EDITORIAL Section Editor Tilde Kline
Prognostic Factors in Breast Cancer: Integrating the Cytology Laboratory Ann D. Thor, M.D.
Surgical, chemotherapeutic, and radiotherapeutic options for breast cancer patients have changed significantly in the last 3 decades. Limited surgical approaches, radiotherapy, adjuvant and neoadjuvant chemotherapy, and most recently, bone marrow transplantation have revolutionized the primary treatment of this common malignancy. Because no one of these treatment modalities is appropriate for all patients, there has been an intense search for prognostic markers that can help to identify patients who might benefit the most from available treatment options. Regrettably, the medical literature dealing with the subject of prognostic markers in breast cancer is overwhelming in volume, sensational in tone, conflicting with regards to conclusions, and lacking in clear guidelines to assist in their appropriate implementation. In addition, issues related to cost, tissue allocation for standard as well as innovative tests, and medical and legal responsibility for those tests utilized have yet to be fully resolved. Together, these many factors have combined to make a seemingly straightforward subject complex and confusing. Furthermore, if my experience is representative, both pathologists and clinicians are being called by anxious patients seeking results from innovative prognostic marker assays that may or may not have been performed on their tumors. Cytologists and pathologists are pivotal in the examination, diagnosis, and allocation of breast cancer cells and/ or tissue. Although the personnel working in cytology laboratories are currently pulled in many directions, the increasing emphasis on cytologic techniques to diagnose breast cancer requires that cytologists become familiar with emerging concepts in this area, so that they may help patients and clinicians make the most informed decisions concerning their many treatment options.
National guidelines for the use of prognostic markers in breast cancer were developed at the Consensus Conference on Early Stage Breast Cancer convened by the National Institutes of Health in 1990. The conference was determined by a diverse panel of experts that heard testimony from scientists, physicians (including cytopathologists), patient advocates, and others. Briefly, 3 characteristics of useful prognostic markers were identified. Each marker should exhibit significant and independent predictive value, validated by clinical testing (i.e., they should not be implemented solely on the basis of retrospective data analysis); the tests involved should be feasible, reproducible, widely available, and subject to quality control; and they should provide data which is readily interpretable by the clinician with therapeutic implications. A subsequently proposed characteristic, particularly applicable to cytology laboratories because of the small samples which they receive, is that the measurement of a factor should not consume tumor needed for other tests, particularly careful cytologic and/or histologic analysis. The conference also sought to deal with the difficult question of which prognostic tests currently fulfill these criteria and therefore should be accepted as standards of care. Six prognostic markers were recognized, including the presence or absence of lymph node metastases, tumor size, nuclear grade, steroid receptor content, histologic tumor type, and cellular proliferation rate. Of these, the first 2 are difficult to determine on cytologic samples. The last 4, however, may be determined by using cytologic samples and should be evaluated by cytologists whenever possible. This is particularly true for those cases where chemotherapy or radiation therapy will be given prior to surgery (i.e., when the surgical specimen may not provide material suitable for factor determination).
Received April 10, 1992. Accepted April 14, 1992. From the Department of Pathology, Massachusetts General Hospital, Boston, MA. Address reprint requests to Ann D. Thor, M.D., Department of Pathology, Massachusetts General Hospital, Fruit Street, Boston, M A 021 14.
Tumor Grade
@I
1992 WILEY-LISS, INC
Several histologic grading schemes have been proposed for grading breast carcinomas. These have generally included architectural cellular arrangement, nuclear features, and Diagnostic Cytoputhology, Vol 8,No 4
319
THOR
mitotic rate, or any combination of the above. Despite the unfortunate lack of consensus about which scheme is superior and the reported interpathologist variability no matter which system is used, the Surveillance, Epidemiology, and End Result (SEER) data from the N I H has shown that breast tumor grading has prognostic significance. The Consensus Conference recommendation that nuclear grade be evaluated is relevant for cytologists. Nuclear grade can be assigned on cytologic specimens aspirated from primary breast cancers. Until a standardized scheme is accepted, a I-III/III nuclear grading system (I for well differentiated, I11 for poorly differentiated) can be utilized for cytology preparations. Grade I nuclei are small, regularly shaped, with inconspicuous nucleoli, delicate chromatin, and only rare mitotic figures. Usually, only about 5 percent of invasive ductal carcinomas, not otherwise specified, fall into this category. Grade I11 nuclei are irregularly shaped, with prominent nucleoli, condensed chromatin, and numerous mitotic figures. Grade I1 tumor nuclei are those with features that lie between Grade I and 111.
Steroid Receptor Analysis Steroid receptors have been routinely determined on surgically resected primary breast cancers since the late 1970s. Receptor-containing tumors have a better shortterm prognosis, although the magnitude of this difference is relatively small (8-10% difference in recurrence rate for node-negative patients at 5 years). Long-term relapse and survival rates between receptor-positive and -negative tumor patients, however, are similar. Despite this, steroid receptor assays are often used to guide therapy, because patients whose tumors have estrogen receptors are most likely to respond to tamoxifen or other forms of hormonal modulation. Therefore, determination of steroid receptors on cytologic preparations of primary breast tumors is appropriate if surgical resection will not be performed or if presurgical chemotherapy or radiotherapy will be given. Receptor determination may also be warranted on tumor metastases if the steroid receptor status was not determined on the primary tumor. Recently developed enzyme linked immunochemical assays for estrogen and progesterone receptors are particularly useful on cytology preparations.
Cancer Subtyping Tumor subtyping has recognized prognostic significance in breast cancer. Ten to 30% of invasive ductal carcinomas are of a special type, many of which can be recognized on cytology preparations. Three of these were recognized by the 1990 N I H Consensus Conference as having a favorable prognosis, the tubular, colloid, and papillary variants. Tubular carcinomas are relatively rare (3-5% of 320
Diagnostic Cytopathoiogy, Vol 8, No 4
all breast cancers), well-differentiated lesions whose cytologic features have recently been reviewed. Patients with relatively pure tubular carcinomas may not require mastectomy or axillary dissection, and some feel that a local excision without concomitant radiation therapy may be sufficient. Whenever suspected, this information may be of therapeutic and prognostic utility, and should be conveyed on the cytology report. Familiarity with this subtype is imperative because it can easily be misdiagnosed as a benign epithelial proliferation. Colloid and papillary carcinomas may also be identified on cytology preparations and, if recognized, should be reported as such. Invasive lobular carcinomas comprise 5-10% of breast cancers and are more often multicentric in the same or opposite breast. These tumors carry the same overall prognosis as invasive ductal carcinomas, although they have a somewhat different pattern of metastatic spread. The lobular subtype can often be recognized using cytology cell preparations, and if suspected should be documented because of potential surgical and biologic implications. Confirmation of these subtypes using histologic criteria on surgically resected tissue is usually recommended whenever possible because of tumor heterogeneity and the limited sample examined by the cytology laboratory.
Proliferation Rate The cellular proliferation rate is the most recently accepted prognostic marker for breast carcinoma. Cells may be in a resting phase known as G o, or may enter the cell replication process at G I , with progression to the phases known as S ( D N A synthesis), G,, and M (mitosis). Mitotic rate, which is not easily evaluated on the limited sample submitted for cytology, identifies those cells undergoing mitosis. Other techniques that estimate the percentage of cells in S phase include flow cytometry, thymidine (or thymidine analog) uptake, and immunohistochemical detection of proliferation associated antigens such as Ki67 or PCNA/cyclin. Of these, flow cytometry or immunohistochemical detection of proliferation associated antigens are the tests most applicable to cytology samples. Some measure of cellular proliferation should be performed on either the surgically resected primary breast carcinoma or cytology samples derived from it. Data interpretation requires historical data on primary breast carcinomas of various subtypes using the same technique in the same laboratory. The proliferation rate estimates which are derived using each of the methodologies listed above are related but not directly comparable.
Clinical Integration of Prognostic Marker Data In a recent issue of the Journal of the National Cancer Institute, “therapeutic modeling” using prognostic markers was discussed in detail.4 Three steps were suggested for clinical integration of prognostic data, including (1)
PROGNOSTIC FACTORS IN BREAST CANCER
analysis of a given patient’s risk of recurrence and survival based on historical outcome and multiple prognostic factors; (2) identification of various treatment options and their potential therapeutic benefit and risk; and (3) an overall assessment of the expected benefit, risks, cost, and other personal factors which might influence treatment decisions and outcome. In short, determination of prognostic factors on breast cancers with subsequent utilization of that data to make therapeutic decisions and predict outcome is complicated but feasible. There is compelling literature which shows that the 6 prognostic markers recognized by the 1990 Consensus Conference should be determined, whenever possible, by the physicians (surgeons, pathologists) who diagnose new breast cancer cases. There is a less established but equally compelling literature which supports the utilization of these prognostic data in the therapeutic decision making process which occurs with each new patient.24 Of particular concern are the unproven prognostic markers which are offered as commercially available tests by a variety of reference laboratories. Often these unproven assays are coupled with the classic prognostic factors, such as steroid receptors, and are offered as a breast panel. Regrettably, this packaging has lured many pathologists into assuming that these are reliable tests with clinical utility, when in fact neither the pathologist or the reference laboratory knows how to interpret data which is obtained. Furthermore, the patient or their insurance are charged for unnecessary tests which are often quite expen-
sive, and there is a risk that data will be utilized to make clinical decisions. In conclusion, cytologists and pathologists must be critical in their evaluation and clinical utilization of prognostic markers for breast cancer. For the time being, perhaps the most prudent path to follow is the recommendation by the NIH convened panel of experts. Lymph node metastases and tumor grade, subtype, proliferation rate, size, and steroid receptor data should be reported whenever possible on pathology or cytology reports.
References 1. N I H Consensus Conference: Treatment of Early Stage Breast Cancer. JAMA 1991;265:391-5. 2. Page DL. Prognosis and breast cancer-Recognition of lethal and favorable prognostic types. Am J Surg Pathol 1991;15:334-49. 3. Hensen DE, Reis L, Freedman LS, Carriaga M. Relationship among outcome, stage of disease, and histologic grade for 22,616 cases of breast cancer: The basis for a prognostic index. Cancer 1991;68: 2142-9. 4. McGuire WL, Tandon AK, Allred DC, Chamness GC, Clark GM. How to use prognostic factors in node negative breast cancer patients. J Natl Cancer Inst 1990;82:1006-15. 5. Henderson IC, Harris JR, Kinne DW, Hellman S. Cancer of the breast. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. CancerPrincipals and practice of oncology. Philadelphia: JB Lippincott, 1989:1197-268. 6. Bondeson L, Lindholm K. Aspiration cytology of tubular breast carcinoma. Acta Cytol 1989;34: 15-20. 7. Baker RR. Unusual lesions and their management. Surg Clin North Am 1990;70:963-75. 8. Vielh P. Guides to clinical aspiration biopsy: Flow cytometry. New York: Igaku-Shoin, 1991.
Diagnostic Cytopathology, Vol 8, No 4
32 1
Prognostic Factors in Breast Cancer: Integrating the Cytology Laboratory Ann D. Thor, M.D.
Surgical, chemotherapeutic, and radiotherapeutic options for breast cancer patients have changed significantly in the last 3 decades. Limited surgical approaches, radiotherapy, adjuvant and neoadjuvant chemotherapy, and most recently, bone marrow transplantation have revolutionized the primary treatment of this common malignancy. Because no one of these treatment modalities is appropriate for all patients, there has been an intense search for prognostic markers that can help to identify patients who might benefit the most from available treatment options. Regrettably, the medical literature dealing with the subject of prognostic markers in breast cancer is overwhelming in volume, sensational in tone, conflicting with regards to conclusions, and lacking in clear guidelines to assist in their appropriate implementation. In addition, issues related to cost, tissue allocation for standard as well as innovative tests, and medical and legal responsibility for those tests utilized have yet to be fully resolved. Together, these many factors have combined to make a seemingly straightforward subject complex and confusing. Furthermore, if my experience is representative, both pathologists and clinicians are being called by anxious patients seeking results from innovative prognostic marker assays that may or may not have been performed on their tumors. Cytologists and pathologists are pivotal in the examination, diagnosis, and allocation of breast cancer cells and/ or tissue. Although the personnel working in cytology laboratories are currently pulled in many directions, the increasing emphasis on cytologic techniques to diagnose breast cancer requires that cytologists become familiar with emerging concepts in this area, so that they may help patients and clinicians make the most informed decisions concerning their many treatment options.
National guidelines for the use of prognostic markers in breast cancer were developed at the Consensus Conference on Early Stage Breast Cancer convened by the National Institutes of Health in 1990. The conference was determined by a diverse panel of experts that heard testimony from scientists, physicians (including cytopathologists), patient advocates, and others. Briefly, 3 characteristics of useful prognostic markers were identified. Each marker should exhibit significant and independent predictive value, validated by clinical testing (i.e., they should not be implemented solely on the basis of retrospective data analysis); the tests involved should be feasible, reproducible, widely available, and subject to quality control; and they should provide data which is readily interpretable by the clinician with therapeutic implications. A subsequently proposed characteristic, particularly applicable to cytology laboratories because of the small samples which they receive, is that the measurement of a factor should not consume tumor needed for other tests, particularly careful cytologic and/or histologic analysis. The conference also sought to deal with the difficult question of which prognostic tests currently fulfill these criteria and therefore should be accepted as standards of care. Six prognostic markers were recognized, including the presence or absence of lymph node metastases, tumor size, nuclear grade, steroid receptor content, histologic tumor type, and cellular proliferation rate. Of these, the first 2 are difficult to determine on cytologic samples. The last 4, however, may be determined by using cytologic samples and should be evaluated by cytologists whenever possible. This is particularly true for those cases where chemotherapy or radiation therapy will be given prior to surgery (i.e., when the surgical specimen may not provide material suitable for factor determination).
Received April 10, 1992. Accepted April 14, 1992. From the Department of Pathology, Massachusetts General Hospital, Boston, MA. Address reprint requests to Ann D. Thor, M.D., Department of Pathology, Massachusetts General Hospital, Fruit Street, Boston, M A 021 14.
Tumor Grade
@I
1992 WILEY-LISS, INC
Several histologic grading schemes have been proposed for grading breast carcinomas. These have generally included architectural cellular arrangement, nuclear features, and Diagnostic Cytoputhology, Vol 8,No 4
319
THOR
mitotic rate, or any combination of the above. Despite the unfortunate lack of consensus about which scheme is superior and the reported interpathologist variability no matter which system is used, the Surveillance, Epidemiology, and End Result (SEER) data from the N I H has shown that breast tumor grading has prognostic significance. The Consensus Conference recommendation that nuclear grade be evaluated is relevant for cytologists. Nuclear grade can be assigned on cytologic specimens aspirated from primary breast cancers. Until a standardized scheme is accepted, a I-III/III nuclear grading system (I for well differentiated, I11 for poorly differentiated) can be utilized for cytology preparations. Grade I nuclei are small, regularly shaped, with inconspicuous nucleoli, delicate chromatin, and only rare mitotic figures. Usually, only about 5 percent of invasive ductal carcinomas, not otherwise specified, fall into this category. Grade I11 nuclei are irregularly shaped, with prominent nucleoli, condensed chromatin, and numerous mitotic figures. Grade I1 tumor nuclei are those with features that lie between Grade I and 111.
Steroid Receptor Analysis Steroid receptors have been routinely determined on surgically resected primary breast cancers since the late 1970s. Receptor-containing tumors have a better shortterm prognosis, although the magnitude of this difference is relatively small (8-10% difference in recurrence rate for node-negative patients at 5 years). Long-term relapse and survival rates between receptor-positive and -negative tumor patients, however, are similar. Despite this, steroid receptor assays are often used to guide therapy, because patients whose tumors have estrogen receptors are most likely to respond to tamoxifen or other forms of hormonal modulation. Therefore, determination of steroid receptors on cytologic preparations of primary breast tumors is appropriate if surgical resection will not be performed or if presurgical chemotherapy or radiotherapy will be given. Receptor determination may also be warranted on tumor metastases if the steroid receptor status was not determined on the primary tumor. Recently developed enzyme linked immunochemical assays for estrogen and progesterone receptors are particularly useful on cytology preparations.
Cancer Subtyping Tumor subtyping has recognized prognostic significance in breast cancer. Ten to 30% of invasive ductal carcinomas are of a special type, many of which can be recognized on cytology preparations. Three of these were recognized by the 1990 N I H Consensus Conference as having a favorable prognosis, the tubular, colloid, and papillary variants. Tubular carcinomas are relatively rare (3-5% of 320
Diagnostic Cytopathoiogy, Vol 8, No 4
all breast cancers), well-differentiated lesions whose cytologic features have recently been reviewed. Patients with relatively pure tubular carcinomas may not require mastectomy or axillary dissection, and some feel that a local excision without concomitant radiation therapy may be sufficient. Whenever suspected, this information may be of therapeutic and prognostic utility, and should be conveyed on the cytology report. Familiarity with this subtype is imperative because it can easily be misdiagnosed as a benign epithelial proliferation. Colloid and papillary carcinomas may also be identified on cytology preparations and, if recognized, should be reported as such. Invasive lobular carcinomas comprise 5-10% of breast cancers and are more often multicentric in the same or opposite breast. These tumors carry the same overall prognosis as invasive ductal carcinomas, although they have a somewhat different pattern of metastatic spread. The lobular subtype can often be recognized using cytology cell preparations, and if suspected should be documented because of potential surgical and biologic implications. Confirmation of these subtypes using histologic criteria on surgically resected tissue is usually recommended whenever possible because of tumor heterogeneity and the limited sample examined by the cytology laboratory.
Proliferation Rate The cellular proliferation rate is the most recently accepted prognostic marker for breast carcinoma. Cells may be in a resting phase known as G o, or may enter the cell replication process at G I , with progression to the phases known as S ( D N A synthesis), G,, and M (mitosis). Mitotic rate, which is not easily evaluated on the limited sample submitted for cytology, identifies those cells undergoing mitosis. Other techniques that estimate the percentage of cells in S phase include flow cytometry, thymidine (or thymidine analog) uptake, and immunohistochemical detection of proliferation associated antigens such as Ki67 or PCNA/cyclin. Of these, flow cytometry or immunohistochemical detection of proliferation associated antigens are the tests most applicable to cytology samples. Some measure of cellular proliferation should be performed on either the surgically resected primary breast carcinoma or cytology samples derived from it. Data interpretation requires historical data on primary breast carcinomas of various subtypes using the same technique in the same laboratory. The proliferation rate estimates which are derived using each of the methodologies listed above are related but not directly comparable.
Clinical Integration of Prognostic Marker Data In a recent issue of the Journal of the National Cancer Institute, “therapeutic modeling” using prognostic markers was discussed in detail.4 Three steps were suggested for clinical integration of prognostic data, including (1)
PROGNOSTIC FACTORS IN BREAST CANCER
analysis of a given patient’s risk of recurrence and survival based on historical outcome and multiple prognostic factors; (2) identification of various treatment options and their potential therapeutic benefit and risk; and (3) an overall assessment of the expected benefit, risks, cost, and other personal factors which might influence treatment decisions and outcome. In short, determination of prognostic factors on breast cancers with subsequent utilization of that data to make therapeutic decisions and predict outcome is complicated but feasible. There is compelling literature which shows that the 6 prognostic markers recognized by the 1990 Consensus Conference should be determined, whenever possible, by the physicians (surgeons, pathologists) who diagnose new breast cancer cases. There is a less established but equally compelling literature which supports the utilization of these prognostic data in the therapeutic decision making process which occurs with each new patient.24 Of particular concern are the unproven prognostic markers which are offered as commercially available tests by a variety of reference laboratories. Often these unproven assays are coupled with the classic prognostic factors, such as steroid receptors, and are offered as a breast panel. Regrettably, this packaging has lured many pathologists into assuming that these are reliable tests with clinical utility, when in fact neither the pathologist or the reference laboratory knows how to interpret data which is obtained. Furthermore, the patient or their insurance are charged for unnecessary tests which are often quite expen-
sive, and there is a risk that data will be utilized to make clinical decisions. In conclusion, cytologists and pathologists must be critical in their evaluation and clinical utilization of prognostic markers for breast cancer. For the time being, perhaps the most prudent path to follow is the recommendation by the NIH convened panel of experts. Lymph node metastases and tumor grade, subtype, proliferation rate, size, and steroid receptor data should be reported whenever possible on pathology or cytology reports.
References 1. N I H Consensus Conference: Treatment of Early Stage Breast Cancer. JAMA 1991;265:391-5. 2. Page DL. Prognosis and breast cancer-Recognition of lethal and favorable prognostic types. Am J Surg Pathol 1991;15:334-49. 3. Hensen DE, Reis L, Freedman LS, Carriaga M. Relationship among outcome, stage of disease, and histologic grade for 22,616 cases of breast cancer: The basis for a prognostic index. Cancer 1991;68: 2142-9. 4. McGuire WL, Tandon AK, Allred DC, Chamness GC, Clark GM. How to use prognostic factors in node negative breast cancer patients. J Natl Cancer Inst 1990;82:1006-15. 5. Henderson IC, Harris JR, Kinne DW, Hellman S. Cancer of the breast. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. CancerPrincipals and practice of oncology. Philadelphia: JB Lippincott, 1989:1197-268. 6. Bondeson L, Lindholm K. Aspiration cytology of tubular breast carcinoma. Acta Cytol 1989;34: 15-20. 7. Baker RR. Unusual lesions and their management. Surg Clin North Am 1990;70:963-75. 8. Vielh P. Guides to clinical aspiration biopsy: Flow cytometry. New York: Igaku-Shoin, 1991.
Diagnostic Cytopathology, Vol 8, No 4
32 1
