Marguerite M. Pinto

Complementary Value of the Ki-67 Proliferation Index to the Oncotype DX Recurrence Score

Oncotype DX is a 21-gene assay that quantifies the recurrence risk in estrogen receptor—positive breast cancer, which is expressed as the recurrence score (RS). Studies have shown that patients with a high-risk RS will most likely benefit from adjuvant chemotherapy, but there is no proven advantage for patients with a low-risk RS who still face an average recurrence risk of 7%. In this study, the relationship between the RS and the cell cycle—related antigen Ki-67 was assessed in 32 breast carcinomas and evaluated for a potential association. Comparison of the RS with tumor type, grade, and the Ki-67 proliferation index (PI) revealed an overall concordance. However, some tumors with a low RS revealed a surprisingly high Ki-67 PI. These cases may correspond to the 7% of low-risk RS carcinomas that recur. Therefore, the authors propose a combined evaluation of the RS and Ki-67 PI to identify tumors with high recurrence potential from the low-risk and intermediate-risk RS groups.

Interobserver variability and aberrant E-cadherin immunostaining of lobular neoplasia and infiltrating lobular carcinoma.

The distinction between lobular neoplasia and infiltrating lobular carcinoma from ductal neoplasia and infiltrating duct carcinoma with equivocal histologic features may present a challenge as this distinction has important therapeutic implications. Although E-cadherin staining has been of value in helping to make this determination, the variability of the E-cadherin staining pattern and the immunohistochemistry techniques can be problematic in clinical practice. A total of 161 cases of breast lesions previously diagnosed as lobular neoplasia and infiltrating lobular carcinoma were selected from the departmental files. Three surgical pathologists interpreted them in a blinded manner for the histology diagnoses and E-cadherin staining. E-cadherin staining was conducted on the paraffin-embedded sections of the breast lesions using two different source antibodies. Our results using morphology and E-cadherin stain agreed with the previous diagnoses of lobular neoplasia and infiltrating lobular carcinoma in 140 of 161 cases (86.9%). Among the 140 cases, three pathologists agreed with the morphologic diagnoses of lobular neoplasia and infiltrating lobular carcinoma in 100 (71.4%), two pathologists in 26 (18.6%) and one pathologist in 14 (10%). All three pathologists disagreed with the previous diagnoses of lobular neoplasia and infiltrating lobular carcinoma but reevaluated as ductal lesions in 21 cases (13.0%). E-cadherin staining was confirmatory in 136 of total 161 cases (84.5%) of both lobular and duct lesions by showing the loss of staining in lobular lesions and the presence of complete membrane staining in duct lesions. Aberrant E-cadherin reactions were retained weak or partial incomplete thin membrane reaction in lobular-type lesions and reduced membrane reaction in ductal-type lesions were seen in 25 of the total 161 cases (15.5%). E-cadherin immunoreaction with two different antibodies showed discrepant results in 5 of 78 cases tested (6.4%). This study illustrates (1) interobserver variability of the morphologic diagnoses of lobular neoplasia/infiltrating lobular carcinoma and duct neoplasia/infiltrating duct carcinoma, (2) the occasional presence of aberrant E-cadherin stain pattern in these breast lesions and (3) variability of E-cadherin immunostaining results by two different antibodies.

Estrogen receptor beta in breast cancer: associations between ERbeta, hormonal receptors, and other prognostic biomarkers.

The estrogen receptor (ER)-beta isoform has been recently identified to be distinct from ERalpha isoform and regulates separate sets of genes, and can exert opposite signaling functions depending on the ligand and response elements. Previous studies of ERbeta have been at the mRNA level and few by immunohistochemistry, and the results are inconsistent. In this study the authors compared expression of ERbeta with those of other prognostic biomarkers by immunohistochemistry on tissue microarray slides, and with morphologic parameters on 147 cases of primary breast cancer. Immunoreactivity of more than 10% of cancer cells was considered to be positive. Associations between categoric variables were analyzed using the chi test, and a P value less than 0.05 was considered to be significant. ERbeta was expressed in benign epithelium and stromal cells, and breast cancer cells in 59% of different histologic types of breast cancer. ERbeta was coexpressed with ERalpha in 45% of cases. There was a statistically significant association between expression of ERbeta and Her-2/neu (P<0.000), cathepsin D (P<0.02), p53 (P<0.03), and PS2 (P<0.002). Ki-67 was almost exclusively expressed in ERbeta-positive cells. No statistically significant association was seen between ERbeta expression and histologic grade, DNA ploidy, or S-phase.

Immunoradiometric assay of CA 125 in effusions comparison with carcinoembryonic antigen

The levels of CA 125 antigen were measured in 167 effusions from 150 patients using radioimmunoassay, and the results compared with the levels of carcinoembryonic antigen (CEA) in the fluids. This study was carried out to test a hypothesis that measuring the combined levels of selected tumor associated antigens in effusions could predict the primary source of malignancy. The results indicate that an elevated fluid CA 125 level (>14,000 U/ml‐68,000 U/ml) and a negative fluid CEA level (<5 ng/ml) is suggestive of serous and endometrioid carcinoma of ovary, and adenocarcinoma of the endometrium and fallopian tube. Alternatively, an elevated fluid CEA level (14 ng/ml‐600 ng/ml) and a negative CA 125 level (20–5000 U/ml) is seen in metastatic carcinomas of breast, lung, gastrointestinal tract, and mucinous cystadenocarcinoma. Lymphomas, melanomas, and benign effusions are negative for both antigens. The combined use of CEA and CA 125 antigen in fluids is useful in the differential diagnosis of adenocarcinoma of unknown primary. Cancer 59:218–222, 1987.

Ki-ras mutations and the carcinoembryonic antigen level in fine needle aspirates of the pancreas

OBJECTIVE To evaluate the sensitivity and specificity of the carcinoembryonic antigen (CEA) immunoassay and Ki-ras genotyping as adjuncts to the cytologic diagnosis of pancreatic fine needle aspirates (FNAs). STUDY DESIGN A retrospective study of 30 patients with pancreatic masses evaluated with CEA immunoassay and gel or hybridization analysis of allele-specific polymerase chain reaction for mutant Ki-ras (codons 12 and 13). DNA was isolated from fixed, paraffin-embedded samples. Diagnoses were correlated with cytologic evaluations and patient outcome. RESULTS Diagnoses included 17 pancreatic carcinomas, 3 other malignancies and 10 benign lesions. Sixty-five percent of all FNAs had mutated Ki-ras, and 42% of samples with altered Ki-ras had multiple mutations. Replicate FNA samplings in five of six patients had concordant genotypes. Sensitivities for diagnosis were as follows: cytology alone, 76%; CEA alone, 82%; Ki-ras alone, 82%; cytology plus CEA, 100%; cytology plus Ki-ras, 94%. Although specificities for Ki-ras (30%) and CEA (50%) individually were low, elevated CEA level and mutated Ki-ras in a sample with negative cytology strongly indicated false negative cytology. CONCLUSION The addition of either or both the CEA assay and Ki-ras mutation analysis enhances the sensitivity of the cytologic diagnosis of pancreatic carcinoma by FNA.

Juvenile Granulosa Cell Tumor of the Infant Testis: Case Report with Ultrastructural Observations

This report describes the light-microscopic and ultrastructural features of a juvenile granulosa cell tumor of infant testis. Microscopic examination revealed a macrofollicular patterns simulating the preovulatory Graafian follicle and the juvenile granulosa cell tumor of the ovary. Ultrastructure confirmed three cell types: granulosa, theca interna, and externa, with occasional luteinized cells lacking crystalloids of Reinke. Charcot-Bottcher crystalloids were not detected, though rare cells contained a complex arrangement of filaments. An ultrastructural comparison was carried out with infant testes (2 cases), preovulatory Graafian follicle (1 case), juvenile granulosa cell tumor of ovary, adult granulosa cell tumor of ovary, and adult Sertoli cell tumor of testis and ovary. Ultrastructural similarities were noted between the present case and primitive Sertoli cells, preovulatory granulosa cells, and juvenile granulosa cell tumor of ovary. This may reflect the common histogenesis of Sertoli/granulosa cells from the common specialized gonadal stroma.

Ovarian malignant melanoma: a clinicopathologic study of 5 cases.

Primary ovarian malignant melanomas are extremely rare. The wide range of morphologic appearances assumed by melanomas in the ovary can cause considerable difficulty in diagnosis. The clinicopathologic features of 4 definite and 1 probable primary ovarian melanomas are presented. The patients ranged in age from 41 to 71 years. Four tumors were within teratomas with 2 showing a lentiginous pattern of melanoma in the squamous epithelium. Unusual histologic features were noted. Immunostains for S-100, HMB-45, and Melan-A were positive in all tumors. Premelanosomes were identified in 2 tumors ultrastructurally. Metastatic sites included regional nodes, peritoneal surfaces, omentum, lung, liver, brain, and bone. All 5 patients died within 18 months. Immunohistochemistry and electron microscopy aid considerably in the diagnosis of ovarian melanomas where pigmentation or teratomatous elements are absent. Familiarity with the wide range of morphologic patterns presented here will raise awareness and facilitate detection of future cases of ovarian melanoma.

CA-15.3 assay in effusions: comparison with carcinoembryonic antigen and CA-125 assay and cytologic diagnosis.

OBJECTIVE To compare the sensitivity of CA-15.3 with cytologic diagnosis and carcinoembryonic antigen (CEA) and CA-125 content and to determine if elevated CA-15.3 suggests a breast primary. STUDY DESIGN A retrospective study of 111 consecutive effusions. CEA was measured by enzyme immunoassay (cutoff > 5 ng/mL), CA-125 by radioimmunoassay (cutoff > 5,000 micron/mL) and CA-15.3 by radioimmunoassay (cutoff > 15 micron/mL). Results were correlated with cytologic diagnosis, histology (when available), clinical and radiologic data, and follow-up. RESULTS The results were: benign, 39; malignant, 72; sensitivities and specificities: cytology, 76%/100%; CEA, 80%/97%; CA-125 22%/100%; and CA-15.3, 69%/89%. The sensitivity of CEA and cytology was 97% and of CA-15.3 and cytology, 87%. Neither mean (293.4 micron/mL) nor range of CA-15.3 predicted a breast primary. Falsely elevated CEA and CA-15.3 were noted in ascites with fecal contents from colonic perforation. High CA-125 and low CEA predicted an ovarian/endometrial primary. CONCLUSION CA-15.3 assay in effusions is not recommended since it neither enhances the sensitivity of cytologic diagnosis nor predicts a breast primary.

Cystic brain lesions: cytologic examination and carcinoembryonic antigen assay in fine needle aspirates.

OBJECTIVE To compare the sensitivities of cytologic diagnosis by fine needle aspiration (FNA) with carcinoembryonic antigen (CEA) content of cystic brain tumors and to determine if CEA assay enhances the sensitivity of cytologic diagnosis and suggests a probable primary in carcinoma with an unknown primary source. STUDY DESIGN Thirteen consecutive aspirates were studied. Cytologic diagnosis was confirmed by histologic examination and follow-up. Fluid varied from 3 to 50 mL and from clear to bloody to mucinous. Cytologic examination was performed on Papanicolaou-stained smears. CEA was measured by enzyme immunoassay, with a cutoff of 5 ng/mL. RESULTS Benign: 3 (subdural hematoma, 2; arachnoid cyst, 1). Malignant: 10 (medulloblastoma, 1; glioblastoma multiforme, 4; metastatic adenocarcinoma with an unknown primary, 1; of breast, 1; oat cell, 3). Sensitivities: cytology, 50%; CEA, 50%; combined, 60%; specificity, 100%. High CEA (> 880 ng/mL) differentiated papillary adenocarcinoma of lung/gastrointestinal tract from renal and thyroid carcinoma. Mean CEA: oat cell, 216.7 ng/mL; adenocarcinoma, 0.5, > 880 ng/mL; glioblastoma and medulloblastoma, 1.6 ng/mL; benign, 0.6 ng/mL. CONCLUSION High CEA content enhanced the sensitivity of cytologic diagnosis of cystic metastases and favored a primary carcinoma of the lung or gastrointestinal tract.

Benign pulmonary epithelial inclusions within the pleura: a case report

BackgroundThe normal visceral and parietal pleura are composed of a mesothelium-lined layer of fibrous connective tissue, consisting predominantly of collagen and elastin fibers, with interspersed nerves, lymphatics, and blood vessels. There is no normal epithelial component to the pleura, and the histologic finding of epithelial cells within pleural tissue typically indicates the presence of a malignant process. The one documented exception to this rule is the occasional occurrence of endometriotic implants, which can result in cyclic thoracic symptomatology and occasionally even hemothorax.Case PresentationWe present a case of seemingly benign epithelial inclusions within the pleura of a sixty year-old male patient who underwent exploratory thoracotomy and subsequent resection of bullous emphysematous blebs. Examination of the surgical specimen revealed well-defined nests of benign-appearing epithelial cells in glandular configurations at multiple sites within the pleura. These cells were immunopositive for TTF-1 and CK7 and immunonegative for calretenin, CK20, and CEA, indicating pulmonary epithelial derivation. Six months after resection, the patient is in stable health, with no clinical or radiologic evidence of bronchogenic carcinoma.ConclusionTo our knowledge, this is the first report of benign pulmonary epithelial inclusions within pleural tissue. It is important to be aware that benign pleural inclusions occur, so as to avoid confusion with more serious processes in a population of patients who may have oncologic risk factors.