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  Table of Contents  
Year : 2015  |  Volume : 52  |  Issue : 1  |  Page : 110-113

Correlation of various histopathologic prognostic factors with Nottingham prognostic index and microvessel density in invasive breast carcinoma: A study of 100 cases

1 Department of Pathology, Hindu Rao Hospital, Malka Ganj, New Delhi, India
2 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Surgery, Hindu Rao Hospital, Malka Ganj, New Delhi, India

Date of Web Publication3-Feb-2016

Correspondence Address:
S Singh
Department of Pathology, Hindu Rao Hospital, Malka Ganj, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.175594

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 » Abstract 

Background: Nottingham prognostic index (NPI) is a widely used integrated prognostic variable in patients with breast cancer. NPI has been correlated with tumor size, grade, lymph node stage and patient survival. The present study aimed at evaluating and correlating the various clinical and pathologic features of breast carcinoma with NPI. Methods: This study included 100 consecutive cases of primary breast carcinoma over a period of 2 years. Demographic data was noted and histomorphological features like tumor size, grade, lymph node involvement, necrosis, vascular invasion etc., were assessed. NPI was calculated as reported in the literature. Immunohistochemical staining for hormone receptors and CD34 (to calculate microvessel density [MVD]) was performed. Statistical analysis was used for correlation. Results: Of the 100 cases, 54% of the tumors were in T2 tumor size category (2-5 cm) and lymph node metastasis in 48% of the cases. NPI ranged from 2.3 to 7.3 with 54% of the cases in the intermediate NPI group (3.41-5.4). The mean MVD was 160.93 (±69.4/mm2). On statistical analysis, tumor size and grade, lymph node stage, mitotic rate, nuclear pleomorphism, necrosis and MVD showed a correlation with NPI (P < 0.05). Conclusion: NPI is an important and useful prognostic indicator for breast cancer patients, which shows the correlation with other histomorphological prognostic features as well.

Keywords: Breast, Carcinoma, Microvessel density, Nottingham prognostic index

How to cite this article:
Kwatra A, Aggarwal D, Gupta R, Chaturvedi A K, Kudesia M, Singh S. Correlation of various histopathologic prognostic factors with Nottingham prognostic index and microvessel density in invasive breast carcinoma: A study of 100 cases. Indian J Cancer 2015;52:110-3

How to cite this URL:
Kwatra A, Aggarwal D, Gupta R, Chaturvedi A K, Kudesia M, Singh S. Correlation of various histopathologic prognostic factors with Nottingham prognostic index and microvessel density in invasive breast carcinoma: A study of 100 cases. Indian J Cancer [serial online] 2015 [cited 2022 May 21];52:110-3. Available from:

 » Introduction Top

Breast carcinoma is one of the leading causes of cancer-related mortality in females.[1] The clinical management of this tumor relies on various prognostic factors, most importantly lymph node stage, tumor size and histologic grade.[2] Numerous other features have been independently shown to have prognostic value. Hence, there have been attempts at integration of these factors into meaningful indices. The most widely used of these is the Nottingham prognostic index (NPI), first described in 1982, incorporates tumor size, lymph node stage and histologic grade.[3]

NPI, in various studies, has been shown to yield a continuum of clinical aggressiveness of breast carcinoma with differing patient survival rates.[4] However, literature is abound with conflicting reports of the utility of NPI in outcome prediction in breast carcinoma.[5],[6],[7] NPI has also been shown to correlate with tumor size, lymph node stage and patient survival. However, its correlation with other histologic features, many of whom have prognostic significance, has not been attempted in the available literature.

The present study was designed with an aim to evaluate the NPI in a group of breast cancer patients in our country and to correlate NPI with other clinical and histomorphological features.

 » Materials and Methods Top

The study included 100 cases of primary breast carcinoma diagnosed at a tertiary referral center over a period of 2 years (2005-2006). Demographic data, including age of the patient, marital status, menstrual history and family history were noted. The surgical specimens, usually from modified radical mastectomy, were processed for routine histopathologic examination. Adequate number of tumor sections were stained with H and E stain and evaluated for tumor type, grade (using modified Bloom-Richardson grading system) and extent of lymph nodal involvement.

NPI was calculated as:

NPI = 0.2 × Tumor size (cm) + Lymph node stage (I/II/III) + Tumor grade (1/2/3)

Thus calculated NPI was classified as low (NPI <3.4, group A), intermediate (NPI 3.41-5.4, group B) and high NPI (>5.4, group C).

In addition, immunohistochemical staining was performed for estrogen receptor (ER, Dako Cytomation, Glostrup, Denmark), progesterone receptor (PR, Dako Cytomation) and CD34 (Biogenex, Fremont, USA). Nuclear staining was considered as positive for ER and PR while cytoplasmic positivity was evaluated for CD34. Tumors with more than 10% nuclear positivity for ER or PR were considered as positive for that particular hormone receptor.[8] CD34-stained sections were evaluated to calculate the microvessel density (MVD) using the “hotspot” method on digital photomicrographs. In brief, any immunostained endothelial cell lying singly or in the cluster or a microvessel with lumen was counted as a vessel. Only those cells which were clearly separated from other stained cells were counted as separate vessel ([Figure 1]). For counting, only the vessels inside the tumor, separate from surrounding fibrosis and necrosis were included. The field area covered in a single photomicrograph was 0.60 mm 2. The counts per mm 2 were then calculated mathematically and MVD was expressed as per mm 2.
Figure 1: Photomicrograph of CD 34-stained section showing numerous microvessels in the tumor sections (×100)

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Statistical analysis

Non-parametric Mann-Whitney test was performed to compare the various clinical and histomorphological features, including MVD, between the three NPI groups. P < 0.05 was considered as significant.

 » Results Top

All our patients were married females with an age range of 25-80 years (mean 48.6 ± 12.6 years). About half of the patients were menopausal at the time of diagnosis. None of the patients had a family history of breast cancer.

Among tumor characteristics, the tumor size varied from 0.5 to 10 cm in largest dimension (mean 3.6 ± 2 cm) with majority (54%) of the cases in the size range of 2-5 cm. Lymph node metastasis was present in 48% of the cases. Categorization of the lymph node involvement was done using the NSABP (National Surgical Adjuvant Breast and Bowel Project) update into stages I, II and III (none, up to three axillary nodes and four or more axillary lymph nodes involved, respectively). Of the 100 cases, 30 had stage II and 18 stage III lymph node involvement.[9]

Tumor grade, using the standard classification showed a predominance of higher-grade tumors (grade 3 in 52% of cases). Only 6% of the tumors were grade 1. Using tumor node metastasis (TNM) staging, maximum number of cases were stage II at diagnosis (IIa in 22% and IIb in 30%) followed by stage III (IIIa in 12% and IIIb in 20%). Sixteen cases (16%) were stage I at diagnosis. Mitotic rate was also high in the majority of tumor; 40% showed 6-10 mitotic figures per 10 high power field while 38% had more than 10 mitoses per 10 high power fields.

Other features noted were microscopic circumscription (present in 14% of cases), necrosis (present in 56%) and lymphocytic infiltration of the tumor (moderate to severe in 52% cases). Invasion of the overlying skin (22%) or nipple (8%) was infrequent in our series. Vascular invasion was noted in only 8% of the cases.

NPI of our patients ranged from 2.3 to 7.2 (mean 4.7 ± 1.2). Majority of the patients (54%) were in the NPI group of 3.4-5.4.

Immunohistochemical positivity for ER and PR was seen in 28% of the cases. The mean MVD, as assessed from CD34-stained sections, was 160.93/mm 2 (±69.41/mm 2).

Statistical analysis

For parameters such as tumor size, lymph node stage, mitotic rate, nuclear pleomorphism, tumor grade and tumor stage, the cases were grouped into two categories: Low (I) and high (II and III) for statistical comparison.

The parameters that were found to have statistically significant difference included tumor size, lymph node stage, mitotic rate, nuclear pleomorphism, tumor grade, tumor stage, MVD, number of metastatic lymph nodes and presence of necrosis. The detailed results of statistical analysis are tabulated in [Table 1].
Table 1: Statistical analysis of various features in breast carcinoma

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 » Discussion Top

Breast carcinoma is the most common malignancy as well as the leading cause of cancer-related death in females. The clinical management of breast carcinoma relies heavily on clinical and pathologic prognostic factors to support decision-making process. The three most important prognostic determinants in operable cases of breast cancer include lymph node stage, size of the primary tumor and histologic grade.[2] The most widely used grading system is the Elston-Ellis modification of Scarff-Bloom-Richardson grading system also known as the Nottingham grading system.[10] Many of the prognostic factors lose their significance in multivariate analysis. Hence, attempts have been made to integrate independently significant factors to form meaningful indices. The most widely used method of integration is NPI, which was first described in 1982.[3] NPI is the only index to have both intra- and inter-center prospective validation.[11],[12] This index was formulated by including three independent prognostic factors, viz. Tumor size, lymph node status and histologic grade. For NPI, a score of 1 depicts no nodal involvement. A score of 2 denotes involvement of three or less axillary lymph nodes or single internal mammary lymph node while a score of 3 is given for involvement of four or more axillary or presence of both internal mammary and axillary lymph node involvement.[13]

As a continuous variable, NPI provides a sensitive method of modelling a continuum of clinical aggressiveness.[4] NPI can define three subsets of patients with variable prognosis: Good (<3.4), moderate (3.41-5.4) and poor (>5.4). At the institute where NPI was devised, maximum number of patients were in the moderate category with 42% 5-year survival followed by good category with 80% 5-year survival.[13] Various studies have shown the utility of NPI in outcome prediction of breast carcinoma patients.[5],[6] However, other studies have debated the importance of NPI over other prognostic factors.[7] In the present study, majority of the patients were in the intermediate (56%) and high (34%) NPI groups. This is similar to earlier results from this subcontinent.[14] The advanced nature of disease in a large number of patients in our study is due to the lack of general awareness and absence of screening programs for the general population, leading to presentation in late stages.

Statistical analysis in our study showed that patients in higher NPI group (group C) had more frequent lymph node metastasis (85%) compared with group A (0%, P < 0.001) and group B (30.4%, P < 0.001). This is in consonance with earlier studies displaying association between high NPI and lymph node involvement.[15] Lymph node metastasis has also been shown to affect survival of breast cancer patients.[16] Tumor size also showed a significant association with NPI with group B and C patients having larger tumors than patients in group A (P = 0.007 and 0.014, respectively). NPI has been reported to be a useful prognostic parameter for both large and small sized breast cancer.[17] The TNM tumor stage was also higher in group B and C patients with borderline statistical significance. This is expected since the components of TNM staging, viz. Tumor size and lymph node stage, also show a correlation with NPI.

The histologic tumor grade, as defined by modified Bloom-Richardson grading system, also showed significant association with NPI, since the grade is one of the components of NPI. Similar results have been found in earlier studies.[15] Other histologic features like nuclear pleomorphism and presence of necrosis also correlated with higher NPI. Presence of necrosis has been shown to be associated with treatment failure and poor survival in breast cancer patients.[18] However, correlation was not found between NPI and other parameters like menopausal status, microscopic circumscription, lymphocytic infiltration, skin or nipple invasion and hormone receptor status.

To the best of our knowledge, the present study is the first one to evaluate and correlate NPI with other clinical and histologic parameters. Earlier studies have correlated NPI with only tumor size, grade, lymph node stage and patient survival. An extensive review of the available indexed English literature failed to reveal any Indian study evaluating NPI in breast cancer patients. The present study hence is the first such study from our country.

Angiogenesis, measured commonly by MVD, has been widely investigated in various malignant tumors.[19] MVD has also been demonstrated as a prognostic indicator of breast cancer aggressiveness.[20] Earlier studies have shown a correlation of low MVD with a good prognosis in node-negative breast cancer patients.[21] In the present study, MVD was shown to correlate with NPI. A significant difference was detected between NPI groups A versus groups B and C with regards to MVD (P = 0.010 and 0.007, respectively). In addition, MVD showed a borderline correlation with tumor grade (P = 0.05).

 » Conclusion Top

NPI is an important and useful prognostic indicator, which should be included in breast cancer reporting by the pathologists. This shall assist the treating physicians in stratifying the risk category the patient belongs to and correlate other prognostic parameters. The correlation of MVD with prognosis suggests the potential utility of anti-angiogenic drugs in breast cancer patients with high angiogenesis.

 » References Top

Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153-6.  Back to cited text no. 1
Rakha EA, El-Sayed ME, Lee AH, Elston CW, Grainge MJ, Hodi Z, et al. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol 2008;26:3153-8.  Back to cited text no. 2
Haybittle JL, Blamey RW, Elston CW, Johnson J, Doyle PJ, Campbell FC, et al. A prognostic index in primary breast cancer. Br J Cancer 1982;45:361-6.  Back to cited text no. 3
Miller DV, Leontovich AA, Lingle WL, Suman VJ, Mertens ML, Lillie J, et al. Utilizing Nottingham Prognostic Index in microarray gene expression profiling of breast carcinomas. Mod Pathol 2004;17:756-64.  Back to cited text no. 4
Lee AH, Ellis IO. The Nottingham prognostic index for invasive carcinoma of the breast. Pathol Oncol Res 2008;14:113-5.  Back to cited text no. 5
Sundquist M, Thorstenson S, Brudin L, Nordenskjöld B. Applying the Nottingham Prognostic Index to a Swedish breast cancer population. South East Swedish Breast Cancer Study Group. Breast Cancer Res Treat 1999;53:1-8.  Back to cited text no. 6
Malmström P, Bendahl PO, Boiesen P, Brünner N, Idvall I, Fernö M, et al. S-phase fraction and urokinase plasminogen activator are better markers for distant recurrences than Nottingham Prognostic Index and histologic grade in a prospective study of premenopausal lymph node-negative breast cancer. J Clin Oncol 2001;19:2010-9.  Back to cited text no. 7
Pertschuk LP, Eisenberg KB, Carter AC, Feldman JG. Immunohistologic localization of estrogen receptors in breast cancer with monoclonal antibodies. Correlation with biochemistry and clinical endocrine response. Cancer 1985;55:1513-8.  Back to cited text no. 8
Fisher B, Bauer M, Wickerham DL, Redmond CK, Fisher ER, Cruz AB, et al. Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update. Cancer 1983;52:1551-7.  Back to cited text no. 9
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology 1991;19:403-10.  Back to cited text no. 10
D'Eredita' G, Giardina C, Martellotta M, Natale T, Ferrarese F. Prognostic factors in breast cancer: The predictive value of the Nottingham Prognostic Index in patients with a long-term follow-up that were treated in a single institution. Eur J Cancer 2001;37:591-6.  Back to cited text no. 11
Balslev I, Axelsson CK, Zedeler K, Rasmussen BB, Carstensen B, Mouridsen HT. The Nottingham Prognostic Index applied to 9,149 patients from the studies of the Danish Breast Cancer Cooperative Group (DBCG). Breast Cancer Res Treat 1994;32:281-90.  Back to cited text no. 12
Galea MH, Blamey RW, Elston CE, Ellis IO. The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 1992;22:207-19.  Back to cited text no. 13
Ahmad Z, Khurshid A, Qureshi A, Idress R, Asghar N, Kayani N. Breast carcinoma grading, estimation of tumor size, axillary lymph node status, staging, and nottingham prognostic index scoring on mastectomy specimens. Indian J Pathol Microbiol 2009;52:477-81.  Back to cited text no. 14
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Hutter RV. The influence of pathologic factors on breast cancer management. Cancer 1980;46:961-76.  Back to cited text no. 16
Blamey RW. The design and clinical use of the Nottingham Prognostic Index in breast cancer. Breast 1996;5:156-7.  Back to cited text no. 17
Parham DM, Hagen N, Brown RA. Simplified method of grading primary carcinomas of the breast. J Clin Pathol 1992;45:517-20.  Back to cited text no. 18
Weis SM, Cheresh DA. Tumor angiogenesis: Molecular pathways and therapeutic targets. Nat Med 2011;17:1359-70.  Back to cited text no. 19
Tsutsui S, Kume M, Era S. Prognostic value of microvessel density in invasive ductal carcinoma of the breast. Breast Cancer 2003;10:312-9.  Back to cited text no. 20
Heimann R, Ferguson D, Powers C, Recant WM, Weichselbaum RR, Hellman S. Angiogenesis as a predictor of long-term survival for patients with node-negative breast cancer. J Natl Cancer Inst 1996;88:1764-9.  Back to cited text no. 21


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