New prognostic histological parameter of invasive ductal carcinoma of the breast: Clinicopathological significance of fibrotic focus

Review Article

New prognostic histological parameter of invasive ductalcarcinoma of the breast: Clinicopathological significance offibrotic focus

Takahiro Hasebe,1 Kiyoshi Mukai,1,3 Hitoshi Tsuda2 and Atsushi Ochiai1

1Pathology Division, National Cancer Center Research Institute East, Chiba, 2Pathology Division, National CancerCenter Research Institute, Tokyo and 3First Department of Pathology, Tokyo Medical University, Tokyo, Japan

determinants of the progression of breast cancer.12–17

However, in routine practice it is difficult to incorporateimmunohistochemistry, DNA analysis or molecular geneticsin all cases. Therefore, if certain histological parameters canaccurately predict the outcome of patients with breast cancer,evaluation of them would be more practical for routine use.

Several studies of histological prognostic parameters ofbreast cancer have suggested that nodal status, histologicalgrade of the tumor, tumor size, and the presence of tumornecrosis are significant prognostic parameters correlatedwith survival of breast cancer patients.18–26 Subsequentstudies have attempted to define the histological para-meters predicting tumor recurrence or death due to breastcancer.27–34 However, all of these studies examined knownhistological parameters in certain subsets of breast cancercases, such as tumors without lymph node metastasis, small-sized tumors, early stage tumors, or male breast cancer.Therefore, there remains a need for more powerful universalhistological prognostic parameters for invasive ductal carci-noma (IDC) that correlate well with patient outcome.

In this review, we describe a new histological prognosticparameter, fibrotic focus (FF), for patients with IDC, andcompare the predictive power of FF with well-known prog-nostic parameters of IDC. The biological differences betweenIDC with and without FF as well as the possible mechanismof the FF formation are also discussed. In addition, a new his-tological prognostic classification scheme incorporating FF isproposed for the more accurate prediction of the outcome ofIDC patients.

FIBROTIC FOCUS AS A NEW HISTOLOGICALPROGNOSTIC PARAMETER FOR INVASIVE DUCTAL

CARCINOMA OF THE BREAST

When the primary site of surgically resected breast cancers isexamined histopathologically, IDC containing an extensive

Pathology International 2000; 50: 263–272

Immunohistochemistry, DNA ploidy analysis and moleculargenetics have made it possible to predict the outcome ofbreast cancer more precisely than routine histological exam-ination alone. However, in routine practice, it is difficult toincorporate these methodologies in all cases. If certain his-tological parameters can accurately predict the outcome ofpatients with breast cancer, they would be more practical forroutine use. We showed that the presence of fibrotic focus(FF) in invasive ductal carcinoma (IDC) is closely associatedwith c-erbB-2 or p53 protein expression, high proliferativeactivity, and high angiogenesis of the tumors. Furthermore,multivariate analyses with well-known prognostic parame-ters for IDC demonstrated that the presence of FF is the mostuseful independent parameter to predict IDC patientoutcome. In addition, our data suggested that the interactionbetween tumor cells and stromal fibroblasts may play animportant role in the formation of FF in IDC based on growthfactor and growth factor receptor protein expression in thetumor cells and fibroblasts forming FF. Based on the resultsof our clinicopathological studies, we propose a new prog-nostic classification scheme for the prediction of IDC patientoutcome, which consists of FF, nuclear atypia, and fat inva-sion. This classification has superior predicting power toexisting prognostic classifications.

Key words: angiogenesis, breast cancer, fibrotic focus, growthfactor, growth factor receptor, histology, invasive ductal carci-noma, prognosis, proliferative activity, tumor grade

Recent developments in immunohistochemistry, DNA ploidyanalysis and molecular genetics have made it possible tomore precisely predict the outcome of breast cancer.1–11

Tumor angiogenesis or extracellular matrix may be important

Correspondence: Takahiro Hasebe, MD, Pathology Division,National Cancer Center Research Institute East, 6-5-1 Kashi-wanoha, Kashiwa, Chiba 277-8577, Japan.

Received 26 October 1999. Accepted for publication 14 December1999.

central FF with actively proliferating tumor cells in the periph-ery is sometimes encountered. It is also noted that manyrecurrent IDC cases have FF within the primary tumors upon histological re-examination. This suggested that thepresence of FF may be an important prognostic parameter ofIDC.

Breast cancer with FF-like lesion was previously reportedas cancer with sclerotic foci by Linell et al.35 and as scarcancer by Fisher et al.36

Fisher et al.36 divided scar cancers into five subtypesaccording to the histological features of the sclerotic foci asfollows: type 1, composed of radiating relatively acellularhyaline containing isolated tubular carcinoma cells andresembling radial scar; type 2, having either edema or adense acellular hyalinized core with tumor cells only rarelyobserved within the scar; type 3, having a more evident radiating core than type 1 or 2, and with tumor cells presentwithin the scar as well as at its periphery; type 4, with afibrous stroma arranged in an interwoven pattern, isolated orcompartmentalized aggregates of tumor cells, where a well-defined core or scar is not obvious within the tumor; and type5, with a circumferential small core and obviously distributedin multiple areas. Therefore, FF, is similar to type 2 or type 3of Fisher’s classification. It was reported that scar cancerstypes 1, 4, and 5 have a better prognosis than non-scarcancers, and the survival period of types 2 and 3 scarcancers was not significantly different from non-scar cancer.Scar cancer was shown to have a better prognosis and to be richer in steroid hormone receptors than non-scarcancers.37,38 However, these studies did not divide the casesby histological subtypes and included not only IDC, but alsoother histological types, such as lobular, mucinous, medullaryor squamous cell carcinoma, and non-invasive ductal carci-noma. To clarify the clinicopathological significance of FF inprimary breast cancer more precisely, it was necessary tostudy tumors of the same histological type. Therefore, weinvestigated whether the presence of FF in IDC, the mostcommon histological type of breast cancer, has prognosticsignificance for patient outcome.

Histological features of fibrotic focus

Fibrotic focus is defined according to the following crite-ria:39–41 (i) FF often consists of fibrous bands radially expand-ing to the surrounding area, and appears as a radiatingfibrosclerotic core or scar. FF is located within the tumor, sur-rounded by a more cellular zone of infiltrating ductal carci-noma cells and occupies various percentages of the tumorarea (Figs 1a,2a); (ii) when FF is 3 mm or smaller, tumor cells are infrequently seen within it. However, tumor cellsgrowing in a scirrhous fashion or in solid nests are seen

264 T. Hasebe et al.

Figure 1 Invasive ductal carcinoma with fibrotic focus (FF). (a) AnFF measuring 25 ¥ 28 mm in size is observed within the tumor(arrowheads). The FF is irregular in shape and surrounded by inva-sive ductal carcinoma cells. Residual tumor islands of various sizesare observed within the FF (HE). (b) The fibroblast and collagenfibers composing the FF show a storiform arrangement (HE).

within FF as size increases (Figs 1b,2b); (iii) fibroblasts orcollagen fibers in FF are arranged in irregular or storiform pat-terns with increased fibroblast cellularity and/or collageniza-tion (Figs 1a,2a). Elastic tissue may be abundant. Thearrangement of fibroblasts or collagen fibers forming FF is dif-ferent from that of the surrounding tumor stroma which ismore orderly than that of the normal breast tissue stroma.The different arrangement of fibroblasts is the most importantcharacteristic that separates fibroblasts forming FF fromthose outside FF. If several FF of various sizes are presentwithin one tumor, the characteristics of the largest one areused for the study. In addition, the diameter of FF is 1 mm orlarger in order to recognize the fibrosclerotic core as FF inIDC.

Prognostic significance of fibrotic focus in patients withinvasive ductal carcinoma

In order to clarify the prognostic significance of FF, we exam-ined 140 consecutive cases of IDC, which had been treatedsurgically with a median follow up of 136 months.41 In thatstudy, the prognostic significance of FF with the followingknown histological parameters was evaluated: (i) age (£ 50or > 50); (ii) histological grade42 (1/2 or 3); (iii) nodal status(absent or present); (iv) T classification (T1/T2 or T3/T4); (v)tumor necrosis (present or absent); and (vi) adjuvantchemotherapy (none or given). In univariate analyses by theKaplan–Meier method,43 the rates of both overall survival(OS) and disease-free survival (DFS) were significantly lowerin the cases with FF than in those without. Multivariate analy-ses of parameters showing significant correlation with DFS orOS by the Cox proportional hazards regression model44

showed significantly higher hazard rates (HR) of tumor recur-rence and death in IDC with FF than in those without FF incases at all stages and in cases at stages I and II (Table 1). Incases with less than four lymph node metastases, the HR oftumor recurrence and death were higher for tumors with FFthan for those without, the increase being significant for thelatter. Furthermore, in cases at stage I, the only factor thatwas significantly correlated with tumor recurrence and deathwas the presence of FF.

In addition, we investigated the significant effect of thepresence of FF on bone metastasis of IDC.45 Bone is one ofthe most common metastatic sites in IDC patients,46 and sys-temic chemotherapy, endocrine therapy or local radiationtherapy for bone metastasis has been shown to be effectivein a significant proportion of patients. Therefore, it would beclinically very useful if IDC, with a high probability of bonemetastasis, could be identified by histopathological examina-tion of the primary lesions. We evaluated 110 primary IDCwith none or less than four lymph node metastases, and

Prognostic factors of breast cancer 265

Figure 2 Invasive ductal carcinoma with fibrotic focus (FF). (a) AnFF measuring 29 ¥ 35 mm in size is observed within the tumor(arrowheads). The FF appears as a radiating fibrosclerotic core orscar. (b) The FF contains residual tumor cells arranged in small solidnests or strands admixed with fibroblast or collagen fibers showingstoriform arrangement (HE).

clearly demonstrated that the presence of FF is a signifi-cant histopathological parameter associated with initial bonemetastasis.

These studies have proven that the presence of FF is notonly a significant histopathological prognostic parameter forIDC, but is also a good marker of initial bone metastasis inIDC patients. These data indicated that FF can be regardedas a marker of aggressive IDC, and may be useful for theselection of proper postoperative treatment.

Differences in oncogene protein expression, nuclearDNA content, proliferative activity, and angiogenesisbetween IDC with and without FF

Some major biological differences have been identifiedbetween IDC with and without FF, based on the examinationof prognostic factors for IDC patients, including c-erbB-2 andp53 protein expression, proliferative activity of tumor cells,tumor nuclear DNA content, and tumor angiogenesis.39,40,47

Overexpression of c-erbB-2 protein, nuclear accumulation of p53, high proliferative cell nuclear antigen (PCNA) index, aneuploidy, and high tumor angiogenesis have been associated with poor prognosis of breast cancerpatients.1–4,6,9,10,12–14,48–52

We examined 153 IDC of the breast consecutively treatedby surgery.39,40 IDC with FF had significantly higher frequen-cies of c-erbB-2 protein expression, abnormal nuclear accu-mulation of p53 protein, and aneuploidy than those withoutFF. In addition, the former showed significantly higher prolif-erative activities than the latter.

In a comparative study of tumor angiogenesis in IDC withand without FF, CD31 microvessel count (MVC) was calcu-lated in central, intermediate and peripheral zones of eachtumor.47 Analysis of variance revealed a significant trend forincreasing mean MVC from the central to the peripheralzones. Multiple regression analysis using FF, T classification,tumor necrosis, and c-erbB-2 protein expression, all of whichwere associated with higher MVC in one or more zones inunivariate analysis, demonstrated that the only factor signifi-cantly correlated with higher MVC in all three zones of thetumor was the presence of FF.

A significant association of the presence of FF with c-erbB-2 or p53 protein expression, high proliferative activity, andhigh MVC of the tumors is probably indicative of the highmalignant potential of IDC with FF. Furthermore, multivariateanalyses with these well-known prognostic parameters forIDC demonstrated that the presence of FF is a most usefulindependent parameter for the prediction of the outcome ofIDC patients.40,47

Mechanism of formation of FF in IDC

FF is composed of fibroblasts mixed with various amounts ofcollagen fibers, and the arrangement of fibroblasts or colla-gen fibers forming FF is different from that of the normalbreast tissue stroma or that of the surrounding tumor stroma.Therefore, factors that induce the proliferation of fibroblastsmay play an important role in the formation of FF.

Basic fibroblast growth factor (bFGF) is a potent stimulatorof fibroblasts,53,54 and in breast tissue the ductal epithelial


Table 1 Multivariate analyses of fibrotic focus in relation to tumor recurrence and death in the National Cancer Center Hospital patients withinvasive ductal carcinoma

Tumor recurrence Tumor deathParameter No. patients TRR (%) HR/95% CI P value MR (%) HR/95% CI P value

All stages (n = 140)Fibrotic focus

Absent 83 13 Referent 10 ReferentPresent 57 47 4.5/1.8–22.0 46 4.0/1.6–9.4

< 0.001 < 0.001

Stages I/II (n = 114)Fibrotic focus


< 0.01 < 0.01

Cases with less than four lymph node metastases (n = 102)Fibrotic focus


NS < 0.001

TRR, tumor recurrence rate; MR, mortality rate; HR, hazard rate; CI, confidence interval; NS, not significant. All stages/stages I and II: adjusted byfibrotic focus, age, chemotherapy, tumor necrosis, nodal status, T classification, and histological grade. Cases with less than four lymph node metas-tases: adjusted by fibrotic focus, age, chemotherapy, tumor necrosis, T classification, and histological grade.

cells express bFGF messenger ribonucleic acid (mRNA) orprotein.55,56 bFGF acts through high-affinity tyrosine kinasereceptors, the fibroblast growth factor receptors (FGFR), thatare encoded by at least four distinct genes.57 The extracellu-lar region of FGFR has an immunoglobulin-like domain, andthese receptors play major roles in organ development.58 Aputative autocrine/paracrine role for the bFGF/FGFR systemhas been suggested in the mitogenic activation of fibroblastsor myofibroblasts.59,60

We compared bFGF protein expression of tumor cells andFGFR protein expression in fibroblasts forming FF byimmunohistochemistry and western blot analysis.61 All tumorswere divided into two groups according to their growthpattern: (i) solid type in which the tumor cells grow in solidnests; or (ii) scirrhous type in which the tumor cells grow inscirrhous fashion.

Tumor cells in scirrhous type with FF showed a significantlyhigher frequency of bFGF protein expression than thosewithout FF (P = 0.017) (Table 2) (Fig. 3b). In contrast, in solidtumors the presence of FF in IDC was not significantly asso-ciated with bFGF protein expression by the tumor cells (P =0.143). IDC growing in scirrhous fashion also showed a sig-nificantly higher frequency of FGFR protein expression by thetumor cells than those growing in solid nests (P = 0.001) (Fig.3c). Furthermore, among IDC with FF that express bFGFprotein, a significantly larger number of fibroblasts express-ing FGFR protein within FF was observed in scirrhous typethan in solid type (Fig. 3e).

Autocrine growth stimulation via FGFR in tumor cells maytherefore contribute to the growth of scirrhous tumors but notof solid tumors, and IDC with FF growing in a scirrhous

fashion may have stronger autocrine function than IDCwithout FF. In addition, a significant correlation betweenFGFR expression by the fibroblasts forming FF and bFGFexpression by the scirrhous tumor cells suggests a paracrineaction of bFGF and FGFR between the tumor cells and thefibroblasts. Thus, their interaction appears to be important forthe formation of FF. In contrast, we have already reported thatcoagulation necrosis of the tumor cells within FF is more fre-quently observed in the solid tumor than in the scirrhoustumor.39 This suggests that FF in the solid tumors are madeup of fibroblasts or collagen fibers that absorb or replacetumor necrosis that may be caused by a lack of blood flow orhypoxia. Therefore, the mechanism of formation of FF in IDCmay differ between tumors growing in a scirrhous fashion andthose growing in a solid nest.

NEW HISTOLOGICAL PROGNOSTIC CLASSIFICATIONFOR PATIENTS WITH IDC

Although FF clearly has a prognostic significance, the fre-quency of tumor recurrence or the mortality rate of IDC is relatively low, which makes it difficult to accurately predictpatient outcome using a single prognostic parameter. There-fore, it seems appropriate to combine powerful histologicalparameters in order to predict IDC patient survival more precisely.

In 1957, Bloom and Richardson proposed a histologicalgrading system for breast cancer, making it more repro-ducible by introducing a scoring system based on three histo-logical features: (i) tubular formation; (ii) nuclear features;and (iii) number of mitotic figures.62 This grading system wasmodified by Le Doussal et al. in 1989 and was called themodified Scarff-Bloom–Richardson (MSBR) histological clas-sification.63 Elston and Ellis have refined the definition and the method of assessing the parameters which constitute theBloom and Richardson grading system, and it is currently themost widely used histological grade (HG) system for breastcancer.42 In addition to these grading systems, the Notting-ham Prognostic Index (NPI) classification has also been pro-posed.64,65 The NPI classification consists of tumor size,nodal status and HG, which is almost identical to a combina-tion of pTNM stage and HG or MSBR. Therefore, the NPIclassification represents the most powerful histological prog-nostic classification for IDC. Lymph node stage of the NPIclassification is classified as follows: (i) stage A; tumor absentfrom all lymph nodes sampled (ii) stage B; tumor in low axil-lary node only, and (iii) stage C; tumor in apical axillary and/orinternal mammary nodes. Stages A, B and C are scored as 1,2 and 3, respectively. The NPI classification is calculatedaccording to the following formula: NPI = 0.2 ¥ tumor size(cm) + stage score + histological grade score. The NPI iscomputed for each of the IDC, and the cases are assigned to


Table 2 Association of the growth types of invasive ductal carci-noma with fibroblast growth factor or fibroblast growth factor recep-tors expression

Total No. patients (%) P value

bFGF expression+ –

All cases 149 104 (70) 45 (30)Growth type

Solid 86 57 (66) 29 (34)Fibrotic focus present 42 25 (59) 17 (41)Fibrotic focus absent 44 32 (73) 12 (27) 0.143

Scirrhous 63 47 (73) 16 (27)Fibrotic focus present 36 31 (86) 5 (14)Fibrotic focus absent 27 16 (59) 11 (41) 0.017

FGFR expression+ –

All cases 149 104 (70) 45 (30)Growth type

Solid 86 51 (59) 35 (41)Scirrhous 63 53 (84) 10 (16) 0.001

bFGF, basic fibroblast growth factor expression; FGFR, fibroblastgrowth factor receptors expression; +, positive; –, negative.

one of three prognostic groups: low (NPI £ 3.4), medium (3.4 < NPI £ 5.4), and high (NPI > 5.4).

Based on these prognostic indications, we have proposeda new prognostic classification scheme for IDC that is supe-rior to the NPI classifications for the prediction of IDC patient

outcome.66 This new histological prognostic classification isbased on nuclear atypia, FF and invasive length of fat inva-sion (ILFI), and is named the nucleus–fibrotic focus–fat inva-sion (NFF) classification. A score of 1 was given to IDC withnuclear atypia 3, those with FF, or those with ILFI of > 2 mm.


Figure 3 (a) Scirrhous tumor with basic fibroblast growth factor (bFGF) and fibroblast growth factor receptors (FGFR) expression (HE). (b,c)Ductal carcinoma cells show intense cytoplasmic staining for bFGF and FGFR protein (immunostain). (e,f) FGFR expression by fibroblastswithin FF. (e) Fibroblasts forming fibrotic focus grow in a storiform pattern mixed with ductal carcinoma cells (HE). (f) Fibroblasts show intensecytoplasmic staining for FGFR protein (immunostain).

If any of the above factors were absent, a score of 0 wasgiven. The total NFF score was calculated. The total score forany patient ranged from 0 to 3.

Multivariate analyses between the NFF and the NPI classi-fications, in all cases and cases at stages I and II, showed asignificantly higher HR of tumor recurrence in IDC with anNFF score of 3 (Table 3). Significantly higher HR of tumorrecurrence or death were also observed in IDC with high NPI,but not in those with medium NPI. In cases without lymphnode metastasis, IDC with NFF scores of 2 and 3 had signifi-cantly higher HR of tumor recurrence than those with NFFscores of 0 and 1 (P < 0.05). In contrast, the HR of IDC with

medium NPI was not different to those of IDC with a low NPI.Similarly, in estrogen receptor (ER)-positive cases, the HR oftumor recurrence was increased with increasing NFF score,and an NFF score 3 was associated with a significantly higherHR of tumor recurrence than an NFF score of 0/1 (P < 0.01).An increasing NPI score, however, was not significantly asso-ciated with increasing HR of tumor recurrence in ER-positivecases.

The superiority of the NFF classification to HG, MSBR orpTNM for the prediction of IDC patient outcome has alsobeen demonstrated.66 As indicated, the NFF classificationseems to be a more sensitive and specific predictor of IDC


Table 3 Multivariate analyses of NFF and NPI classifications for tumor recurrence and tumor death of invasive ductal carcinoma of all cases,cases at stages I/II, those without lymph node metastasis, and those that are ER positive#

Cases TRR (%) HR 95% CI MR(%) HR 95% CI

All casesNFF 201 36 18

Score 0/1 142 12 (8) Referent 3 (2) ReferentScore 2 41 13 (32) 1.8 0.8–4.1 8 (20) 4.7c 1.3–18.8Score 3 18 11 (61) 4.4b 1.7–11.1 7 (39) 6.7b 1.5–29.7

P for trend: 0.002 P for trend: 0.015NPI 196 35 17

Low 56 2 (4) Referent 0 ReferentMedium 91 10 (10) 1.9 0.4–9.7 3 (3) ReferentHigh 49 23 (47) 7.1c 1.2–42.3 14 (29) 13.2b 2.9–61.5

P for trend: 0.004 P for trend: < 0.001

Cases at stages I and IINFF 150 21 10

Score 0/1 114 8 (7) Referent 1 (1) ReferentScore 2 27 8 (30) 3.4 0.9–12.7 5 (19) 6.7 0.6–79.8Score 3 9 5 (56) 3.5c 1.1–10.9 4 (44) 34.6b 2.9–415.4

P for trend: 0.030 P for trend: 0.049NPI 149 21 10

Low 55 2 (4) Referent 0 ReferentMedium 73 8 (11) 1.7 0.3–9.9 3 (4) ReferentHigh 21 11 (52) 10.6c 1.5–74.9 7 (33) 86.4a 6.5–1149.6

P for trend: < 0.001 P for trend: < 0.001

Cases without lymph node metastasisNFF 93 8

Score 0/1 76 2 (3) ReferentScore 2/3 17 6 (35) 4.0c 1.2–13.3

NPI 93 8Low 50 2 (4) ReferentMedium 43 6 (14) 0.2 0.01–3.5

ER-positive casesNFF 107 12

Score 0/1 83 4 (5) ReferentScore 2 14 3 (21) 2.4 0.4–15.4Score 3 10 5 (50) 15.5b 2.1–105.2

P for trend: 0.005NPI 105 12

Low 36 2 (6) ReferentMedium 47 4 (9) 1.1 0.2–14.0High 22 6 (27) 1.1 0.1–13.2

P for trend: 0.905#This table is modified from reference 66. NFF, nucleus–fibrotic focus–fat invasion; NPI, Nottingham prognostic index; TRR, tumor recurrence rate; MR,

mortality rate; HR, hazard rate; CI, confidence interval. ER, estrogen receptor. P value: a, < 0.001; b, < 0.01; c, < 0.05. Each multivariate analysis wasadjusted for NFF, NPI, chemotherapy and hormone therapy.

patient outcome than other commonly used histological clas-sification schemes. The NFF classification was also able tofurther separate IDC with the lowest malignant potential in theconventional sense into low- and high-risk groups in ourstudy.

FUTURE PROSPECTS

We have clearly demonstrated that the presence of FFcauses differences in malignant potential in IDC. FF belongsto the tumor stroma, which indicates that malignant potentialof IDC not only depends on the biological characteristics ofthe tumor cell, but also on those of the tumor stroma. FF con-sists of fibroblasts or collagen fibers admixed with microves-sels, and the interaction between tumor cells and stromalfibroblasts influences the progression of IDC with FF. Wehave clearly demonstrated that the proliferative activity of thestromal fibroblasts plays a very important role in lymph nodeor distant organ metastasis of IDC,67 and also have additionalpreliminary result suggesting that growth factor expression ofthe stromal fibroblasts influences tumor progression. In addi-tion, stromal fibroblasts secrete matrix metalloproteinase orurokinase-type plasminogen activator, which is a very impor-tant factor of tumor progression.68–70 Therefore, any studyinvestigating the biological aggressiveness of IDC mustexamine the biological characteristics of the stromal fibro-blasts as well as those of the tumor cells. It is also probablethat the biological characteristics of fibroblasts forming FFare quite different from those of fibroblasts outside FF. Thisindicates that there is a heterogeneity in the biological char-acteristics of the stromal fibroblasts like the tumor cells, whichprobably influences the outcome of IDC patients. Therefore,detailed examination of the tumor stroma consisting of fibro-blasts, collagen fibers, microvessels or inflammatory cells, inaddition to the tumor cells, should better facilitate the predic-tion of IDC patient outcome in the future.

In treatment trials of IDC, the combination of chemotherapyand anti-HER2 antibody has shown greater inhibition oftumor growth than chemotherapy alone.71 Angiostatin, anendogenous inhibitor of tumor-related angiogenesis, has asuppressive effect on tumor growth in vivo.72 We havealready demonstrated that the presence of FF is significantlyassociated with overexpression of c-erbB-2, or high tumorangiogenesis in IDC. Therefore, the presence of FF mayselect patients responsive to adjuvant chemotherapy andanti-HER2 antibody, or antitumor angiogenesis factor for IDC. This may give patients with IDC the best survival advantage.

Treatment of breast cancer without nodal metastasis hasinvolved a marked reduction in the extent of tumor resec-tion.73–77 This can make it difficult for the pathologist toperform studies on breast cancer, because the material

obtained from surgery may be limited. However, this situationalso provides a chance for the pathologist to perform studiesthat may have a greater impact on clinical oncology. There-fore, further studies based on classical histological examina-tions as well as those based on new methodologies to further define markers of malignant potential should be performed.

ACKNOWLEDGMENTS

The authors thank Drs Setsuo Hirohashi (National CancerCenter Research Institute), Yukio Shimosato (Keio Univer-sity), Tadaaki Koyama (Kamitsuga General Hospital), andYoko Jitsuiki (National Okayama Hospital) for their collabora-tive efforts and support. We also thank Dr Shigeru Imoto forsupplying the specimens of breast cancer tissue and clinicaldata. This work was supported in part by a Grant-in-Aid forCancer Research from the Ministry of Health and Welfareand by a Grant-in-Aid for Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Healthand Welfare in Japan.

REFERENCES

1 Wright C, Angus B, Nicholson S et al. Expression of c-erbB-2oncoprotein: a prognostic indicator in human breast cancer.Cancer Res. 1989; 49: 2087–2090.

2 Iwaya K, Tsuda H, Hiraide H et al. Nuclear p53 immunoreactionassociated with poor prognosis of breast cancer. Jpn. J. CancerRes. 1991; 82: 835–840.

3 Barnes DM, Dublin EA, Fisher CJ, Levison DA, Millis RR.Immunohistochemical detection of p53 protein in mammary car-cinoma: An important new independent indicator of prognosis?Hum. Pathol. 1993; 24: 469–476.

4 Tahan SR, Neuberg DS, Dieffenbach A, Yacoub L. Prediction ofearly relapse and shortened survival in patients with breastcancer by proliferating cell nuclear antigen score. Cancer 1993;71: 3552–3559.

5 Barnes R, Masood S, Barker E et al. Low nm23 protein expres-sion in infiltrating ductal breast carcinomas correlates withreduced patient survival. Am. J. Pathol. 1991; 139: 245–250.

6 Fallenius AG, Auer GU, Carstensen JM. Prognostic significanceof DNA measurements in 409 consecutive breast cancerpatients. Cancer 1988; 62: 331–341.

7 Cornelisse CJ, van de Velde CJH, Caspers RJC, Moolenaar AJ,Hermans J. DNA ploidy and survival in breast cancer patients.Cytometry 1987; 8: 225–234.

8 Witzig TE, Gonchoroff NJ, Therneau T et al. DNA content flowcytometry as a prognostic factor for node-positive breastcancer. Cancer 1991; 68: 1781–1788.

9 Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuireWL. Human breast cancer: Correlation of relapse and survivalwith amplification of the HER-2/neu oncogene. Science 1987;235: 177–182.

10 Clark GM, McGuire WL. Follow-up study of HER-2/neu amplifi-cation in primary breast cancer. Cancer Res. 1991; 51:944–948.


11 Tsuda H, Hirohashi S, Shimosato Y et al. Correlation betweenlong-term survival in breast cancer patients and amplification oftwo putative oncogene-coamplification units: hst-1/int-2 and c-erbB-2/ear-1. Cancer Res. 1989; 49: 3104–3108.

12 Weidner N, Folkman J, Pozza F et al. Tumor angiogenesis: Anew significant and independent prognostic indicator in early-stage breast carcinoma. J. Natl Cancer Inst. 1992; 84:1875–1887.

13 Jacquemier JD, Penault-Llorca FM, Bertucci F et al. Angio-genesis as a prognostic marker in breast carcinoma with conventional adjuvant chemotherapy: A multiparametric andimmunohistochemical analysis. J. Pathol. 1998; 184: 130–135.

14 Kumar S, Ghellal A, Li C et al. Breast carcinoma: Vasculardensity determined using CD105 antibody correlates with tumorprognosis. Cancer Res. 1999; 15: 856–861.

15 Umeda T, Eguchi Y, Okino K, Kodama M, Hattori T. Cellularlocalization of urokinase-type plasminogen activator, itsinhibitors, and their mRNAs in breast cancer tissues. J. Pathol.1997; 183: 388–397.

16 Knoop A, Andreasen PA, Andersen JA et al. Prognostic signifi-cance of urokinase-type plasminogen activator and plasmino-gen activator inhibitor-1 in primary breast cancer. Br. J. Cancer1998; 77: 932–940.

17 Ahmad A, Hanby A, Dublin E et al. Stromelysin 3: An indepen-dent prognostic factor for relapse-free survival in node-positivebreast cancer and demonstration of novel breast carcinoma cellexpression. Am. J. Pathol. 1998; 152: 721–728.

18 Cutler SJ, Black MM, Mork T, Harvei S, Freeman C. Furtherobservations on prognostic factors in cancer of the femalebreast. Cancer 1969; 24: 653–667.

19 Fisher B, Slack NH, Bross IDJ. Cooperating investigators.Cancer of the breast: Size of neoplasm and prognosis. Cancer1969; 24: 1071–1080.

20 Bloom HJG, Field JR. Impact of tumor grade and host resis-tance on survival of women with breast cancer. Cancer 1971;28: 1580–1589.

21 Say CC, Donegan WL. Invasive carcinoma of the breast. Prog-nostic significance of tumor size and involved axillary lymphnodes. Cancer 1974; 34: 468–471.

22 Fisher ER, Palekar A, Rockette H, Redmond CK, Fisher B.Pathologic findings from the National Surgical Adjuvant BreastProject (Protocol no. 4) – V. Significance of axillary nodal micro-and macrometastases. Cancer 1978; 42: 2032–2038.

23 Fisher B, Bauer M, Wickerham L, Redmond CK, Fisher ER.Relation of number of positive axillary nodes to the prognosis ofpatients with primary breast cancer. Cancer 1983; 52:1551–1557.

24 Carter CL, Allen C, Henson DE. Relation of tumor size, lymphnode status, and survival in 24 740 breast cancer cases.Cancer 1989; 63: 181–187.

25 Wolman SR, Feiner HD, Schinella RA et al. A retrospectiveanalysis of breast cancer based on outcome differences. Hum.Pathol. 1991; 22: 475–480.

26 Gilchrist KW, Gray R, Fowble B, Tormey DC, Taylor IV. Tumornecrosis is a prognostic predictor for early recurrence and deathin lymph node-positive breast cancer: A 10-year follow-up studyof 728 Eastern Cooperative Oncology Group patients. J. Clin.Oncol. 1993; 11: 1929–1935.

27 Younes M, Laucirica R. Lack of prognostic significance of histo-logical grade in node-negative invasive breast carcinoma. Clin.Cancer Res. 1997; 3: 601–604.

28 Albert R, Muller JG, Kristen P, Harms H. Objective nucleargrading for node-negative breast cancer patients: comparisonof quasi-3D and 2D image-analysis based on light microscopicimages. Lab. Invest. 1998; 78: 247–259.

29 Lampe B, Hantschmann P, Dimpfl T. Prognostic relevance ofimmunohistology, tumor size and vascular space involvement inaxillary node negative breast cancer. Arch. Gyn. Obst. 1998;261: 139–146.

30 Saiz E, Toonkei R, Poppiti RJ, Robinson MJ. Infiltrating breastcarcinoma smaller than 0.5 cm. Is lymph node dissection nec-essary? Cancer 1999; 85: 2206–2211.

31 Chen YY, Schnitt SJ. Prognostic factors for patients with breastcancer 1 cm and smaller. Breast Cancer Res. Treat. 1998; 51:209–225.

32 Barth A, Craig PH, Silverstein MJ. Predictors of axillary lymphnode metastasis in patients with T1 breast carcinoma. Cancer1997; 79: 1918–1922.

33 Lauria R, Perrone F, Carlomagno C et al. The prognostic valueof lymphatic and blood vessel invasion in operable breastcancer. Cancer 1995; 76: 1772–1778.

34 Joshi MG, Lee AKC, Loda M et al. Male breast carcinoma: anevaluation of prognostic factors contributing to a pooreroutcome. Cancer 1996; 77: 490–498.

35 Linell F, Ljungberg O, Andersson I. Breast carcinoma. Aspectsof early stages, progression, and related problems. Acta Pathol.Microbiol. Scand. 1980; (Suppl. 272): 1–233.

36 Fisher ER, Palekar AS, Sass R, Fisher B. Scar cancers: patho-logic findings from the National Surgical Adjuvant Breast Project(protocol no. 4) – IX. Breast Cancer Res. Treat. 1983; 3: 39–59.

37 Toikkanen S, Joensuu H. Long-term prognosis of scar and non-scar cancers of the breast. APMIS 1990; 98: 1033–1038.

38 Partanen S, Hyvarinen H. Scar and non-scar ductal cancer ofthe female breast. Observations on patient age, tumour size,and hormone receptors. Virchows Arch (A) Pathol. Anat. 1987;412: 145–149.

39 Hasebe T, Tsuda H, Hirohashi S et al. Fibrotic focus in invasiveductal carcinoma: an indicator of high tumor aggressiveness.Jpn. J. Cancer Res. 1996; 87: 385–394.

40 Hasebe T, Tsuda H, Tsubono Y, Imoto S, Mukai K. Fibrotic focusin invasive ductal carcinoma: a histopathological prognosticparameter for tumor recurrence and tumor death within threeyears after the initial operation. Jpn. J. Cancer Res. 1997; 88:590–599.

41 Hasebe T, Tsuda H, Hirohashi S et al. Fibrotic focus in infiltrat-ing ductal carcinoma of the breast: a significant histopathologi-cal prognostic parameter for predicting the long-term survival ofthe patients. Breast Cancer Res. Treat. 1998; 49: 195–208.

42 Elston CW, Ellis IO. Pathological prognostic factors in breastcancer. I. The value of histological grade in breast cancer: Expe-rience from a large study with long-term follow-up. Histopathol-ogy 1991; 19: 403–410.

43 Kaplan EL, Meier P. Nonparametric estimation from incompleteobservations. J. Am. Stat. Assoc. 1958; 53: 457–481.

44 Cox DR. Regression models and life-tables. J. R. Stat. Soc.1972; 34: 187–220.

45 Koyama T, Hasebe T, Tsuda H et al. Histological factors associ-ated with initial bone metastasis of invasive ductal carcinoma ofthe breast. Jpn. J. Cancer Res. 1999; 90: 294–300.

46 Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma.Cancer 1950; 3: 74–85.

47 Jitsuiki Y, Hasebe T, Tsuda H et al. Optimizing microvesselcounts according to tumor zone in invasive ductal carcinoma ofthe breast. Mod. Pathol. 1999; 12: 492–498.

48 Silvestrini R, Benini E, Daidone MG et al. p53 as an indepen-dent prognostic marker in lymph node-negative breast cancerpatients. J. Natl Cancer Inst. 1993; 85: 965–971.

49 Aaltomaa S, Lipponen P, Papinaho S, Syrjanen K. Proliferating-cell nuclear antigen (PC10) immunolabelling and other prolifer-ation indices as prognostic factors in breast cancer. J. CancerRes. Clin. Oncol. 1993; 119: 288–294.


50 Auer G, Eriksson E, Azavedo E, Caspersson T, Wallgren A.Prognostic significance of nuclear DNA content in mammaryadenocarcinomas in humans. Cancer Res. 1984; 44: 394–396.

51 Hedley DW, Friedlander ML, Taylor IW. Application of DNA flowcytometry to paraffin-embedded archival material for the studyof aneuploidy and its clinical significance. Cytometry 1985; 6:327–333.

52 Peiro G, Lerma E, Climent MA, Segui MA, Alonso MC, Prat J.Prognostic value of s-phase fraction in lymph-node-negativebreast cancer by image and flow cytometric analysis. Mod.Pathol. 1997; 10: 216–222.

53 Rifkin DB, Moscatelli D. Recent developments in the cell biologyof basic fibroblast growth factor. J. Cell Biol. 1989; 109: 1–6.

54 Gospodarowicz D. The fibroblast growth factor. Oncogenesis1989; 1: 1–25.

55 Souttou B, Hamelin R, Crepin M. FGF2 as an autocrine growthfactor for immortal human breast epithelial cells. Cell GrowthDifferen. 1994; 5: 615–623.

56 Luamani YA, Graham M, Coombes RC. Expression of basicfibroblast growth factor, FGFR1 and FGFR2 in normal andmalignant breast, and comparison with other normal tissues. Br.J. Cancer 1992; 66: 273–280.

57 Jonson DE, Williams LT. Structural and functional diversity inthe FGF receptor multigene family. Adv. Cancer Res. 1993; 60:1–41.

58 Jacquemier J, Adelaide J, Parc P et al. Expression of theFGFR1 gene in human breast carcinoma cells. Int. J. Cancer1994; 59: 373–378.

59 Rosenbaum J, Blazejewski S, Anne-Marie P, Mallat A,Dhumeaux D, Mavier P. Fibroblast growth factor 2 and trans-forming growth factor b1 interactions in human liver myofibrob-lasts. Gastroenterology 1995; 109: 1986–1996.

60 Wilson SE, Lioyd SA, He YG. Fibroblast growth factor-1 recep-tor messenger RNA expression in corneal cells. Cornea 1993;12: 249–254.

61 Hasebe T, Imoto S, Ogura T, Mukai K. Significance of basicfibroblast growth factor and fibroblast growth factor receptorprotein expression in the formation of fibrotic focus in invasiveductal carcinoma of the breast. Jpn. J. Cancer Res. 1997; 88:877–885.

62 Bloom HJG, Richardson WW. Histological grading and progno-sis in breast cancer. Br. J. Cancer 1957; 11: 359–377.

63 Le Doussal V, Tubiana-Hulin M, Friedman S, Hacene K,Spyratos F, Brunet M. Prognostic value of histologic gradenuclear components of Scarff- Bloom-Richardson (SBR). Animproved score modification based on a multivariate analysis of1262 invasive ductal breast carcinomas. Cancer 1989; 64:1914–1921.

64 Todd JH, Dowle C, Williams MR et al. Confirmation of a prog-nostic index in primary breast cancer. Br. J. Cancer 1987; 56:489–492.

65 Galea MH, Blamey RW, Elston CE, Ellis IO. The Nottinghamprognostic index in primary breast cancer. Breast Cancer Res.Treat. 1992; 22: 207–219.

66 Hasebe T, Imoto S, Sasaki S, Mukai K. A proposal for a new his-tological classification scheme for predicting short-term tumorrecurrence and death in patients with invasive ductal carcinomaof the breast. Jpn. J. Cancer Res. 1998; 89: 1358–1373.

67 Hasebe T, Sasaki S, Imoto S, Ochiai A. Proliferative activity ofintratumoral fibroblasts is closely correlated with lymph nodeand distant organ metastasis of invasive ductal carcinoma ofthe breast. Am. J. Pathol. 2000; (in press).

68 von Marshall Z, Riecken EO, Rosewicz S. Stromelysin 3 is over-expressed in human pancreatic carcinoma and regulated byretionic acid in pancreatic carcinoma cell lines. Gut 1998; 34:692–698.

69 Okusa Y, Ichikura T, Mochizuki H. Prognostic impact of stromalcell-derived urokinase-type plasminogen activator in gastriccarcinoma. Cancer 1998; 85: 1033–1038.

70 Boyd RS, Balkwill FR. MMP-2 release and activation in ovariancarcinoma: the role of fibroblasts. Br. J. Cancer 1999; 80:315–321.

71 Baselga J, Norton L, Albanell J, Kim YM, Mendelsohn J.Recombinant humanized anti-HER2 antibody (Herceptin)enhances the antitumor activity of paclitaxel and doxorubicinagainst HER2/neu overexpressing human breast cancerxenografts. Cancer Res. 1998; 58: 2825–2831.

72 Krsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM.Angiostatin suppress malignant glioma growth in vivo. CancerRes. 1998; 58: 4654–4659.

73 Parmigiani G, Berry DA, Winer EP et al. Is axillary lymph nodedissection indicated for early-stage breast cancer? A decisionanalysis. J. Clin. Oncol. 1999; 17: 1465–1473.

74 Reynolds C, Mick R, Donohue JH et al. Sentinel lymph nodebiopsy with metastasis: Can axillary dissection be avoided insome patients with breast cancer? J. Clin. Oncol. 1999; 17:1720–1726.

75 Imoto S, Hasebe T. Initial experience with sentinel node biopsyin breast cancer at the National Cancer Center Hospital East.Jpn. J. Clin. Oncol. 1999; 29: 11–15.

76 Diab SG, Clark GM, Kent Osborne C et al. Tumor characteris-tics and clinical outcome of tubular and mucinous breast carci-nomas. J. Clin. Oncol. 1999; 17: 1442–1448.

77 Casey M, Rosenblatt R, Zimmerman J, Fineberg S. Mastec-tomy without malignancy after carcinoma diagnosed by largecore stereotactic breast biopsy. Mod. Pathol. 1997; 10:1209–1213.


Documents

New prognostic histological parameter of invasive ductal carcinoma of the breast: Clinicopathological significance of fibrotic focus