A patient with carcinoma of the right breast and coincidental primary hyperparathyroidism is presented. The distinction between hypercalcemia of malignant and hyperparathyroid origins is based on biochemical analysis and localisation of parathyroid adenoma on a computer tomogram of the neck.
Fine needle aspiration (FNA) cytology is now an integral part of the pre-operative investigation of breast lesions and the therapeutic protocol is today often planned on the basis of cytodiagnosis. However, from time to time the cytological picture may be equivocal or inconclusive. In recent years, nucleolar organizer region (NOR) scores have been explored for potential value in the diagnosis of malignancy as the scores in malignant nuclei are seen to be higher than in benign or reactive nuclei. With a view to applying NOR scoring in the evaluation of cytologically equivocal cases, we adopted the argyrophil technique for staining NOR s (AgNOR) in FNA cytological smears of 56 breast lesions, comprising 31 benign and 25 malignant lesions. Histological correlation was possible in 26 of these cases (17 malignant and 9 benign) and AgNOR scoring was done on paraffin sections of these as well. There was a significant difference between mean AgNOR scores in benign and malignant lesions in the cytological smears (P < 0.001). The AgNOR scores ranged from 2.5 to 5.0 per cell in benign lesions and 5.8 to 17.2 per cell in malignant lesions. None of the cases fell into the gray zone of overlap. One malignant lesion that was cytologically equivocal showed a mean AgNOR score of 6.08. The AgNOR scores on histological sections also showed a statistically significant difference (P < 0.001) between benign and malignant lesions with mean scores ranging from 1.34 to 2.58 dots per cell in benign lesions and scores of 2.42 to 5.28 dots per cell in malignant lesions. However, the scores overlapped in four cases and therefore it was considered unsuitable for routine diagnostic work. From this preliminary study, we conclude that an FNA AgNOR score of 5.0 and less strongly favours a benign lesion whereas a score above 5.0 would be in favour of a malignant lesion. A larger study would be needed to verify our impression that AgNOR scoring can be useful in cytologically equivocal cases.
Discriminant analysis of six trace element concentrations measured by instrumental neutron activation analysis (INAA) in 26 paired-samples of malignant and histologically normal human breast tissues shows the technique to be a potentially valuable clinical tool for making malignant-normal classification. Nonparametric discriminant analysis is performed for the data obtained. Linear and quadratic discriminant analyses are also carried out for comparison. For this data set a formal analysis shows that the elements which may be useful in distinguishing between malignant and normal tissues are Ca, Rb and Br, providing correct classification for 24 out of 26 normal samples and 22 out of 26 malignant samples.
One hundred and twelve infiltrating ductal carcinoma of breast were studied by the standard avidinbiotin complex immunoperoxidase method on formalin-fixed, paraffin-embedded tissue sections, using a monoclonal antibody to c-erbB-2 oncoprotein. The same tumours were assessed and scored according to the Bloom and Richardson criteria into three histological grades. The distribution of tumours according to grade were: 8 Grade I, 34 Grade II and 70 Grade III. Forty-three (38.4%) tumours showed positive membrane staining for c-erbB-2 oncoprotein. These comprised 7 Grade II and 36 Grade III tumours with c-erbB-2 immunopositivity rates of 20.6% and 51.4% respectively. The oncoprotein was not expressed by Grade I tumours. This study shows a good correlation between c-erbB-2 expression and histological grade, a known prognostic indicator of invasive breast carcinoma. Because the c-erbB-2 oncogene has extensive structural homology to the epidermal growth factor receptor gene, its overexpression can be expected to result in more aggressive tumour behaviour. While it may be regarded as another indicator of poor prognosis breast cancers, its value in the selection of carcinomas less responsive to hormonal therapy and those more suitable for immunotherapy than chemotherapy has been mooted but remains to be clarified.
Fresh frozen neoplastic tissues from 70 infiltrating ductal breast carcinomas were analysed for cytosolic oestrogen receptor (ER) protein content using a solid phase enzyme immunoassay (EIA) method based on a "sandwich" principle (Abbott ER-EIA monoclonal). Formalin-fixed, paraffin-embedded sections from the same carcinomas were examined for nuclear immunoreactivity against a monoclonal antibody for ER protein (Dako) using the standard avidin-biotin complex immunoperoxidase (IP) method after microwave antigen retrieval. The degree of ER positivity by IP was also scored according to a visual estimation of the percentage of cells expressing immunopositivity and the intensity of staining. Twenty-eight (40%) of the carcinomas were ER-positive by EIA and 34 (48.6%) were positive by IP. Twenty-five (35.7%) were ER-positive and 33 (47.1%) were ER-negative by both methods. Nine (12.9%) were ER-negative by EIA but were positive by IP, this discrepancy being ascribed to sampling inadequacy for EIA. However, 3 (4.3%) tumours were ER-positive by EIA and negative by IP. This discrepancy may be variously due to inadequate antigen retrieval, faulty technique and the possibility that the two methods do not measure identical ER proteins. IP appears to have an advantage over EIA in that it has a higher pick-up rate, does not require fresh tissue and can be applied to archival material. However, to reduce false negative estimations, it may be necessary to run IP staining using more than one ER antibody. Standardisation of the IP method for ER is desirable before this method is to be widely adopted in Malaysian laboratories. Quantitation of ER positivity by IP scoring correlated poorly with actual cytosolic levels. Caution should be exercised in attaching patient management value to visual IP scoring.
Recent studies have demonstrated a reduction in the morbidity and mortality of pancreatic resection and improvement in the actuarial 5-year survival for patients with resected ductal adenocarcinoma. We reviewed the clinico-pathological characteristics of patients who underwent resection with curative intent for ductal adenocarcinoma of the pancreas between 1980 and 1993.
To clarify the correlation between apoptosis and tumor cell proliferative activity in human breast cancer and to investigate their relevance to p53 protein.
Eighty-six infiltrating ductal carcinoma of breast were studied by the standard avidin-biotin complex immunoperoxidase method on formalin-fixed, paraffin-embedded tissue sections, for oestrogen receptor (ER) protein and c-erbB-2 oncoprotein expression. They were categorized according to the modified Bloom and Richardson criteria into three histological grades. 21% tumours were ER positive while 44% were c-erbB-2 positive. Of ER positive tumours, 33.3% were c-erbB-2 positive whereas the c-erbB-2 positivity rate was much higher (47.1%) in ER negative tumours. Only 16% of c-erbB-2 positive tumours were ER positive while 25% of c-erbB-2 negative tumours were ER positive. This negative relationship between ER and c-erbB-2 expression was statistically significant (Mc Nemar's test, p < 0.005). The ER positivity rate did not vary significantly with histological grade. However, c-erbB-2 overexpression was significantly more prevalent in grade III tumours compared with grade I and II tumours (Chi-square test, p < 0.005). Since the c-erbB-2 oncogene has extensive structural homology to the epidermal growth factor receptor (EGFR) gene, we expect that c-erbB-2 oncoprotein would share functional similarities with EGFR leading to both loss of oestrogen receptor and poor prognosis in breast cancer. Its overexpression can be expected to relate to more aggressive tumour proliferation and may explain its correlation with high histological grade, a known indicator of aggressive cancer behaviour. As there is no indication that ER protein activity contributes to advancement in histological grade, it would appear that cellular dedifferentiation precedes ER loss during malignant transformation. It has been mooted that ER positive breast cancers which also show c-erbB-2 oncoprotein overexpression have a poorer response to hormonal therapy. The use of this parameter in the routine assessment of breast cancer patients may identify subsets of patients for more aggressive therapy.
Expression of c-erbB3 protein was investigated in 104 primary breast carcinomas comprising nine comedo ductal carcinoma in situ (DCIS), 91 invasive ductal carcinomas and four invasive lobular carcinomas using two monoclonal antibodies, RTJ1 and RTJ2. Of the 91 invasive ductal carcinomas, seven contained the comedo DCIS component adjacent to the invasive component. An immunohistochemical technique was used to evaluate the association between expression of c-erbB3 and clinical parameters and tumour markers such as epidermal growth factor receptor (EGFR), c-erbB2, cathepsin-D and p53 in archival formalin-fixed paraffin-embedded tumour tissues. Our results indicated that RTJ1 and RTJ2 gave identical staining patterns and concordant results. It was found that the overexpression of c-erbB3 protein was observed in 67% (6/9) of comedo DCIS, 52% (44/84) of invasive ductal carcinomas, 71% (5/7) of carcinomas containing both the in situ and invasive lesions and 25% (1/4) of invasive lobular carcinomas. A significant relationship (P < 0.05) was observed between strong immunoreactivity of c-erbB3 protein and histological grade, EGFR and cathepsin-D, but not with expression of c-erbB2, p53, oestrogen receptor status, lymph node metastases or age of patient. However, we noted that a high percentage of oestrogen receptor-negative tumours (59%), lymph node-positive tumours (63%) and c-erbB2 (63%) were strongly positive for c-erbB3 protein. We have also documented that a high percentage of EGFR (67%), c-erbB2 (67%), p53 (75%) and cathepsin-D-positive DCIS (60%) were strongly positive for c-erbB3. These observations suggest that overexpression of c-erbB3 protein could play an important role in tumour progression from non-invasive to invasive and, also, that it may have the potential to be used as a marker for poor prognosis of breast cancer.
Expression of p53 protein was investigated by immunohistochemical techniques in archival cases of 134 primary breast carcinomas comprising 13 comedo ductal carcinoma in situ (DCIS), 105 invasive ductal carcinomas, 7 contained the comedo DCIS component adjacent to the invasive ductal component, 5 invasive lobular carcinomas, three colloid carcinomas and one medullary carcinoma. Overexpression of p53 gene product was studied to determine the association with clinico-pathological parameters and also its relationship to c-erbB2. Overexpression of p53 protein was observed in 31% (4/13) of comedo DCIS, 37% (39/105) of invasive ductal carcinomas, 57% (4/7) of carcinomas containing both the in situ and invasive lesions and all medullary carcinomas. A significant relationship (p < 0.05) was observed between strong immunoreactivity of p53 protein and absence of estrogen receptor, histological grade and c-erbB2 but not with lymph node metastases or age of patient. These observations suggest that overexpression of p53 protein may play an important role in tumor progression from noninvasive to invasive in some breast carcinomas and may have potential as an indicator for poorer prognosis.
Tumor cytogenetic analysis from 27 patients with breast cancer diagnosed at the Singapore General Hospital revealed complex karyotypic aberrations in 12 cases. The study group comprised 25 women and 2 men, ranging in age from 33 to 78 years (median 52 years). Ethnic distribution consisted of 22 Chinese, 3 Malaysian, and 2 Indian patients. Pathologic assessment disclosed 24 invasive ductal, 2 invasive mucinous, and 1 mixed invasive mucinous and ductal carcinomas. Histologic grading showed 3 grade 1, 10 grade 2, and 12 grade 3 tumors; 2 cancers were not graded, because they had been subjected to prior chemotherapy. Tumor sizes ranged from 1.5 to 10 cm (median 3 cm). Eleven cases were axillary node negative, whereas the remaining 16 node-positive cancers affected as many as 3 nodes in 8 cases and 4 or more nodes in another 8. Twenty cases demonstrated estrogen-receptor positivity, and 8 cases progesterone-receptor positivity. The spectrum of cytogenetic abnormalities involved chromosomes 1, 3, 6, 7, 8, 11, 16, and 17 and ranged from gains and deletions of both long and short arms, trisomy, monosomy, and other rearrangements. There was a trend toward the presence of karyotypic abnormalities in tumors of higher grade.
Breast carcinoma is the most common primary tumor producing intraocular metastasis. Metastases to the iris and ciliary body are relatively rare. The authors report a case of a 61-year-old lady, operated for carcinoma of the left breast 3 years back, who presented with symptoms and signs of acute narrow-angle glaucoma in the right eye. A diffuse whitish plaque-like mass in the upper nasal quadrant of the iris with an episcleral nodule on the limbus in the corresponding area and all the signs of acute narrow-angle glaucoma were present in the right eye. Intraocular pressure was controlled medically. Fine-needle aspiration cytology from the episcleral nodule showed malignant cells. Histopathology of the excised nodule showed metastatic poorly differentiated carcinoma, and the cellular pattern was similar to the carcinoma of the breast. There was no other metastasis anywhere in the body. Fine-needle aspiration cytology from an external lesion of the eye is a less invasive and easier procedure than paracentesis to diagnose the metastatic nature of the lesions. The rare features in our case are the clinical presentation as acute glaucoma and the ocular structures being the first and only site of metastasis.
This investigation was carried out to gain insight into the prevalence of pS2 expression in invasive ductal breast carcinoma in the Malaysian population and its correlation with oestrogen receptor (ER) protein expression and tumour aggressiveness. Seventy consecutive infiltrating ductal breast carcinomas treated with mastectomy and axillary lymph node clearance were investigated, using the standard avidin-biotin complex immunoperoxidase method with microwave antigen retrieval and commercial monoclonal antibodies (Dako), for expression of pS2 and human ER. This was correlated against histological grade (modified Bloom and Richardson) and the presence of axillary lymph node metastasis of these carcinomas. Four (5.7%) were grade 1, 40 (57.1%) grade 2 and 26 (37.1%) grade 3 tumours. A total of 45 (64%) showed histological evidence of axillary lymph node metastasis. Forty (57%) were ER-positive, while 31 (44%) were pS2-positive. There was a statistically significant correlation between pS2 and ER expressions (chi2-test with Yates correction: P<0.005). There was no correlation between pS2 expression and histological grade (P>0.1) and the presence of lymph node metastasis (P>0.1). Our findings support the views that pS2 may be a co-marker of endocrine responsiveness in invasive breast cancer and that it does not influence breast cancer biology in terms of potential for metastatic spread.
Metastatic eyelid tumours are rare and account for less than 2% of all eyelid neoplasms. We report a case of metastatic breast carcinoma to the eyelid in a 60-year-old Chinese lady presenting with a 2-year history of enlarging, painless nodular lower eyelid swelling. The 1 cm diameter lesion was provisionally diagnosed as a sebaceous cyst. However the excision biopsy revealed a mucinous carcinoma expressing oestrogen receptor protein. She had a past history of mastectomy one year previously and histology showed an infiltrating ductal carcinoma (oestrogen receptor status negative) without evidence of axillary lymph node metastasis. She had completed adjuvant radio- and chemotherapy. Further treatment of the current lesion involved a wide excision which did not show any residual malignancy. She had no other evidence of metastasis and was treated with letrozol. We highlight this case to create awareness among clinicians and opthalmologists on the possibility of metastatic disease as a cause of eyelid swelling, especially in patients with a history of cancer. It may also be the first sign of metastatic disease of an internal malignancy. A review of the literature is also presented.
Metastasising ability connotes one of the most important life-threatening properties of malignant neoplasms. Recent studies indicate that CD44 proteins, multifunctional cell adhesion molecules which contribute to "homing" of lymphocytes to lymph nodes as well as cell-cell and cell-matrix interactions, are potential markers of tumour progression. However, whether CD44 expression by human tumours contribute to increased metastatic risk remains controversial. In an attempt to clarify its role in breast cancer, we have investigated the correlation between CD44 expression by breast carcinoma and the presence of axillary lymph node metastases. CD44 expression was detected using a standard immunoperoxidase method on formalin-fixed, paraffin-embedded, primary infiltrating ductal breast carcinoma tissues taken from 60 female patients who underwent mastectomy with axillary node clearance. Tumours were graded according to the modified Bloom and Richardson criteria. 62% of patients had histologically-proven lymph node metastasis. 40% of primary cancers exhibited cytoplasmic membrane immunopositivity for CD44. 46% of primary tumours which have metastasied to axillary lymph nodes were CD44 positive whereas 30% of tumours which have not metastasised expressed CD44. CD44 positivity was expressed by 20% of grade 1, 31% grade 2 and 58% grade 3 tumours. Our results suggest that CD44 may have a role in the progression of breast cancer and emphasise the need to investigate its interaction with other mechanisms of cancer advancement.
Survivin is a 16.5-kDa intracellular protein also known as AP14 or BIRC5. It inhibits apoptosis and regulates cell division and belongs to the inhibitors of apoptosis (IAP) gene family. In the majority of neoplasms investigated for survivin expression, high levels of the IAP proteins were predictive of tumour progression, either in terms of disease-free survival or overall survival, thus providing significant prognostic information. Hence, the prognostic value of survivin expression in tumour masses of invasive ductal carcinoma has been investigated. It was found that negative and low expression of survivin correlated significantly with favourable outcomes. Conversely, high expression correlated with unfavourable outcomes. The five-year survival rate was higher among the cases with low and negative survivin expression, compared to those with higher survivin expression. However, this correlation was found to be insignificant statistically. Furthermore, a statistical model has been devised to explain the combined effects of survivin expression and its sub-cellular localisation, p-53 expression and lymph nodal involvement, on the outcomes of these patients.
The p27 V109G polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Malaysian population. Peripheral blood samples were collected from 230 breast cancer patients and 200 normal and healthy women who had no history of breast disease or breast cancer. We evaluated the association between the p27 polymorphism and breast cancer risk, and clinico-pathological parameters in the population. The distribution of genotype and allele frequencies of p27 V109G polymorphism were not significantly different between the breast cancer cases and normal subjects (P=0.376). Women who were homozygous (OR=1.73; 95% CI, 0.62-4.92) or heterozygous (OR=1.26; 95% CI, 0.75-2.12) for G allele, or carriers of G allele genotype (OR=1.34; 95%, 0.83-2.16) or G allele (OR=1.36; 95% CI, 0.90-2.05) were not associated with breast cancer risk. No significant correlation was noted between G allele genotype and breast cancer risk among patients under 50 (OR=1.28; 95% CI, 0.62-2.66) or 50 years and older (OR=1.38; 95% CI, 0.71-2.66) at diagnosis. The G allele genotype was significantly associated with lymph node metastases but independent of ER status and histological grade. In conclusion, the polymorphic variant at codon 109 of p27 gene may not be a marker for determining patients' risk of developing breast cancer but it may be a potential genetic marker for poor prognosis, thereby a marker for tumor prognosis.
INTRODUCTION: Survivin is a 16.5-kDa intracellular protein that inhibits apoptosis and regulates cell division, and belongs to the inhibitors of apoptosis gene family. It appears to have an important role in regulating apoptosis at the cell cycle checkpoints. Survivin has been found to have a differential distribution in cancer compared to normal tissue, as it is over-expressed in malignant tumours.
METHODS: In addition to the demographical analysis of the disease, data from 382 women with invasive ductal carcinoma of the breast were collected from three hospitals in Northeast Malaysia, and analysed for survivin expression by immunohistochemistry.
RESULTS: Invasive ductal carcinoma of the breast was found to be the most prevalent breast cancer type. Survivin was detected in 260 (68.1 percent) study cases. In addition, significant correlations have been shown between survivin expression on one hand, and tumour size and lymph node involvement on the other hand (p-value is less than 0.05). However, no significant correlations were found with other clinicopathological factors, such as tumour histological grade, tumour side, oestrogen and progesterone receptors. Nuclear expression of survivin was detected in 16.5 percent of the study cases, cytoplasmic expression was detected in 24.1 percent, and 27.5 percent of the cases expressed survivin in both nuclear and cytoplasmic locations simultaneously. The subcellular localisation of survivin was significantly correlated (p is less than 0.001) with the lymph node involvement indicating its value in predicting the aggressiveness of tumour cells, since it increases the resistance to apoptosis and promotes cell proliferation.
CONCLUSION: This is the fi rst known report on survivin expression in cancer in West Malaysia and Southeast Asia. It emphasises the importance of the detection of survivin in breast cancer to aid in diagnosis, confirm malignancy, and to assess the disease progress and response to therapy.