack of tumor-killing cytotoxic T lymphocytes in invasive micropapillary carcinoma may explain, in part, the adverse association of tumor infiltrating lymphocytes with the biological behavior of invasive micropapillary carcinoma of the breast.

Guo X, Fan Y, Lang R, et al. Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast. Mod Pathol. 2008;21:1101–1107.

Correspondence: Dr. L. Fu at
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Mature and immature extracranial teratomas in children Mature and immature extracranial teratomas in children

The authors studied the features, treatment, and risk factors for relapse of children with mature teratomas and immature teratomas to enhance future treatment plans. They studied patients younger than 16 years of age who were referred to U.K. Children’s Cancer Study Group centers with biopsy-proven extracranial mature teratomas (MT) and immature teratomas (IT) and who had not had chemotherapy. Complete excision, with the coccyx in sacrococcygeal patients, and followup, including serum α-fetoprotein monitoring for early detection of malignant yolk sac tumor recurrence, were recommended. Carboplatin, etoposide, and bleomycin (JEB) were given for yolk sac tumor relapse, whereas relapsed MT and IT were treated at the clinician’s discretion, usually surgically. The authors reviewed the pathology and assessed treatments, outcome, and prognostic features for 351 patients—227 with MT and 124 with IT. Tumor sites were testis (n=53), ovary (n=130), sacrococcygeal region (n=98), thorax (n=23), and other (n=47). Surgical resection was incomplete in 26 percent of MT and 40 percent of IT patients. Five-year event-free survival was 92.2 percent and 85.9 percent, respectively, and five-year overall survival was 99 percent and 95.1 percent. Poorer outcome occurred with incomplete resection, tumor rupture, nongonadal site (particularly sacrococcygeal), young age, higher stage and grade, and gliomatosis peritonei, but not with cyst fluid aspiration/spillage, tumor enucleation, nodal gliomatosis, or microfoci of yolk sac tumor in the tumor (Heifetz lesions). JEB was effective for yolk sac tumor recurrence but not for MT or IT. The authors concluded that treatment remains primarily surgical, with JEB chemotherapy for yolk sac tumor relapse. No definite response followed JEB for pure MT and IT. They do not advocate adjuvant chemotherapy after surgery for sacrococcygeal patients.

Mann JR, Gray ES, Thornton C, et al. Mature and immature extracranial teratomas in children: the UK Children’s Cancer Study Group experience. J Clin Oncol. 2008;26:3590–3597.

Correspondence: Jillian R. Mann at
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Immunophenotyping of serous carcinoma of the female genital tract Immunophenotyping of serous carcinoma of the female genital tract

To update data on the expression of mesothel­i­oma markers by serous carcinomas of various sites, the authors studied cases from ovary (n=56), endometrium (n=37), fallopian tube (n=6), primary peritoneum (n=5), and cervix (n=3) using a panel of antibodies, including Wilms tumor 1, p53, estrogen receptors, HER2/neu, D2-40, cyto­keratin 5/6, and E-cadherin. Ovarian carcinomas demonstrated D2-40 and cytokeratin 5/6 immunoreactivity in 23.2 percent and 55.4 percent of cases, respectively. Endometrial carcinomas demonstrated D2-40 and cytokeratin 5/6 immunoreactivity in 43.2 percent and 37.8 percent of cases, respectively. D2-40 staining pattern was predominantly focal; however, strong reactivity was identified in 16.2 percent of endometrial and 10.7 percent of ovarian carcinomas. HER2/neu oncoprotein overexpression was demonstrated in seven of 37 (18.9 percent) uterine serous carcinomas. In contrast, all serous carcinomas of the other sites were HER2/neu negative. The proportion of positive cases was significantly different in ovarian versus endometrial carcinomas regarding Wilms tumor 1 (ρ=.0458), estrogen receptor reactivity (ρ<.001), and HER2/neu overexpression (ρ=.0025). D2-40 and cytokeratin 5/6 are expressed in a considerable proportion of serous carcinomas and should be used cautiously in a mesothelioma panel in situations where serous carcinoma is in the differential diagnosis. HER2/neu was overexpressed exclusively in serous carcinomas of endometrial origin.

Nofech-Mozes S, Khalifa MA, Ismiil N, et al. Immunophenotyping of serous carcinoma of the female genital tract. Mod Pathol. 2008;21:1147–1155.

Correspondence: Dr. S. Nofech-Mozes at
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ZEB1 expression in type I versus type II endometrial cancers ZEB1 expression in type I versus type II endometrial cancers

Zinc-finger E-box-binding homeobox 1 (ZEB1) is a transcription factor containing two clusters of Kruppel-type zinc-fingers, by which it binds E-box-like sequences on target DNAs. A role for ZEB1 in tumor progression, specifically epithelial to mesenchymal transitions, has recently been revealed. ZEB1 acts as a master repressor of E-cadherin and other epithelial markers. The authors previously demonstrated that ZEB1 is confined to the stromal compartment in normal endometrium and low-grade endometrial cancers. The authors conducted this study to quantify ZEB1 protein expression in endometrial samples from 88 patients and to confirm that it is expressed at significantly higher levels in the tumor-associated stroma of low-grade endometrioid adenocarcinomas (type I endometrial cancers) compared to hyperplastic or normal endometrium. In addition, as they previously reported, ZEB1 is aberrantly expressed in the epithelial-derived tumor cells of highly aggressive endometrial cancers, such as FIGO grade 3 endometrioid adenocarcinomas, uterine serous carcinomas, and malignant mixed Mullerian tumors (classified as type II endometrial cancers). The authors demonstrated in endometrial cancer specimens and cell lines that when ZEB1 is inappropriately expressed in epithelial-derived tumor cells, E-cadherin expression is repressed, and that this inverse relationship correlates with increased migratory and invasive potential. Forced expression of ZEB1 in the nonmigratory, low-grade, relatively differentiated Ishikawa cell line renders it migratory. Conversely, reduction of ZEB1 in a highly migratory and aggressive type II cell line, Hec50co, results in reduced migratory capacity. Therefore, ZEB1 may be a biomarker of aggressive endometrial cancers at high risk of recurrence. It may help identify women who would benefit most from chemotherapy. Furthermore, if expression of ZEB1 in type II endometrial cancers could be reversed, it might be exploited as therapy for these highly aggressive tumors.

Singh M, Spoelstra NS, Jean A, et al. ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol. 2008;21:912–923.

Correspondence: J. K. Richer at
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Prognostic factors for lymph node metastases in prostatic cancer Prognostic factors for lymph node metastases in prostatic cancer

The authors conducted a study in which they analyzed tumor characteristics and the prognostic significance of prostatic cancers with extranodal extension of lymph node metastases in 102 node-positive, hormone treatment-naive patients undergoing radical prosta­t­ectomy and extended lymphadenectomy. The median number of nodes examined per patient was 21 (range, 9 to 68), and the median follow-up time was 92 months (range, 12 to 191 months). Extranodal extension of lymph node metastases (ENE) was observed in 71 patients (70 percent). Patients with ENE had significantly more, larger, and less differentiated nodal metastases, paralleled by significantly larger primary tumors at more advanced stages and with higher Gleason scores, than patients without ENE. ENE defined a subgroup of patients with significantly decreased biochemical recurrence-free (ρ=.038) and overall survival (ρ=.037). In multivariate analyses, the diameter of the largest metastasis and Gleason score of the primary tumor were independent predictors of survival. The authors concluded that ENE in prostatic cancer is an indicator lesion for advanced/aggressive tumors with poor outcome. However, the strong correlation with larger metastases suggests that ENE may result from the size of a metastasis, which was the only independent risk factor in the metastasizing component. Consequently, histopathological reports should specify the true indicator of poor survival with lymphadenectomy specimens, which is the size of the largest metastasis in each patient.

Fleischmann A, Schobinger S, Markwalder R, et al. Prognostic factors in lymph node metastases of prostatic cancer patients: the size of the metastases but not extranodal extension independently predicts survival. Histopathology. 2008;53:468–475.

Correspondence: A. Fleischmann at
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Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Melissa Kesler, MD, and Rouzan Karabakhtsian, MD, assistant professors of pathology and laboratory medicine, University of Kentucky College of Medicine; and Megan Zhang, MD, visiting fellow, Division of Dermatopathology, University of California, San Francisco.