Departments of 1 Gynecology and Obstetrics, 4 Surgery and 6 Medical Oncology, University Hospital Basel, Switzerland; 2 Institute of Pathology, University of Basel, Switzerland; 3 JPS Institute for Biomathematics, Basel, Switzerland; 5 Women's Hospital and Breast Center Rheinfelden, Rheinfelden, Germany
* Correspondence to: Dr U. Güth, University Hospital Basel, Department of Gynecology and Obstetrics, Spitalstrasse 21, 4031 Basel, Switzerland. Tel: +41-61-2659028; Fax: +41-61-2659037; E-mail: ugueth{at}uhbs.ch
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and methods: We compared the clinical course of patients with histologically proven non-inflammatory skin involvement: 119 (65.4%) with clinically obvious classical skin changes (Group A) and 63 (34.6%) with no or only discreet changes (Group B). A questionnaire was circulated to pathology departments in 24 countries to assess the practice concerning the placement of skin- involved breast carcinomas in the TNM classification.
Results: Patients in Group B showed a significantly better disease specific survival (P = 0.0002). Eighty-six respondents (70.5%) of the survey preferred the histological view and classified tumors with only histological proven skin involvement as T4b/stage IIIB. The opposing classification principle (clinical view), which dictates that T4b breast cancer is a clinical diagnosis and the classical signs must be present, was supported by 31 respondents (25.4%).
Conclusions: A large number of breast cancer patients with non-inflammatory skin involvement are only histologically proven and show, compared with cases exhibiting the classical clinical signs, significant differences in clinical course and prognosis. In general, both subsets were aggregated in one T category/stage (T4b/IIIB). This results in a considerable distortion of the reported statistical data.
Key words: breast carcinoma, skin involvement, TNM classification, prognostic factors, survey
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Only tumors accompanied by macroscopic and typically readily discernible classical skin changes, such as ulceration, edema, peau dorange and satellite skin nodules, should be placed in the T4b category. It is stated explicitly that discreet skin changes, such as dimpling, retraction of the nipple and other changes, often caused by shortening of Cooper's ligaments due to infiltration by malignant disease, may occur in T13 disease and, therefore, do not allow classification in the T4 category. Tumors that showed histologically proven skin involvement but not the accompanying classical clinical changes have been in a grey area of the TNM nomenclature and allowed a certain leeway in the interpretation of these cases. It was only in 2001 that the 2nd edition of the TNM Supplement [3] established how to classify this subgroup of cases within the T category. It is required that for a lesion to be classified as T4b, the previously mentioned clinical (macroscopic) features must be present. Microscopic invasion of the dermis alone, without the accompanying classical clinical signs is not sufficient for placing a lesion in the T4b category and the T classification is based solely on tumor size (T13).
The goal of the current review was, on one hand, to assess via an international survey the classification practice of breast cancer cases with non-inflammatory skin involvement in the period before precise recommendations were drafted (in the 1990s). On the other hand, we demonstrate distinct clinical entities with significant differences in terms of long-term clinical outcome of patients who exhibit histologically proven non-inflammatory skin involvement with and without classic clinical signs. Our report shows that a lack of uniformity in the classification of these cases results in considerable distortions in the epidemiological picture of T4b breast cancer.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Bilaterality, multicentricity and male gender were also exclusion criteria. Two patients who presented with additional histologically proven chest wall involvement (pT4c) were not considered in the analysis.
The data of 182 breast cancer patients (accounting for 7.8% of all newly diagnosed breast carcinomas within the study period) were the basis of the current analysis. Staging was performed for all patients in accordance with the current (6th) edition of the UICC/AJCC TNM classification. As a second step, reclassification was undertaken to assess the disease stage (tumor size and lymph node involvement) of tumors independent of the morphologic parameter skin involvement. This clinical/histopathological feature was no longer taken into consideration and was eliminated from our classification. All tumors were reclassified based on tumor size and, therefore, the category T4b was replaced with the categories T13. In this manner, patients who had stage IIIB disease underwent restaging.
Based on the clinical degree of skin involvement reported in the patient's records, all patients were placed into one of two groups. One hundred and nineteen patients (65.4%) presented with clinically obvious classical skin changes (ulceration, edema, peau dorange and satellite skin nodules), and therefore fulfilled the current criteria for the T4b classification (Group A). Sixty-three patients (34.6%) had histologically proven skin involvement but no or only discreet (e.g. retraction or dimpling) clinical changes to the overlying skin or the nipple (Group B).
Histopathological analyses were performed at the Institute of Pathology, University of Basel. A differentiation between pathological skin involvement of the epidermis and the dermis was not conducted. Histopathological analyses also included grading according to the BloomRichardsonElston scheme and immunohistochemical staining for estrogen and progesterone receptors. Each patient underwent a staging work-up, which included a recording of clinical history, physical examination, routine blood studies, chest X-ray, sonography of the liver and additional diagnostic studies that were needed to rule out metastatic disease. To discuss the clinical and pathological features, all cases were evaluated in a multidisciplinary tumor board. There was no standard therapeutic approach during the study period (Table 3). All patients were followed until their death or for a minimum of 5 years if they remained alive. These patients were seen a maximum of 3 months before conclusion of the study.
|
The survey
A questionnaire was designed to assess the practice concerning the placement of breast cancer cases with non-inflammatory skin involvement within the TNM classification (Table 1). Four distinctive clinicopathological constellations of skin involvement, including different degrees of clinical skin changes, had to be assessed as to whether the criteria of the T4b category were fulfilled (answer choice: T4b), or if the criteria were not fulfilled and the case had to be classified according to tumor size (answer choice: T13).
|
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Within the entire group of patients with non-inflammatory skin involvement, the subset of patients without the classical clinical signs is not negligible, but accounts for 35% of cases. The aggregation of both entities within one category violates the rules of the stage model upon which the TNM system is based. The TNM concept means that only clearly defined homogenous entities with similar prognostic impact may be placed together in one category/stage and placement in a higher category/stage generally corresponds to a poorer prognosis. When both entities are aggregated in one category, considerable heterogeneity of the T4b category with a broad distribution of cases among the subsets of disease stages is inevitable. Approximately 70% of the cases without the clinical features (group B) have malignant locoregional extent of TNM stage I/II. These patients run the risk of being falsely regarded as having more advanced disease.
The results of our survey show that historically the majority of both distinct entities were not differentiated in terms of tumor classification. A total of 25.4% of the respondents reported that breast cancer cases with skin involvement were recorded in the adjusted form (only cases with histologically proven skin involvement accompanied by classical clinical changes were classified as T4b). The majority of the respondents (70.5%), however, also classified tumors with only histological proven skin involvement but without the clinical correlate as pT4b/stage IIIB. Due to the non-uniformity in the practice of classification, heterogeneous data from this T category/stage, which are retrospectively difficult to control and reproduce, were compiled in the tumor registries and database collections. Our survey encompasses the years from 1990 to 2000, a period from which a large part of the currently accepted epidemiological data is derived. Therefore, while interpreting the data of the T4 category and stage III (especially T4b category and stage IIIB), distortions could be present resulting from the fact that tumors with more favorable prognoses were falsely classified, from the current view, as T4.
The survey reveals two incompatible points of view concerning the classification in the TNM system of breast cancer cases with non-inflammatory skin involvement: the histological and the clinical point of view. The clinical view defined T4 carcinoma to be a clinical diagnosis where the typically readily discernible skin changes, such as exulceration, edema, peau dorange and satellite skin nodules, must be present. Advocates of the histological view were of the opinion that clinical staging may be performed in some cases, but pathologic staging is more accurate [19], and also classified tumors with only histological skin involvement and no corresponding clinical features in the T4 category. Through a lack of clear guidelines in the TNM classification, there were ambiguities and a certain amount of leeway concerning the definition of skin involvement in the past. These inconsistencies are reflected in six different answers of the four clinicopathological constellations in our survey. When the TNM Supplement in 2001 established recommendations about how to use the TNM classification uniformly in these cases, the dispute seemed to be resolved in favor of the clinical view. It was once again substantiated that only the recognized classical clinical signs (edema, peau d orange or ulceration of the skin, satellite skin nodules) are to be classified as T4. Any other skin changes, as well as microscopic invasion of the skin (dermis) without the above-mentioned clinical features, do not affect the classification [3
]. Our survey demonstrates that the clinical view that is currently accepted as valid was put into practice by only a minority of the respondents (25.4%) as a basis for classification. Nevertheless, this recommendation also allows for leeway of interpretation. The following example shows that the confusion concerning classification principles could not be entirely dispelled. An enquiry was posed to the AJCC in summer 2004 on how to classify an invasive ductal carcinoma with histological infiltration of the epidermis but no associated classical clinical signs. The curator stated that direct skin invasion is defined as full thickness involvement including the epidermis; if the epidermis is intact with only focal dermal involvement, then it is not considered to be T4 but classified by the size of the primary tumor (G. MacGrogan, personal communication). This statement emphasizes again a histological feature, i.e. skin involvement of the epidermis to the border of deeper skin layers, as being crucial for classification. This view is only an individual interpretation of the TNM Supplement and cannot be by all means supported by the TNM nomenclature or in the literature.
The following critical points of the survey must be discussed.
Although our survey depicted the classification practices of the 1990s, we believe that our results also mirror the current standard. Most participants were contacted personally by phone to introduce the study questions. A frequent answer given was that classification of breast cancer with non-inflammatory skin involvement, lacking the classical clinical signs, is a well known and often discussed, but unresolved, problem. We had the impression that the contents of the TNM Supplement concerning this subject was often not recognized or put into practice. Only three respondents supplemented the questionnaire with a commentary that classification principles had changed in their departments since the year 2000.
The following factors could also lead, regardless of clear guidelines, to persistent non-uniform use of the TNM classification for breast cancer with non-inflammatory skin involvement in the future.
Our analysis indicates a need for further debates concerning a revision of the T4 category. A conceivable proposal could be that cases with non-inflammatory skin involvement should no longer be classified in a separate T category (T4b) but rather simply through their size (T13). Further studies should be conducted to support our proposal to assess the prognostic impact of the morphologic parameter skin involvement independent of tumor size and disease stage.
![]() |
Notes |
---|
Received for publication May 2, 2005. Revision received June 13, 2005. Accepted for publication June 14, 2005.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Sobin L, Wittekind C (eds). TNM Classification of Malignant Tumors, 6th edition. New York: John Wiley & Sons 2002.
3. Wittekind C, Henson DE, Hutter RVP et al. (eds). TNM Supplement. A Commentary on Uniform Use, 2nd edition. New York: Wiley-Liss 2001.
4. El-Tamer M, Hussain S, Weedon J et al. Prognoses of T4 breast cancer subsets. Ann Surg Oncol 2002; 9: 340345.
5. Guth U, Moch H, Herberich L, Holzgreve W. Noninflammatory breast carcinoma with skin involvement. Cancer 2004; 100: 470478.[CrossRef][ISI][Medline]
6. Poole GV, Thigpen JT, Vance RB, Barber WH. Management of women who present with T4 breast cancer. Am Surg 2004; 70: 662667.[ISI][Medline]
7. Price A, Kerr GR, Rodger A. Primary radiotherapy for T4 breast cancer. Clin Oncol (R Coll Radiol) 1992; 4: 217221.[Medline]
8. Rao DV, Bedwinek J, Perez C et al. Prognostic indicators in stage III and localized stage IV breast cancer. Cancer 1982; 50: 20372043.[ISI][Medline]
9. Rubens RD, Armitage P, Winter PJ et al. Prognosis in inoperable stage III carcinoma of the breast. Eur J Cancer 1977; 13: 805811.[ISI][Medline]
10. Sutherland CM, Mather FJ. Long-term survival and prognostic factors in patients with regional breast cancer (skin, muscle, and/or chest wall attachment). Cancer 1985; 55: 13891397.[ISI][Medline]
11. Touboul E, Lefranc JP, Blondon J et al. Multidisciplinary treatment approach to locally advanced non-inflammatory breast cancer using chemotherapy and radiotherapy with or without surgery. Radiother Oncol 1992; 25: 167175.[CrossRef][ISI][Medline]
12. Touboul E, Lefranc JP, Blondon J et al. Primary chemotherapy and preoperative irradiation for patients with stage II larger than 3 cm or locally advanced non-inflammatory breast cancer. Radiother Oncol 1997; 42: 219229.[CrossRef][ISI][Medline]
13. Valagussa P, Zambetti M, Bignami P et al. T3b-T4 breast cancer: factors affecting results in combined modality treatments. Clin Exp Metastasis 1983; 1: 191202.[CrossRef][ISI][Medline]
14. Valagussa P, Zambetti M, Bonadonna G et al. Prognostic factors in locally advanced noninflammatory breast cancer. Long-term results following primary chemotherapy. Breast Cancer Res Treat 1990; 15: 137147.[CrossRef][ISI][Medline]
15. Wieland AW, Louwman MW, Voogd AC et al. Determinants of prognosis in breast cancer patients with tumor involvement of the skin (pT4b). Breast J 2004; 10: 123128.[CrossRef][Medline]
16. Yildirim E, Semerci E, Berberoglu U. The analysis of prognostic factors in stage III-B non-inflammatory breast cancer. Eur J Surg Oncol 2000; 26: 3438.[CrossRef][ISI][Medline]
17. Zucali R, Kenda R. Small size T4 breast cancer. Natural history and prognosis. Tumori 1981; 67: 225230.[ISI][Medline]
18. Hortobagyi GN, Ames FC, Buzdar AU et al. Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 1988; 62: 25072516.[ISI][Medline]
19. Rosen P. Invasive duct carcinoma. Assessment of prognosis, morphologic prognostic markers, and tumor growth rate. In Rosen P (ed.): Rosen's Breast Pathology, 2nd edition. Philadelphia: Lippincott Williams & Wilkins 2001; 325364.
20. Wittekind C, Greene FL, Henson DE et al. TNM Supplement. A Commentary on Uniform Use, 3rd edition. New York: Wiley-Liss 2004.
21. Sau P, Solis J, Lupton GP, James WD. Pigmented breast carcinoma. A clinical and histopathologic simulator of malignant melanoma. Arch Dermatol 1989; 125: 536539.[Abstract]
22. Azzopardi JG, Eusebi V. Melanocyte colonization and pigmentation of breast carcinoma. Histopathology 1977; 1: 2130.[ISI][Medline]
23. Morrow M. Physical examination of the breast. In Harris J, Lippman ME, Morrow M, Osborne CK (eds): Diseases of the Breast, 3rd edition. Philadelphia: Lippincott Williams & Wilkins 2004; 2932.
24. Speyer J, Muggia F. Management of locally advanced breast cancer. In Roses D (ed.): Breast Cancer, 1st edition. Philadelphia: Churchill Livingstone 1999; 493502.
25. Rosen P. Unusual clinical presentations of carcinoma. In Rosen P (ed.): Rosen's Breast Pathology, 2nd edition. Philadelphia: Lippincott Williams & Wilkins 2001; 653687.
26. Sloane J. Infiltrating carcinoma-pathological types. In Sloane J (ed.): Biopsy Pathology of the Breast, 2nd edition. London: Arnold 2001; 170214.
|