College of American Pathologists
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  Q & A





May 2008

Question Q. Should estrogen receptor and progesterone receptor status be routinely determined in cases of pure ductal carcinoma in situ, or DCIS?

A. Estrogen receptor, or ER, status for DCIS may be evaluated for multiple reasons. The primary use of this information is to determine if patients with DCIS would benefit from hormonal therapy.

Two studies have addressed outcomes for patients with DCIS who were treated with tamoxifen. Both studies showed that fewer women in the tamoxifen-treated group developed subsequent breast cancers—18 percent versus 14 percent in the United Kingdom/Australia/New Zealand study1 and 13.4 percent versus 8.2 percent in the NSABP B-24 study.2 However, this result was statistically significant only in the NSABP B-24 study. It is possible that the younger age of the patients in the latter study could have influenced these results, as a smaller benefit was observed in women over the age of 50. There was no benefit for survival in either study.

A subsequent analysis of ER status for DCIS in a subset of patients in the NSABP B-24 study showed that the reduction in subsequent breast cancers was greatest for women with ER-positive DCIS who were treated with tamoxifen.3 Little benefit was found in women with ER-negative DCIS, but due to the small number of events, a small clinically significant benefit was not excluded.

The Update Committee of the American Society of Clinical Oncology recently concluded that current data are insufficient to make a general recommendation for the use of ER status of DCIS to make decisions about tamoxifen treatment.4 Nonetheless, individual clinicians may find this information helpful for advising patients about hormonal treatment.

In addition to considerations for hormonal treatment, information about ER, progesterone receptor, and HER2/neu status in DCIS may be useful for other reasons in some settings. As in invasive carcinoma, these three markers may identify different types of DCIS, including ER-positive, HER2/neu-positive, and “triple-negative” cancers.5, 6 For invasive cancers, these immunoprofiles identify groups with different prognoses and responses to treatments. Ongoing studies are evaluating whether these markers will be helpful in determining the best treatment for DCIS. For example, one study found that the ER-positive/PR-negative/ HER2/ neu-positive profile was found in only nine percent of cases of DCIS, but accounted for half of the recurrences.7 Since invasive recurrences, in general, have a similar immunoprofile as the prior DCIS,8, 9 this information may be helpful for some patients and clinicians in making decisions about local treatment that could affect the likelihood of such a recurrence (for example, deciding between breast conservation and mastectomy). In addition, there are also ongoing treatment protocols for DCIS that require marker information for entry—for example, neoadjuvant treatment of patients with lapatinib for HER2/neu-positive DCIS.

Because ER, PR, and HER2/neu status in DCIS is used for investigational protocols and not for diagnosis (except in some cases, such as to help distinguish Toker cells in nipple skin from Paget disease cells), determination of ER, PR, and HER2/neu for DCIS is not routinely required for all patients at this time. The decision to perform these markers on cases of DCIS should be made in conjunction with the clinicians who will use this information.

Susan Lester, MD, PhD
Department of Pathology
Brigham and Women’s Hospital

Patrick L. Fitzgibbons, MD
Department of Pathology
St. Jude Medical Center
Fullerton, Calif.

Monica E. de Baca, MD
Physicians Laboratory
Sioux Falls, SD

Yunn-Yi Chen, MD, PhD
Department of Pathology
UCSF Medical Center
San Francisco

Shikha Bose, MD
Department of Pathology
Cedars-Sinai Medical Center
Los Angeles

Members of the CAP
Cancer Committee
Breast Cancer Review Panel

  1. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;362:95–102.
  2. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999;353:1993–2000.
  3. Allred DC, Bryant J, Land S, et al. Estrogen receptor expression as a predictive marker of the effectiveness of tamoxifen in the treatment of DCIS: findings from NSABP Protocol B-24 [abstract]. Presented at: 25th Annual San Antonio Breast Cancer Symposium; Dec. 11–14, 2002; San Antonio, Tex.
  4. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287–5312.
  5. Bryan BB, Schnitt SJ, Collins LC. Ductal carcinoma in situ with basal-like phenotype: a possible precursor to invasive basal-like breast cancer. Mod Pathol. 2006;19:617–621.
  6. Steinman S, Wang J, Bourne P, et al. Expression of cytokeratin markers, ER-­alpha, PR, HER-2/neu, and EGFR in pure ductal carcinoma in situ (DCIS) and DCIS with coexisting invasive ductal carcinoma (IDC) of the breast. Ann Clin Lab Sci. 2007;37:127–134.
  7. Kepple J, Henry-Tillman RS, Klimberg VS, et al. The receptor expression pattern in ductal carcinoma in situ predicts recurrence. Am J Surg. 2006;192:68–71.
  8. Bijker N, Peterse JL, Duchateau L, et al. Histological type and marker expression of the primary tumour compared with its local recurrence after breast-conserving therapy for ductal carcinoma in situ. Br J Cancer. 2001;84:539–544.
  9. Idvall I, Ringberg A, Anderson H, et al. Histopathological and cell biological characteristics of ductal carcinoma in situ (DCIS) of the breast—a comparison between the primary DCIS and subsequent ipsilateral and contralateral tumours. Breast. 2005;14:290–297.

Question Q. What do you think of doing HER2/neu testing on ductal carcinoma in situ?

A. The purpose of HER2/neu testing is to determine the feasibility of systemic treatment with Herceptin and/or high-dose Adriamycin. That being said, neither of these treatments is currently indicated in intraductal carcinoma. There is therefore no role for routine HER2/neu testing in cases of pure intraductal carcinoma. Ironically, though, it was first described in intraductal carcinoma and is essentially limited to high nuclear grade lesions. The current American Society of Clinical Oncology/CAP guidelines recommend only testing invasive carcinoma and only reading the staining of invasive carcinoma when DCIS is also present (though there is typically strong concordance between the two) (Wolff AC, Hammond ME, Schwartz JN, et al. Arch Pathol Lab Med. 2007;131:18–43).

Ira J. Bleiweiss, MD
Professor of Pathology
Director of Surgical Pathology
Director, Division of Breast Pathology
Mount Sinai Medical Center
New York

Question Q. A six-sample needle biopsy was done on a patient who had a prostate-specific antigen (total) of 4.6 ng/mL. Two weeks after the biopsy, the PSA was again tested and was 1.6 ng/mL and 1.7 ng/mL on duplicate runs. Can you explain what happened?

A. Assuming that the same PSA test methodology was used for all of the pre- and post-biopsy determinations, and that the pre-biopsy value of 4.6 ng/mL was not in error, then the explanation is intrapatient PSA variability.

In perhaps as many as 10 percent of men who have a serum PSA value of greater than 4.0 ng/mL, we can see repeat serum PSA determinations of less than 2.0 ng/mL. In one case that I can recall as giving the greatest variability, a patient’s serum PSA ranged from 2.0 to 8.4 ng/mL, and he was found to be cancer-negative after two sets of 10 core biopsies. We have never seen the degree of serum PSA variability shown by the subject in question occur in men who are diagnosed with prostate cancer. This serum PSA variability is probably due to the presence of asymptomatic prostatitis.

So, if a prostate biopsy is to be done on the basis of an elevated serum PSA, our recommendation is to confirm the elevated serum PSA value before the biopsy is performed with one or two subsequent PSA measurements to confirm the presence of a stable, elevated PSA value.

Herbert A. Fritsche, PhD
Chief of Clinical Chemistry and
Professor of Laboratory Medicine
The University of Texas
M.D. Anderson Cancer Center

Question Q. As units of red blood cells and other blood products are issued as emergent releases, they are issued with emergency release forms that require the ordering physician’s signature. Usually only licensed nursing personnel (and, of course, physicians) are permitted to have these products issued to them by the blood bank staff. Secretaries, clerks, and other patient-care assistants are not allowed to pick up such products. What is the reasoning behind this practice?

A. To respond to your inquiry, I first reviewed the applicable regulations and requirements pertaining to emergent release of blood products. Several are listed here for reference:

  • CAP TRM.40770
    Have adequate policies and procedures been established for the investigation and handling of life-threatening situations . . . that include the documented authorization of a qualified physician?
  • 21CFR606.151 (e)
    Records of all such incidents shall be maintained, including complete documentation justifying the emergency action, which shall be signed by a physician.
  • 21CFR606.160 (b)(3)(v)
    Emergency release of blood, including signature of requesting physician obtained before or after the release.

In essence, these require justification by a physician that the need for transfusion was immediate and outweighed the risks of transfusing blood prior to the completion of testing. The transfusion service must then have policies and procedures in place to ensure that a rapid response is available in these situations and that appropriate documentation exists for each episode.

Methods to ensure documentation of need vary among institutions. Some facilities opt to dispense products only after receipt of a form signed by a physician. Thus, they have documentation in hand before the blood components are released. Other facilities will issue the blood on a verbal order before a signed order is received. In such situations, the transfusion service should ensure appropriate justification is present by maintaining close communication with the clinical team. One method may be to dispense blood only to a licensed caregiver. The emergency release form is then issued along with the blood, with instructions provided to the clinical staff that the form must be signed and returned as soon as possible. If staffing levels are adequate, transfusion service personnel may opt to deliver the blood to the patient-care area. This allows for a direct handoff to the clinical team, and a signature can be obtained before returning to the laboratory. Both scenarios allow for timely communication with the caregivers and assessment of the situation.

Given the size of a facility, the need for blood may require shipment via pneumatic tube system or provision of group O blood in a remote refrigerator. These scenarios, too, will require that procedures be developed to ensure close interaction and coordination with the transfusion service.

To determine the best approach for your facility, it is appropriate to review usage patterns, assess future needs, and outline available per­sonnel and transportation logistics. All applicable state and national regulations should be reviewed. Then, a meeting with key members of the clinical staff will be needed to develop channels of communication. A successful process will meet the patients’ needs in emergency situations and ensure compliance is maintained.

Lesley A. Kresie, MD
Medical Director, Laboratory Services
Carter BloodCare
Bedford, Tex.