A. Michael Bilous

Prognostic importance of tumor size for localized conventional (clear cell) renal cell carcinoma: assessment of TNM T1 and T2 tumor categories and comparison with other prognostic parameters.

The T1 and T2 classifications of the International Union Against Cancer TNM classification system for renal cell carcinoma are based on primary tumor size, and in various editions of the classification, the cut points between T1 and T2 have been amended to provide clinical utility. In the current edition, the T1/T2 cut point is less than or equal to and greater than 7 cm. and more recently a subdivision of the T1 classification (less than or equal to and < 4 cm) has been proposed to identify patients suitable for partial nephrectomy. This study investigates the prognostic significance of tumor size in a series of organ‐confined clear cell renal cell carcinomas.

Progesterone receptor A and B protein expression in human breast cancer

The human progesterone receptor (PR) is a ligand-activated nuclear transcription factor which mediates progesterone action in target tissues. Two PR proteins, PR A (81-83 kDa) and PR B (116-120 kDa), have been described and different physiological activities ascribed to each on the basis of in vitro studies, suggesting that their ratio of expression may control progesterone responsiveness in target cells. Presence of PR in breast tumors is an important indicator of likely responsiveness to endocrine agents. However, the relative expression of PR A and B in breast cancer has not been described and its clinical significance has not been addressed. We have examined the expression of PR A and B in PR-positive breast tumors and found that while in most tumors PR A and B were expressed in similar amounts there was a broad overall distribution of PR A:B ratio which deviated significantly from a normal log distribution with tumors containing a PR A:B ration greater than 4 being over-represented in the group. Linear regression analysis revealed that high PR A:B ratios, in general, derived from a low concentration of PR B rather than high expression of PR A. PR A:B protein ratios were not correlated with the age of the patient or with total PR concentration. A third PR protein band (PR 78 kDa) was detected which comprised greater than 20% of total PR protein in a quarter of the tumor samples examined. The characteristics of tumors containing PR 78 kDa were not different from the overall group. In summary, in PR-positive breast tumors the ratio of expression of PR A and B proteins is close to unity as is seen in a number of other progestin target tissues. However, a significant proportion of tumors expressed very low levels of PR B and a consequently high PR A:B ration. Although the clinical consequence of this observation is not known, the in vitro findings that PR A may act as a repressor for PR B suggests that tumors containing primarily PR A may identify a subset of patients with low or aberrant response to endocrine agents.

Malignant fibrous histiocytoma developing in bone 44 years after shrapnel trauma

Tumors induced by foreign bodies are uncommon in humans, but they are a relatively common occurrence in some experimental animals. the development of sarcoma in association with metallic foreign bodies has rarely been reported. the development of a malignant fibrous histiocytoma in a 65‐year‐old man 44 years after shrapnel fragments lodged in his left arm is described. the literature regarding metallic foreign body‐induced cancer in humans is reviewed.

Breast conservation: long-term australian data

Long-term data on the management of early breast cancer in Australia by conservative surgery and radiation therapy is limited. To examine this issue we reviewed our experience of 131 patients with Stage I or II breast cancer treated between November 1979 and December 1985. Ninety patients had a T1 tumor and 41 a T2 tumor. The extent of surgery varied from a local excision (LE), a wide local excision, to a quadrantectomy or partial mastectomy. Sixty-two per cent of patients also had an axillary dissection. One hundred and nineteen patients were treated using 6Mev photons to the whole breast (Median dose; 50 Gy) +/- regional nodes followed by a single plane Iridium-192 boost to the primary tumor site (median dose; 30 Gy). Ten patients did not receive a boost and two elderly patients were treated with an implant only. The median follow-up of surviving patients was 83 months (range, 51-133 months). Six other patients were lost to follow-up at a median of 48 months (range, 4-62). The pattern of first relapse is: breast alone, 7.0%; breast + distant, 0.75%; breast + nodes, 0.75%; regional nodes only, 0.75%; and distant disease, 18%. The extent of surgery did not influence the probability of a recurrence in the primary tumor region. The time to a breast recurrence ranged from 12 to 127 months (median, 61 months). The 5-year actuarial rate of a breast recurrence was 4.5%. The 5-year freedom from distant relapse was 80%. The complications of treatment were acceptable. These included rib fracture (5%), symptomatic pneumonitis (4%), fat necrosis or fibrosis requiring surgery (4.5%), severe arm edema (4.5%). The treatment of the axilla by both surgery plus radiation therapy was associated with a moderate or severe arm edema rate of 29% compared to 8% for surgery alone and 6% for radiation therapy alone. Our long-term data indicate that conservative surgery plus radiation therapy is associated with low rates of breast cancer recurrence which are independent of the extent of surgical resection. Complications were acceptably low provided that the axilla was treated by surgery or radiation therapy but not by both modalities.

Is survival from infiltrating lobular carcinoma of the breast different from that of infiltrating ductal carcinoma

Abstract:  Previous studies of patients with breast cancer have compared survival of invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) with contradictory results. This study examines the effect of the diagnosis of IDC or ILC in conjunction with age at diagnosis, pathologic tumor size, pathologic stage, histologic grade, and lymph node status of 307 women with IDC or ILC in 1992 in the Greater Western region of Sydney in Australia. Survival analysis was conducted using the Kaplan–Meier method. Relative risks associated with IDC or ILC and other important prognostic factors and adjusted for each other were computed using Cox proportional hazard regression. The proportion of grade I tumors was significantly higher in ILC (41%) than in IDC (16%). Conversely, the proportion of grade III tumors was only 18% in ILC as against 41% in IDC (p = 0.020). The 10‐year survival of women with IDC was 69%, compared to 84% for ILC (p = 0.073). However, the 15 percentile point difference between overall survival of IDC and ILC was markedly reduced after adjustment for nodal status. The difference was eight percentile points for node‐negative patients (p = 0.361) and five percentile points for node‐positive patients (p = 0.464). Age at diagnosis, tumor size, pathologic stage, and lymph node status were independent prognostic indicators for 10‐year survival. There was no prognostic difference between IDC and ILC. The result shows the importance of adjusting for other important clinicopathologic characteristics before comparing the overall survival of IDC and ILC.

The prognostic value of Ki67 in systemically untreated patients with node-negative breast cancer

Aim To evaluate the utility of Ki67 as a prognostic marker in a series of patients with node-negative breast cancer untreated with adjuvant systemic therapy. Methods The cohort consisted of 203 cases treated with breast conserving surgery and radiation only; median follow-up was 183 months (range 156–277 months). An immunohistochemical panel of oestrogen receptor (ER), progesterone receptor (PR), cytokeratin (CK)5/6 and Ki67 and human epidermal growth factor 2 in situ hybridization (HER2-ISH) was performed on the tumour samples. Ki67 scores were evaluable in 193/203 patients (95.1%). The primary outcome was breast cancer specific survival (BCSS). Results Of the cohort, 29 (14.2%) died of breast cancer. A cut off of 10% separated tumours into a ‘Ki67-low’ (n=70) or ‘Ki67-high’ group (n=123). The breast cancer specific survival was 97.1% and 77.6% for Ki67-low and Ki67-high groups, respectively. Univariate analysis showed that in this lymph node-negative cohort, the predictors for BCSS were tumour size, Ki67, LVI, age and histological grade 3. Multivariable analysis showed that Ki67 index and lymphovascular space invasion were independent predictors of breast cancer death. To examine the utility of Ki67 in assignment of immunohistochemically molecular subtypes, cases were assigned into Luminal A (ER-positive, HER2-negative, Ki67 ≤14%), Luminal B (ER-positive, HER2-negative, Ki67 >14%) and triple negative (ER/PR-negative and HER2-negative, any Ki67). The 15-year breast cancer specific survival was 91.7%, 79.4% and 75.8%, respectively. Conclusions A statistically significant difference in breast cancer specific survival is seen in groups defined using Ki67 and receptor status, whereas histological grading was not a significant predictor of survival. Ki67 immunostaining provides prognostic information beyond traditionally assessed clinicopathological variables.

Characteristics of HER2-positive breast cancer diagnosed following the introduction of universal HER2 testing

The aim of this study was to determine the impact of universal HER2 testing on the clinico-pathologic profile of HER2+ breast cancer. Data were extracted from breast cancer pathology reports spanning two periods: before (2003/4, n = 379), and after (2008/9, n = 560) the introduction of universal testing. In 2003/4, 43.3% of breast cancers were tested for HER2 with 16% of tested cases HER2+. In 2008/9, 98.4% of cases were tested with 14.7% HER2+. In 2008/9, HER2+ status was associated with younger age, higher grade, increased tumour size, lymph node involvement, negative oestrogen and/or progesterone receptor status. HER2+ cases diagnosed in 2003/4 were not significantly different in respect of these features. The rate of HER2+ breast cancer amongst screen detected cases in 2008/9 was 8.3%. The phenotype of HER2+ breast cancer was stable following the introduction of universal testing. The overall rate of HER2+ breast cancer was influenced by screen detection.

A comparison between Ki-67 antibody reactivity and other pathological variables in breast carcinoma

Summary Methods of assessing tumor proliferation rates include mitosis counting, flow cytometry and thymidine labelling. While the former is inaccurate and poorly reproducible, the latter methods are time consuming and expensive to perform. Ki‐67 is a monoclonal mouse antibody which has been shown to react with a nuclear antigen in proliferating cells. Frozen sections from 75 specimens of breast carcinoma were immunostained with this antibody using an immunoperoxidase technique. The percentage of tumor cells stained, the Ki‐67 score, was then compared with a number of pathological and clinical variables in the patients concerned. A positive correlation was seen between the Ki‐67 score and mitotic rate (r = 0.71); and a negative correlation was seen between Ki‐67 score and estrogen receptor status (r = ‐0.4). Ki‐67 immunostaining may represent a cheap and reproducible method of assessing proliferation rates of breast carcinomas which is applicable in routine laboratories. Further prospective studies are being undertaken to assess its contribution to prognosis.

The value of S-phase and DNA ploidy analysis as prognostic markers for node-negative breast cancer in the Australian setting

This study aimed to determine the prognostic significance of DNA ploidy and S-phase fraction (SPF) measurements in our laboratory for patients with node-negative breast cancer. Frozen tumors from axillary node-negative breast cancer patients (n = 50) treated at Westmead Hospital, NSW, between 1988 and 1991 were analysed by flow cytometry. The median duration of follow-up for all patients was 8.4 years. Forty-six specimens provided evaluable DNA histograms with 43% (n = 20) diploid and 56% (n = 26) aneuploid tumors identified. Comparisons of DNA ploidy status and SPF were made with traditional prognostic variables, which included age, menopausal status, tumor size, histologic grade and hormone receptor status. Our results showed that there was no significant difference in disease-free or overall survival between patients with diploid and aneuploid tumors. Histologic grade 3 tumors were more likely to be aneuploid and had higher SPF than grade 1 or 2 tumors. Patients with grade 3 tumors and a high SPF were four times more likely to relapse than the rest of the population. These results indicate that DNA flow cytometric analysis in our laboratory provides additional prognostic data that could be utilised alongside traditional clinical and histopathologic indicators for predicting outcome for patients.

Diagnostic evaluation of papillary lesions of the breast on core biopsy

The management of asymptomatic intraductal papillary lesions of the breast diagnosed on core biopsy poses a challenge for patients and clinicians, as the distinction between common benign lesions and atypical or malignant varieties may be difficult without formal excision. The aim of this study was to determine whether a combination of histopathologic and biomarker features could be used to accurately identify benign papillary lesions on core biopsy. An inclusive group of 127 excised papillary lesions was characterized by detailed histopathologic review and immunohistochemical staining for the basal markers cytokeratin 5/6 (CK5/6) and P63 and the proliferation marker Ki67. Comparison of benign, atypical, and malignant lesions revealed that the combination of broad, sclerotic fibrovascular cores, and epithelial CK5/6 staining was most commonly seen in benign papillomas. Ki67 staining revealed striking intralesional heterogeneity, but there was no difference between the high scores of benign, atypical, or malignant lesions (P=0.173). In a non-overlapping set of 42 cases, a binary classifier specifying benign lesions on the basis of thick fibrovascular cores and epithelial CK5/6 staining on core biopsy gave an overall misclassification rate of 4/42 (10%) when compared with the final excision diagnosis. Misclassified cases included 2/27 lesions ultimately diagnosed as benign and 2/2 atypical papillomas. All malignant lesions (n=13) were correctly assigned. The combined assessment of fibrovascular core thickness and CK5/6 staining on core biopsy distinguished benign from malignant papillary lesions, but did not separate benign from atypical cases. This approach may form a useful addition to the clinicopathologic evaluation of papillary lesions of the breast.