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MINI SYMPOSIUM: BREAST CANCER
Year : 2013  |  Volume : 50  |  Issue : 1  |  Page : 58-64
 

Histopathologic changes following neoadjuvant chemotherapy in locally advanced breast cancer


1 Department of Pathology, Pt. B. D. Sharma Post Graduate Institute of Medical Sciences, Rohtak, India
2 Department of Surgery, Pt. B. D. Sharma Post Graduate Institute of Medical Sciences, Rohtak, India
3 Department of Radiology, Pt. B. D. Sharma Post Graduate Institute of Medical Sciences, Rohtak, India

Date of Web Publication20-May-2013

Correspondence Address:
D Sethi
Department of Pathology, Pt. B. D. Sharma Post Graduate Institute of Medical Sciences, Rohtak
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.112301

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 » Abstract 

Aims: To compare the clinical and pathologic assessment of response to neoadjuvant chemotherapy and describe the various histopathologic changes observed. Materials and Methods: We studied a group of 40 patients with locally advanced breast cancer who had their initial workup in the form of clinico-imaging assessment of the size and pretreatment biopsy from the lesion. All the patients received two to six cycles of neoadjuvant chemotherapy, either cyclophosphamide 50 to 60 mg/m 2 IV, doxorubicin 40 to 50 mg/m 2 IV and 5-fluorouracil 500 to 800 mg/m 2 IV (CAF) or cyclophosphamide, epirubicin, and 5-fluorouracil (CEF). Clinical and pathologic assessment of response to chemotherapy was done based on the UICC guidelines. Result: Complete clinical response (cCR) was seen in 10% cases (4/40), thirty percent patients had (12/40) partial response and 60% (24/40) had stable disease after neoadjuvant chemotherapy. Pathologic complete response (pCR) with no evidence of viable tumor was observed in 20% patients (8/40). Fifteen patients (37.5%) showed partial response and 42.5% patients (17/40) had a stable disease. No patient progressed during the course of chemotherapy. Changes in the tumor type were observed following chemotherapy, most common being the mucinous change. Histologic changes like dyscohesion, shrinkage of tumor cells, elastosis, collagenization, necrosis, lymphocytic reaction, giant cell response are some of the common observations seen following treatment with neoadjuvant chemotherapy. Conclusion: Pathologic assessment of response to neoadjuvant chemotherapy is a better predictor than the clinical response. The chemotherapy drugs can be modified based on the response observed after 1-2 cycles of neoadjuvant, the response being based on both tumor and patient's responsiveness.


Keywords: Clinical response, histologic changes, neoadjuvant chemotherapy, pathologic response


How to cite this article:
Sethi D, Sen R, Parshad S, Khetarpal S, Garg M, Sen J. Histopathologic changes following neoadjuvant chemotherapy in locally advanced breast cancer. Indian J Cancer 2013;50:58-64

How to cite this URL:
Sethi D, Sen R, Parshad S, Khetarpal S, Garg M, Sen J. Histopathologic changes following neoadjuvant chemotherapy in locally advanced breast cancer. Indian J Cancer [serial online] 2013 [cited 2021 Dec 4];50:58-64. Available from: https://www.indianjcancer.com/text.asp?2013/50/1/58/112301



 » Introduction Top


Locally advanced breast cancer (LABC) is the cancer that has spread to large parts of the breast or the nearby lymph nodes but not to distant organs. The treatment typically includes neo-adjuvant chemotherapy, surgery, and radiation therapy with or without endocrine therapy depending on hormone receptor status. Inoperable tumors are converted to operable ones with primary systemic chemotherapy and some may become candidates for breast conservation surgery. It has been recommended that response to chemotherapy be assessed prospectively with each chemotherapy cycle and analysis of pretreatment sample on serial core biopsies. [1]

Assessment of response to chemotherapy can be done by two ways-assessment of clinical response and pathologic response. Pathological assessment of response to chemotherapy has been found to be superior to the clinical assessment of response. Pathological assessment of response to induction chemotherapy will suggest whether there is a likelihood of additional benefit to be obtained by continuing the same drugs in the postoperative adjuvant setting. In those patients having an unsatisfactory response to induction chemotherapy (pathologically assessed), different drugs could be tried postoperatively. [2]

The present study compares the clinical and pathologic assessment of response to neoadjuvant chemotherapy and describes the various histopathologic changes observed such as change in size, type of tumor. These changes could predict the prognosis and chemotherapy drugs to be used after surgery.


 » Aims Top


To compare the clinical and pathologic assessment of response to neoadjuvant chemotherapy and describe the various histopathologic changes observed.


 » Materials and Methods Top


The present prospective study was carried out on 40 patients with locally advanced carcinoma breast over a period of one and half year. Inclusion criteria included: patients with prechemotherapy clinico-imaging assessment of tumor size, with an established histological diagnosis of carcinoma on biopsy, and who had received at least two cycles of neoadjuvant chemotherapy.

After initial tissue diagnosis, the patients were clinically examined in detail and investigated including radiological, imaging and other laboratory tests to decide the stage of the cancer. The initial biopsies were subjected to routine formalin fixation and paraffin processing with microscopic analysis on hematoxylin and eosin stained sections supplemented by special stains including immunohistochemistry to decide histological type and grade of the tumor according to WHO classification. Detailed histopathological examination was carried out especially looking for chemotherapy induced histopathologic changes like necrosis, fibrosis, inflammatory reaction and other retrogressive changes.

The neoadjuvant chemotherapy regimens either included cyclophosphamide 50 to 60 mg/m 2 IV, doxorubicin 40 to 50 mg/m 2 IV and 5-fluorouracil 500 to 800 mg/m 2 IV (CAF) or cyclophosphamide, epirubicin and 5-fluorouracil (CEF), 21 days apart. Number of chemotherapy cycles varied from two to six depending on the initial tumor size to make it operable. The drugs and doses of neoadjuvant chemotherapy given to the patient were recorded in the proforma.

The tumor resection specimens received after surgery following neoadjuvant chemotherapy were subjected to detailed gross examination; the size of the tumor was measured carefully using calipers to obtain two largest orthogonal diameters and the product of the two was calculated as area (UICC recommendation). [3]

Regional lymph nodes were isolated and grossed with carefully recording the details like size, shape, presence of necrosis, calcification etc. Representative pieces from the specimens were processed by formalin fixed paraffin embedding technique and stained with hematoxylin and eosin staining for detailed microscopic examination for changes in tumor cells and stromal reaction.

The clinical response was graded according to International union against cancer (UICC) criteria which are used to define objective clinical response, changes in the calculated product of bi-dimensional tumor measurements. Complete response (CR) was defined as no residual palpable abnormality, partial response (PR) as greater than 50% tumor shrinkage, stable disease (SD) as less than 50% tumor shrinkage or no change, and progressive disease as an increase of at least 25% (PD). [3]

Pathologic response grading was done as follows: pathologic complete response (pCR) was defined as no residual viable tumor cells (DCIS included), partial response (PR) as greater than 50% reduction in number of viable tumor cells, stable disease (SD) as less than 50% reduction in number of viable tumor cells or no change, and progressive disease as an increase of at least 25% viable tumor cells (PD).

The tumor cells were evaluated for dissociation, dyscohesion, and loss of organization of the tumor cells, necrobiotic changes such as necrosis, vacuolation of nucleus and cytoplasm, karyorrhexis, pyknosis, karyolysis.

Dissociation, dyscohesion, and loss of organization are subjective findings comparing the pattern seen in usual ductal carcinoma in patients who did not receive chemotherapy prior to resection. Necrosis was interpreted as loss of all viable cells.

The stroma was examined for host response including fibrosis, elastosis, collagenization and infiltration by lymphocytes, plasma cells, fibroblasts, histiocytes and giant cell formation were observed. Similar changes were looked for in lymph nodes. A note was made on the tumor type for any change after chemotherapy.

Lymphocytic response was graded as: Grade 1-scattered lymphocytes in between tumor cells; Grade 2-formation of microaggregates of lymphocytes; Grade 3-dense infiltration of lymphocytes destroying tumor cells or forming masses.

The results obtained were interpreted and correlated statistically. Mean, median and mode of various parameters were derived. Pearson's coefficient of correlation was applied to correlate the three types of response patterns with all the parameters observed. A value of the coefficient 'r' was obtained which was used to calculate the 'P' value by using critical value table for Pearson's coefficient of correlation. A 'P' value ≤ 0.05 was considered as significant.


 » Results Top


In the present study, the median age of the breast carcinoma patients was 46 years. The mean size of tumor calculated before induction of chemotherapy was 22.16 cm 2 and after chemotherapy it was 11.74 cm 2 indicating a reduction in mean tumor size by 47%. Size decreased consistently after neoadjuvant chemotherapy, however, no correlation of size with response was observed, i.e., size reduction after chemotherapy was seen in both small and large tumors and was not restricted to any one group [Table 1].
Table 1: Comparison of size of the tumor (product of two largest orthogonal diameters) before andafter neoadjuvant chemotherapy

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On clinical assessment, complete response was seen in 10% cases (4/40), thirty percent patients had (12/40) partial response and 60% (24/40) had stable disease after neoadjuvant chemotherapy, no patient progressed during the treatment with chemotherapy.

On histologic examination, complete pathologic response with no evidence of viable tumor was observed in 20% patients (8/40). Fifteen patients (37.5%) showed partial response and 42.5% patients (17/40) had a stable disease with no progression of disease in any patient.

The most common type observed in the study was ductal carcinoma NOS; mucinous change appeared in three patients after chemotherapy who were diagnosed with ductal carcinoma NOS type in the initial biopsy. A transformation from ductal to metaplastic carcinoma and from papillary pattern to ductal NOS was seen in one case each. Complete response was seen in one case of apocrine carcinoma and disappearance of apocrine component in mixed ductal with apocrine differentiation in another. One case each of schirrhous and tubular carcinoma had complete pathologic response. Response in ductal carcinoma NOS was not significantly different from that observed in invasive lobular carcinoma [Table 2].
Table 2:

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A spectrum of histopathologic changes was observed with the use of chemotherapy. The effects were divided as pathologic changes in tumor cells and changes in the stroma.

In the present study, loss of architecture, dyscohesion, shrinkage of tumor cells with retrogressive changes like karyorhexis, karyolysis, pyknosis, were observed in addition to the above-mentioned changes. In view of the presence of a large variety of retrogressive changes, the emphasis was more on trying to recognize viable tumor cells morphologically identified as cells with distinct nuclear chromatin with intact nuclear and cytoplasmic membrane in the absence of criteria of necrosis (karyorhexis, karyolysis, pyknosis). Necrosis was the most common event observed [Figure 1],[Figure 2] and [Figure 3].
Figure 1: No tumor cells left, complete pathologic response with prominent histiocytic giant cell reaction and lymphoplasmacytic response; postchemotherapy (H and E; 200´)

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Figure 2: Ductal carcinoma, NOS with mucinous change; postchemotherapy (H and E; 200´)

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Figure 3: Ductal carcinoma, NOS with marked necrobiotic changes like dyscohesion, nuclear shrinkage after chemotherapy (H and E; 200´)

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In the stroma, some prominent findings were elastosis/collagenization, hyalinization of the walls of the blood vessels and atrophy of adjacent breast parenchyma and cancerization of ducts even in atrophic lobules. Other changes included stromal fibrinoid necrosis and mucinous change. Collagenization was found to be significantly correlated to pathologic response and tumor regression grade (P < 0.05).

The most common inflammatory host response observed in the present study was lymphocytic, others included mixed inflammation, plasmacytic, prominent histiocytic, giant cell type. Giant cell reaction was significantly correlated to all types of tumor responses (P < 0.05) [Table 3]A and B.
Table 3:

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 » Discussion Top


Although clinical response is being used as an indicator of response to chemotherapy, it has many fallacies as the fibrosis which occurs following chemotherapy can be so extensive so as to give a false impression of increase in tumor size and on the other side, a large tumor which seems to have responded quite well to chemotherapy might still be harboring carcinoma making patient unfit for breast conserving surgery. A better and more objective way to measure the response is by assessing the pathologic response which can even be better, if assessed after each cycle. [1],[2]

There have been a few studies on assessment of pathologic response but none has been elaborative enough to include all the parameters like necrobiotic changes, viability of the tumor cells and host tissue response, etc., which could predict the response to chemotherapy. A significant correlation has also not been seen with most of the parameters excepting a few in some studies. Such studies could prove useful and be predictors of overall response including regression of tumor size and long-term prognosis.

The differences in the complete clinical and complete pathologic response observed by various workers have been compared in [Table 4]. Many researchers observed greater number of patients showing complete pathologic response as compared to complete clinical response, possibly due to healed areas of fibrosis and calcification etc. mistaken as tumor; some have also recorded greater complete clinical response as compared to complete pathologic response possibly due to microscopic foci of tumor surviving in nonschirrhous stroma.
Table 4: Carcinoma breast-comparison of complete clinical and pathologic response

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In the present study, there was a generalized increase in mucinous change and metaplstic change after neoadjuvant chemotherapy. Many authors did not observe any change in the tumor type following chemotherapy. [5],[10],[11] However, Honkoop et al. noted that in a case with mixed ductal-mucinous carcinoma before chemotherapy, only the mucinous component was left after chemotherapy. [11] It was noted by some that lobular carcinoma was not or less responsive to chemotherapy probably because of its high stromal content. [12],[13] However, Masters et al. noted no difference in the responsiveness of invasive ductal or lobular carcinoma. [14] Well differentiated tubular carcinomas were found to be resistant to primary chemotherapy by Sinn et al. [13]

The changes similar to those observed in the present study have also been observed independently in other studies. In the tumor cells, nuclear enlargement, nuclear shrinkage, necrosis, vacuolation of nucleus, cytoplasm, pyknotic nuclei, degenerative changes have been described in literature. [2],[15],[16],[17],[18],[19]

In the stroma, fibrosis, elastosis, collagenization, hyalinization, microcalcification, neovascularisation have been observed and described. [11],[12],[15],[16],[18],[19],[20],[21]

Lymphocytic reaction, presence of plasma cells and macrophages with formation of histiocytic giant cells observed in many studies may be indicative of host tissue response to necrobiotic tumor. [11],[12],[15],[20] Other changes less commonly described in the literature were periductal inflammatory infiltrate (ductulitis), lobular atrophy, ductal and lobular atypia. [19],[20]

Response to chemotherapy in the presence of necrosis and elastosis has been observed to be better by Fisher et al. and Masters et al. [14],[22]

Though these changes have been observed by many authors, yet positive correlation of the presence of these changes with the effect to chemotherapy has not been significant in many studies. According to them, the presence of fibrosis, elastosis, collagenization, hyalinization, necrosis, inflammatory infiltrate, lymphocytic response, giant cell reaction, plasma cells, foamy macrophages, microcalcification, neovascularisation were not significantly related to the response to chemotherapy. [2],[19] Honkoop et al. concluded that none of the pretreatment pathologic or biologic characteristics were predictive of a good pathologic response. [11]


 » Conclusion Top


Although clinical and pathologic assessment of response to chemotherapy are significantly related to each other, yet pathologic response might prove to be a better predictor of survival and may help in deciding the chemotherapy drugs to be used after surgery. Changes which were significantly correlated to the response were collagenization and giant cell reaction and their presence was associated with better overall response to chemotherapy.

 
 » References Top

1.Burstein HJ, Harris JR, Morrow M. Malignant tumors of breast. In: DeVita Jr VT, Lawrence TS, Steven A, editors. DeVita, Hellman and Rosenberg's Cancer: Principles and practice of oncology 8 th ed. Philadelphia: Lippincott Williams and Wilkins; 2008. p. 1606-54.  Back to cited text no. 1
    
2.Khanna AK, Saxena SK, Khanna S, Kumar A. Histopathological changes following anterior chemotherapy in advanced breast cancer. Indian J Cancer 1990;272:109-15.  Back to cited text no. 2
    
3.Hayward JL, Carbone PP, Heuson JC, Kumaoka S, Segaloff F, Ruben RD. Assessment of response to therapy in advanced breast cancer. A project of the programme on Clinical Oncology of the International Union Against Cancer, Geneva, Switzerland. Cancer 1977;39:1289-94.  Back to cited text no. 3
    
4.Swain SM, Sorace RA, Bagley CS, Danforth DN. Bader J, Wesley MN, et al. Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer. Cancer Res 1987;47:3889-94.  Back to cited text no. 4
    
5.Van der Wall E, Rutgers EJ, Holtkampl MJ, Baars JW, Schornagell JH, Peterse JL, et al. Efficacy of up-front 5-fluorouracil - epidoxorubicin - cyclophosphamide FEC chemotherapy with an increased dose of epidoxorubicin in high-risk breast cancer patients. Br J Cancer 1996;73:1080-5.  Back to cited text no. 5
    
6.Cameron DA, Gregory WM, Bowman A, Anderson ED, Levack P, Forouhi P, et al. Identification of long term survivors in primary breast cancer by dynamic modeling of tumor response. Br J Cancer 2000;83:98-103.  Back to cited text no. 6
    
7.Sorace RA, Bagley C, Lichter AS, Danforth DN Jr, Wesley MW, Young RC, et al. The management of nonmetastatic locally advanced breast cancer using primary induction chemotherapy with hormonal synchronization followed by radiation therapy with or without debulking surgery. World J Surg 1985;9:775-85.  Back to cited text no. 7
    
8.Moon YW, Rha SY, Jeung HC, Yang WI, Suh CO, Chung HC. Neoadjuvant chemotherapy with infusional 5-fluorouracil, adriamycin and cyclophosphamide (iFAC) in locally advanced breast cancer: An early response predicts good prognosis. Ann Oncol 2005;16:1778-85.  Back to cited text no. 8
    
9.Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P. Inflammatory breast cancer: Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol 1993;16:223-8.  Back to cited text no. 9
    
10.Demaria S, Volm MD, Shapiro RL, Yee HT, Oratz R, Formenti SC, et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 2001;7:3025-30.  Back to cited text no. 10
    
11.Honkoop AH, Pinedo HM, De Jong JS, Verheul HM, Linn SC, Hoekman K, et al. Effects of chemotherapy on pathologic and biologic characteristics of locally advanced breast cancer. Am J Clin Pathol 1997;107:211-8.  Back to cited text no. 11
    
12.Gazet JC, Coombes RC, Ford HT, Griffin M, Corbishley C, Makinde V, et al. Assessment of the effect of pretreatment with neoadjuvant therapy on primary breast cancer. Br J Cancer 1996;73:758-62.  Back to cited text no. 12
    
13.Sinn HP, Schmid H, Junkermann H, Huober J, Leppien G, Kaufmann M, et al. Histologic regression of breast cancer after primary (neoadjuvant) chemotherapy. Geburtshilfe Frauenheilkd 1994;54:552-8.  Back to cited text no. 13
    
14.Masters JR, Camplejohn RS, Millis RR, Rubens RD. Histological grade, elastosis, DNA ploidy and the response to chemotherapy of breast cancer. Br J Cancer 1987;55:455-7.  Back to cited text no. 14
    
15.Morrow M, Braveman A, Thelmo W, Sohn CK, Sand J, Mora M, et al. Multimodal therapy for locally advanced breast cancer. Arch Surg 1986;121:1291-6.  Back to cited text no. 15
    
16.Faneyte IF, Schrama JG, Peterse JL, Remijnse PL, Rodenhuis S, van de Vijver MJ. Breast cancer response to neoadjuvant chemotherapy: Predictive markers and relation with outcome. Br J Cancer 2003;88:406-12.  Back to cited text no. 16
    
17.Burcombe RJ, Makris A, Richman PI, Daley FM, Noble S, Pittam M, et al. Evaluation of ER, PgR, HER-2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer. Br J Cancer 2005;92:147-55.  Back to cited text no. 17
    
18.Rasbridge SA, Gillett CE, Seymour AM, Patel K, Richards MA, Rubens RD, et al. The effects of chemotherapy on morphology, cellular proliferation, apoptosis and oncoprotein expression in primary breast carcinoma. Br J Cancer 1994;70:335-41.  Back to cited text no. 18
    
19.Aktepe F, Kapucuoglu N, Pak I. The effects of chemotherapy on breast cancer tissue in locally advanced breast cancer. Histopathology 1996;29:63-7.  Back to cited text no. 19
    
20.Moreno A, Escobedo A, Benito E, Serra JM, Gumà A, Riu F. Pathologic changes related to CMF primary chemotherapy in breast cancer. Pathological evaluation of response predicts clinical outcome. Breast Cancer Res Treat 2002;75:119-25.  Back to cited text no. 20
    
21.Hasebe T, Tsuda H, Hirohashi S, Shimosato Y, Tsubono Y, Yamamoto H, et al. Fibrotic focus in infiltrating ductal carcinoma of the breast: A significant histopathological prognostic parameter for predicting the long-term survival of the patients. Breast Cancer Res Treat 1998;49:195-208.  Back to cited text no. 21
    
22.Fisher ER, Redmond C, Fisher B. Pathologic findings from the National Surgical Adjuvant Breast Project VIII. Relationship of chemotherapeutic responsiveness to tumor differentiation. Cancer 1983;51:181-91.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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