Rethinking TNM: Breast cancer TNM classification for treatment decision-making and research

ARTICLE IN PRESS The Breast (2006) 15, 3–8

THE BREAST www.elsevier.com/locate/breast

REVIEW

Rethinking TNM: Breast cancer TNM classification for treatment decision-making and research Umberto Veronesia,, Giuseppe Vialeb, Nicole Rotmensza, Aron Goldhirscha a

European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy University of Milan School of Medicine, Milan, Italy

b

Received 5 October 2005; accepted 16 November 2005

KEYWORDS Breast cancer; TNM classification; Biological variables

Summary Current classification for solid tumors is based upon characteristics of their extent. Size of the primary tumor, presence of metastatic regional lymph nodes and/or of distant metastases are the key elements for their categorization. Treatment decision-making may depend upon defined extent of disease, but it requires the knowledge of several other factors. Furthermore, effective therapeutics is less dependent upon extent of disease, biological features being increasingly instrumental for treatment choice. A new classification that integrates both requisites is proposed. The scope of this proposal is to transform the current rigid and gross categorization into a more analytical and fine tuned listing including biological variables, making staging allocation more flexible and functional for proper clinical and research needs in the present and for the future. The significant changes we propose are:


Abolishing the term of carcinoma for non-invasive cancer





Complete metric description of all parameters, rather than categorization Assessment of biological features as predictive of response.

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Background Corresponding author. Tel.: +39 02 574 891;

fax: +39 02 5748 9120. E-mail address: [email protected] (U. Veronesi).

The TNMUICC classification was created to allow the definition of ‘‘categories’’ indicating the degree of local, regional and general extension of the disease at the time of primary treatment, thus providing a

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ARTICLE IN PRESS 4 description that is objective and permanent (e.g., T1N1M0). Various categories with similar prognostic value may be grouped together to define the ‘‘stages’’ of the disease (e.g., stage I or III, etc.) which are arbitrary and transitory. Specifically for breast cancer, the TNMUICC classification provides some disease-related features, which derive from indicators of prognosis.1 The TNMUICC classification failed, however, to provide a reasonable tool for therapeutic decisions, with some noteworthy exceptions. These include conditions, which relate to the size of the primary tumor, and to the extent of axillary involvement. Several features are not mentioned in the TNMUICC classification, thus not allowing the information on a meaningful treatment choice to be properly communicated. Indicators for endocrine responsiveness, like expression of estrogen or progesterone receptors (ER, PgR) in tumor tissue, or the presence of special histology may guide care providers to offering systemic endocrine treatments. On the other hand, lack of expression of ER and PgR, and over-expression or amplification of c-erbB2 likely are indicators for non-responsiveness to endocrine therapies, and might be important information for predicting potential efficacy of cytotoxics. We were therefore challenged by the need to adapt a currently available categorization adding several descriptive items in a dynamic fashion (i.e., allowing continuous updating with novel technical developments derived from research), providing the maximal information for therapeutic decisionmaking. Such classification should respond to two further needs besides continuous renewal. The first relates to the possibility to compare data from previous series, based upon previous classifications. The second concerns the need to recognize that biological systems rarely present cut-off points, thus, the best available information should be displayed as a continuum.

The need for a change The first problem we had to face was the difficulty to accept the intraductal proliferation of tumor cells being defined as a malignant tumor (LCIS, DCIS). By definition the difference between malignant and benign is expressed by the ability of malignant tumors to metastasize. Therefore, as the in-situ carcinomas do not metastasize they cannot be defined malignant and the term ‘‘carcinoma’’ should be abolished. We decided therefore that a better classification would be that defined by

U. Veronesi et al. Tavassoli (LIN1, LIN2, LIN3 and DIN1, DIN2, DIN3). As these neoplasias do not metastasize the categories N and M do not apply. Therefore there is no reason to keep them inside the TNM classification. ‘‘Intralobular and intraductal carcinoma’’ being substituted with Lobular or Ductal Intraepithelial Neoplasia (LIN or DIN) there is no more reason to add the adjective ‘‘invasive’’ to the non-intraductal carcinoma. Carcinoma itself by definition is a term which includes its malignant characteristics, like invasion and metastatization. Although many changes have been introduced in the TNM classification during the last decades, the main categories have been maintained unchanged. The size is still divided in T1 T2 T3 categories according to the maximum diameter of the tumor (less than 2 cm, from 2 to 5 cm and more than 5 cm) plus the T4 category with special features. In the 1960s the great majority of breast cancers were in the middle category (T2) but after the introduction of early detection programs and new diagnostic tools the majority of patients, in Western Countries, present themselves with T1 tumors. This has made necessary the subdivision in subcategories (T1a o5 mm, T1b 5–10 mm, T1c 10–20 mm) but again at present most carcinomas are in the T1c category. However, the difference in prognosis of tumors classified in the same category or subcategory may be great. For example, a tumor with a diameter of 1.1 cm (average volume of 0.6 cm3) and a tumor of 1.9 cm in diameter (average volume of 4.0 cm3), although both in T1c subcategory show great differences in survival. Things are even worse in the T2 category where a tumor of 2.1 cm in diameter (average volume 4.5 cm3) and a tumor of 4.9 cm in diameter (average volume 60 cm3) have an immense difference in outcome. There is therefore no logical reason to keep them in the same category which, in principle, should express a similar prognosis. We believe that categorization according to the size of the breast carcinoma today has very little meaning. It was certainly the only way to classify cancer some 60 years ago, when the TNM system was created. Today, in the era of computerized medicine, there is no reason to include different tumors with different prognosis in the same box, while it appears much wiser that every single case is defined precisely as it is measurable at the time of primary treatment. If a breast carcinoma has a maximum diameter of 1.3 cm it will appear as T1,3, if it has a diameter of 4.5 cm it will be defined T4,5. This definition will connotate that tumor with a precise definition which will remain for ever and will represent the original portrait of the primary

ARTICLE IN PRESS Rethinking TNM classification

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carcinoma. When a statistician will need to evaluate cases say, up to 7 mm, the computer will immediately sort out the cases, if the need will be the evaluation only of the cases with a diameter of 1.3 cm, the computer will immediately select the cases of that dimension. This is the reason why we propone a classification based on a ‘‘continuous’’ metric description of the dimension of the tumor. The same criteria apply to the description of the lymph node invasion where it is simpler to define the number of the involved nodes out of the examined ones (examples N0/21, N3/19, Ns0/2) including also the number of sentinel nodes examined. Finally, and very importantly, we considered it fundamental to characterize the biological features of breast carcinomas, including endocrine receptors positivity, C-erbB2 expression, and peritumoral vascular invasion. The definition of characteristics of the disease is focused on features related to the primary tumor (T), to the regional lymph nodes, including those of the ipsilateral axilla, supraclavicular and internal mammary sites (N), and of distant metastases. The presence of distant metastases (M) is indicated as in previous TNMUICC classifications, followed by the acronym of the organ or organs involved with the disease, either macroscopically or microscopically. Typically, metastatic sites are defined according to available clinical or imaging-based assessment. Additional, readily available information should include details on specific histological type, steroid hormone receptor expression in the primary tumor, over-expression and/or amplification of HER2/neu, and presence and degree of vascular invasion.

The European Institute of Oncology Dynamic TNM Classification (TNMEIO)

modalities. Prediction of efficacy of specific treatments is likely to change with progress of therapeutics and improved knowledge on the molecular basis for response and resistance. Therefore, the EIO classification provides an opportunity for integrating new prognostic and predictive information by being flexible and allowing ‘‘new entries’’.

The primary tumor Some semantic issues must be clarified. As already mentioned intraepithelial proliferations are classified separately as LIN and DIN according to Tavassoli2 (Table 1). The dimension of the largest primary tumor mass is described based upon pathological size, referring to the largest diameter. All the other components of characteristics of the primary tumor are displayed and discussed in Table 2.

The regional lymph nodes Table 3 displays the features related to the regional lymph nodes with specific attention to all variables for axillary and internal mammary chain and pathological assessment. New staging procedures like sentinel node biopsy belong to the global evaluation of regional extension of the disease. The dimension of metastases in involved lymph nodes is not taken into account as a routine procedure. Additional information that might be relevant to the accuracy of nodal status is added with specific pN extension-suffix (sn ¼ sentinel node, i.m. ¼ internal mammary nodes, ExCap ¼ extra capsular, BLN ¼ Bunch Lymph Nodes). All the other components of characteristics of regional lymph nodes are shown in Table 3.

The distant metastases The current proposal is specific for breast cancer and should serve as both, a tool for presenting those features which carry therapeutic relevance, and be useful for evaluation of specific treatment Table 1

Table 4 summarizes the features related to the site of overt metastases. Generally, imaging and/or biopsy proven metastases in distant sites carry

New terminology for ‘‘intraepithelial lesions’’.

Intralobular

Intraductal

LIN1—atypical lobular hyperplasia

DIN1a—flat epithelial atypia

LIN2—LCIS, classic type LIN3—LCIS, high grade/ pleomorphic

DIN1b—ADH DIN1c—old DCIS grade I (cribriform or micropapillary) DIN2—old DCIS grade II (crib/micropap with necrosis or atypia); or special types DIN3—old DCIS grade III (anaplastic DCIS, +/ necrosis)

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U. Veronesi et al. Table 2

The EIO TNM classification (TNMEIO).

T Stage

Definition

Tx T0 Tmic T(size) Tsize(EIC)

Primary tumor cannot be assessed No evidence for a primary tumor DIN with micro-invasion (p1 mm) Invasive carcinoma (41 mm) Carcinoma with extensive foci of intraductal component (X25% of area and beyond the invasive component) Carcinoma with peritumoral vascular invasion (Clinical evidence of) Inflammatory (or lymphangitic) carcinoma

Tsize(PVI) Tinfl

Table 3

Example

T1,4 T2,2 T1,7 T4,5

EIC

PVI infl

The EIO TNM classification (TNMEIO).

pN

Legend

Examples

0/y

No metastasis to axillary lymph nodes examined number of axillary, internal mammary lymph nodes positive/number examined Positive ipsilateral axillary lymph nodes, one or more extended beyond the capsule (Extra Capsular) Positive ipsilateral axillary lymph nodes fixed to one another (Bunch Lymph Nodes) Not assessable at the present surgery (previously removed/never removed)

pN (0/23) pNsn0 (Nsn0/3)

(x/y) ExCp

BLN X

Table 4

or Tinflammatory

pN (3/23)

pNI.M. (2/2)

pNExCp (5/23)

pNBLN (8/29) pNX

The EIO TNM Classification (TNMEIO).

M

Legend

Example

0 1

No distant metastasis Distant metastasis

M1LP

1susp

Suspicious evidence of metastasis (e.g., very elevated blood

M1susp

markers, unclear imaging with no certain evidence for overt metastasis). Might require work-up to clarify with imaging, biopsy or follow-up. x

Systemic staging not performed

M Description is displayed in first column, characteristics in the second column. Only then addition of M1susp is a new entity with respect to TNMUICC.  Of uncertain clinical relevance.

prognostic relevance. The site itself might have significant therapeutic consequences, thus is important to display. Often the clinical situation does not offer certainty about metastatic involvement of organs, though there is a strong clinical or laboratory-related wariness for progression of disease in distant sites. This might be related to increase in serum marker levels, or to a suspicious finding in radiological imaging and might

further require either new imaging, biopsy or follow-up to clarify its nature. All the other components of characteristics of overt metastases are displayed in Table 4. To improve the quality of the information extensions—suffix of M are recommended—(S): metastasis to the skin, (N): metastasis to the lymph nodes, (H): metastasis to the liver (hepatic), (L): metastasis to the lungs, (P): metastasis to the pleura, (O): metastasis to the

ARTICLE IN PRESS Rethinking TNM classification bones (osseous), (B): metastasis to the brain, (M): metastasis to the bone marrow, (C): metastasis circulating in blood.

Contralateral breast tumor Simultaneous bilateral or metachronous contralateral breast cancer should be classified independently to allow the evaluation of prognosis and especially to assess treatment options separately, if applicable.

Biological information Several other features currently belong to the reporting of characterization of breast cancer. Many of these items are of significant value for a proper therapeutic decision making process. The recognition of the fact that systemic treatment for individual patients is primarily tailored according to endocrine responsiveness of the disease3 increased the relevance of pathological evaluation of biological features. Despite severe issues of reproducibility and quality control for such biological variables, their role in allowing the definition of treatments (both in adjuvant and advanced disease settings) requires that they be displayed together with the TNM features. The listing of morphologically identified tumor types is, with some exceptions, of uncertain relevance. Some types are associated with predictive features (e.g., tubular cancer is usually endocrine responsive; apocrine cancer does not express steroid hormone receptors, etc.). It is, however, common to list the main morphological characteristics of the primary tumor with an assumption that it might be either useful

7 for interpreting biological features or be instrumental for identification of as yet unknown markers with some specific predictive potential. Our recommendation is to list the main biological features: ER, PgR, ERB, while others may be added if available (Table 5). Example of TNMEIO description: T1,3 ER+PgR+HER2+(OE/Amp) N2/23 MO.

Discussion and conclusions There are several reasons for adapting a classification to allow a proper display of characteristics of clinical and pathological relevance. This specific proposal for a listing of features, which are relevant for therapeutic decision-making, was born to aid the communication within an interested interdisciplinary group of specialists of the European Institute of Oncology. The items which appeared to be significant for any therapeutic choice were progressively included in the list, and were then tested for their continuous ‘‘role’’ among the features of the newly developing classification. This dynamic process took about 3 years and 6000 patients to reach stability, which motivated our current attempt to share it with the medical and scientific community. There are several aspects that make this proposal both practical and open for innovation. The first aspect that allows flexibility is related to the display of measured parameters as a continuum. This consents the evaluation of several features as for genetic profiling in a biologically sound fashion.4–6 Furthermore, the fact that description of the disease is open for adding new variables is a

Table 5 List of biological features, which represent the requirement of citation, together with other TNM items, for estimation of prediction of response. Feature

Display

ER (Oestrogen receptors)

% of cells showing definite nuclear immunoreactivity over at least 2000 neoplastic cells. For invasive carcinomas only the invasive component must be evaluated. Tumors with less than 1% immunoreactive cells are scored negative

PgR (Progesterone receptors)

% of cells showing definite nuclear immunoreactivity over at least 2000 neoplastic cells. For invasive carcinomas only the invasive component must be evaluated. Tumors with less than 1% immunoreactive cells are scored negative

HER2 overexpression

scored in a 4-tier scale (0–3+) according to the intensity and completeness of membrane staining (FDA recommendations). Add in brackets the percentage of neoplastic cells showing the highest immunoreactivity score. For invasive carcinomas only the invasive component must be evaluated. Tumors with less than 10% immunoreactive cells are scored negative

HER2 amplification

amplified/non amplified/polisomy of chromosome 17. Add in brackets the estimated number of copies of the gene (absolute or relative to the number of chromosomes 17)

ARTICLE IN PRESS 8 guarantee for its continuous innovation. Several new findings will probably enrich the way we deal with breast cancer, and it is likely that novel treatments will be specifically designed to interact with some cellular targets. Obviously, continuous innovation represents a caveat, due to endangered consistency over time. This is, however, not different from several consecutive editions of classifications, which are unavoidable, due to advances in technology and progress in knowledge. One of the most intriguing arguments in favour of the ‘‘original’’ TNMUICC classification is related to the ability to have stages compared across trials, series and during time periods. Description of a continuum within the TNMEIO classification entirely dismisses this argument, because lack of categorization allows comparison at any time with any data set that uses similar display. On the contrary, changes through updates within the TNMUICC classification might be much more difficult, especially with the new categories of definitions to nodal involvement. One of the most important developments in expressing an increasing number of biological variables is the one related to quality control of the features. To ensure reproducibility in the evaluation of the different biological parameters, special attention must be paid to the pre-analytical, analytical and interpretative phases of the assay. Length and type of fixation and of the antigen retrieval treatments are especially critical for the best immunostaining results. Also, adoption of readyto-use staining kits and of automated immunostainers significantly reduce the risk of inaccurate performance of the assay. The evaluation of the immunostaining results must be performed by trained pathologists (with or without the help of image analysis equipments) well aware of the clinical significance of their scoring activity. Enrolment in external quality control programs for immunocytochemistry (like the one run by the NEQAS in the UK) is highly recommended. Alternatively, the evaluation of the biological parameters should be referred to specialized centers or central laboratories with more than 250 cases assayed per year. The integrated work and interactive discussion among members of several specialties are required

U. Veronesi et al. for proper treatment of a woman with breast cancer today. Evidence on therapies is typically based on results of clinical trials conducted in the past, which provide information on the average patient. Tailoring therapies require personalized details that are not available due to excessive and rigid categorization. The current attempt to move on for a finer resolution of details is a first step in the right direction.

Acknowledgments We thank F.A. Tavassoli for providing the concept of exclusion of non-invasive cancer from the strict categorization of malignancies; the members of the European Institute of Oncology Task Force for Breast Cancer for their contibution when preparing the manuscript (Peter Boyle, Enrico Cassano, Marco Colleoni, Alberto Costa, Andrea Decensi, Giuseppe Della Porta, Pier Paolo Di Fiore, Viviana Galimberti, Roberto Gennari, Irene Giannetti, Cristina Leonardi, Alberto Luini, Franco Nole `, Roberto Orecchia, Giovanni Paganelli, Salvatore Pece, Sergio Pecorelli, Piergiuseppe Pelicci, Jean Yves Petit, Giuseppe Renne, Paolo Veronesi, Gaetano Villa, Stefano Zurrida) and the American Italian Cancer Foundation for their financial support.

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