and Aysegul A. Sahin2
(1)
Division of Pathology, Singapore General Hospital, Singapore, Singapore
(2)
The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
Keywords
NeoadjuvantPreoperativeChemotherapyTumour bedRadiationChanges Related to Neoadjuvant Chemotherapy
Definition
Neoadjuvant, primary, or preoperative chemotherapy refers to the treatment of patients with systemic agents before definitive surgical removal of a tumour. Neoadjuvant chemotherapy was introduced in the early 1970s as the treatment of choice for inoperable, locally advanced breast cancer. This approach resulted in significant responses and downstaging of many tumours, permitting mastectomy in some patients. Gradually, the idea of neoadjuvant chemotherapy was extended to include patients with large but operable early-stage breast cancer, allowing the same possibility of tumour downstaging and breast-conserving surgery. Additionally, several randomised clinical trials and meta-analyses showed similar disease-free and overall survivals for patients who received chemotherapy in either an adjuvant or neoadjuvant setting. Today, based on these findings, neoadjuvant chemotherapy is considered an appropriate treatment option for most patients diagnosed with breast cancer where adjuvant chemotherapy was indicated [1–5]. For patients with inflammatory breast cancer, neoadjuvant therapy is regarded as the standard of care. It is the preferred option for locally advanced breast cancer, and this approach allows both clinicians and patients to have an in vivo assessment of therapeutic efficacy, which can then be used as a surrogate marker to predict long-term survival [6–8]. Additionally, neoadjuvant trials have been increasingly recognised as a promising platform for efficient testing of investigational compounds and experimental targeted therapies. Most of the current neoadjuvant therapy regimens include a combination of cytotoxic agents. In recent years, with the development of targeted therapy options, many different treatment protocols, which include hormonal and target-specific agents, have been used in the neoadjuvant setting. Assessment of the quantity and biology of the residual tumour can provide further prognostic information for patients receiving neoadjuvant therapy. The possibility of collecting tumour samples before, during, and after the neoadjuvant treatment offers a unique translational research opportunity to delineate the biologic actions of the often personalised, targeted compounds in vivo. Identifying response markers provides a valuable platform from which to advance personalised cancer therapy [8].
Clinical Considerations: Pretreatment Assessment
Breast Evaluation
Assessment of the extent of the breast lesion should begin with a careful physical examination including imaging studies (mammography and ultrasound, with MRI in selected patients) as recommended by the National Comprehensive Cancer Network (NCCN) guidelines [9]. An MRI of the breast is more sensitive in determining the extent of the tumour, but it may also overestimate tumour size. An MRI may be performed if another area of concern highlighted by the initial imaging indicates need for further evaluation [10].
According to NCCN guidelines, an image-guided core needle biopsy with placement of an image-detectable marker of the breast abnormality is necessary to confirm the diagnosis (Fig. 15.1) [9]. This biopsy will also provide tissue to assess histopathologic features (documentation of invasion, histologic type, and grade) and biomarkers (oestrogen and progesterone receptors, c-erbB-2, and Ki-67), as well as to demarcate the tumour bed for post-neoadjuvant management. Additional molecular testing on tissue is not the current standard of care in the preoperative setting at this time; it should not routinely be obtained outside of the context of a clinical trial. Many biomarkers are currently under investigation and may become the standard of care in the future, based on the results of further research. Accurate documentation of the extent of the disease prior to therapy is also very important. If clinical or imaging studies show multiple lesions, biopsy documentation of the additional lesions is recommended.
Fig. 15.1
Biopsy clip. (a) Specimen X-ray showing clip at the centre of the lesion. (b) Gross photograph showing biopsy clip in the centre of the dense, grey-white tumour bed
Axillary Evaluation
Patients being considered for neoadjuvant chemotherapy should undergo a careful physical examination of the axilla, with review of all imaging available, including mammography and ultrasonography [9]. If the clinical or breast imaging results are suspicious for lymphadenopathy, a dedicated axillary ultrasound is recommended for further evaluation [10, 11]. Fine needle aspiration (FNA) or core needle biopsy should be performed on any suspicious-appearing lymph nodes [12]. Placement of a biopsy clip into the biopsied node may improve the accuracy of surgical resection of biopsy-proven metastasis to axillary lymph nodes, allowing a more accurate assessment of pathologic response in the axilla [12].
For patients with clinically node-negative breast cancer at diagnosis, the role of a sentinel lymph node biopsy (SLNB) procedure prior to or following neoadjuvant chemotherapy is controversial [13–15]. One key limitation of SLNB prior to neoadjuvant therapy is that the removal of affected nodes prior to treatment precludes the ability to assess pathologic response. In most centres, performing SLNB after neoadjuvant therapy is preferred for patients with a clinically node-negative axilla at presentation, but it is most important that patient management in this setting must be individualised.
Surgery After Neoadjuvant Systemic Therapy
The aim of surgery after neoadjuvant therapy should be to remove all detectable residual disease with clear margins. In the case of a complete clinical response, the centre of the tumour bed should be removed, including any biopsy clips. Surgical resection volume will be based on preoperative imaging [15].
Evaluation of Breast Specimens After Neoadjuvant Systemic Therapy
Based on clinical and imaging findings, either a segmental resection or total mastectomy may be performed after neoadjuvant systemic therapy. The intention of pathology evaluation of breast specimens after systemic neoadjuvant therapy is to identify the tumour bed, document the response to therapy (including the size, extent, and cellularity of any residual tumour), assess the margins, and review the potential prognostic/predictive markers, if indicated [16, 17].
Accurate, reproducible documentation of pathologic response to neoadjuvant therapy requires the combination of imaging with gross and microscopic findings [17].
Identification of the Residual Tumour/Tumour Bed
Neoadjuvant systemic therapy may produce a variety of physical changes in breast tissue. Residual tumours may look significantly different from an untreated breast cancer. As the stroma of invasive carcinomas after systemic therapy is usually less cellular than that of untreated invasive carcinomas, changes in the previously desmoplastic cellular stroma lead to a softer tumour on palpation, which is more difficult to distinguish from adjacent normal breast parenchyma on gross inspection. In some cases, the tumour shrinks symmetrically, making the identification of residual tumour relatively direct (Fig. 15.2). In some cases, however, the therapeutic response is patchy, and tumours dissipate into scattered nodularity on gross inspection (Figs. 15.3 and 15.4). In these cases, specimen radiography and careful comparison of the imaging studies obtained before and after therapy are essential in order to identify any residual carcinoma (Fig. 15.5) [17].
Fig. 15.2
Gross photograph of breast cancer after chemotherapy. A large area of necrosis and haemorrhage is seen in the lower portion of the well-defined tumour. The remaining grey-white portion in the upper part is viable tumour
Fig. 15.3
Gross photograph of breast cancer after chemotherapy. This tumour is semi-defined, with still-identifiable borders; viable tumour can be seen as distinct from adjacent normal breast tissue
Fig. 15.4
Gross photograph of breast cancer after chemotherapy. Grey-white tissue blends into adjacent breast parenchyma, with ill-defined borders (arrow)
Fig. 15.5
Patterns of response to neoadjuvant therapy. After chemotherapy, tumours can completely disappear (complete pathologic response) (middle panel). They can shrink symmetrically (left panel), with a single tumour focus getting smaller with each therapy cycle, or they can break into multiple foci covering a similar area to that of the mass before chemotherapy (right panel), with each focus being much smaller than the original
Histologic Sampling
If the resection specimen is small (e.g., less than 2–3 cm), it is reasonable to submit the entire resected breast tissue for microscopic evaluation. For larger segmental resections and total mastectomy specimens, the number of sections that must be submitted for accurate assessment depends on the size, number, and location of the tumour(s) prior to therapy [17, 18]. At least one to two sections per centimetre of the tumour is recommended if there is a macroscopically evident residual tumour [17, 19, 20]. If no residual tumour is evident on gross inspection of the specimen, the original tumour site (tumour bed) should be identified and sampled extensively [17, 20]. Overly exhaustive random sampling of the entire fibrotic breast parenchyma is not recommended. Obtaining specimen X-rays and carefully comparing imaging findings before and after therapy—including the identification of biopsy marking clips and other imaging abnormalities such as microcalcifications associated with the tumour site—are critical for the selection of histologic samples. Furthermore, X-ray images of the sliced breast specimen can be used as a map on which paraffin-embedded tissue blocks can be annotated. These maps help the pathologists to reconstruct the extent and location of residual disease during the process of evaluating histopathologic sections prepared from these blocks [17]. This technique is essential, as it provides a more standardised and accurate evaluation of the residual tumour and generally requires processing of fewer tissue blocks than with a random sampling of what appears to be fibrotic breast tissue. Histologic sampling should include grossly visible tumour or tumour bed, as well as the immediately adjacent breast parenchyma. The extent of sampling should be based on the size and extent of the pretreated tumour, using findings from the specimen’s radiography. In some cases, additional sampling may be necessary once the initial sections are reviewed, so keeping the sliced specimens in correct order and orientation is critical (Figs. 15.6, 15.7, 15.8, and 15.9) [20, 21].
The recommendation of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) is to measure the largest contiguous focus of invasive carcinoma, excluding intervening fibrotic areas [20, 22]. This approach is appropriate for tumours with symmetrical shrinkage, but it may cause artificial downstaging of the residual tumour size for those tumours showing scattered tumour nests that were an integral part of a single tumour mass before treatment. To consider tumours multifocal, residual tumour foci should be separated by abundant non-neoplastic breast parenchyma or adipose tissue and should be measured independently. In this situation, dimensions from the largest tumour deposit should be used for AJCC staging, with “m” indicating the presence of multiple tumours.
Fig. 15.6
Identification of tumour bed. (a) Specimen X-ray of mastectomy slices shows dense, fibrous tumour bed. (b) Gross photograph of corresponding fibrous tumour bed. (c) H&E-stained section of the fibrous tumour bed consists predominantly of hypocellular stroma with a few residual glandular elements. (d) Higher magnification shows hypocellular, dense stroma with prominent vessels in the tumour bed
Fig. 15.7
Breast cancer with complete response to chemotherapy. (a) Breast MRI shows a large, irregular mass suspicious for invasive carcinoma, next to a smaller lesion with imaging characteristics of a fibroadenoma. (b) Core needle biopsy of the larger mass shows an invasive ductal carcinoma. (c) Breast MRI of the same patient after 6 months of chemotherapy shows complete disappearance of the large mass; the small lesion remains. (d) X-ray of the sliced specimen of the segmental resection. (e) Gross photograph of the fibrous tumour bed from the same patient. (f) H&E-stained histologic section of the fibrous tumour bed shows dense stroma with inflammatory cells, without any residual invasive carcinoma. (g) Note the almost total lack of glandular structures next to the previous biopsy site
Fig. 15.8
Breast cancer without any response to chemotherapy. (a) Core needle biopsy shows solid proliferation of high-grade carcinoma. Tumour cellularity is more than 70 %. (b) Specimen X-ray of mastectomy shows large tumour with biopsy clip. (c, d) Histologic sections of tumour after chemotherapy. The tumour cellularity is similar to that of the pre-chemotherapy biopsy (a); the presence of geographic necrosis is most likely due to chemotherapy
Fig. 15.9
Breast cancer without significant change after chemotherapy. (a) Pre-chemotherapy mammogram shows a large, irregular mass in the central portion of the breast. (b) Pre-chemotherapy biopsy shows an invasive lobular carcinoma. (c) Post-chemotherapy mammogram shows no appreciable change in tumour size. (d, e) Specimen X-rays of mastectomy slices from the same patient show a well-defined mass involving multiple slices. (f–j) H&E-stained histologic sections from different areas of the tumour show invasive lobular carcinoma with varying degrees of cellularity
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