November 2009

Editors:
Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy

The authors conducted a study to determine whether immunohistochemical HER2 status (2+ or 3+), degree of FISH amplification according to HER2/CEP17 ratio or HER2 gene copy number, or polysomy significantly influenced clinical outcome for patients with HER2-positive breast cancer enrolled in the Herceptin Adjuvant (HERA) trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy. Immunohistochemical (IHC) or fluorescence in situ hybridization (FISH) analyses, or both, were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the one-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival after a median two years of followup. Central FISH results were available for 2,071 (61 percent) of the 3,401 patients randomized to the two arms. Among patients with FISH-positive disease, the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95 percent confidence interval [CI], 0.32–0.99) for locally IHC2+ cases (n=340) and 0.80 (95 percent CI, 0.40–1.61) for centrally IHC2+ cases (n=299). There was no significant prognostic relationship between HER2 FISH ratio, HER2 copy number, or polysomy and disease-free survival in the control arm or predictive relationship defining differential benefit from trastuzumab. The authors concluded that there was no evidence for reduced benefit of trastuzumab in HER2 IHC2+FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy.

Dowsett M, Procter M, McCaskill-Stevens W, et al. Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA trial. J Clin Oncol. 2009;27:(18):2962–2969.

Correspondence: Dr. Mitch Dowsett at mitch.dowsett@icr.ac.uk
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Analysis of endocervical adenocarcinomas with ovarian metastases

Approximately 90 percent of endocervical adenocarcinomas are high-risk human papillomavirus-related neoplasms, with the remainder unrelated to HPV. Both types seldom metastasize to the ovaries. The authors conducted a study in which they analyzed the clinicopathologic features of 29 cases of synchronous and metachronous endocervical and ovarian tumors (26 HPV related and three unrelated to HPV). The cervical tumors were clearly invasive in 18 cases, and the cases included five clinically evident tumors diagnosed before the ovarian metastases (immediately preoperatively to seven years), 11 clinically unsuspected tumors diagnosed concurrently in specimens obtained for evaluation of ovarian/pelvic masses, one case with concurrent clinically evident cervical and ovarian masses, and one clinically occult tumor diagnosed subsequent to ovarian metastasis. Cervical tumors were more limited in 11 cases and included five tumors predominantly composed of adenocarcinoma in situ with small foci of superficial invasion diagnosed before the ovarian metastases (three months to seven years) and six tumors composed of extensive adenocarcinoma in situ lacking unequivocally recognizable stromal invasion diagnosed before (nine months to seven years; n=4), concurrently with (n=1), or subsequent to (n=1) ovarian metastases. Fifteen cervical tumors involved lower uterine segment corpus endometrium or endo-myometrium, including four tumors of the cervix that were minimally invasive or not recognized as being invasive. The ovarian tumors ranged in size from 2.1 to 30 cm (mean/median, 12.7/13.5). They were unilateral in 19 cases (65.5 percent), and 12 of these were unilateral and 10 cm or greater. In 26 cases, including the 19 unilateral tumors, the ovarian tumors exhibited borderline-like, confluent glandular, cribriform, or villoglandular patterns simulating primary ovarian atypical proliferative (borderline) tumors or well-differentiated carcinomas. These patterns were pure in 24 and admixed with minor infiltrative foci in two. The ovarian tumors had features typical of metastases (bilateral and infiltrative) in only three cases. In all HPV-related cases, the paired endocervical and ovarian tumors contained identical HPV types, establishing the ovarian tumors as metastases. The authors concluded that endocervical adenocarcinomas, including microinvasive forms and some not recognized as invasive, have the potential to metastasize to the ovaries. Extension into the lower uterine segment/corpus endometrium may be a risk factor, with retrograde uterine/transtubal spread as a possible mechanism.

Ronnett BM, Yemelyanova AV, Vang R, et al. Endocervical adenocarcinomas with ovarian metastases: analysis of 29 cases with emphasis on minimally invasive cervical tumors and the ability of the metastases to simulate primary ovarian neoplasms. Am J Surg Pathol. 2008;32:1835–1853.

Correspondence: Dr. Brigitte M. Ronnett at bronnett@jhmi.edu
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Squamous morules: functionally inert elements of premalignant endometrial neoplasia

Squamous morules are a common component of premalignant glandular lesions that are followed by glandular, rather than squamous, carcino-mas. The authors tested the hypothesis that the appearance of glands associated with morules predicts cancer risk, and they undertook molecular testing to determine the clonal and hormonal response properties of admixed squamous and glandular elements. The authors studied 66 patients with squamous morules in an index endometrial biopsy that had followup clinical data (average followup interval, 31 months, 2.5 biopsies) show-ing development of carcinoma in 11 percent (7/66) of cases. The histological appearance of morule-associated glands in the index biopsy was significantly associated with this clinical outcome, with 71 percent (5/7) of cancer occurrences following an overtly prexmalignant lesion (endometrial intraepithelial neoplasia) with squamous morules. Eight endometrial intraepithelial neoplasias with squamous morules were examined by immunohistochemistry for estrogen and progesterone receptors and mitotic activity (Ki-67 antigen percent stained). Glandular components had abun-dant estrogen and progesterone receptors and high levels of mitotic activity in all cases. In sharp contrast, all squamous morules were devoid of sex hormone receptors and had undetectable or extremely low proliferation rates. When mutated, the same specific PTEN mutation was detected in squamous and glandular elements, indicating that they are of common lineage. The clinical and laboratory data are consistent with a model of morule biology in which squamous morules are a hormonally incompetent subpopulation of endometrial glandular lesions. Isolated morules might result from artifactual displacement from their native glandular context or selective hormonally induced regression of the glandular but not squamous components over time. Subsequent cancer risk, as promoted by estrogens, is greatest when the glandular component has the appearance of endometrial intraepithelial neoplasia. However, even isolated morules should be followed carefully to exclude a coexisting undersampled, or occult, glandular lesion.

Lin MC, Lomo L, Baak JP, et al. Squamous morules are functionally inert elements of premalignant endometrial neoplasia. Mod Pathol. 2009;22:167–174.

Correspondence: Dr. G. L. Mutter at gmutter@rics.bwh.harvard.edu
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Prognostic impact of D2-40 emboli in breast cancer

Peritumoral emboli assessed on hematoxylinandeosinstained slides are taken into account for treating patients with operable breast cancer. The authors assessed whether immunostaining with D2-40 improves the prognostic significance of emboli in a group of tumors with a large immu-nohistochemical sampling and long-term followup. Topography, number, and extension of hematoxylinandeosin (H&E) and D2-40 emboli were compared in 94 node-negative breast cancers (median number of immunostained slides per tumor, three). The authors evaluated the metastasis-free survival rates of patients with or without H&E or D2-40 emboli, or both (median followup, 178 months). H&E emboli were detected in 14 (15 per-cent) tumors and were located a distance from the tumor. D2-40 emboli were detected in 39 (41 percent) tumors and were often multiple (n=30), ex-tensive (n=23), located within (n=13), close to (n=10), or a distance from the tumor (n=16). The 12 distant H&E and D2-40 emboli were located in the same vessels. (Seven of them were missed at the first H&E examination and secondarily diagnosed by D2-40 staining.) A difference in metastasis-free survival rates was found only between patients with no D2-40 emboli and those with distant D2-40 emboli (P=.02). D2-40 emboli located within or close to the tumor had no prognostic value. Comparing the metastasis-free survival rates of patients with or without H&E emboli, the prognostically unfavorable significance of H&E emboli was improved when taking into account the seven patients with missed emboli at the first examination and secondarily diagnosed by D2-40 staining (P=.006 versus P=.003). The authors concluded that D2-40 increases the diagnostic sensitivity of emboli in breast carcinoma and that the high incidence of D2-40 emboli might be related to the number of immunostained slides per case. Never-theless, only distant D2-40+ emboli had a prognostic impact. In practice, D2-40 might be useful to detect missed H&E emboli, especially in cases without any other prognostically unfavorable criterion.

de Mascarel I, MacGrogan G, Debled M, et al. D2-40 in breast cancer: Should we detect more vascular emboli? Mod Pathol. 2009;22(2):216–222.

Correspondence: I. de Mascarel at mascarel@bergonie.org
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