Invasive Ductal Carcinoma: Assessment of Prognosis with Morphologic and Biologic Markers
SYED A. HODA
INVASIVE DUCTAL CARCINOMA, NOT OTHERWISE SPECIFIED
Invasive ductal carcinoma is the largest group of malignant mammary tumors, comprising approximately 75% of mammary carcinomas.1,2 Included under this heading are tumors identified previously by such terms as ductal carcinoma with productive fibrosis, scirrhous carcinoma, carcinoma simplex, and a host of other names. A generic term sometimes employed is invasive ductal carcinoma, not otherwise specified (NOS), or of no special type (NST). These are useful designations, because they recognize the distinction between the majority of invasive ductal carcinomas and the several infrequent specific “special” forms of ductal carcinoma, such as tubular, medullary, metaplastic, mucinous, and adenoid cystic carcinoma (AdCC). There is accumulating evidence that many of the other 25% of invasive breast carcinomas have not only special phenotypical appearances but also specific genetic attributes; for example, AdCC has the (6;9) MYB-NFIB translocation, secretory carcinoma has the t(12;15) translocation that helps form the ETV6-NTRK3 fusion gene, and lobular carcinoma exhibits inactivation of the CDH1 gene3 that is reflected in the absence of E-cadherin immunoreactivity.
In the latest WHO lexicon,4 the term invasive ductal carcinoma is replaced by invasive carcinoma of NST, since in the authors’ collective opinion “the use of the term ‘ductal’ perpetuates the traditional but incorrect concept that these tumors are derived exclusively from mammary ductal epithelium in distinction from lobular carcinomas, which were deemed to have arisen from within lobules, for which there is also no evidence.” Nonetheless, the WHO classification retains the term invasive lobular carcinoma, not to mention atypical ductal hyperplasia and ductal carcinoma in situ (DCIS). The authors of this volume are not persuaded that this change is warranted at the present time and recommend the continued use of the term “invasive ductal carcinoma” until more compelling evidence is presented. Unless otherwise stated, the term “invasive ductal carcinoma” as used here refers to “invasive ductal carcinoma, NOS.” (See Introduction for further comments on this issue.)
INVASIVE DUCTAL CARCINOMA WITH MIXED HISTOLOGIC FEATURES
Invasive ductal carcinoma, NOS includes a histologically diverse group of tumors that may express, at least in part, one or more characteristics of the specific types of breast carcinoma but do not constitute pure examples of the individual tumors. Examples of this phenomenon are invasive ductal carcinomas that have limited foci of tubular, medullary, papillary, or mucinous differentiation. When a mixed growth pattern is present in a needle core biopsy, the diagnosis should be descriptive, with final classification reserved for the excisional biopsy. The relatively favorable prognosis associated with some specific histologic types has been found to apply only to those tumors that are composed entirely or in large part of the designated pattern. Where these features are less extensively represented, the tumors are appropriately relegated to the broader group of invasive ductal carcinoma. The prognosis is likely to be that of the dominant invasive ductal carcinoma component. Tumors combining invasive ductal carcinoma with either primary or secondary forms of Paget disease are classified as invasive ductal carcinoma.
Approximately one-third of the lesions characterized as invasive ductal carcinoma in one detailed review of 1,000 carcinomas expressed one or more combined features.5 Slightly more than one-half of the combined tumors were invasive ductal carcinomas with a tubular carcinoma component. Combinations with invasive lobular carcinoma were detected in 6% of the tumors. Tumors with such combined morphology can either exhibit “hybrid” morphology or show a “mixed” pattern of two (or more) well-defined histologic types. A study by Rakha et al.6 described the “biologic and clinic characteristics of breast carcinoma with mixed ductal and lobular morphology.” The 140 tumors alleged to have “mixed” morphology based on histologic examination alone were 3.6% of all cases studied. However, the identification of a lobular component was evidently not substantiated by the use of the E-cadherin stain in all cases since “absent or reduced E-cadherin” was found only in 70% (47 cases) of the tumors tested. It is clear from this study and many previously cited in the literature that there is a need to reassess carcinomas classified as invasive ductal
carcinoma, mixed type with the growing number of markers associated with specific types of carcinoma in an effort to develop a more meaningful subclassification of this heterogeneous entity.
carcinoma, mixed type with the growing number of markers associated with specific types of carcinoma in an effort to develop a more meaningful subclassification of this heterogeneous entity.
Thus far, no significant prognostic differences have been identified for most of the combined histologic patterns, and, as a consequence, they have frequently been grouped together as invasive ductal carcinoma, NOS. This section considers invasive ductal carcinoma in the context of this broad definition. Reference will be made to specific combined histologic patterns wherever relevant, in this and in other chapters.
DCIS IN INVASIVE DUCTAL CARCINOMA
The growth pattern of a coexisting intraductal component is usually reflected in the structure of the invasive carcinoma. There is a significant association between the grade of DCIS and invasive ductal carcinoma in tumors that have both components.7 This observation suggests that important prognostic features of the tumor are established in the preinvasive stage and that the clinical course may possibly be predetermined by the component before invasion occurs. Studies of genetic alterations in the intraductal and invasive components of individual tumors have also shown similar patterns of loss of heterozygosity (LOH) in both parts, a finding which further supports this hypothesis.
Tubular carcinoma almost always arises from an orderly micropapillary and/or cribriform DCIS that features cytologically low-grade nuclei and can be associated with classical type of lobular carcinoma in situ (LCIS). The intraductal component of medullary carcinoma is typically solid with high-grade nuclei. Invasive poorly differentiated ductal carcinoma tends to develop from solid intraductal carcinoma, with or without necrosis. Comedo-type necrosis may occur in invasive areas of a tumor with high-grade solid DCIS duplicating the intraductal pattern. It can be difficult to distinguish between intraductal and invasive components in such tumors. Foci that resemble DCIS with central necrosis can be encountered in metastatic lesions derived from such tumors.8
Moderately differentiated invasive ductal carcinoma most often originates from cribriform or papillary intraductal components. Invasive cribriform carcinoma is a subtype of invasive ductal carcinoma with a prominent cribriform structure. These tumors arise from cribriform DCIS. The presence of invasive components that mimic cribriform intraductal carcinoma can complicate the measurement of the invasive tumor area, and foci with an in situ cribriform pattern can occur in metastatic lesions. Invasive carcinomas that are entirely cribriform and those with a mixture of cribriform and tubular components are relatively low grade and have an excellent prognosis. If less-well-differentiated elements are present in the tumor, the prognosis is not as favorable. Invasive cribriform carcinoma is sometimes mistaken for AdCC.9
THE COMPLEXITY OF ASSESSING PROGNOSIS
Prognostic and Predictive Factors
Breast carcinoma is a clinically and pathologically heterogeneous disease. As noted by Sistrunk and MacCarty10 decades ago, “it is impossible to foretell the duration of life of all patients with carcinoma of the breast, because the degree of malignancy varies widely, and persons react differently to the disease.”
Innumerable studies have attempted to assess the prognosis of breast carcinoma patients on the basis of clinical and pathologic parameters, and several recommendations for the use of various prognostic and predictive factors from various groups have appeared in recent years.11,12,13 These and other recommendations regarding prognostic and predictive factors represent the current state of knowledge at the time of publication, based on an analysis of existing data in relation to use in clinical practice, especially for planning therapy and during clinical follow-up. Some factors are recommended and others are not by various organizations and institutions that supported these reviews, but there is not necessarily unanimity in the recommendations set forth in the different documents. And sometimes the conclusion in a report about a particular maker is not clear cut. This latter point is illustrated by the discussion of “flow cytometry-based proliferation markers” in recommendations published by the American Society of Clinical Oncology (ASCO) in 2007.11 In summary, the document states that “data are insufficient to recommend use of DNA content, S-phase, or other flow cytometry-based markers of proliferation to assign patients to prognostic groupings.” Reading further in this section, it becomes apparent that this conclusion was based at least, in part, on concern over “technical variation in flow cytometry determination of S-phase,” but “if the flow cytometry-determined S-phase is determined using a validated method, in a laboratory with experience using the technique, it appears that an elevated S-phase fraction (SPF) is associated with a worse outcome.” In contrast to the ASCO 2007 recommendations that did not specify the types of specimens analyzed for markers, Rakha and Ellis12 emphasized the reliability of needle core biopsy samples for the assessment of selected markers, including flow cytometry, for the determination of proliferative activity.
A prognostic factor is a characteristic that can be used to estimate the chance of recovery from a disease or its recurrence (e.g., size of tumor), whereas a predictive factor is a characteristic that can be used to help predict the response of a particular tumor to a specific treatment (e.g., human epidermal growth factor 2 [HER2]). Because nearly threefourths of the patients have invasive ductal carcinoma, the characteristics of these tumors have a considerable influence on laboratory, clinical, or pathologic studies of breast carcinoma. The emerging prognostic value of multigene expression assays including Oncotype DX and the 70-gene prognostic signature developed by investigators from Amsterdam will be addressed in Chapter 45.
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Race
Data relating race to prognosis have mainly compared African American and White patients. Overall, African American women have a lower incidence of breast carcinoma than White women; however, the incidence is higher among African American women younger than 40 than among White women in the same age group, and the incidence is reversed in women older than 40.14,15 African American patients were more likely to have larger tumors and tumors with necrosis. Analysis of a national database composed of more than 115,000 breast carcinoma patients by Edwards et al.16 revealed that when compared with Whites African American women had a reduced likelihood of cure and had a shorter survival after diagnosis in those who were not cured.
Heterogeneity
The issue of heterogeneity of breast carcinoma was summarized by Heimann and Hellman17:
The varied outcomes of similarly staged patients is most consistent with breast cancer not being a homogeneous disease, but rather a spectrum of disease states that have varying capacities for growth and metastasis ….Required of tumors is the development of critical phenotypic attributes: growth, invasion, metastagenicity, and angiogenesis…. Recognizing tumor heterogeneity emphasizes the need to determine an individual tumor’s place in the evolutionary spectrum. This may be accomplished using clinical features such as size, nuclear grade, and patient age, as well as by examining angiogenesis, metastatic capacity, and proliferation. Identification of the extent of tumor progression with regard to these major tumor phenotypes should allow individual therapy to be fashioned for each patient.
In a subsequent report, Heimann and Hellman18
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