p63 is useful in the diagnosis of mammary metaplastic carcinomas

AIMS: p63 has been recently reported to be expressed in sarcomatoid/metaplastic carcinoma of the breast, in addition to its role as a myoepithelial marker. A large series of 34 metaplastic carcinomas, including cases with pure epithelial component (squamous cell and adenosquamous carcinomas), biphasic tumours with carcinomatous and sarcomatoid components and monophasic tumours with only spindle cell component, were evaluated for p63 expression with respect to the different cellular components. METHODS: All of the metaplastic carcinomas were assessed for p63 and conventional epithelial and mesenchymal markers of AE1/3, CAM5.2 and vimentin by immunohistochemistry. RESULTS: All of the different categories of metaplastic carcinomas showed similar clinico-pathological features (patient age, tumour size, nuclear grade, mitotic activity, lymph node status and hormonal receptor status). For metaplastic carcinoma with epithelial component only, p63 was only expressed in the squamous cell component, but not the adenocarcinoma component. Eight of the 10 tumours were positive for p63. For the tumours with sarcomatoid component, either singly or together with carcinomatous component, p63 was positive in 14 of 24 cases. Pure sarcomas and carcinomas were all negative for p63 staining by immunohistochemistry, thus rendering p63 staining highly specific for diagnosing metaplastic carcinoma. CONCLUSIONS: Using p63 for diagnosis of metaplastic carcinoma gives a sensitivity of 65%, a specificity of 96%, a positive predictive value of 96%, and a negative predictive value of 66% and an accuracy of 78%. p63 may be used as an adjunct marker in the diagnosis of metaplastic carcinoma.     

Fine-needle aspiration cytology of metaplastic carcinoma of the breast

BACKGROUND: Metaplastic carcinoma of the breast encompasses a heterogeneous group of tumours with variable components of sarcomatoid, squamous or poorly differentiated carcinomas. AIM: To review a series of 19 cytological preparations of metaplastic carcinomas to assess diagnostic cytological features. METHODS: 17 cases of fine-needle aspirates of histologically proven metaplastic carcinomas (4 monophasic spindle cell carcinomas, 4 squamous cell carcinomas and 11 biphasic tumours) were reviewed, with an emphasis on the presence of poorly differentiated carcinoma, squamous cell carcinoma, atypical spindle cells, benign stromal fragments and necrosis. RESULTS: All cases were diagnosed as malignant, with 68% of cases showing moderate to high cellularity, and 47% showing necrosis. If the tumours were analysed according to the constituting components histologically, 7, 15 and 8 cases, respectively, possess poorly differentiated carcinoma cells, sarcomatoid malignant cells and squamous carcinoma cells, whereas these components were cytologically identified in 11, 10 and 7 cases, respectively. Dual tumour populations were identified in only 5 of the 11 biphasic carcinomas in the cytological preparations; and the stromal material was cytologically identified in the only case with chondroid stroma. CONCLUSIONS: Identification of metaplastic carcinoma in cytology remains problematic. There seems to be morphological overlap between various components. The identification of dual components, unequivocal squamous carcinoma cells and chondroid stroma is helpful for diagnosis, but it is uncommon. The presence of poorly differentiated carcinoma cells with a suggestion of focal spindle morphology is another clue to the suggestion of metaplastic carcinoma.     

Prognostic factors in bladder carcinoma: histologic parameters and expression of a cell cycle-related nuclear antigen (Ki-67).

A total of 316 biopsies from patients with bladder carcinoma who entered a trial of the genito-urinary group of the European Organization for Research and Treatment of Cancer (EORTC) were reviewed. The histological data were subsequently correlated with the clinical course. A strong correlation between the number of mitoses and the time of first recurrence, muscle invasion, and death was noted. Next the expression of Ki-67 in frozen sections from 49 transitional cell carcinomas (TCCs) and the DNA content of the tumour cells were determined. The frequency of Ki-67-positive tumour cells increased with tumour grade and stage. Grade II TCCs and superficially infiltrating TCCs showed a wide range of Ki-67 scores. There was a significant difference in Ki-67 score between non-infiltrating (Ta) and superficially infiltrating (T1) grade II TCCs. All DNA-aneuploid carcinomas but also 15 out of 36 DNA-diploid tumours contained more than 10 per cent Ki-67-positive cells. Only some of these tumours were DNA-aneuploid or -tetraploid. The results indicate that the number of Ki-67-positive cells in grade II tumours may be a useful aid in separating grade II TCCs with a favourable prognosis from those with a poor clinical outcome.     

DIFFERENTIATION PATHWAYS IN PRIMARY INVASIVE BREAST CARCINOMA AS SUGGESTED BY INTERMEDIATE FILAMENT AND BIOPATHOLOGICAL MARKER EXPRESSION

The expression of intermediate filament proteins (IFPs) in 65 primary breast carcinomas was analysed by a panel of specific antibodies. Results were integrated with the oestrogen and progesterone receptor (ER and PGR) status, Ki-67 marking, and epidermal growth factor receptor (EGFr) expression. Invasive breast carcinomas could be divided into three main groups: group 1 revealed positivity only for ‘simple epithelial’ cytokeratins (CKs 7, 8, 18, and 19); group 2 also stained with the antibodies K8.12 and 34βE12; while group 3 showed co-expression of CKs 14 and 17, vimentin, and α-smooth muscle actin. Group 3 consistently comprised tumours with the highest Ki-67 levels, EGFr positivity, and ER-PGR negative status. On the other hand, groups 1 and 2 usually exhibited a positive hormonal status, lower proliferative activity, and EGFr negativity. The results of this study indicate that the determination of IFPs can significantly contribute to the identification of groups of patients with different biopathological settings and possibly different clinical behaviour.     

Mucin antigens expression and Ki-67 labeling in breast cancer: The peculiarity in scirrhous carcinoma

The expression of mucin-related antigens (Tn, T, Sialosyl-Tn [STn], DF3 [mammary-type apomucin related antigen], and intestinal-MRP [intestinal-type apomucin related antigen]) as well as Ki-67 labeling was examined in 58 mammary invasive ductal carcinomas (IDC) divided into 26 scirrhous subtype (SC) and 32 non-scirrhous subtype comprising papillotubular carcinoma and solid-tubular carcinoma (PT-ST). These data were analyzed in connection with the various pathological prognostic factors such as nodal status, tumor size, estrogen receptor status and histological grading of carcinomas. The results were as follows: (a) in SC, the expression rate of Tn was significantly higher in the cases with positive lymph node metastasis or with large tumor size (>2cm) than in those with negative lymph node metastasis or with small tumor size (>2 cm); (b) in PT-ST, the expression rate of STn was higher in the cases with positive lymph node metastasis or with large tumor size than in those with negative lymph node metastasis or with small tumor size; (c) in SC, Ki-67 labeling was significantly higher in the cases with positive lymph node metastasis than in those with negative lymph node metastasis; and (d) in PT-ST, Ki-67 labeling was lower in the cases with positive lymph node metastasis than in those with negative lymph node metastasis. In conclusion, Tn antigen expression was correlated with pathological prognostic factors in SC but not in PT-ST, whereas STn antigen expression was correlated with pathological prognostic factors in PT-ST but not in SC. Moreover, lnverse relationship between Ki-67 labeling and nodal status was observed in PT-ST. These differences between SC and PT-ST may be related to their different biological behaviors.     

p53 expression in carcinoma of the cervix.

AIM: To assess overexpression of the proposed tumour suppressor gene product p53 using the mouse monoclonal antibody DO-7 in the three main subtypes of carcinoma of the uterine cervix and to evaluate its value as a prognostic indicator. METHODS: Eighty two cases of FIGO Stage IB/IIA uterine cervical carcinoma were studied retrospectively. The tumours had been previously typed into adenocarcinomas, squamous carcinomas and adenosquamous carcinomas after the tissue had been fixed in formalin and embedded in paraffin wax. p53 protein expression was assessed using a standard immunohistochemical technique and the findings were correlated with tumour type, lymph node status and clinical outcome. RESULTS: In total, the p53 gene product was overexpressed in 17.1% (14/82) of all carcinomas and also in areas of cervical intraepithelial neoplasia grade III adjacent to invasive squamous carcinoma. Where present, the normal epithelium was uniformly negative. No association was found between p53 overexpression and tumour subtype, lymph node status or clinical outcome. CONCLUSIONS: It seems unlikely that p53 analysis will be of value in determining prognosis in carcinoma of the uterine cervix.     

Immunohistochemical analysis of bcl-2 and p53 expression in breast carcinomas: their correlation with Ki-67 growth fraction

We examined 59 breast cancers for p53 and bcl-2 protein expression by immunohistochemistry. The results were correlated with Ki-67 immunostaining. p53-negativity was noted in 40 cases and the remaining 19 tumours were p53-positive. Thirty-six tumours showed strong expression of bcl-2 and in 23 no staining for this protein was observed. We found statistically significant reverse correlation between expression of p53 and bcl-2 in majority of carcinomas: 31 cases were bcl-2 positive and p53-negative, and 14 tumours were bcl-2-negative and p53-positive. Six carcinomas showed no nuclear staining for Ki-67 and in the remaining 53 the percent of cancer cells positive for Ki-67 ranged from 1 to 60 (mean: 14.6). In these 53 cases we found that bcl-2-positive tumours were characterized by lower proliferation than bcl-2-negative tumours, the mean value of Ki-67 immunostaining being 10.7% and 23.0%, respectively. p53-negative tumours showed lower proliferation than p53-positive tumours: mean Ki-67 index was 10.2% and 23.9%, respectively.We conclude that immunohistochemically detected p53 and bcl-2 proteins show a significant inverse relationship in majority of breast carcinomas and their expression correlates with tumour proliferation (Ki-67 immunostaining).     

MIB-1 proliferative activity in invasive breast cancer measured by image analysis.

AIMS: To determine cell proliferation in infiltrating breast carcinomas. METHODS: Using the MIB-1 monoclonal antibody, the proliferation index was measured in paraffin wax sections of 871 breast cancers. The MIB-1 proliferation index was compared with other markers of disease progression: size, lymph node status, histotype, oestrogen and progesterone receptor status, expression of p53 and Neu, and DNA ploidy. All parameters were measured using image analysis. In 347 tumours, the MIB-1 and Ki-67 proliferation indexes were compared. Follow up data were available for 170 cases (median 66.5 months). RESULTS: Of the tumours, 314 (36%) had a high proliferation index. The MIB-1 proliferation index was correlated directly with size, nodal status, overexpression of p53 and Neu, and the DNA index; and inversely with oestrogen and progesterone receptor status. The correlation between MIB-1 and Ki-67 proliferation indexes was statistically significant. In patients with pT1 tumours, a low proliferation index correlated with a longer relapse-free interval and overall survival; node negative patients with a low proliferation index had a longer overall survival. CONCLUSIONS: The MIB-1 proliferation index is a reliable, practical and useful method of measuring proliferative activity and is an important predictor of clinical behaviour.     

Expression of the receptor for parathyroid hormone-related protein in normal and malignant breast tissue

Parathyroid hormone-related protein (PTHrP) is the cause of humoral hypercalcaemia of malignancy and interacts with parathyroid hormone (PTH) receptors. Breast cancer cells produce PTHrP in vitro and in vivo. The breast cancer cell line MCF-7, which products PTHrP and expresses PTHrP receptors, proliferates in response to PTHrP. The aim of these studies was to determine the tissue location of PTHrP/PTH receptors (PTHrPR) in primary breast carcinomas and to establish whether they had the potential to respond to PTHrP. The cellular location of mRNA for the PTHrP/PTH receptor was identified using in situ hybridization in primary breast carcinomas and normal breast tissue. Immunohistochemistry for PTHrP was carried out on the same specimens. Tumours were assessed and scored by two observers using the product of intensity of signal and number of positive tumour cells (possible range 0–9). Tumours were also assessed for Ki-67 expression by counting positive nuclei. Non-malignant ductular epithelium expressed mRNA for the PTHrP receptor (mean score 2·6, range 1–4). Breast carcinomas (mean score 4·4, range 0–9) showed variable expression of PTHrP receptor mRNA: eight tumours were negative, 50 had scores similar to normal breast tissue, and 49 had higher scores for the receptor. Levels of expression of the receptor within the primary breast carcinomas were unrelated to immunohistochemical detection of PTHrP or to any standard prognostic factor. There was a significant (P=0·05) relationship between Ki-67 and PTHrPR expression in individual tumours. The presence of PTHrP and its receptor in normal breast epithelium and breast carcinomas demonstrates that most breast tumours are able to respond to PTHrP. The Ki-67 data suggest that PTHrP is a potential autocrine growth factor in primary breast carcinoma. © 1997 John Wiley & Sons, Ltd.     

Ki-67 derived proliferative activity in colorectal adenocarcinoma with prognostic correlations

Cryostat sections from samples of 108 colorectal carcinomas were stained with the murine monoclonal antibody Ki-67, which is expressed in proliferating cells. Ki-67 immunoreactivity was assessed independently by two pathologists using a semi-quantitative method. There was excellent correlation between the two observers. Ten cases were assessed quantitatively by counting at least 2000 cells and there was a very good correlation between this method and the semi-quantitative method. The carcinomas showed a wide range of Ki-67 labelling, reflecting a variation in proliferative activity. The tumour labelling index ranged from 1 to 80 per cent positivity: there was also heterogeneity of labelling within many of the tumours. There was no correlation between Ki-67 derived proliferative score and known prognostic parameters, including Dukes stage, New Prognostic Classification grade, lymph node status, tumour differentiation, venous spread, invasive margin, lymphocytic infiltrate, and curative versus palliative surgery. Nevertheless, it is concluded that Ki-67 immunohistochemistry provides a reliable and reproducible method of assessment of proliferative activity in colorectal cancer. Ki-67 immunohistochemistry may have a clinical application in the selection of patients with colorectal cancers who might benefit from radiotherapy and/or chemotherapy, particularly those with unresectable or locally recurrent tumours.     

Lymphatic vascular density and lymphangiogenesis during tumour progression of carcinoma ex pleomorphic adenoma

AIMS: To assess lymphatic vascular density (LVD) and lymph vessel endothelial proliferation in a series of carcinoma ex pleomorphic adenoma (CXPA) that represents the tumour in the different carcinogenesis phases and tumour progression. METHODS: In 8 cases of early CXPA (intracapsular and minimally invasive tumours), 8 of advanced CXPA (widely invasive tumours) and 10 of pleomorphic adenoma (PA) without malignant transformation, lymphatic vessels and proliferating cells were detected using the antibodies D2-40 and Ki-67 respectively. RESULTS: Comparing early tumours with advanced ones, LVD was not significantly different at the tumour margin. In contrast, regarding intratumoural lymphatics, PA without malignant transformation and early CXPA contained rare, if any, lymph vessels, whereas in widely invasive carcinomas they were more numerous. However, neither intratumoural nor peritumoural LVD were increased in comparison to adjacent normal salivary gland tissue. In no case did dual immunohistochemistry using D2-40 and the cell proliferation marker Ki-67 reveal the existence of proliferating lymphatics. Carcinomatous emboli were found in peritumoural as well as in intratumoural lymphatics only in advanced CXPA without myoepithelial differentiation. CONCLUSION: In CXPA, the lymphatic network is mainly composed of pre-existing lymphatics which are rare in tumours that have not infiltrated outside the confines of the original PA. In the widely invasive CXPA, intratumoural as well as peritumoural lymphatics are a conduit for carcinoma cells, but in carcinomas with myoepithelial differentiation, the neoplastic cells seem to have a lower invasion capacity.     

The cytokeratin profile of medullary carcinoma of the breast

AIMS: The cytokeratin (CK) phenotype and vimentin expression of 31 medullary carcinomas was studied using commercially available antibodies on archived material. Comparing the phenotype of typical and atypical tumours and the phenotype of metastases, the biological significance of cytokeratin and vimentin expression in medullary carcinomas of the breast was determined. METHODS AND RESULTS: Antibodies to CK4, CK5 and 6, CK7, CK14, CK8 and 18, CK19, CK20 and to vimentin were used. All the typical and atypical medullary carcinomas and the metastases (10 cases) stained negatively for CK4 and positively for CK8-18 (CAM5.2). Almost all the tumours were CK7 and CK19 positive and CK20 negative. Twelve per cent of the tumours contained CK14. Twenty-five per cent of the typical, 43% of the atypical and 20% of the metastatic medullary carcinomas showed CK5-6 positivity. No association between the cytokeratin-vimentin profile of the tumours and axillary node metastases, tumour size or oestrogen receptor status was found but instability of CK expression was demonstrated by comparing the primary tumours with their metastases. CONCLUSIONS: : Medullary carcinomas of the breast express all the glandular type CKs including CK19 and additionally a proportion of the tumours expresses some of the CKs typical for myoepithelial cells. There was no correlation with prognostic factors.     

Expression of cyclin D1, Ki-67 and PCNA in non-small cell lung cancer: prognostic significance and comparison with p53 and bcl-2

Uncontrolled cell proliferation is the hallmark of malignant tumours. Thus, the proliferative potential of tumour cells is an important prognostic factor. However, evaluation of the prognostic significance of the expression of proteins involved in regulation of cell proliferation remains controversial. In the present study, expression of Ki-67, PCNA and cyclin D1 was estimated in a group of 89 surgically resected non-small cell lung carcinomas using immunohistochemistry. The results were compared with expression of bcl-2 and p53 and with clinicopathological parameters including patients' survival. Ki-67 and PCNA were found to be moderately and highly expressed in 39% and 44% of the tumours, respectively. There was a strong correlation between Ki67 and PCNA expression. Forty five of 88 tumours (51%) showed overexpression of cyclin D1. Surprisingly, cyclin D1 was mainly localized in the cytoplasm and only a small group of tumours (9/88, 10%) showed nuclear staining as well. Bcl-2 and p53 expression was observed in 69% and 30% of the tumours, respectively. All these markers were found to be independent of clinicopathological parameters, except for Ki-67 and bcl-2 expression, which was associated with squamous cell carcinomas. It is concluded that none of the markers that were studied can be used as an independent prognostic factor, whereas the following combinations of markers may have favourable prognostic value: p53 positivity and low Ki-67 expression, p53 positivity and lack of cyclin D1 expression, bcl-2 positivity and low Ki-67 expression, and lack of cyclin D1 expression and low Ki-67 expression.     

Immunohistochemistry on cell blocks from fine-needle cytopunctures of primary breast carcinomas and lymph node metastases.

We assessed the reliability of prognostic biologic markers by means of immunohistochemistry on cell blocks obtained from diagnostic fine-needle cytopunctures of breast carcinomas and their lymph node metastases. Immunohistochemical studies of MIB-1 (Ki-67), estrogen receptors (ER), progesterone receptors (PR), p53, and c-erb-B-2 were performed in 55 cases of primary breast carcinoma on cell blocks (cytoblock technique) and on their corresponding tissue samples (46 mastectomy specimens and 9 Trucut biopsies) and in 38 cases on cell blocks from fine-needle cytopunctures of both the primary breast tumors and their concurrent lymph node metastases. Interobserver reproducibility ranged from 87 to 100%, depending on the marker. A good correlation was observed between immunostaining assessment on cell blocks and on the corresponding tumor tissues as follows: Ki-67 (85%), ER (96%), PR (82%), p53 (76%), and c-erb-B-2 (84%). An excellent correlation was observed between cell-block results for primary tumors and node metastases; however, a far higher percentage of Ki-67-positive nuclei was observed in the nodes than in the corresponding tumors in seven cases. All nodes corresponding to ER- or PR-negative tumors were also negative, whereas the nodes corresponding to two ER-positive and one PR-positive tumor were negative. Marked discrepancies were also noted with p53 in two cases and with c-erb-B-2 in two cases. Most discrepancies occurred with Trucut biopsies and with breast tumors that contained a large intraductal component. We conclude that cell blocks prepared from fine-needle cytopuncture specimens of breast carcinomas and their node metastases are useful when planning neoadjuvant treatment.     

Increased alpha-B-crystallin expression in mammary metaplastic carcinomas

Chan S‐K, Lui P C W, Tan P‐H, Yamaguchi R, Moriya T, Yu A M C, Shao M‐M, Hliang T, Wong S‐I & Tse G M
(2011) Histopathology 59 , 247–255 Increased alpha‐B‐crystallin expression in mammary metaplastic carcinomas Aims: Mammary metaplastic carcinoma is a rare breast carcinoma, and may present diagnostic difficulty. Alpha‐B‐crystallin has been recently reported to be expressed in basal‐like and metaplastic carcinomas. Methods and results: Thirty‐three metaplastic carcinomas, 44 conventional high‐grade carcinomas and 28 mesenchymal spindle cell neoplasms as controls were assessed for their expression of αB‐crystallin and conventional basal‐like phenotypic markers CK5/6, CK14, p63, c‐kit and epidermal growth factor receptor (EGFR) by immunohistochemistry. Alpha‐B‐crystallin staining was positive in 68% of the metaplastic carcinomas with cytoplasmic staining in all tumour cell components. CK5/6, CK14, p63, c‐kit and EGFR stained 43%, 68%, 45%, 21% and 25% of the metaplastic carcinomas, respectively. Combining these markers, 84% of the metaplastic carcinomas expressed either αB‐crystallin or CK14. In comparison, only 14% (six cases) of conventional high‐grade carcinoma and 7% (two cases) of mesenchymal spindle cell neoplasm expressed αB‐crystallin; all but one of these carcinomas were ER/PR/HER2 triple‐negative. Conclusions: Using αB‐crystallin for diagnosis of metaplastic carcinoma gives a 68% sensitivity, 88% specificity, 74% positive predictive value, 85% negative predictive value and 78% accuracy. The sensitivity is enhanced to 84% with combinations of αB‐crystallin/CK14. Alpha‐B‐crystallin may be used as an adjunct marker in the diagnosis of metaplastic carcinoma.     

Expression of topoisomerase II and Ki-67 in cervical carcinoma--clinicopathological study using immunohistochemistry

AIM: To study the correlation between the expression of topoisomerase II and Ki-67 antigen and disease outcome in cervical squamous cell carcinomas. EXPERIMENTAL DESIGN: Forty-nine cervical carcinomas, 10 cases of high-grade cervical intraepithelial neoplasia (CIN II-III) and 5 control cervices were stained by monoclonal antibodies for topoisomerase II and Ki-67 (MIB-1 clone). Nuclear counts were correlated with patient age, tumor stage, histological grade and survival. RESULTS: Thirteen patients died of disease, 35 remained free of disease, and one patient was lost to follow up. Ki-67 counts were higher in CIN lesions, when compared to both invasive carcinomas and control cervices. Topoisomerase II counts were comparable for CIN and invasive tumors. No immunoreactivity for topoisomerase was detected in control cases. Neither stage nor grade was associated with nuclear counts using either marker. In multivariate survival analysis, stage (p=0.001), grade (p=0.03) and older patient age (p=0.02) predicted poor survival. Ki-67 counts predicted survival with borderline significance (p=0.07), while topoisomerase II counts were not related to survival. CONCLUSION: Ki-67 and topoisomerase II counts do not appear to have a significant role in the prediction of survival in cervical squamous cell carcinoma.     

Differential expression of cyclin D1 in breast papillary carcinomas and benign papillomas: an immunohistochemical study

OBJECTIVES: Distinguishing intraductal papilloma from papillary carcinoma of the breast can be difficult using histologic criteria. Since cyclin D1, a G1 cell-cycle regulatory protein, is detectable immunohistochemically in a subset of breast carcinomas but not in benign breast tissues, we hypothesized that cyclin D1 immunoreactivity may be a marker for identifying papillary carcinoma. METHODS: Using an immunohistochemical method, we assessed for cyclin D1 expression in 8 breast papillomas and 6 papillary carcinomas, all of which were formalin fixed, routinely processed, and paraffin embedded. Cyclin D1 positivity also was compared with the overall proliferation rate, which was assessed by using the proliferation marker Ki-67. In each case, a 200-cell count was performed to obtain the percentage of cells positive for these 2 markers. RESULTS: The percentage of cyclin D1-positive cells was significantly higher in papillary carcinomas (89%+/-18%; range, 53%-98%) than in papillomas (8%+/-7%; range, 0%-19%). This difference was highly statistically significant (P < .0001). Although the difference in Ki-67 positivity between these 2 groups was also statistically significant (P = .01), separation of papillary carcinomas and papillomas by Ki-67 immunoreactivity was less clear because of overlapping values between groups: 13% +/-6%; range, 9% to 23% for papillary carcinomas versus 8%+/-2%; range, 6% to 12% for papillomas. CONCLUSIONS: These results support the notion that cyclin D1 is a useful marker for distinguishing breast papillomas from papillary carcinomas. The marker Ki-67 is also helpful, but is less useful than cyclin D1, owing to the overlap in Ki-67 results in papillomas and papillary carcinomas.     

Mixed small cell carcinomas of the uterine cervix: prognostic impact of focal neuroendocrine differentiation but not of Ki-67 labeling index

Small cell neuroendocrine carcinomas sometimes represent a non-small cell component. Because of infection with the high-risk human papillomavirus of small cell carcinomas (SmCCs), several host cell regulatory proteins are altered, thus causing altered proliferative activity. Knowledge regarding the prognostic impact of focal neuroendocrine differentiation in mixed SmCCs and the value of proliferative activity in these tumors is very limited. Small cell carcinomas were selected for immunohistochemical staining with neuroendocrine markers and Ki-67. In cases with mixed tumors, the percentage of the SmCC component was calculated and correlated with survival. Of 677 tumors, 9 (1.3%) were classified as SmCCs after Grimelius staining (8/9 positive tumors) and immunohistochemical reaction against neuron-specific enolase, chromogranin A, synaptophysin (7/9 positive tumors), and CD56 (8/9 positive tumors); all specimens were positive for at least 2 of these. CD99 staining was completely negative. Two thirds of the SmCCs showed non-small cell differentiation. Four patients died of the tumor after a median time of 36.7 months (range, 15-56 months). Even an SmCC component of 17% was associated with a fatal course. Small cell carcinoma represented a significantly lower proliferation (Ki-67 labeling index) than did the non-small cell component in the same tumor (12.8% vs 70.8%; P < .001). Even a small SmCC component in mixed carcinomas of the uterine cervix was associated with adverse outcome. Proliferative activity, determined by Ki-67 labeling index, is of no prognostic value.     

Proliferative Activity of Synovial Sarcoma: An Immunohistochemical Evaluation of Ki-67 Labeling Indices of 52 Primary and Recurrent Tumors

The relationship between cell differentiation and proliferation in biphasic synovial sarcoma (BSS) and the connection between the two components of these tumors and monophasic synovial sarcoma (MSS) are still unknown. In this study we specifically compared the Ki-67 labeling indices (Ki-67-LI) in the solid/glandular and spindle cell components of primary BSS (n = 8) as well as the values thus obtained in primary BSS both outside clear-cut biphasic areas (n = 7) and in primary MSS (n = 23). We also compare the Ki-67-LI of primary tumors (seven BSS, seven MSS) and their respective first recurrences. We observed that the cells of the solid/glandular component of BSS proliferate significantly faster (p = 0.007) than those of spindle cell areas. No significantly different Ki-67-LI were observed in the comparison of the solid/glandular areas of BSS with the spindle/epithelioid component of BSS without clear-cut biphasia and MSS. No significant differences of Ki-67-LI were observed in the comparison of primary tumors of both subtypes with their respective first recurrences. The implications of the low proliferative activity of the spindle cell component of BSS exhibiting clear-cut biphasia, which was also confirmed in a concurrent study using anti-proliferating cell nuclear antigen/Cyclin PC10, remains to be clarified.     

Spindle cell tumours of the breast: practical approach to diagnosis

Spindle cell tumours of the breast are uncommon and often present diagnostic challenges. The most important is the sarcomatoid/metaplastic carcinoma, which has monophasic and biphasic variants. Each of these groups presents special diagnostic difficulties. In the monophasic variant the mesenchymal component predominates and the epithelial element forms a minor component often detected only after immunohistochemical study. The spindle cell areas may be bland and therefore under-diagnosed as nodular fasciitis or fibromatosis. Alternatively they may be highly malignant with a pattern that is misinterpreted as primary sarcoma of the breast. In the biphasic variant, the difficulty is in distinguishing between sarcomatoid carcinoma, myoepithelial carcinoma or malignant phyllodes tumour. Other spindle cell lesions of the breast include the various myofibroblastic tumours, the spindle cell variant of adenomyoepithelioma, the varied primary breast sarcomas, metastatic tumours with spindle cell morphology and, finally, the very rare follicular dendritic cell tumour. A simple practical approach to the diagnosis of spindle cell lesions is presented to help the general surgical pathologist to compile a differential diagnosis and to arrive at the correct conclusion