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ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 1  |  Page : 29-33
 

Consequence of neo-adjuvant chemotherapy on morphology of breast carcinoma: A systematic evaluation


1 Department of Pathology, ESI PGIMSR, Manicktala, West Bengal, India
2 Department of Hematology, NRS Medical College and Hospital, Kolkata, West Bengal, India
3 RG Kar Medical College, Kolkata, West Bengal, India

Date of Web Publication28-Apr-2016

Correspondence Address:
S Chakrabarti
Department of Pathology, ESI PGIMSR, Manicktala, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.180850

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 » Abstract 

Background: Neo-adjuvant chemotherapy (NAC) in locally advanced breast cancer is the present trend. Following NAC, a considerable alteration of morphology occurs in the tumor. Aims: To study effects of NAC on morphology of breast carcinoma and to evaluate the pathologic response (PR).Materials and Methods: A total of 39 surgically resected mastectomy specimens of patients of invasive locally advanced breast carcinoma who received NAC were evaluated for macroscopic and microscopic (by routine stains and immunohistochemistry) alteration of morphology. Results: Macroscopically well-defined tumor noted in 25 cases (64.1%) and in the rest (14 cases, 35.9%), only fibrotic areas identified. Microscopic examination identified malignant cells in 29 (74.4%), significant chronic inflammation in 24 (61.5%), hyalinized fibrosed stroma in 25 (64.1%) and necrosis in 11 (28.2%) cases. Immunohistochemistry assisted in differentiating malignant cells from histiocytes. In 15 cases (38.5%), axillary lymph nodes isolated where fibrosis seen in 12 (30.8%) and malignant cell in 8 (20.5%) cases. In 34 cases where the pre-treatment biopsy were available, complete pathologic response (pCR) and partial pathologic response (pPR) were achieved in 7 (20.6%) and 23 (67.4%) cases respectively. Discussion: Protocol of systematic evaluation of morphological changes is different in cases of a patient treated by NAC. Nature of malignancy was difficult to categorize as morphology of typical breast carcinomas were altered. Sometimes, immunohistochemistry is advantageous as routine H and E stains are not sufficient to isolate malignant cells in fibrotic and necrotic areas. Appropriate morphological evaluation of the mastectomy specimen is absolutely crucial for assessment of PR and subsequent management.


Keywords: Breast carcinoma, histopathology, morphology, neo-adjuvant chemotherapy, pathologic response


How to cite this article:
Chakrabarti S, Mandal P K, Chowdhury A R, Das S. Consequence of neo-adjuvant chemotherapy on morphology of breast carcinoma: A systematic evaluation. Indian J Cancer 2016;53:29-33

How to cite this URL:
Chakrabarti S, Mandal P K, Chowdhury A R, Das S. Consequence of neo-adjuvant chemotherapy on morphology of breast carcinoma: A systematic evaluation. Indian J Cancer [serial online] 2016 [cited 2019 Aug 19];53:29-33. Available from: http://www.indianjcancer.com/text.asp?2016/53/1/29/180850



 » Introduction Top


Neo-adjuvant chemotherapy (NAC) is being increasingly offered to patients with primary breast cancer. NAC is was pioneered in the setting of locally advanced breast cancer (LABC)[1] and is currently the standard of care for treatment in such condition.[2]

The aim of NAC is to shrink the tumor in order to enable to perform the wide local excision rather than radical mastectomy, so called “downstaging” the disease.[3] NAC is applied based on the clinical stage as determined by size, local invasiveness of the tumor and is not altered on the basis of histologic type and grade.

According to Rosen,[4] residual intraductal carcinoma and invasive carcinoma cells can appear morphologically unaltered after neo-adjuvant therapy, but in most cases they exhibit the following cytological changes that reflect treatment effect viz., cytomegaly, vacuoles within cytoplasm, pleomorphism, hyperchromasia and may also resemble histiocytes. Evaluation about the complete pathologic response (pCR) and partial pathologic response (pPR) is crucial for subsequent management.

The present study was undertaken to determine the spectrum of morphological changes in breast carcinoma after NAC on and to evaluate the pathologic response (PR) of NAC.


 » Materials and Methods Top


The present study was conducted at a referral teaching institution of Kolkata, India over a period of 2 years. Inclusion criteria of the present study were female patients having LABC who were administered 3 cycles of NAC prior to mastectomy.

LABC is defined as any primary breast tumor that is more than 5 cm or that involves the skin or chest wall. LABC also includes patients with metastasis to axillary lymph nodes or ipsilateral supraclavicular, infraclavicular, or internal mammary nodal involvement. Thus, stage IIB (T3N0) and all of stage III disease is categorized as locally advanced.[5]

Patients having invasive carcinoma who did not receive NAC and cases where mastectomy performed for recurrence were excluded from the study. Based on these criteria, 39 female patients were selected as the study population. A detail history, including that of previous therapy especially NAC was recorded. In 37 patients, NAC was applied by a combination of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC). NAC by docetaxel and doxorubicin were administered in two cases where FAC was not applied due to advanced age. All patients underwent modified radical mastectomy and specimens of were received at the histopathology laboratory. After gross examination of the breast specimens, adequate and appropriate tissue samples were taken for histopathological study according to the standard guideline.[6] Thorough sampling of the mastectomy specimen has been done. More blocks were prepared than from an equivalent specimen of a patient who has not received neo-adjuvant treatment [3] to minimize the error rate. Wherever no discernable tumor mass was found, blocks were prepared from areas of scars and necrosis. In addition, number and size of lymph axillary nodes if present were noted and tissue sampling was done for histopathological study.

Section from paraffin blocks were stained by Hematoxylene and Eosin (H and E) and periodic acid Schiff stains. Following features were noted in histopathological study: (1) tubule formation, (2) hyperchromatic nuclei, (3) mitotic figures, (4) necrosis, (5) fibrosis, (6) macrophages and inflammatory cells, (7) detectable malignant cells. Immunohistological (IHC) marker of receptors like estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2/Neu (HER2/Neu) were performed. Identification of malignant cell (by cytokeratin AE1/AE3) were undertaken in six cases as routine H and E, stain were inconclusive for identification of malignant cells. Appropriate controls for routine and IHC stains were performed to comply with the internal quality systems. All cases were evaluated by three observers to minimizing variability in specimen sampling, macroscopic description and histological reporting.

The response of NAC was categorized by National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. The response was categorized as pCR when no recognizable invasive tumor cells present, pPR when there are the presence of scattered individual or small clusters of tumor cells in a desmoplastic or hyaline stroma and no pathologic response (pNR) when tumors not exhibiting the changes listed in for two categories.[7]


 » Results Top


Age range of patients receiving NAC was between 35 and 52 years (mean 43.6 years). Well-defined tumor mass found in 25 cases (64.1%) and in the rest (14 cases, 35.9%) only irregular fibrotic areas representing the tumor bed were identified without any definite tumor mass [Figure 1]. In cases where a definite tumor mass was identified, the maximum diameter of tumor ranged from 1.0 cm to 2.5 cm.
Figure 1: Specimen of mastectomy in a case of partial pathologic response after neo-adjuvant chemotherapy (NAC). There is a residual tumor mass (thick arrow) and fibrotic area around the tumor (thin arrow) (a). A tumor mass after NAC showing very little of response to therapy (b)

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Malignant cells were noted in 29 cases (74.4%), significant chronic inflammatory cells including histiocytes were present in 24 cases (61.5%) and hyalinized, fibrosed stroma in 25 cases (64.1%). The area of the tumor bed was represented by stromal fibroelastosis and chronic inflammatory cell infiltrate including sheets of large, foamy histiocytes [Figure 2]a. Malignant cells were either arranged either in nests [Figure 2]b, cords and forming distorted tubule like structures [Figure 3]a or scattered in the hyalinized, fibrosed stroma. Nuclei of malignant cells were hyperchromatic, irregular, pleomorphic with multi-nucleation forming giant cells. There were increased amount of cytoplasm with vacuolization and increased eosinophilia [Figure 4]a. Sometimes there was difficulty in identification of malignant cells as they were mimicking histiocytes [Figure 4]b. IHC by cytokeratin were applied in difficult cases for identification of malignant epithelial cells. In some cases of pPR, here were isolated degenerated tumor cells showing hyperchromasia, and smudging of nuclei were frequent which making them difficult to detect on routine H and E, stain. Mitotic figures and necrosis were noted in 12 cases (30.8%) each while tubule formation by the tumor cells was noted in only six cases (15.4%). In 10 cases (25.6%), only fibrosis and inflammatory cells were noted without any malignant cell. In 11 (28.2%) cases, both necrosis as well as malignant cells were evident. In three cases (7.7%) there was fibrosis along with presence of unequivocal malignant cells with hyperchromatic nuclei along with inflammatory cells were evident. Sclerosis and nuclear enlargement were noted in the non-tumorous areas in 11 (28.2%) and 16 (41.0%) cases respectively. In 15 cases (38.5%), axillary lymph nodes were detected in the resected specimen, numbering 3 to 11. Residual malignant cell were identified in 8 (20.5%) cases. However the most frequent observation was enlarged lymph node with fibrosis (in 12 cases, 30.8%) [Figure 3]b. In the surround normal breast tissue, there were sclerosis of basement membranes of the terminal duct lobular unit noted along with nuclear and cytoplasmic enlargement and hyperchromasia.
Figure 2: Microscopically the tumor bed showing sheets of foamy histiocytes along with some lymphocytes without any malignant cells in a case of complete pathologic response (H and E, ×100) (a). Clusters of malignant cells (arrows) surrounded by chronic inflammatory cells in a fibrosed stroma seen in a case of partial pathologic response (H and E, ×100) (b)

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Figure 3: Another case of partial pathologic response showing wide areas of hyalinized fibrosed stroma and small cluster malignant cells with an attempt of formation of tubules and cord like structure (H and E, ×100) (a). Lymph node in the same case showing wide area of fibrosis (H and E, ×100) (b)

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Figure 4: Nuclei of malignant cells showing hyperchromasia, pleomorphism and multi-nucleation forming a giant cell (thick arrow). Another cell (thin arrow) showing increased amount of cytoplasm with vacuolization along with a mitotic figure (H and E, ×400) (a). Clusters of histiocytes (arrow) in a tubular structure (H and E, ×400) (b)

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In 34 cases, pre-treatment specimens were available. Among the post-treatment cases, the most frequent morphological features were decreased cellularity (30/34), residual tumor tissue (20/34) and necrosis (10/34). Fibrosis were noted in 23/34 cases while chronic inflammatory cells were noted in 20/34 cases. An area of hyalinized stroma with stromal edema and absence of ducts and lobules denotes represented the site of the tumor bed. The old areas of tumor necrosis could be identified by histiocytes and cholesterol clefts. In many cases, there were infiltration by sheets of foamy histiocytes lymphocytes, and hemosiderin pigment. pCR and pPR were achieved in 7/34 (20.6%) and 23/34 (67.4%) cases respectively. Rest (four cases, 11.8%) cases did not revealed any response of chemotherapy and were categorized as pNR.

In post NAC mastectomy specimen, detection of ER, progesterone receptor and HER2/Neu by IHC were performed in 28 cases. Among these, all three markers were positive in three cases (10.7%), both ER and progesterone receptor positive in 16 cases (57.1%), only ER positive in three cases (10.7), while only HER2/Neu detected in one case [Figure 5].
Figure 5: Scattered and clusters of weakly estrogen receptor (ER) positive malignant cells in the tumor (Immunohistochemical stain, ×100) (a). Lymph node of the same patient showing strong ER positive malignant cells forming tubules and acini (Immunohistochemical stain, ×400) (b)

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 » Discussion Top


In 1973, the Milan Cancer Institute started the first prospective NAC in locally advanced inoperable breast cancer. The aim of NAC was to achieve prompt tumor shrinkage thus facilitating subsequent radical mastectomy or radiotherapy. The role of NAC was extended to operable breast cancers requiring mastectomy, with a view to downstage such tumors so that breast-conserving surgery could be considered as a surgical option.[8] The choice of drugs depends on age, cardiac status, co-morbidity and economic status (affordability) of the patient.

During the present study period, 39 cases underwent mastectomy after receiving NAC were evaluated. The small sample size is due to the fact that only cases having LABC who had received NAC were included. Moreover, the study was done among patients of only one institution over a period of 2 years. Frequent morphological changes in histological examination were decreased cellularity, chronic inflammatory cells (61.5%), fibrosis (64.1%) and necrosis (30.8%). There was considerable difficulty in the histological typing of malignancy. Site of infiltrating carcinoma in cases of healed lesion can be identified by residual architectural distortion produced by fibrosis, stromal edema, increased vascularity and a chronic inflammatory cell infiltrate.[4]

There are several systems for assessment of PR after NAC. In most studies the degree of PR to treatment can be correlated with survival. In general, all of the systems recognize a category of pCR and a category of little or no response.[9] Major systems for evaluation of PR includes NSABP B-18,[7] Miller-Payne system,[10] Chevallier method,[11] Sataloff method,[12] RCB system [13] and AJCC ''y'' classification.[14] In the present study, the PR were was evaluated by NSABP B-18 criteria.[7]

A study by Kuerer et al.,[15] of 372 patients with locally advanced breast carcinoma found that 60 (16%) had a pCR after NAC and that 43 (12%) had no histological evidence of carcinoma in the breast or axillary nodes. There was a significant correlation between pCR in the tumor as well as axillary lymph nodes. Factors predictive of pCR are: Poorly differentiated nuclear grade, negative ER status and high histologic grade. In a study by Wang et al.,[16] 12 out of 82 patients had a pCR after NAC and nuclear grade as well as mitotic activity of pre-treatment tumors were correlated significantly with pCR. Patients with a pCR had significantly better 5 year survival rates than those with a pPR. The present cohort of patients from one institution have a pCR of 20.6%. However as the total number of cases are small, such pCR rate may not be statistically significant. The rate of pCR in different clinical trials of the classical anthracycline-based chemotherapy without the addition of taxanes range from 4% to 29%, respectively.[17]

Fisher et al.,[7] observed that, complete clinical response does not imply pCR. Between 60 and 80% of patients considered to have a clinical complete response have residual tumor detected by pathologists in the surgical specimens. On the other hand, about 20% of patients with clinically suspected residual disease have pCR after microscopic examination. Charfare et al.,[8] observed that identification of exact tumor location following a complete clinical response is difficult. Conventional methods such as clinical examination, mammography and ultrasonography may not be able to distinguish chemotherapy induced fibrosis from residual tumor. Magnetic resonance imaging has shown to be the most accurate for assessment of residual disease.

There are two concepts of pCR. One concept is that no invasive carcinoma was recognized, but a few intraductal components were found and another is no invasive carcinoma or intraductal component was found. For the true pCR assessment, multiple sections of the resected specimen must be examined. There is also variation exist regarding the evaluation of residual intraductal carcinomas. The presence of an intraductal component might be negligible in Fisher's criteria,[7] but in the Japanese general rules as reported by Kurosumi,[18] intraductal carcinoma and axillary lymph node metastasis are evaluated separately. The pCR rate might be changed by the method of pathological examination.

In the present study, it has been noticed that there are considerable obstacle in the morphological assessment of the mastectomy specimen. In most cases, no or very small areas of tumor noted after extensive dissection of the specimen. Even in some cases, only the scar tissue was found representing the tumor bed. In routine H and E, stained sections tumors was sometimes difficult to categorize histopathologically as typical cells found in classical breast carcinomas were not observed in these specimens. Extensive fibrosed or necrotic areas along with inflammatory cells were noted and neoplastic cells within these areas were very difficult to be identified. Even some cancer cells may mimic histiocytes, where IHC study by cytokeratin helped to detect these malignant epithelial cells. The tubule formation was limited. Similarly many enlarged lymph nodes showed only fibrosis without malignant cells. Pinder et al.,[3] have dealt with the details of laboratory handling and histology reporting of breast specimens who have received NAC.

The cytoplasm of neoplastic cells after NAC is often eosinophilic with swelling and vesicular changes with many vacuoles. Pyknosis, karyorrhexis and the shrinkage of nuclei are often recognized. In addition, massive necrosis of carcinoma cells with numerous foamy cells and lymphocytic infiltration, and fibrotic changes with slit-like spaces are often found to various degrees.[18] The greatest histopathologic effects are found in patients who appear clinically to have complete resolution of their neoplasm. It is possible to observe dissociation between the clinical picture after therapy and the histologic findings when the patients seem to have a complete response, but histologic examination of breast reveals a substantial amount of residual tumor. When no residual tumor is detectable grossly in the breast, about 60% of patients are found to have persistent carcinoma histologically.[4] The clinical assessment of axillary lymph nodes after chemotherapy can be difficult. Patients who have a response in the breast usually have decreased clinical evidence of axillary disease, which may manifest as smaller metastases in fewer lymph nodes in the axillary specimens than were present prior to chemotherapy.[4]

In the present cases status of tumor marker by IHC is compatible with the patient who are not treated by IHC. Usually, tumor markers remain the same before and after treatment.[19] The inconsistencies of such case may be due to laboratory error in testing, interpretation of the stains, small amount of tumor tissue sampling and tumor heterogeneity. In some cases, a change in tumor marker expression is the result of specific types of neo-adjuvant therapy like loss of progesterone receptor after treatment with aromatase inhibitors, but not with tamoxifen.[20] HER2/Neu expression rarely changes after chemotherapy.[21]

For compliance with the internal quality systems, thorough and appropriate sampling of the tissue is mandatory to confirm the status of PR.[3] To minimize the variability of evaluation, a review system is helpful for internal quality assurance.[22] Appropriate internal as well as external quality control and assessment schemes are helpful to assess the precision and accuracy of histopathological evaluation.[23]

Therefore, proper morphological evaluation of mastectomy specimen is absolutely critical for assessment of PR to NAC. The importance of both routine and IHC markers are indispensable modalities for evaluation of breast cancer cases after NAC and their appropriate management.

 
 » References Top

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Fisher ER, Wang J, Bryant J, Fisher B, Mamounas E, Wolmark N. Pathobiology of preoperative chemotherapy: Findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 2002;95:681-95.  Back to cited text no. 7
    
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Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: A determinant of outcome. J Am Coll Surg 1995;180:297-306.  Back to cited text no. 12
    
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Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25:4414-22.  Back to cited text no. 13
    
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Wang J, Buchholz TA, Middleton LP, Allred DC, Tucker SL, Kuerer HM, et al. Assessment of histologic features and expression of biomarkers in predicting pathologic response to anthracycline-based neoadjuvant chemotherapy in patients with breast carcinoma. Cancer 2002;94:3107-14.  Back to cited text no. 16
    
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Kurosumi M. Significance and problems in evaluations of pathological responses to neoadjuvant therapy for breast cancer. Breast Cancer 2006;13:254-9.  Back to cited text no. 18
    
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Arens N, Bleyl U, Hildenbrand R. HER2/neu, p53, Ki67, and hormone receptors do not change during neoadjuvant chemotherapy in breast cancer. Virchows Arch 2005;446:489-96.  Back to cited text no. 19
    
20.
Dowsett M, Ebbs SR, Dixon JM, Skene A, Griffith C, Boeddinghaus I, et al. Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: Influence of hormonal status and HER-2 in breast cancer – A study from the IMPACT trialists. J Clin Oncol 2005;23:2477-92.  Back to cited text no. 20
    
21.
Vincent-Salomon A, Jouve M, Genin P, Fréneaux P, Sigal-Zafrani B, Caly M, et al. HER2 status in patients with breast carcinoma is not modified selectively by preoperative chemotherapy and is stable during the metastatic process. Cancer 2002;94:2169-73.  Back to cited text no. 21
    
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Zardawi IM, Bennett G, Jain S, Brown M. Internal quality assurance activities of a surgical pathology department in an Australian teaching hospital. J Clin Pathol 1998;51:695-9.  Back to cited text no. 22
    
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Iyengar JN. Quality control in the histopathology laboratory: An overview with stress on the need for a structured national external quality assessment scheme. Indian J Pathol Microbiol 2009;52:1-5.  Back to cited text no. 23
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