Evaluation of the international Ki67 working group cut point recommendations for early breast cancer: comparison with 21-gene assay results in a large integrated health care system.

PURPOSE: The International Ki67 Working Group (IKWG) has developed training for immunohistochemistry (IHC) scoring reproducibility and recommends cut points of ≤ 5% and ≥ 30% for prognosis in ER+, HER2-, stage I/II breast cancer. We examined scoring reproducibility following IKWG training and evaluated these cut points for selecting patients for further testing with the 21-gene Recurrence Score (RS) assay. METHODS: We included 307 women aged 50+ years with node-negative, ER+PR+HER2- breast cancer and with available RS results. Slides from the diagnostic biopsy were stained for Ki67 and scored using digital image analysis (IA). Two IHC pathologists underwent IKWG training and visually scored slides, blinded to each other and IA readings. Interobserver reproducibility was examined using intraclass correlation (ICC) and Kappa statistics. RESULTS: Depending on reader, 8.8-16.0% of our cohort had Ki67 ≤ 5% and 11.4-22.5% had scores ≥ 30%. The ICC for Ki67 scores by the two pathologists was 0.82 (95% CI 0.78-0.85); it was 0.79 (95% CI 0.74-0.83) for pathologist 1 and IA and 0.76 (95% CI 0.71-0.80) for pathologist 2 and IA. For Ki67 scores ≤ 5%, the percentages with RS < 26 were 92.6%, 91.8%, and 90.9% for pathologist 1, pathologist 2, and IA, respectively. For Ki67 scores ≥ 30%, the percentages with RS ≥ 26 were 41.5%, 51.4%, and 27.5%, respectively. CONCLUSION: The IKWG's Ki67 training resulted in moderate to strong reproducibility across readers but cut points had only moderate overlap with RS cut points, especially for Ki67 ≥ 30% and RS ≥ 26; thus, their clinical utility for a 21-gene assay testing pathway remains unclear.

EGFR Mutated Lung Adenocarcinoma Metastasis to the Pancreas Mimicking Primary Pancreatic Ductal Carcinoma.

BACKGROUND: The occurrence of lung adenocarcinoma metastasizing to the pancreas is overall rare and can histologically imitate primary pancreatic ductal carcinoma (PDAC). CASE REPORT: This is a case report of a 70-year-old female with a history of surgically resected right lung adenocarcinoma presenting for routine follow up without symptoms. CT scans revealed a pancreatic cystic mass with ductal dilatation that was sampled via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and thought to be a primary pancreatic mucinous neoplasm with high grade dysplasia suspicious for carcinoma based on smear cytology. On repeat EUS-FNA and biopsy (FNB) with additional immunohistochemical testing for lung adenocarcinoma markers thyroid transcription factor (TTF1) and Napsin A and molecular testing, the lesion was identified as a metastasis of lung adenocarcinoma with an epidermal growth factor receptor (EGFR L858R) mutation; subsequently, the patient underwent targeted therapy that yielded an almost complete response. CONCLUSION: To the best of our knowledge, this is the first documented case in English literature of a lung adenocarcinoma metastasis to the pancreas mimicking a pancreatic primary neoplasm and highlights the potential pitfalls of EUS-FNA for the diagnosis of certain metastases to the pancreas.

Routine endometrial sampling of asymptomatic premenopausal women shedding normal endometrial cells in Papanicolaou tests is not cost effective.

BACKGROUND: Following The Bethesda System 2001 (TBS 2001) recommendation to report normal endometrial cells (nEMC) in women ages >or=40 years, studies have shown that endometrial (EM) sampling has increased, but detection of significant EM pathology has not increased. The cost implications of this increased EM sampling have not been specifically addressed. The aim of this study was to assess the cost effectiveness of EM sampling in women ages >or=40 years with nEMC in their Papanicolaou tests. METHODS: The authors reviewed 499 cases at a large academic women's hospital where nEMC had been reported in Papanicolaou tests followed by EM tissue sampling. Relevant clinical information was obtained from cytopathology and surgical pathology reports. Data on costs of EM sampling were obtained from business offices. RESULTS: Of 1049 women ages >or=40 years who were shedding nEMC, 499 (48%) had follow-up EM sampling. In follow-up EM sampling, 6 cases of significant pathology (atypical complex EM hyperplasia or adenocarcinoma) were detected. Asymptomatic women totaled 350, and the total cost for EM sampling of asymptomatic patients shedding nEMC was estimated at 107,272 dollars. Three of the asymptomatic patients had significant EM pathology, but all 3 were postmenopausal. Three additional premenopausal patients with significant pathology were symptomatic with vaginal bleeding. CONCLUSIONS: No asymptomatic premenopausal patients shedding nEMC either before or after Day 12 of their menstrual cycle were found to have significant EM pathology in this large study of almost 500 women with nEMC in their Papanicolaou tests. The total costs, when projected nationally, for EM sampling in asymptomatic premenopausal women were highly significant. Educational discussions with clinicians in this community are underway to reduce the number of women who undergo EM sampling after Papanicolaou test findings of nEMC. Routine EM sampling of asymptomatic premenopausal women with nEMC in Papanicolaou tests is not cost-effective.

Phyllodes tumor: a clinicopathologic and immunohistochemical study of 30 cases.

CONTEXT: Phyllodes tumors (PTs) of the breast are biphasic neoplasms composed of epithelium and a spindle-cell stroma. Currently, PTs are classified as benign, borderline, or malignant based on histopathologic features. However, histologic classification does not always predict outcome. Objective.-To determine the prognostic value of a variety of clinicopathologic features and immunoreactivities in PTs. DESIGN: Sixteen benign, 8 borderline, and 6 malignant PTs with follow-up were examined for reactivity across a panel of immunohistochemical stains, including c-Kit, endothelin 1, p16, p21, p53, and Ki-67. Clinicopathologic features, including stromal cellularity, mitotic rate, and margin status, were also assessed. Tumor variables were compared among tumor subgroups and between tumors that did and did not recur. RESULTS: Of the 30 PTs, 4 recurred (1 benign, 2 borderline, 1 malignant). One patient with a malignant tumor died of metastatic disease 34 months after initial diagnosis. The overall positive rate of c-Kit immunoreactivity was 13% in benign, 63% in borderline, and 67% in malignant PTs. Endothelin 1 epithelial cytoplasmic staining was seen in 100% of benign, 50% of borderline, and 17% of malignant PTs. Additionally, p16, p21, p53, and Ki-67 were differentially expressed among benign, borderline, and malignant tumors. Positive surgical resection margins was the only variable that significantly predicted recurrent disease (P = .02). CONCLUSIONS: Stromal c-Kit positivity and epithelial endothelin 1 negativity are more often associated with malignant PTs; however, only positive margin status is significantly associated with tumor behavior.

Centrosome abnormalities in ovarian cancer.

Centrosome abnormalities have been found in various cancer types and are thought to be involved in early development of cancer and/or progression. The contribution of centrosome abnormalities to ovarian tumorigenesis has not been previously evaluated. We sought to determine whether centrosome dysfunction occurs in ovarian tumorigenesis, and whether it could be used as an indicator of early neoplastic changes in ovarian surface epithelium (OSE). Primary cultures of normal OSE and ovarian tumors, as well as paraffin-embedded normal ovaries and ovarian tumors of different stages, were used for immunostaining with a gamma-tubulin antibody. Centrosomes were considered abnormal if there were more than 2 per cell, if their sizes were greater than 2-fold of a normal centrosome, and/or if they were abnormal in shape. Centrosomes in normal tissue were uniform in size, whereas centrosomes in ovarian tumors tended to be abnormal in size, number and shape. On average, 4.7% of cells in 5 primary normal OSE cultures had more than 2 centrosomes, whereas 14.1% of primary cells from 5 ovarian tumors displayed centrosome abnormalities (p = 0.008). Centrosome abnormalities were present in 60.9% of stage I (n = 23), 83.3% of stage II (n = 30) and all stage III (n = 10) paraffin-embedded ovarian tumor samples examined, but not in normal tissues. In addition, centrosome abnormalities occurred more frequently in ovarian tumors with higher grade and aggressive serous subtype. This is the first demonstration that centrosome abnormalities occur in ovarian tumors. Centrosome dysfunction may be an early event in ovarian carcinogenesis and involved in ovarian tumor progression.

Impact of the 1998 World Health Organization/International Society of Urological Pathology classification system for urothelial neoplasms of the kidney.

The classification of urothelial neoplasms of the kidney traditionally has been similar to that of urinary bladder tumors. Several years ago, the classification of papillary urothelial neoplasms was revised. The current study focuses on the application of the 1998 World Health Organization (WHO)/International Society of Urological Pathology classification system to 102 renal pelvic urothelial neoplasms and compares it to the 1973 WHO classification scheme. In this study, all tumors were classified as urothelial carcinomas, and the majority (85%) were papillary. Most patients with papillary tumors presented with 'superficial' disease (< or = pT1). With the 1998 system, most papillary carcinomas were high grade, and were more often invasive as compared to low-grade tumors. Only 34% were low-grade papillary tumors and, of these, most (93%) were noninvasive. With the 1973 system, most papillary tumors were grade 2 or 3, with invasion more common in grade 3 tumors. By 1973 criteria, grade 2 tumors were a heterogeneous group; with 1998 criteria, nearly one-half were high grade and the other half low grade. The grade of papillary urothelial carcinomas with both the 1973 and 1998 grading methods was associated with stage (P=0.001). Our study reveals that papillomas and papillary urothelial neoplasms of low malignant potential are uncommon tumors in the kidney. Renal pelvic papillary urothelial neoplasms are most often carcinomas and are more commonly high grade than low grade. Although both the 1973 and 1998 systems showed a significant association with tumor stage, grade 2 papillary carcinomas are a heterogeneous group by 1973 criteria. The 1998 system provides useful information in that it more clearly defines a papillary tumor's grade and selects for a group of tumors, namely low-grade papillary urothelial carcinomas, for which a low likelihood of invasion can be predicted.