ORIGINAL ARTICLE
Changes in Breast Cancer Reports after Pathology Second Opinion1 Vicente Marco, MD,* Teresa Muntal, PhD,* Felip Garcıa-Hernandez, MD,* na Gonzalez, RN,† and Isabel T Rubio, MD† Javier Cortes, MD,† Bego~ *Department of Pathology, Hospital Quiron Barcelona, Barcelona, Spain; †IOB, Hospital Quiron Barcelona, Barcelona, Spain
n Abstract: Breast cancer pathology reports contain valuable information about the histologic diagnosis, prognostic factors and predictive indicators of therapeutic response. A second opinion may be requested by medical oncologists and surgeons, when a patient is referred from another institution for treatment. We report the experience with pathology second opinion in selected patients referred to the Breast Oncology Unit. 205 cases referred to the Breast Oncology Unit were selected for second opinion after clinical evaluation, between 2002 and 2012. The cases reviewed included 102 core needle biopsies, 88 surgical specimens from the breast and 18 lymphadenopathies, 14 from the axillary region. Pathology second opinion was based on a review of hematoxylin-eosin preparations, recuts of submitted paraffin blocks and written external pathology reports. Immunohistochemical studies for hormone receptors, HER2, myoepithelial cells, and other markers were performed in selected cases. A case was reclassified as showing major change when second opinion showed a potential for significant change in prognosis or treatment. Otherwise, it was considered to represent minor change or to be concordant. In 52 cases (25.4%), the pathology review showed changes. Thirty-three (16%) patients were reclassified for major changes and 19 (9.2%) as minor changes. In six patients, more than one major change was identified. The major discrepancies identified were related to the histologic classification (12 cases), the presence or absence of invasion in ductal carcinoma (15 cases), the results of hormone receptors (5 cases), and HER2 (7 cases). Major changes in histologic classification included two cases diagnosed as invasive ductal carcinoma and reclassified as benign, four cases with diagnosis of breast cancer reclassified as metastatic lung cancer, one case diagnosed as small cell carcinoma of lung metastatic in the breast, reclassified as primary carcinoma of the breast, and three cases with diagnosis of breast cancer in the axilla reclassified as primary cutaneous adnexal carcinomas (2) and metastatic melanoma (1), respectively. In two cases, the histologic type of the primary breast tumor was changed. Second opinion in breast pathology may uncover significant discrepancies that impact on patient management and prognosis. Major discrepancies are most frequently related to the assessment of the presence or absence of invasion in ductal carcinoma, the results of predictive makers of therapeutic response, and the differential diagnosis of breast cancer and nonmammary tumors in the breast, the axilla, and at distant sites. n Key Words: breast cancer, pathology, second opinion
A
ccurate histologic diagnosis of breast cancer, and assessment of prognostic and markers of therapeutic response are of paramount importance (1). Current literature indicates that there are significant differences among pathologists in the reporting of breast cancer in some cases (2–7). Therefore, a second opinion in pathology may be requested, by clinicians, when a patient with a
Address correspondence and reprint requests to: Dr. Vicente Marco, Department of Pathology, Hospital Quiron Barcelona, Plaza Alfonso Comin 5-7, Barcelona 08023, Spain, or e-mail: [email protected] 1 Presented in an abstract form at the 102nd annual meeting of the United States and Canadian Academy of Pathology, Baltimore, March 2–8, 2013. DOI: 10.1111/tbj.12252 © 2014 Wiley Periodicals, Inc., 1075-122X/14 The Breast Journal, Volume 20 Number 3, 2014 295–301
diagnosis of breast cancer is referred from another hospital for diagnosis and treatment (8,9). The main issues of concern are the confirmation of the histologic diagnosis of breast cancer, the histologic type and grade, the status of the margins of resection, the results of hormone receptors and of HER2 (10,11). Also patients with a history of breast cancer may present with new lesions in the breast or in other organs that need to be histologically diagnosed and the markers of therapeutic response assessed (12). In breast cancer, secondary pathology review may have the greatest chance of optimizing treatment regimens, and an incorrect diagnosis may lead to unnecessary treatments especially in major histologic changes.
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We report on the experience with second opinion in breast pathology, in selected patients consulting the Breast Oncology Unit. METHODS Two hundred and five patients referred to the Breast Oncology Unit were selected for second opinion after clinical evaluation, between 2002 and 2012. The material reviewed included 102 core needle biopsies, 88 breast surgical specimens, and 18 lymph node biopsies, 14 of them from the axillary region. The slides and paraffin blocks were selected by the referring institutions and were thought to be representative of the pathologic features of each case concerned. In addition, in two patients with history of breast cancer, a brain biopsy, and a lung and pleural biopsy were reviewed, respectively. Pathology second opinion was based on review of hematoxylin-eosin (H&E) preparations, recuts of submitted paraffin blocks and written pathology reports. Immunohistochemical (IHC) studies for hormone receptors, HER2, and other markers were performed in selected cases. In some cases, the results of IHC studies performed by the referring hospital, and by the treating hospital were compared. Immunohistochemical was performed on 4-lm-thick sections cut from formalin-fixed, paraffin embedded tissue blocks using different antibodies on a Ventana Bechmark LT automated immunostainer (Ventana Medical Systems, Tucson, AZ) according to standard protocols. For identification of the myoepithelial layer in the differential diagnosis of invasive versus in situ carcinoma p63, cytoketatin 5-6, and cytokeratin 14 were most often used. Other antibodies used in the study included TTF-1, Napsin A, S100 protein, HMB-45, anti-D2-40 (podoplanin) and E-cadherin. For estrogen receptors, clone SP1 (Ventana) was used, and for progesterone receptors Clone PgR636 (Ventana). For HER2 IHC, the primary antibodies used were rabbit polyclonal, Dako K5307 and HER2 Pathway antibody (rabbit monoclonal clone 4B5; Ventana). The interpretation followed the American Society of Clinical Oncology/College of American Pathologists guidelines (negative 0/1+, indefinite 2+, and positive 3+) (13).
In selected cases, FISH (Path Vysion, Vysis, Downer Grove, IL) or SISH (Dual color ISH, Ventana) testing for HER2 was performed. The American Society of Clinical Oncology/College of American Pathologists scoring guideline criteria were used: Negative: HER2/CEN17 < 1.8, equivocal: 1.8 ≥ HER2/ CEN17 ≤ 2.2 and positive: HER2/CEN17 > 2.2 (13). For the cases reviewed prior to the publication the ASCO/CAP scoring guideline system, recommendations in the College of American Pathologists Consensus Statement 1999 were followed (14). RESULTS Concordant results were found in 153 patients (74.6%), and discrepancies were found in 52 patients (25.4%). Table 1 shows the diagnosis performed after second opinion review. Major discrepancies were identified in 33 patients (16%), and minor discrepancies in 19 patients (9.2%). Results of IHC studies for hormone receptors, estrogen and progesterone, could be compared in 72 cases, and for HER2 in 60 cases. Major Discrepancies (33 patients) The major discrepancies identified were related to the histologic diagnosis of the lesion (12 patients), the presence or absence of invasion in ductal carcinoma (15 patients), the result of hormone receptors (5 patients), and HER 2 results (7 patients) (Table 2). In six patients with major discrepancies, two changes were noted. Changes in Histologic Diagnoses (12 patients) In two patients, a diagnosis of invasive ductal carcinoma was changed to benign lesion. One case corresponded Table 1. Second Opinion Diagnoses in 205 Cases Histologic diagnosis Invasive ductal carcinoma, NOS Ductal carcinoma in situ Ductal carcinoma with microinvasion Breast carcinoma, special type Invasive lobular carcinoma In situ lobular carcinoma Other primary breast tumors (phyllodes, granular cell tumor, angiosarcoma) Benign and atypical breast lesions Tumors of nonmammary origin in breast, axilla, lymph node or distant organ (brain biopsy)
N (%) 122 15 4 19 13 1 5
(59.5) (7.3) (1.4) (9.6) (6.3) (0.5) (2.4)
17 (8.3) 9 (4.4)
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Table 2. Major Discrepancies after Second Opinion in 33 Patients First diagnosis Invasive breast cancer
Lung cancer metastasis to breast Changes in histologic type of primary breast tumor Invasive ductal carcinoma DCIS with microinvasion DCIS Estrogen receptor negative Estrogen receptor positive HER2 positive
Second opinion
N
Benign Lung cancer Cutaneous adnexal carcinoma Melanoma Primary breast cancer
2 4 2 1 1 2
DCIS DCIS with microinvasion DCIS DCIS with invasive carcinoma Estrogen receptor positive Estrogen receptor negative HER2 negative
8 2 2 3 4 1 7
(a)
(b)
to a needle core biopsy showing a fibroadenoma with sclerosing adenosis. The other case was a surgical biopsy showing apocrine adenosis with post-chemotherapy changes, thought to be recurrent carcinoma by the referring institution (Fig. 1). In both cases, markers of myoepithelium showed an intact myoepithelial layer in acini suspected to represent invasive carcinoma. In four patients, the diagnosis of breast cancer was changed to metastatic lung cancer after histologic and IHC evaluation, in biopsies of breast, brain and lymph node (2 cases), respectively. Three cases were adenocarcinomas with positive TTF-1 and Napsin A (Fig. 2), and the fourth was a large cell carcinoma of the lung diagnosed as triple negative breast cancer by the referring institution. Other changes included spindle cell carcinoma misdiagnosed as phyllodes tumor in a core needle biopsy, and ductal cribriform carcinoma diagnosed as adenoid-cystic carcinoma. A small cell carcinoma diagnosed in a breast biopsy was considered to represent metastasis of a primary lung carcinoma by the referring institution. However, after histologic review and clinicopathologic evaluation, it was considered to be a small cell carcinoma primary in the breast. A male patient with an axillary mass diagnosed as metastatic ductal carcinoma consistent with an occult breast cancer, was referred for chemotherapy treatment. Mastectomy performed at the referring institution showed no evidence of carcinoma. Histologic review of the axillary biopsy was diagnosed as primary cutaneous adnexal tumor of low malignant potential. Another male patient with a 7-cm mass in the right axilla was thought to have a metastatic
(c)
Figure 1. A 60-year-old woman with history of medullary carcinoma, showing a nodular lesion in the breast, thought to be recurrent carcinoma. H&E, 94 (a). The lesion shows tightly packed acini lined by cells with clear cytoplasm. H&E, 9100 (b). p63 shows preserved myoepithelial layer; 9200 (c). Second opinion diagnosis: Apocrine adenosis.
carcinoma of breast origin; upon histologic review and clinical evaluation, the case was diagnosed as primary apocrine carcinoma of sweat gland origin.
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(a)
(b)
(c)
IHC study was positive for S100 protein and HMB45. Review of a previous skin biopsy from the arm was considered to be diagnostic of melanoma. Changes in the Diagnosis of Ductal Carcinoma in situ, Microinvasive and Invasive (15 patients) Ten cases diagnosed as invasive ductal carcinoma (8 cases) or microinvasive (2 cases) were diagnosed upon review as ductal carcinoma in situ (DCIS), often associated with sclerosing lesions (Fig. 3). In three cases the diagnosis of DCIS was changed to invasive ductal carcinoma, measuring the invasive component from 2, 3, and 7 mm, respectively. In two cases, the diagnosis of invasive ductal carcinoma was changed to DCIS, with microinvasion measuring 1 mm or less. In these cases, ancillary IHC studies for detection of the myoepithelial layer were performed. Changes in the Result of IHC Evaluation of Estrogen Receptors and HER2 (12 patients) Seven cases were reported to show overexpression of HER2-neu (3+), however, expression was considered negative (0/1+) or indetermined (2+), with amplification studies being negative. Estrogen receptors reported negative by the referring hospitals, were found to be positive upon review in four cases. In one case the estrogen receptor reported as positive was negative in the second opinion study. Minor Discrepancies (19 patients)
Figure 2. A 37-year-old woman presenting with axillary mass, with first diagnosis of metastatic ductal carcinoma of breast on core needle biopsy. (a) The tumor shows nests of epithelial cells with signet ring configuration. H&E 9 200. Immunohistochemical study with TTF-1 (b) and Napsin A (c) was positive. Second opinion diagnosis was metastatic adenocarcinoma consistent lung primary.
A female patient with an axillary mass diagnosed initially as metastastic ductal carcinoma of the breast, was found to have metastatic melanoma upon review,
Changes in Histologic Diagnosis (11 cases) In four cases, the histologic type of carcinoma changed, without modifying significantly the prognosis or treatment. In one case the diagnosis of phyllodes tumor was further classified as malignant. A case of spindle cell sarcomas was classified as angiosarcoma postradiotherapy. In a mucinous carcinoma a high grade component was not identified. An invasive ductal carcinoma with pagetoid involvement of the nipple was diagnosed as invasive lobular carcinoma without nipple involvement. In three cases there was disagreement about the presence or absence of atypical ductal hyperplasia. Changes in Tumor Size and Grade (2 cases) The size of a DCIS changed from 10 mm to 5 mm. An invasive ductal carcinoma grade 2 was reclassified as grade 3 with microvascular invasion.
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(a)
(b)
Figure 3. A 46-year-old woman with diagnosis of invasive ductal carcinoma HER2 positive. Second opinion diagnosis: Ductal carcinoma in situ, HER2 negative. (a) Ductal carcinoma in situ showing irregular duct spaces mimicking invasion. H&E 9 100. (b) p63 shows preserved myoepithelial layer; 9100.
Changes in IHC not Significantly Modifying Management (6 cases) In four cases, there were discrepancies in the results of progesterone receptors. In two cases, the result of HER2 in DCIS changed from indeterminate (2+), to negative (1+) and positive (3+), respectively. DISCUSSION Significant discrepancies in breast pathology reports, represents a rather heterogeneous group of situations dependent on the selection criteria applied, i.e., if they are selected by pathologists because they are diagnostically challenging, by the medical oncologists or surgeons in order to confirm the diagnosis and prognostic/ predictive markers before considering additional treatment, or if a systematic review of every case referred to the treating institution is undertaken (9,15,16).
If cases are selected by pathologists, it is likely that problematic proliferative lesions covering the spectrum of hyperplasia, atypical ductal hyperplasia, DCIS, and microinvasion will predominate, as well as rare tumors and tumor-like lesions (16). In our study, most cases were selected by the medical oncologists, being interested in confirming the diagnosis of breast cancer, and the results of tumor markers, before chemotherapy or hormone therapy. The major discrepancies can be grouped in three categories. The first related to the histologic diagnosis of the lesion, the second to the presence or absence of invasion in ductal carcinoma, and the third to the results of IHC in the study of estrogen receptors and HER2. The category of histologic diagnosis included two benign lesions diagnosed as carcinoma, and cases of primary carcinoma of the breast with changes in the histologic subtype. However, it also included cases diagnosed as breast cancer that represented non mammary tumors, several of these diagnosed after reviewing lymph node biopsies or masses from the axillary region. In these cases histologic assessment of H&E slides, and IHC studies were of paramount importance. The distinction between breast cancer and carcinomas of nonmammary origin can be problematic. This problem may present in different clinical situations, i.e., tumors with unusual morphology presenting in the breast, tumors presenting in the axilla without an evident breast lesion, and patients with history of breast cancer, presenting a tumor at different organs. In these situations careful histologic evaluation and clinical correlation are needed to arrive to the correct diagnosis. IHC studies are important to confirm the origin of the tumor (12). Around 70% of primary tumors of the breast are ER positive, and 15% are HER2 positive. Tumors that more often enter in the differential diagnosis are malignant melanomas, carcinomas of the lung, prostate gland, gastrointestinal tract, and ovary, among others, for which useful histologic markers are available (S100, HMB-45,TTF-1, Napsin A, PSA, CDX-2, PAX-8 etc.). The origin of tumors presenting in the axilla may be challenging. They may represent metastases from occult primary breast tumors, but they also may be of nonmammary origin, as it occurred in our series. If they represent metastases from nonmammary origin adequate clinical history and IHC studies are important, and the possibility of primary origin in skin
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adnexa should be considered. Because primary skin adnexal tumors may be similar to breast tumors, histologically and in IHC studies, careful clinical evaluation and imaging studies should be performed (17,18). The changes in the diagnosis of invasion, microinvasion and DCIS account for the largest category in the present study. In a significant number of cases the main problem was related to the coexistence of DCIS and sclerosing lesions, mimicking invasion. In these cases, IHC study of markers of myoepithelium may help to better define the presence or lack of invasion (19). Microinvasive carcinoma as defined by the 1997 TNM criteria should have a dimension of 1 mm or less, and it occurs most often in the setting of DCIS or lobular carcinoma in situ. Several reports indicate that it tends to be overdiagnosed when DCIS is altered by sclerosing lesions and inflammation. The reported incidence of microinvasive carcinoma is less than 1% of all breast carcinomas, and is present in between 5% and 13.5% of DCIS cases. The recurrence rate is estimated to be 5.3%, and the incidence of lymph node metastases is low (2.8%) (20,21). Differences in the results of IHC studies of estrogen receptors and HER2 were found in five and seven cases, respectively. These changes significantly influence the choice of treatment in breast cancer. The importance of following adequate staining protocols and scoring system has been previously emphasized (10,11,13,22,23). The results of IHC studies in hormone receptors are influenced by different factors (fixation, type of antibody, and interpretation, among others). In the assessment of ER, the main problem relates to the identification of cases with a low percentage of positive cells, some of which may benefit from hormone treatment, the false-negative rate ranges from 30% to 60% (10). As for the study of HER2, there seems to be a high degree of agreement in cases that are negative (0/1+) or indeterminate (2+), however, the rate of false positive (3+) is considered to be high, around a 25% of the cases reviewed, as reported in the literature (22,23). The rate of major discrepancies after second opinion and pathology review reported in relevant literature varies. Staradub et al. in a study of 340 cases found complete agreement in only 20% and major changes in 7.8% (7).
Kennecke et al. in a review of 405 cases of node negative breast cancer patients found changes in 20% of the cases which resulted in treatment modifications among 25 patients (6%) (2). Newman et al. in a study including review of the pathology in 149 breast cancer patients found changes in 29% of the patients, which resulted in changes of surgical management in 9% (6). In conclusion, major discrepancies are most frequently related to the assessment of the degree of invasion of breast carcinoma and the result of IHC studies. However, the assessment of axillary lesions and distant metastasis in patients suspected of having breast cancer or with a history of treated breast cancer, may reveal nonmammary tumors. These patients represent a relevant group to consider for pathology review as these findings may severely affect the patient’s treatment and prognosis. Significant improvement in the concordance among pathologists in the assessment of breast cancer lesions can be achieved by careful histologic study, following standardized criteria, and using high quality IHC techniques. These will improve the results of markers of prognosis and therapeutic response, as well as the differential diagnosis between breast cancer and nonmammary breast tumors. REFERENCES 1. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Th€ urlimann B, Senn HJ, Panel members. Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011;22:1736–47. 2. Kennecke HF, Speers CH, Ennis CA, et al. Impact of routine pathology review on treatment for node-negative breast cancer. J Clin Oncol 2012;30:2227–31. 3. Kronz JD, Westra WH, Epstein JI. Mandatory second opinion surgical pathology at a large referral hospital. Cancer 1999; 86:2426–35. 4. Susan G. Komen for the Cure White Paper: June 2006. Why Current Breast Pathology Practices Must Be Evaluated. Available at: Ww5.Komen.org/uploded files/content_Binaries/PathologyWhite PaperB2.pdf (accessed March 8, 2014). 5. Masood S. Editorial. Raising the bar. A plea for standarization and quality improvement in the practice of breast pathology. Breast J 2006;12:409–12. 6. Newman EA, Guest AB, Helvie AB, et al. Changes in surgical management resulting from case review at a breast cancer multidisciplinary tumor board. Cancer 2006;107:2346–51. 7. Staradub VL, Messenger KA, Hao N, et al. Changes in breast cancer therapy because of pathology second opinions. Ann Surg Oncol 2002;9:982–7. 8. Frable WJ. Surgical pathology-second reviews, audits, and correlations. What0 s out there? Error or diagnostic variation? Arch Pathol Lab Med 2006;130:620–5.
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9. Tomaszewski JE, Bear HD, Connally JA, et al. Consensus conference on second opinions in diagnostic anatomic pathology: who, what, and when. Am J Clin Pathol 2000;114:329–35. 10. Hammond MH, Hayes DH, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer (Unabridged Version). Arch Pathol Lab Med 2010;134:e48–72. 11. Pathmanathan N, Bilous N. HER2 testing in breast cancer: an overview of currenttechniques and recent developments. Pathology 2012;44:587–95. 12. Viale G, Mastropasqua MG. What can the pathologist offer for optimal treatment choice? Ann Oncol 2010;21(Suppl 7):vii27–9. 13. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118–45. 14. Fitzgibbons PL, Page DL, Weaver D, et al. Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124:966–78. 15. Jara-Lazaro AR, Tan PH. Pattern and spectrum of morphology referrals in breast pathology consultation. Pathology 2008; 40:564–72.
16. Ellis IO, Coleman D, Wells C, et al. Impact of a national external quality assessment scheme for breast pathology in UK. J Clin Pathol 2006;59:138–45. 17. Santa Cruz D. Sweat gland carcinomas: a comprehensive review. Sem Diagnostic Pathol 1987;4:38–74. 18. Brandt SM, Swistel AJ, Rosen PP. Secretory carcinoma in the axilla. Probable origin from axillary skin appendage glands in a young girl. Am J Surg Pathol 2009;33:950–3. 19. Dewar R, Fadare O, Gilmore H, Gown A. Best practices in diagnostic immunohistochemistry. Myoepithelial markers in breast pathology. Arch Pathol Lab Med 2011;135:422–9. 20. Prasad ML, Osborne MP, Giri DD, Hoda SA. Microinvasive carcinoma (T1mic) of the breast. Clinicopathological profile of 21 cases. Am J Surg Pathol 2000;24:422–8. 21. Hoda RS, Chiu A, Hoda SA. Microinvasive carcinoma of breast. A commonly misdiagnosed entity. Arch Pathol Lab Med 2001;125:1259–60. 22. Br€ ugmann A, Lelkaitis G, Nielsen S, et al. Testing HER2 in breast cancer. A comparative study on BRISH, FISH, and IHC. Appl Immunohistochem Mol Morphol 2011;19:203–11. 23. O’Malley FP, Thomson T, Julian J, et al. HER2 testing in a population-based study of patients with metastatic breast cancer treated with Trastuzumab. Arch Pathol Lab Med 2008;132:61–5.
Changes in Breast Cancer Reports after Pathology Second Opinion1 Vicente Marco, MD,* Teresa Muntal, PhD,* Felip Garcıa-Hernandez, MD,* na Gonzalez, RN,† and Isabel T Rubio, MD† Javier Cortes, MD,† Bego~ *Department of Pathology, Hospital Quiron Barcelona, Barcelona, Spain; †IOB, Hospital Quiron Barcelona, Barcelona, Spain
n Abstract: Breast cancer pathology reports contain valuable information about the histologic diagnosis, prognostic factors and predictive indicators of therapeutic response. A second opinion may be requested by medical oncologists and surgeons, when a patient is referred from another institution for treatment. We report the experience with pathology second opinion in selected patients referred to the Breast Oncology Unit. 205 cases referred to the Breast Oncology Unit were selected for second opinion after clinical evaluation, between 2002 and 2012. The cases reviewed included 102 core needle biopsies, 88 surgical specimens from the breast and 18 lymphadenopathies, 14 from the axillary region. Pathology second opinion was based on a review of hematoxylin-eosin preparations, recuts of submitted paraffin blocks and written external pathology reports. Immunohistochemical studies for hormone receptors, HER2, myoepithelial cells, and other markers were performed in selected cases. A case was reclassified as showing major change when second opinion showed a potential for significant change in prognosis or treatment. Otherwise, it was considered to represent minor change or to be concordant. In 52 cases (25.4%), the pathology review showed changes. Thirty-three (16%) patients were reclassified for major changes and 19 (9.2%) as minor changes. In six patients, more than one major change was identified. The major discrepancies identified were related to the histologic classification (12 cases), the presence or absence of invasion in ductal carcinoma (15 cases), the results of hormone receptors (5 cases), and HER2 (7 cases). Major changes in histologic classification included two cases diagnosed as invasive ductal carcinoma and reclassified as benign, four cases with diagnosis of breast cancer reclassified as metastatic lung cancer, one case diagnosed as small cell carcinoma of lung metastatic in the breast, reclassified as primary carcinoma of the breast, and three cases with diagnosis of breast cancer in the axilla reclassified as primary cutaneous adnexal carcinomas (2) and metastatic melanoma (1), respectively. In two cases, the histologic type of the primary breast tumor was changed. Second opinion in breast pathology may uncover significant discrepancies that impact on patient management and prognosis. Major discrepancies are most frequently related to the assessment of the presence or absence of invasion in ductal carcinoma, the results of predictive makers of therapeutic response, and the differential diagnosis of breast cancer and nonmammary tumors in the breast, the axilla, and at distant sites. n Key Words: breast cancer, pathology, second opinion
A
ccurate histologic diagnosis of breast cancer, and assessment of prognostic and markers of therapeutic response are of paramount importance (1). Current literature indicates that there are significant differences among pathologists in the reporting of breast cancer in some cases (2–7). Therefore, a second opinion in pathology may be requested, by clinicians, when a patient with a
Address correspondence and reprint requests to: Dr. Vicente Marco, Department of Pathology, Hospital Quiron Barcelona, Plaza Alfonso Comin 5-7, Barcelona 08023, Spain, or e-mail: [email protected] 1 Presented in an abstract form at the 102nd annual meeting of the United States and Canadian Academy of Pathology, Baltimore, March 2–8, 2013. DOI: 10.1111/tbj.12252 © 2014 Wiley Periodicals, Inc., 1075-122X/14 The Breast Journal, Volume 20 Number 3, 2014 295–301
diagnosis of breast cancer is referred from another hospital for diagnosis and treatment (8,9). The main issues of concern are the confirmation of the histologic diagnosis of breast cancer, the histologic type and grade, the status of the margins of resection, the results of hormone receptors and of HER2 (10,11). Also patients with a history of breast cancer may present with new lesions in the breast or in other organs that need to be histologically diagnosed and the markers of therapeutic response assessed (12). In breast cancer, secondary pathology review may have the greatest chance of optimizing treatment regimens, and an incorrect diagnosis may lead to unnecessary treatments especially in major histologic changes.
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We report on the experience with second opinion in breast pathology, in selected patients consulting the Breast Oncology Unit. METHODS Two hundred and five patients referred to the Breast Oncology Unit were selected for second opinion after clinical evaluation, between 2002 and 2012. The material reviewed included 102 core needle biopsies, 88 breast surgical specimens, and 18 lymph node biopsies, 14 of them from the axillary region. The slides and paraffin blocks were selected by the referring institutions and were thought to be representative of the pathologic features of each case concerned. In addition, in two patients with history of breast cancer, a brain biopsy, and a lung and pleural biopsy were reviewed, respectively. Pathology second opinion was based on review of hematoxylin-eosin (H&E) preparations, recuts of submitted paraffin blocks and written pathology reports. Immunohistochemical (IHC) studies for hormone receptors, HER2, and other markers were performed in selected cases. In some cases, the results of IHC studies performed by the referring hospital, and by the treating hospital were compared. Immunohistochemical was performed on 4-lm-thick sections cut from formalin-fixed, paraffin embedded tissue blocks using different antibodies on a Ventana Bechmark LT automated immunostainer (Ventana Medical Systems, Tucson, AZ) according to standard protocols. For identification of the myoepithelial layer in the differential diagnosis of invasive versus in situ carcinoma p63, cytoketatin 5-6, and cytokeratin 14 were most often used. Other antibodies used in the study included TTF-1, Napsin A, S100 protein, HMB-45, anti-D2-40 (podoplanin) and E-cadherin. For estrogen receptors, clone SP1 (Ventana) was used, and for progesterone receptors Clone PgR636 (Ventana). For HER2 IHC, the primary antibodies used were rabbit polyclonal, Dako K5307 and HER2 Pathway antibody (rabbit monoclonal clone 4B5; Ventana). The interpretation followed the American Society of Clinical Oncology/College of American Pathologists guidelines (negative 0/1+, indefinite 2+, and positive 3+) (13).
In selected cases, FISH (Path Vysion, Vysis, Downer Grove, IL) or SISH (Dual color ISH, Ventana) testing for HER2 was performed. The American Society of Clinical Oncology/College of American Pathologists scoring guideline criteria were used: Negative: HER2/CEN17 < 1.8, equivocal: 1.8 ≥ HER2/ CEN17 ≤ 2.2 and positive: HER2/CEN17 > 2.2 (13). For the cases reviewed prior to the publication the ASCO/CAP scoring guideline system, recommendations in the College of American Pathologists Consensus Statement 1999 were followed (14). RESULTS Concordant results were found in 153 patients (74.6%), and discrepancies were found in 52 patients (25.4%). Table 1 shows the diagnosis performed after second opinion review. Major discrepancies were identified in 33 patients (16%), and minor discrepancies in 19 patients (9.2%). Results of IHC studies for hormone receptors, estrogen and progesterone, could be compared in 72 cases, and for HER2 in 60 cases. Major Discrepancies (33 patients) The major discrepancies identified were related to the histologic diagnosis of the lesion (12 patients), the presence or absence of invasion in ductal carcinoma (15 patients), the result of hormone receptors (5 patients), and HER 2 results (7 patients) (Table 2). In six patients with major discrepancies, two changes were noted. Changes in Histologic Diagnoses (12 patients) In two patients, a diagnosis of invasive ductal carcinoma was changed to benign lesion. One case corresponded Table 1. Second Opinion Diagnoses in 205 Cases Histologic diagnosis Invasive ductal carcinoma, NOS Ductal carcinoma in situ Ductal carcinoma with microinvasion Breast carcinoma, special type Invasive lobular carcinoma In situ lobular carcinoma Other primary breast tumors (phyllodes, granular cell tumor, angiosarcoma) Benign and atypical breast lesions Tumors of nonmammary origin in breast, axilla, lymph node or distant organ (brain biopsy)
N (%) 122 15 4 19 13 1 5
(59.5) (7.3) (1.4) (9.6) (6.3) (0.5) (2.4)
17 (8.3) 9 (4.4)
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Table 2. Major Discrepancies after Second Opinion in 33 Patients First diagnosis Invasive breast cancer
Lung cancer metastasis to breast Changes in histologic type of primary breast tumor Invasive ductal carcinoma DCIS with microinvasion DCIS Estrogen receptor negative Estrogen receptor positive HER2 positive
Second opinion
N
Benign Lung cancer Cutaneous adnexal carcinoma Melanoma Primary breast cancer
2 4 2 1 1 2
DCIS DCIS with microinvasion DCIS DCIS with invasive carcinoma Estrogen receptor positive Estrogen receptor negative HER2 negative
8 2 2 3 4 1 7
(a)
(b)
to a needle core biopsy showing a fibroadenoma with sclerosing adenosis. The other case was a surgical biopsy showing apocrine adenosis with post-chemotherapy changes, thought to be recurrent carcinoma by the referring institution (Fig. 1). In both cases, markers of myoepithelium showed an intact myoepithelial layer in acini suspected to represent invasive carcinoma. In four patients, the diagnosis of breast cancer was changed to metastatic lung cancer after histologic and IHC evaluation, in biopsies of breast, brain and lymph node (2 cases), respectively. Three cases were adenocarcinomas with positive TTF-1 and Napsin A (Fig. 2), and the fourth was a large cell carcinoma of the lung diagnosed as triple negative breast cancer by the referring institution. Other changes included spindle cell carcinoma misdiagnosed as phyllodes tumor in a core needle biopsy, and ductal cribriform carcinoma diagnosed as adenoid-cystic carcinoma. A small cell carcinoma diagnosed in a breast biopsy was considered to represent metastasis of a primary lung carcinoma by the referring institution. However, after histologic review and clinicopathologic evaluation, it was considered to be a small cell carcinoma primary in the breast. A male patient with an axillary mass diagnosed as metastatic ductal carcinoma consistent with an occult breast cancer, was referred for chemotherapy treatment. Mastectomy performed at the referring institution showed no evidence of carcinoma. Histologic review of the axillary biopsy was diagnosed as primary cutaneous adnexal tumor of low malignant potential. Another male patient with a 7-cm mass in the right axilla was thought to have a metastatic
(c)
Figure 1. A 60-year-old woman with history of medullary carcinoma, showing a nodular lesion in the breast, thought to be recurrent carcinoma. H&E, 94 (a). The lesion shows tightly packed acini lined by cells with clear cytoplasm. H&E, 9100 (b). p63 shows preserved myoepithelial layer; 9200 (c). Second opinion diagnosis: Apocrine adenosis.
carcinoma of breast origin; upon histologic review and clinical evaluation, the case was diagnosed as primary apocrine carcinoma of sweat gland origin.
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(a)
(b)
(c)
IHC study was positive for S100 protein and HMB45. Review of a previous skin biopsy from the arm was considered to be diagnostic of melanoma. Changes in the Diagnosis of Ductal Carcinoma in situ, Microinvasive and Invasive (15 patients) Ten cases diagnosed as invasive ductal carcinoma (8 cases) or microinvasive (2 cases) were diagnosed upon review as ductal carcinoma in situ (DCIS), often associated with sclerosing lesions (Fig. 3). In three cases the diagnosis of DCIS was changed to invasive ductal carcinoma, measuring the invasive component from 2, 3, and 7 mm, respectively. In two cases, the diagnosis of invasive ductal carcinoma was changed to DCIS, with microinvasion measuring 1 mm or less. In these cases, ancillary IHC studies for detection of the myoepithelial layer were performed. Changes in the Result of IHC Evaluation of Estrogen Receptors and HER2 (12 patients) Seven cases were reported to show overexpression of HER2-neu (3+), however, expression was considered negative (0/1+) or indetermined (2+), with amplification studies being negative. Estrogen receptors reported negative by the referring hospitals, were found to be positive upon review in four cases. In one case the estrogen receptor reported as positive was negative in the second opinion study. Minor Discrepancies (19 patients)
Figure 2. A 37-year-old woman presenting with axillary mass, with first diagnosis of metastatic ductal carcinoma of breast on core needle biopsy. (a) The tumor shows nests of epithelial cells with signet ring configuration. H&E 9 200. Immunohistochemical study with TTF-1 (b) and Napsin A (c) was positive. Second opinion diagnosis was metastatic adenocarcinoma consistent lung primary.
A female patient with an axillary mass diagnosed initially as metastastic ductal carcinoma of the breast, was found to have metastatic melanoma upon review,
Changes in Histologic Diagnosis (11 cases) In four cases, the histologic type of carcinoma changed, without modifying significantly the prognosis or treatment. In one case the diagnosis of phyllodes tumor was further classified as malignant. A case of spindle cell sarcomas was classified as angiosarcoma postradiotherapy. In a mucinous carcinoma a high grade component was not identified. An invasive ductal carcinoma with pagetoid involvement of the nipple was diagnosed as invasive lobular carcinoma without nipple involvement. In three cases there was disagreement about the presence or absence of atypical ductal hyperplasia. Changes in Tumor Size and Grade (2 cases) The size of a DCIS changed from 10 mm to 5 mm. An invasive ductal carcinoma grade 2 was reclassified as grade 3 with microvascular invasion.
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(a)
(b)
Figure 3. A 46-year-old woman with diagnosis of invasive ductal carcinoma HER2 positive. Second opinion diagnosis: Ductal carcinoma in situ, HER2 negative. (a) Ductal carcinoma in situ showing irregular duct spaces mimicking invasion. H&E 9 100. (b) p63 shows preserved myoepithelial layer; 9100.
Changes in IHC not Significantly Modifying Management (6 cases) In four cases, there were discrepancies in the results of progesterone receptors. In two cases, the result of HER2 in DCIS changed from indeterminate (2+), to negative (1+) and positive (3+), respectively. DISCUSSION Significant discrepancies in breast pathology reports, represents a rather heterogeneous group of situations dependent on the selection criteria applied, i.e., if they are selected by pathologists because they are diagnostically challenging, by the medical oncologists or surgeons in order to confirm the diagnosis and prognostic/ predictive markers before considering additional treatment, or if a systematic review of every case referred to the treating institution is undertaken (9,15,16).
If cases are selected by pathologists, it is likely that problematic proliferative lesions covering the spectrum of hyperplasia, atypical ductal hyperplasia, DCIS, and microinvasion will predominate, as well as rare tumors and tumor-like lesions (16). In our study, most cases were selected by the medical oncologists, being interested in confirming the diagnosis of breast cancer, and the results of tumor markers, before chemotherapy or hormone therapy. The major discrepancies can be grouped in three categories. The first related to the histologic diagnosis of the lesion, the second to the presence or absence of invasion in ductal carcinoma, and the third to the results of IHC in the study of estrogen receptors and HER2. The category of histologic diagnosis included two benign lesions diagnosed as carcinoma, and cases of primary carcinoma of the breast with changes in the histologic subtype. However, it also included cases diagnosed as breast cancer that represented non mammary tumors, several of these diagnosed after reviewing lymph node biopsies or masses from the axillary region. In these cases histologic assessment of H&E slides, and IHC studies were of paramount importance. The distinction between breast cancer and carcinomas of nonmammary origin can be problematic. This problem may present in different clinical situations, i.e., tumors with unusual morphology presenting in the breast, tumors presenting in the axilla without an evident breast lesion, and patients with history of breast cancer, presenting a tumor at different organs. In these situations careful histologic evaluation and clinical correlation are needed to arrive to the correct diagnosis. IHC studies are important to confirm the origin of the tumor (12). Around 70% of primary tumors of the breast are ER positive, and 15% are HER2 positive. Tumors that more often enter in the differential diagnosis are malignant melanomas, carcinomas of the lung, prostate gland, gastrointestinal tract, and ovary, among others, for which useful histologic markers are available (S100, HMB-45,TTF-1, Napsin A, PSA, CDX-2, PAX-8 etc.). The origin of tumors presenting in the axilla may be challenging. They may represent metastases from occult primary breast tumors, but they also may be of nonmammary origin, as it occurred in our series. If they represent metastases from nonmammary origin adequate clinical history and IHC studies are important, and the possibility of primary origin in skin
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adnexa should be considered. Because primary skin adnexal tumors may be similar to breast tumors, histologically and in IHC studies, careful clinical evaluation and imaging studies should be performed (17,18). The changes in the diagnosis of invasion, microinvasion and DCIS account for the largest category in the present study. In a significant number of cases the main problem was related to the coexistence of DCIS and sclerosing lesions, mimicking invasion. In these cases, IHC study of markers of myoepithelium may help to better define the presence or lack of invasion (19). Microinvasive carcinoma as defined by the 1997 TNM criteria should have a dimension of 1 mm or less, and it occurs most often in the setting of DCIS or lobular carcinoma in situ. Several reports indicate that it tends to be overdiagnosed when DCIS is altered by sclerosing lesions and inflammation. The reported incidence of microinvasive carcinoma is less than 1% of all breast carcinomas, and is present in between 5% and 13.5% of DCIS cases. The recurrence rate is estimated to be 5.3%, and the incidence of lymph node metastases is low (2.8%) (20,21). Differences in the results of IHC studies of estrogen receptors and HER2 were found in five and seven cases, respectively. These changes significantly influence the choice of treatment in breast cancer. The importance of following adequate staining protocols and scoring system has been previously emphasized (10,11,13,22,23). The results of IHC studies in hormone receptors are influenced by different factors (fixation, type of antibody, and interpretation, among others). In the assessment of ER, the main problem relates to the identification of cases with a low percentage of positive cells, some of which may benefit from hormone treatment, the false-negative rate ranges from 30% to 60% (10). As for the study of HER2, there seems to be a high degree of agreement in cases that are negative (0/1+) or indeterminate (2+), however, the rate of false positive (3+) is considered to be high, around a 25% of the cases reviewed, as reported in the literature (22,23). The rate of major discrepancies after second opinion and pathology review reported in relevant literature varies. Staradub et al. in a study of 340 cases found complete agreement in only 20% and major changes in 7.8% (7).
Kennecke et al. in a review of 405 cases of node negative breast cancer patients found changes in 20% of the cases which resulted in treatment modifications among 25 patients (6%) (2). Newman et al. in a study including review of the pathology in 149 breast cancer patients found changes in 29% of the patients, which resulted in changes of surgical management in 9% (6). In conclusion, major discrepancies are most frequently related to the assessment of the degree of invasion of breast carcinoma and the result of IHC studies. However, the assessment of axillary lesions and distant metastasis in patients suspected of having breast cancer or with a history of treated breast cancer, may reveal nonmammary tumors. These patients represent a relevant group to consider for pathology review as these findings may severely affect the patient’s treatment and prognosis. Significant improvement in the concordance among pathologists in the assessment of breast cancer lesions can be achieved by careful histologic study, following standardized criteria, and using high quality IHC techniques. These will improve the results of markers of prognosis and therapeutic response, as well as the differential diagnosis between breast cancer and nonmammary breast tumors. REFERENCES 1. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Th€ urlimann B, Senn HJ, Panel members. Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011;22:1736–47. 2. Kennecke HF, Speers CH, Ennis CA, et al. Impact of routine pathology review on treatment for node-negative breast cancer. J Clin Oncol 2012;30:2227–31. 3. Kronz JD, Westra WH, Epstein JI. Mandatory second opinion surgical pathology at a large referral hospital. Cancer 1999; 86:2426–35. 4. Susan G. Komen for the Cure White Paper: June 2006. Why Current Breast Pathology Practices Must Be Evaluated. Available at: Ww5.Komen.org/uploded files/content_Binaries/PathologyWhite PaperB2.pdf (accessed March 8, 2014). 5. Masood S. Editorial. Raising the bar. A plea for standarization and quality improvement in the practice of breast pathology. Breast J 2006;12:409–12. 6. Newman EA, Guest AB, Helvie AB, et al. Changes in surgical management resulting from case review at a breast cancer multidisciplinary tumor board. Cancer 2006;107:2346–51. 7. Staradub VL, Messenger KA, Hao N, et al. Changes in breast cancer therapy because of pathology second opinions. Ann Surg Oncol 2002;9:982–7. 8. Frable WJ. Surgical pathology-second reviews, audits, and correlations. What0 s out there? Error or diagnostic variation? Arch Pathol Lab Med 2006;130:620–5.
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