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REVIEW ARTICLE
Year : 2020  |  Volume : 57  |  Issue : 2  |  Page : 144-157
 

Grossing and reporting of breast cancer specimens: An evidence-based approach


1 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Surgery, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission26-Feb-2020
Date of Decision03-Apr-2020
Date of Acceptance14-Apr-2020
Date of Web Publication17-May-2020

Correspondence Address:
Tanuja Shet
Department of Pathologist, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_157_20

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 » Abstract 


A histopathology report offers important prognostic and predictive information that helps plan systemic therapy in breast cancer. However, in many cases a pathologist fails to provide relevant information chiefly due to the lack of awareness of the impact of these parameters in clinical decision-making. This review seeks to put forth common practice points in grossing and reporting of specimens harboring breast cancer with focus on latest revisions in the same. Just as it is important to document tumor size, tumor type, margins, estrogen receptor/progesterone receptor, and human epidermal growth factor (ER/PR/HER2) in breast cancer, we need to also focus on sentinel node grossing, nodal burden, size of nodal metastasis, and extranodal extension. In parallel, increasing number of patients are getting neoadjuvant chemotherapy in breast cancer and points in grossing and reporting of such specimens are also alluded to. This article will serve as reference guide to pathologists on what we do and why we do the same.


Keywords: Breast cancer, grossing, minimum data sets, microscopy, macroscopy


How to cite this article:
Shet T, Pai T, Wadasadawala T, Nair N, Gulia S. Grossing and reporting of breast cancer specimens: An evidence-based approach. Indian J Cancer 2020;57:144-57

How to cite this URL:
Shet T, Pai T, Wadasadawala T, Nair N, Gulia S. Grossing and reporting of breast cancer specimens: An evidence-based approach. Indian J Cancer [serial online] 2020 [cited 2020 May 28];57:144-57. Available from: http://www.indianjcancer.com/text.asp?2020/57/2/144/284469





 » Introduction Top


Even in the era of molecular risk stratification of breast cancer a routine histopathology report in a breast cancer forms the backbone that helps management of almost 90% of the patients. Although most pathologists would document tumor type, tumor size, tumor grade, margins, and nodal status in a histopathology report, little attention is paid to controlling pretesting variables and finer nuances such as lymphovascular emboli (LVE), size of nodal metastasis, and extranodal extension (ENE). Oncopathology practices in India are heterogeneous and surgical practices such as oncoplasty, use of radiological marker clips, and targeted axillary dissection may not be practiced by most centers, nevertheless awareness of such practices is required. This article is not drafted to describe every step in grossing but aims to addresses salient features of grossing breast specimens and the importance of various parameters in a routine histopathology report viz. What are the points that are quintessential in a histopathology report on breast cancer and why?

The discussion will be divided into the following sections:

  1. Common practice points in specimens with breast cancer
  2. Types of specimens and grossing
  3. Essential points in histopathology report and their importance
  4. Grossing in special situations
  5. Impact of histopathology on surgical and adjuvant decisions


I. Common practice points in specimens with breast cancer

  1. Importance of rapid fixation: Given the importance of biomarkers in theranostics in breast cancer,American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) has come with guideline recommendations for tumor marker testing in breast cancer.[1],[2] The most important point they address is that rapid transport and fixation of breast specimens for accurate biomarker testing is a joint responsibility of the surgeon &/ operation theatre staff and time to fixation from surgery (cold ischemia time) has to be recorded in every specimen. All the samples should be fixed in 10% neutral buffered formalin (pH 7.4) and the cold ischemia time should be <1 h, with fixation for not <6 h and no >72 h.[2] Though ASCO-CAP does not recommend fixation for periods beyond 72 h, studies show that overfixation does not result in a reduction in assay sensitivity of estrogen receptor/progesterone receptor and human epidermal growth factor (ER, PR, or HER2) immunohistochemical status.[3] On the contrary, delayed or improper fixation causes autolysis and irreversible harm due to loss of tissue antigenicity. The extreme delay beyond which critical damage or false negativity occurs is 8 h for ER, overnight for PR and 2 h for HER2 fluorescence in situ hybridization (FISH).[4] One group of authors showed that a strong ER was reduced to negative after a 48 h delay in fixation.[5] If immediate transport of specimen is not possible, then it should be immediately placed in a fixative whose volume is at least twice (preferable 10 times) that of the specimen size. In case an unusual delay in transport is expected, slice the specimen to ensure proper formalin penetration during transport and this is especially crucial for a mastectomy specimen. The incision should be always made from the posterior aspect through the tumor without harming the orientation. Refrigerating the specimen delays but does not avoid loss of tissue antigenicity.[5] As part of biosafety practice most institutes fix specimen overnight and take sections the next day.
  2. Clinical details: Always confirm clinical stage (operable breast cancer [OBC] or locally advanced breast cancer [LABC]) and other details such as prior history of surgery or neoadjuvant chemotherapy (NACT). In today's era, a lumpectomy is first surgery of choice and the reason for a mastectomy should always be checked.
  3. Sample acquisition, identification, and orientation: Always insist on requisition forms (online or paper) with the specimen. Specimen should be transported either fixed in spacious containers or freshly in plastic Ziploc bags/packets to avoid loss of orientation. Specimens are oriented by surgeons with sutures or clips placed while delivering the lump out of the patient's body.
  4. Mapping of tumor size: Although traditional teaching tells us that four sections of tumor with adjacent breast tissue are enough, given the tremendous importance of tumor size in management of patients, it is essential to sample a slice of longest dimension of tumor and submit section in a grid for histology so that the longest tumor dimension can be microscopically verified [Figure 1]. Always include the adjacent breast parenchyma so that extensive intraductal component (EIC), LVE can be assessed and it will also provide normal breast as internal control for hormone receptor evaluation. Tumors <2 cm should be submitted entirely. If the microscopic examination reveals that the gross “mass ” is mostly ductal carcinoma in situ (DCIS), microscopic reconstruction of tumor (DCIS) size should be done and verified. In patients who have undergone multiple core biopsies, excision biopsy, large bore or vacuum assisted biopsy measuring only the residual lesion could result in under-reporting of the tumor size. Always cross check gross findings with preoperative staging mammography or ultrasound and clinical tumor size.
  5. Submit sections in a definite protocol: Same protocol should be followed for one type of specimen so it is easy to retrieve and cross check. Sections or blocks have to be labeled in particular manner, for example, we use Arabic numbers (1, 2, 3,…) for each block and if there are subsets to that blocks than alphabets are added (1A and 1B).
Figure 1: (a) Slice of largest dimension of tumor––grossly size estimated was as shown in dotted arrow. (b) On microscopy only the sections within the circle showed tumor and hence revised microscopic gross size was given

Click here to view


II. Grossing of excision specimens with breast cancer

The different type of excisions done for breast cancer include the following:

1. Lumpectomy (breast conservation surgery): This is a wide excision with clear margins and is performed in all OBC and in LABC after neoadjuvant therapy. The only absolute contraindications to BCS are

  • Patients unable to take radiation therapy, due to patient's logistics or connective tissue disorders
  • Persistent positive margins, after multiple revisions
  • Extensively multicentric tumors
  • Inflammatory breast cancer or skin involvement


2. Mastectomy: This entails removal of the entire breast tissue and modifications thereof. The various types of mastectomies include:

  1. Simple mastectomy: This involves complete removal of the breast tissue, with no axillary surgery. The pectoralis muscle is also spared.
  2. Modified radical mastectomy (MRM): It includes complete removal of the breast tissue and axillary surgery (axillary sentinel lymph node (LN) biopsy, axillary sampling or complete axillary dissection). The pectoralis major and minor muscle is preserved and all of breast tissue anterior to it is removed. A large volume of the overlying skin and nipple areola are also excised.
  3. Skin sparing mastectomy: In a skin-sparing mastectomy, only the nipple areola, skin scars with underlying breast is excised and the overlying skin is spared. This allows breast reconstructions using patient's natural skin. Rest of the surgery is same as that in an MRM.
  4. Nipple sparing mastectomy is done in patients being offered reconstructive surgeries. It involves subcutaneous mastectomy with preservation of the skin envelope and the nipple areolar complex.
  5. Radical mastectomy: In this surgery the pectoralis muscle (often only the pectoralis major muscle) is removed along with the mastectomy. This is performed in male patients with pectoralis major involvement and malignant phyllodes for mastectomy.


In India, the incidence of mastectomy is higher than that of breast conservation, due to many patient and surgeon related factors.

Steps in grossing a lumpectomy specimen.[6]

1. Check orientation of the specimen:

Why? For sampling of the six surface margins it is essential that the surgeon orient the specimen.

How? A three-suture orientation is usually necessary for accurate orientation, and the rule followed is:

Short suture = superior aspect of specimen

Long suture = lateral aspect of specimen

Anterior = A black suture or a sliver of skin may be present.

2. Inking external surface of a lumpectomy:

Why? To distinguish a surgeon's knife plane from a grossing knife cut, the external surface of a lump is inked.

How? We use various water proof inks such as the Davidson's marking inks, Dhobi ink used in laundry, Indian ink, Alcian blue, dyed gelatine, and Fevicryl fabric paints. The use of different color inks/markers for an individual surface can assist microscopic identification of the corresponding surface. The use of six different color inks/markers on an individual section can assist microscopic identification of specific margins; a color code normally used is Superior––Blue, Inferior––Green, Medial––Brown/Orange or Purple, Lateral––Yellow, Superficial––Red, and Deep––Black. For drying the ink and to avoid running of the fluid ink into the cervices of a lumpectomy, dabbing the surface of ink with acetic acid or alcohol or Bouin's solution helps.

3. Slice the lump into thin slices:[7],[8],[9] Although it is easiest to slice medial to lateral or sagittally, pathologist should slice along largest dimension of tumor because along this length all relevant prognostic factors would be better displayed. Slices should be uniform and approximately 5 mm thick. The other techniques that can be used for slicing a lumpectomy are:

  1. Coronal slicing: This involves serial slicing of specimen from a superficial to the deep plane (antero–posterior) and is preferred for microdochectomy specimen.
  2. Enblock method: To pick up all margins radially, most pathologists prefer to slice the middle part of lump sagittally and the medial and lateral ends are then sliced in perpendicular manner.
  3. Crucial slicing or radial block method: In this technique, a cross is etched on the posterior aspect with two cuts perpendicular to each. On completion of sectioning, the lump is divided into four quartets such as an orange.


4. Sampling and measurement of margins:

Why? The surface of the lumpectomy is the plane through which the surgeon has cut and this represents a margin of a lumpectomy. Presence of tumor at margins is an indication to consider a revision surgery.

How? To completely evaluate the margin of a 3 cm lump it would take nearly 3000 sections, which is not practical. The next best practice is to convert a lump into a box with six surfaces and sample each of them with respect to the tumor. Measure the distance of tumor from the six surfaces anterior, posterior, medial, lateral inferior and superior. Take a section of tumor with the inked margin. It is always recommended taking a radial or perpendicular margin so that actual distance of surface from tumor can be measured [Figure 2]. Shave margin or en face margin are not preferred due to errors involved. Please remember that margin assessment is actually just a sampling and is not 100% accurate. The more extensively a margin is sampled the more chances of reporting an accurate margin.
Figure 2: (a) Lumpectomy margins marked with color and sliced sagitally before submitting sections. (b) Radial margin is taken with tumor and inked surface

Click here to view


How to gross separately sent or revised margins?[10] At times the surgeon shaves the wall of the cavity after completion of lumpectomy and such cavity wall margins are inked or clipped on the abluminal surface. The ink should be reinforced and specimen sliced radially with ink on one side and cavity on the opposite side, as shown in [Figure 3].
Figure 3: (a) Grossing of a separately sent revised margin inked on one surface. (b) Margin is flattened out, ink reinforced, and submitted as shown

Click here to view


5. Tumor sectioning and description: As mentioned in common practice points submit sections from one whole slice of tumor with adjacent breast along its longest dimension.

6. Axillary LN evaluation[6]:

Why? Nodes are the first station for metastasis and one of the most important predictor for systemic therapy and prognosis in breast cancer

How? Axillary lymph node dissection (ALND) is associated with lot of local morbidity which impacts quality of life of patients and in patients with negative or low nodal burden this could be reduced or avoided. The different types of axillary nodal dissection are:

i. Sentinel lymph node biopsy (SLNB): SLNB is the first node draining the tumor in the axilla and if it is negative such patients may be spared of the ALND. SLNB can be evaluated intraoperatively or performed before the main surgery on outpatient basis using the blue dye method, gamma probe, or indocyanine green.

Intraoperative evaluation of SLNB: Intraoperative assessment of SLN has the advantage of allowing breast cancer patients with tumor-positive SLNs to avoid a second surgery by immediately preceding to ALND. Frozen section sensitivity for detection of macrometastases in SLNB is 89% but for micrometastasis is lower (64%).[11] Bisect or serially slice an SLNB depending on the size and submit one node per frozen chuck/block. It is essential to quantify the size of node metastasis in frozen if one or two nodes are positive as it might influence decision to complete the axillary nodal dissection.

How to gross an SLNB? A sentinel lymph node (SLN) is serially sliced at 2 mm interval and submitted entirely. One hematoxylin and eosin (H and E) section of this node is then studied

Why only one section? About a decade ago, chasing micrometastasis in an SLNB was critical to ensure completion of axillary dissection in case the sentinel node was involved. However, a paradigm shift has occurred in the management of low burden axillary-metastatic disease following SLNB in breast cancer in the last decade and this has changed our pathology practice as well.[12] The ACOSOG Z0011 trial has proved that women with T1 or T2 invasive primary breast cancer and 1 or 2 SLN metastases without axillary node dissection done had similar 10-year overall survival as those treated with complete ALND.[13] This data however has to be extrapolated with caution to T1–T2 tumors with 1–2 nodes positive in our practice, due to the difference in tumor burden in our country from the above study population. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 showed that in the sentinel node negative population only sentinel node removal did not compromise nodal recurrence.[14] Patients enrolled in the study were staged and treated based on the information obtained on H and E stained sections only (with no routine levels or cytokeratin stains). Participating sites were instructed to slice SLNs at 2 mm intervals so that 2 mm metastasis could be picked up and to examine one H and E-stained slide only from each block. In a substudy of the NSABP-B-32 trial, all negative nodes were then additionally sectioned at 0.5 and 1 mm stained with H and E and cytokeratin immunostains were also done to pick up occult metastasis.[15] Occult metastases were identified in 616 of 3887 patients which included 11.1% isolated tumor cells, 4.4% micrometastases and 0.4% macrometastases.[15] A follow-up of survival analysis concluded that though presence of occult metastases was an independent prognostic variable, in patients with sentinel nodes that were negative on initial examination, the magnitude of the survival difference was small.[16] Hence, they concluded that serial sections or immunohistochemical analysis is not advocated when single section from 2 mm sliced SLN is negative. A SEER meta-analysis showed that prognosis of patients with micro-metastatic carcinoma was worse than node-negative patients but was significantly better than for patients with macro-metastatic disease.[17] Thus, recording micro-metastases is necessary but the chasing of Lymph Node (LN) metastasis by doing additional H and E and immunostaining is no longer recommended. Targeted axillary dissection technique is done before start of chemotherapy whereby the suspected enlarged node is tagged with a clip so that if this node is a non-sentinel node it can still be removed and addressed too intraoperatively.[18]

ii. Axillary lymph node dissection (ALND): The axillary tissue is usually separately sent in a BCS specimen. In axillary dissection, Level I node dissection entails removal of fat/nodes lateral to pectoralis minor muscle. Level II nodes are between medial and lateral border of pectoralis minor muscle and interpectoral nodes. Level III nodes are the apical nodes: medial to the medial margin of the pectoralis minor muscle and inferior to the axillary vein.[19] Intramammary nodes are counted as axillary nodes. Internal mammary node dissection is additionally done for inner quadrant tumors. The extent of node dissection is based on results of clinical staging methods.

How to gross? Although nodes are better felt in fresh state, in our laboratory, we gross nodes after fixing axillary tissue due to safety concerns. Make incisions in the fat medial to lateral direction, to ensure proper fixation and avoid cutting into the underlying nodes. After fixation, dissect the nodes making a note of how many nodes were seen, and record number of nodes per block so that over counting of nodes is not done. Record size of the largest node and its cut surface. Remember to include a thin rim of perinodal fat around each node so that microscopic extra nodal extension may be commented upon. LNs >5 mm in maximum size should be sliced at intervals of approximately 2–3 mm or less perpendicular to the long axis chiefly to detect small metastatic deposits and embed one node per block. One section from grossly metastatic node suffices. Remember in present era it is essential to capture the size of nodal metastasis for assessing nodal burden and hence section of full face of metastasis should be given. If there are many nodes each could be sliced such as a book and embed such that the largest circumference can be examined. Nodes <5 mm in size should be submitted in their entirety.

iii. Axillary sampling: Low axillary sampling (LAS) is an anatomical guided sampling of axillary nodes that removes low Level I fat with nodes below the second Intercosto-brachial nodes.[20] LAS has an overall false negative rate of 8.8% with five nodes in LAS and a 1.5% false negative rate with six nodes in sampling. The procedure is cost effective, low technology requiring (no gamma probe or blue dye required) and thus a reliable alternative to SLNB for an axillary staging procedure. We serially slice five largest LAS nodes and embed one node per block and a single H and E section is studied.

Summary of sections of breast lumpectomy

  1. Tumor grid with adjacent breast
  2. Skin, if present
  3. Margins––anterior, posterior, superior, inferior, medial, and lateral
  4. Nodes––low axillary/sentinel and/apical interpectoral.


Steps in grossing a mastectomy specimen

  1. The surgeon may orientate mastectomy specimens, by placing a suture in the axillary tail. If not oriented anatomically, orient the specimen by placing axillary contents laterally.
  2. Usual measurements are taken of skin and breast parenchyma with examination of skin and nipple areola for puckering, scars, and peau d' orange.
  3. Sectioning: Ink the deep resection plane (i.e.) the base of resection and serially slice through posterior surface into 1 cm slices. Axillary fat is not inked. Some pathologists slice the mastectomy in diagrammatically opposite directions to ensure better sampling. In nipple sparing mastectomy and skin sparing, inking of superior, inferior and posterior part must be done as margins from these surfaces are required. Separation of superior and inferior surfaces in skin sparing mastectomy is determined by a horizontal line passing through the center of nipple areola complex. In non-skin sparing mastectomy, the center of skin ellipse is used to delineate these surfaces.[10]
  4. Tumor examination: Document tumor dimensions, containing quadrant, consistency, borders, and distance from overlying skin/nipple and the base of resection. All radiologically suspicious areas should be sampled.
  5. Nipple grossing: Nipple may be cut either in longitudinal or coronal sections after examination. There are no margins in an MRM, except base. In nipple sparing mastectomy the area of nipple is marked by 5 clips or inks––four for each sides and one in center. Perpendicular margins from these areas should be taken. In skin sparing mastectomy superior, anterior (superficial), inferior and posterior margins are taken.[10] In a Nipple sparing mastectomy the retroareolar surface is important margin and is usually indicated by the surgeon. Usually this margin is sent for frozen section to confirm absence of in situ or invasive tumor.
  6. Axillary node dissection: Dissect out LNs from the axillary tissue. Rest of evaluation is same as that given in the lumpectomy section.


Sections from mastectomy

  1. Tumor grid
  2. Nipple/areola
  3. Base/overlying skin (margin, if applicable)
  4. Axillary nodes
  5. Adjacent breast


III. Grossing in special situations

Grossing of a non-palpable abnormalities/wire localized excision: Lesions that are detected on mammography are localized by inserting/and hooking a wire into the lesion under mammographic guidance and subsequently the lump is excised with the wire in situ, placed with the distal segment positioned adjacent to the abnormality and the proximal segment remaining outside the breast. A specimen radiograph is done to ensure that needle is within the mammographically seen abnormality. The area around the needle is the focus of grossing. In some instances, the needle shifts or localization fails and hence grossing under mammography supervision is essential. Steps in wire localization are as follows.

  1. The enblock slicing method is best for assessing margins in wire localization or sagittal slicing is also an alternate method. During slicing, make sure that the needle is not displaced.
  2. Mammography of these slices is done and slices are serially arranged. The slice with the mammographically detected abnormality should be entirely submitted for histology after recording margin distance and size of lesion.
  3. The slice adjacent to the lesion is also sampled thoroughly. All grossly felt or radiologically seen abnormal areas are also sampled. Remember to map each slice so that if there is malignant lesion then the size can be reconstructed.


The traditional wire method has disadvantages such as wire breakage/transection, wire migration, patient discomfort, discrepancy between wire entry site and preferred surgical approach, and, scheduling constraints due to wire placement coordination with the surgery time. Non-wire procedures[21],[22] include (a) RSL (radioactive seed localization) whereby a titanium clip containing an iodine-125 I seed is placed into the lesion and (b) SAVI SCOUT system which uses an infrared electromagnetic wave reflector to localize the breast lesion. The reflector is passive until activated from the console by a hand piece (as this is done at time of excision). Magseed uses magnetic fields to localize the lesion and guide excision. All of the above have advantages of better localization with lower margin positivity and uncouple the need for radiology and surgery to be coordinated on the same day because the radioactive seed can be placed up to 5 days prior to surgery and reflector in SAVI SCOUT can be placed as 30 days before surgery[22]

In RSL, the grossing personnel has to retrieve the radioactive seed before standard tissue processing and place it in a lead-lined container for safe storage and disposal.[22]

How to gross and measure ductal carcinoma in situ (DCIS)? Size of DCIS has direct relation with the outcome but unfortunately it is often hard to measure. Serial sequential sampling is best method for DCIS.[6],[7] The entire specimen is blocked in such a way that the entire tumor area can be mapped and the extent of the DCIS can be calculated by using a diagram of the specimen. Pathologist many times may not be aware that the case is a palpable DCIS before grossing and a tumor grid may not be possible. In such instances all palpable abnormality should be submitted and search for invasive tumor should be made in orderly fashion especially when palpable DCIS is >5 cm in size. Ideally sampling the entire specimen and mapping entire tumor is critical to ensure that palpable DCIS has no associated invasion.

How to gross post-NACT breast specimens:

Why is NACT given?: NACT is the standard treatment for patients with large operable and LABC so that it allows for shrinkage of tumor and breast conservation. It is now also being used even in early breast cancers. Though it does not offer survival benefit, it allows assessingin vivo drug sensitivity and downsizes the tumor to allow for conservative surgery. Complete pathologic response or PCR is now the end point of new drug treatment validation for many clinical trials.[23],[24] A histopathology report can help capturein vivo drug sensitivity and help manage patients better

How to gross post-NACT specimens? Besides the usual steps in the gross examination, the critical point is identification of tumor bed. Close examination of fresh specimens and slicing into thin 5 mm sections is recommended.[23] Submitting entire specimen will ensure accurate tumor bed area sampling but as this is not practical, pathologist should spend time in identifying a putative tumor bed area either by correlating with radiology or based on clips inserted in tumor bed before chemotherapy or based on operative notes. After thin slicing, the slice that harbors the largest cross-section of tumor bed should be embedded in a grid fashion. Recommendations for extent of post-NACT tumor sampling vary and include either one or two tissue blocks/1 cm of pretreatment tumor or five representative blocks of a cross-section of pretreatment area of involvement per 1–2cm of pretreatment size up to a total maximum of ∼25 blocks.[23],[25] It is imperative to provide some diagram of gross area so that if reporting pathologist feels that tumor bed has not been sampled then it is easy to take additional sections.

IV. Essential points in histopathology report and their importance

The following are the essential parameters in the histopathology report on breast cancer that help manage patients.

  1. Tumor size:


  2. Why to measure tumor size? Tumor size is integral part of TNM staging of breast cancer and is used to plan adjuvant therapy in breast cancer

    How to measure? Measure the longest dimension of the tumor to the closest millimeter. Tumor size by palpation correlates better than visual examination and it should be measured.[19]

    What are the errors in tumor size estimation? One group of authors reported that the grossly measured and microscopically estimated tumor sizes are concordant only in 56% of cases with one third impacting stage classification.[26] Gross tumor size may be larger than microscopic tumor size when there is EIC present or when tumor is associated with dense fibrosis or proliferative breast disease in background. In such instances microscopic tumor size take precedence provided the tumor has been grossed in a way that tumor size can be reconstructed. It is known that in lobular carcinomas tumor size is underestimated on gross and only the extensive mapping or tumor grid will help define an accurate size.[27] Surprisingly maximum errors in tumor size estimation occur with smaller sized tumors. In a post biopsy setting, the tumor size as estimated on clinical examination or mammographically before biopsy is likely to be more accurate.[28]

  3. Tumor grade:


  4. Why give tumor grade? Tumor grade directly reflects the tumor differentiation and proliferation. Nearly 90% 10-year survival in tumors is seen in grade 1 breast cancers and it falls proportionately from grade II to grade III.[28]

    How to give tumor grade? The Nottingham modification of the Scarff-Bloom-Richardson (NSBR) grading scheme that uses tubular differentiation, nuclear grade and mitosis to grade breast cancers from grade I to grade III[29]

    Errors in tumor grade? Interobserver variability is the chief limitation of the NSBR scoring system. Maximum grade discrepancy occurs around the cut off of score 5–6 between Grades 1 and 2 lowering its utility.[30] The SEER review of 161708 cases of Breast Cancer however confirmed that histologic grade continues to be of prognostic importance for overall survival despite tumor size and nodal status. They proved that across the large data set, assignment of the histologic grade has been consistent among pathologists.[31]

  5. Tumor type:


  6. Why histologic type? Histological type refers to the growth pattern of the tumour and as some subtypes behave better, tumor type could be used to aid decision on adjuvant chemotherapy in a population where oncotype-Dx for stratification is not feasible.

    What are the different histologic types? The commonest type of breast carcinoma is the so-called invasive breast carcinomas no special type (IBC-NST) which is a diagnosis of exclusion and comprises tumors that fail to show sufficient characteristics to warrant their classification in one of the special types. The other types are called “special ” and include invasive lobular carcinoma, mucinous carcinoma, and metaplastic carcinoma. Each of these represents a special molecular event, behavior or growth which is exciting for pathologist but in the present era investigation into them has reduced as molecular subtypes have taken precedence in providing the prognostic and predictive information about tumor biology. The tumors with 80%–90% 10-year survival include tubular carcinoma, tubulolobular carcinoma, Infiltrating cribriform carcinoma, Low grade adenosquamous carcinoma, Solid variant of papillary carcinoma-intraductal or mucinous variants, Secretory carcinoma in children, and Adenoid cystic carcinoma.

  7. Margins:


  8. What is the definition of a positive margin? Any tumor on the inked surface is a positive margin. Although close margins may be recorded they are not presently used to define positivity. In DCIS, a 2 mm margin width is considered as a free margin

    Why this definition of margins is used? With multimodality therapies the width of margin required to be labeled as “free ” has reduced. In 2014 after a large metanalysis, the Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) concluded that no tumor on ink is adequate margin for invasive carcinomas.[32] These guidelines were subsequently endorsed by the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines. However, in patients with pure DCIS there was a significantly reduced risk of ipsilateral breast tumor recurrence (IBTR) with a 2 mm wide negative margin and hence the guideline recommends a 2 mm adequate margins in patients with pure DCIS treated with breast conserving therapy (BCT).[33] While reporting revised margins, care should be taken to quantify extent of involvement in positive margins, for example, size of invasive tumor or DCIS and the distance of this focus from inked surface as this may impact the decision for margin revision vs mastectomy.

    Errors in margin estimation: In transit from the operation theatre to the histopathology lab, specimens flatten or “pancake ” due to their weight and loose around 50% of their height, and thus some of the orientation by surgeon is lost. Most important distortion takes place along the junction between posterior- inferior- superior plane.[34] Recently several new techniques are available for marking margins of lumpectomy including molecular inks, but for economic viability intraoperative margin inking is gaining popularity.[35]

  9. Extensive Intraduct component(EIC):


  10. What is EIC? EIC-positive carcinomas are defined by >25% of the area within the invasive carcinoma being composed of DCIS and DCIS is also present outside the area of invasive carcinoma. The extent of carcinoma outside of the invasive tumor border is not quantified. It also includes DCIS which is associated with a “small ” (<1 cm) invasive carcinoma or carcinomas.

    Is EIC relevant? The concept of EIC was introduced in late 1980's and early 1990's, when it became crucial to understand factors associated with recurrence in BCS.[36] It was seen that 5-year rate of IBTR for patients with focally positive margins was 9% but with positive margins it was 28%. Within the later it was 19% for EIC-negative and 42% for EIC-positive patients. Thus, EIC positive and positive margin meant revision surgery for patients.[36] Approximately a third of patients with EIC positive cancers have DCIS beyond 2 cm of the primary tumor, indicating that a substantial number of patients with an EIC treated by excision to grossly negative margins have a heavy residual tumor burden.[37] Studies in the more recent era have not documented an increased risk of local recurrence with EIC.[38] We believe that EIC has to be interpreted with tumor biology and size. In substantial proportion, EIC is associated with HER2 positive disease and hence carries ominous significance only if patient receives no adjuvant Herceptin therapy.

  11. LN metastasis:


  12. Why is evaluation of metastatic nodes critical? LN metastasis is the single most important prognostic factor that influences adjuvant therapy decisions and prognosis in breast cancer. An accurate assessment of the number of positive LNs is a critical prognostic indicator so much so that some pathologists label nodes with different colors before slicing so that an accurate count of positive nodes can be obtained.[39]

    Definition and how to count metastatic nodes: Macrometastasis are tumor deposits >2 mm, whereas micrometastasis is a metastasis >0.2 mm with none >2.0 mm and isolated tumor cell clusters are small clusters of cells not larger than 0.2 mm or fewer than 200 cells in a single histologic cross section. The total number of positive nodes should include macrometastasis and micrometastasis and nodes with ITC are not included in final count.[40] The size of the node metastasis includes the tumor cells, the desmoplastic response and even the area of invasion outside of LN capsule. If there are tumor nodules >3 mm in axillary fat without lymphoid tissue, they are to be counted as nodes with ENE. Lymphatic emboli are not counted as metastasis but if lymphatic emboli in subcapsular lymphatics they are considered as micrometastasis.

    Errors and problems in evaluating LN metastasis: Although there is no issue with documenting macrometastases, multiple small volume metastasis needs to be interpreted in individual context. If there is 1 metastasis greater than 2 mm and 3 micrometastases, it should be counted as 4 positive nodes. On the contrary, if there is one metastasis >2 mm and 3 nodes with ITCs, it still remains one positive node.[39] If there are multiple clusters of tumor cells, the size of the largest contiguous cluster of tumor cells dictates the classification as macro or micrometastasis. If there is difficulty in assigning the N classification, it is recommended that the reason be provided in a note.[39]

  13. ENE or extracapsular extension of nodal metastasis:


  14. What is ENE? ENE is defined as extension of neoplastic cells through the nodal capsule into the perinodal adipose tissue.[19]

    Why is ENE important to document? Because patients with positive SLNs routinely underwent completion ALND regardless of ENE status in the past, the presence of ENE was of little clinical relevance.[41] However with results of ACOSOG Z0011 study,[13] efforts are being made to predict non-sentinel nodes metastasis using several nomograms and ENE has emerged as an important factor in these nomograms. Approximately 40%–60% of single node SLNB positive patients will have no positive nodes in the rest of axillary dissection and could be spared a complete axillary node dissection.[42] The MSKCC and MD Anderson nomograms are the most popular ones used to predict non sentinel node involvement in breast cancer.[42],[43] The MD Anderson nomogram for predicting non sentinel node metastases uses histology grade, tumor size, number of nodes removed, number of positive sentinel nodes, maximum size of metastasis, extracapsular extension, and LVI and hence these factors should be made available in a histopathology report of breast cancer.[43] The largest size of nodal metastasis should be incorporated as deposits >10 mm in size predict risk for non-sentinel node involvement.[44] Presence of ENE on SLN dissection is associated with N2 disease and ENE influences survival only via a higher number of positive nodes.[45] The extent of ENE as > or <2 mm should be defined, as despite increased nodal burden, patients with 1 or 2 positive SLNs but ENE <2 mm have recurrence and survival rates similar to those of patients without ENE.[46]

  15. Lymphovascular invasion (LVI):


  16. Why is LVI important? The presence of carcinoma cells in either lymphatics or blood vessels (lymphovascular invasion) is a significant prognostic factor in invasive breast cancer, with respect to local and distant recurrence both in node positive and node negative patients.[47],[48] LVI are usually associated with unfavorable pathological features, and usually correlate with the tumor size, nodal status, age, and histological grade in invasive breast cancer.[49],[50],[51] LVI is also a contraindication for use of brachytherapy techniques to radiate the tumor bed.

    How to report LVI: LVI is defined as carcinoma cells present within a definite endothelial-lined space (lymphatic or blood vessel). LVI includes lymphatic and blood vessel invasion. These usually loop around blood vessels. LVI should be reported 1 mm away or one field from tumor

    Issues in reporting LVI: The issue with LVI is their definition and questions surrounding importance of their extent. The Nottingham group documented that lymphatics in the peritumoral and peripheral areas in breast cancer are associated with disease progression and hence only peritumoral LVI are recorded in a report.[52] Studies have stressed that more than H and E, emboli confirmed by immunostains such as D240 or CD31/34 are prognostically relevant.[53] There is always a dilemma about distinguishing retraction artifacts from LVI and doing immunostains for every case is impractical. However, we agree with concept that retraction spaces are not artifacts but true niches created by tumor following stromal destruction. It signifies tumor-stromal interactions that contribute to lymphatic spread and tumor progression.[54] Thus if there are extensive retraction artifacts, there will be emboli and it should be labeled as such. There is no system for quantifying LVI especially as what should be called extensive and if developed this will help manage adjuvant brachytherapy for early low-risk breast cancer patients.

  17. Multiple tumors:


  18. Definition: Multicentricity is occurrence of more than one site of tumor, more than 5 cm apart, usually in another quadrant. Multifocality is defined as multiple foci of the tumor, relatively close to each other, and usually in the same quadrant. How far apart do tumor nodules have to be to be considered as separate? The AJCC eighth edition clearly states that as long as there is 0.5 cm distance between tumors they could be considered separate.[40] It is generally felt that multicentric disease and multifocal disease have worst prognosis and high tumor burden; hence, just managing these patients on size of largest tumor may not be appropriate.[55]

    How to assess: Submit the intervening parenchyma separately. While giving sections from intervening parenchyma always try and include both tumors in section if they are close. In case it is not possible, then only give the free area. If only one tumor with intervening tissue is given then it may cause problems in interpretation.

  19. Microscopic reporting of post-NACT specimens:


  20. Essential point is to capture the extent of post chemotherapy tumor shrinkage and not to miss pathologic complete response (pCR). US Food and Drug Administration (USFDA) accepts two definitions of pCR viz. (1) absence of residual invasive cancer in the resected breast specimen and all sampled regional LNs following NACT (i.e., ypT0/Tis ypN0 in the current AJCC staging system) or (2) absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional LNs following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 in the current AJCC staging system).[56] Residual DCIS without disease in nodes and primary site is accepted as pCR by USFDA led pooled analysis of 12 neoadjuvant randomized trials undertaken by the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) found that there was similar survival in patients without residual invasive carcinoma irrespective of residual DCIS.[24] On the contrary, LVI represents resistant tumor post-NACT and hence are not considered pCR but rather an adverse prognostic factor post-NACT.[25] Tumor bed area shows distinct collagen changes or foamy macrophage infiltration that aids its identification microscopically. Several systems to grade post-NACT response exist and include the Miller–Payne system, Chevalier method, Sataloff method and residual cancer burden (RCB) calculator. Each of these varies in methodology and definition. For example, Millard Payne considers pre and post therapy cellularity differences, whereas RCB considers only post therapy cellularity.[57],[58] Which system to choose will depend on individual or institutional practice. The RCB advocated by the MD Anderson group is the most clinically validated system and requires documentation of largest contiguous tumor diameter, percentage of DCIS, cellularity within tumor bed area, number of positive nodes, and largest size of nodal metastases.[58] A web-based calculation script is freely available to calculate the scores (http://www.mdanderson.org/breastcancer_RCB). Tumor size post-NACT includes the cell clusters and intervening fibrous tissue. Miller Payne system grades responses from Grade 1 to Grade 5––whereby Grade 1 is no alteration in tumor and Grade 5 is pCR, whereas the other grades use cutoffs of 30%–90%.[57] The procedure for evaluating SLNs and axillary LNs post-NACT is the same as for non-neoadjuvant specimens. All surgically removed LNs should be sectioned at 2mm intervals and entirely submitted for histologic evaluation.[23] In NSABP-18, it was realized that patients with micrometastases have same survival as those with macrometastasis and hence micrometastasis are counted as macrometastasis in a node post-NACT.[59] American Joint Committee on Cancer TNM recommends isolated tumor cells after chemotherapy be called node negative (ypN0itc) but not regarded as pathological complete response, whereas World Health Organization recommends isolated tumor cells after chemotherapy be called node positive.[23] A sensible option is to look for fibrous response. If no associated fibrosis, call it node negative, whereas if fibrosis is seen count as node positive.[23] The presence of treatment effect in the LNs in the form of fibrosis, mucin pools, or large aggregates of foamy histiocytes identifies a subset of patients with an outcome intermediate between that of completely node negative and node positive after neoadjuvant systemic therapy.[60] Essential parameters to be included in postchemotherapy breast carcinoma report are listed in [Table 1].
    Table 1: Essentials in a histopathology report post-neoadjuvant therapy

    Click here to view


  21. Biomarkers in breast cancer:[61] The ER, PR, and HER2 estimation is mandatory in all primary breast cancers and relapses >6 months' duration. As preanalytical factors are more controlled in a core biopsy, we agree with recommendation that biomarkers should be tested on core biopsy and ASCO CAP have given distinct guidelines when to re-test on the resection specimen, in general when tumor in core vs. specimen looks different or not concordant with biomarkers on core biopsy re-testing on excision specimens is advised.


V. Impact of histopathology on surgical and adjuvant decisions

Use of histology in surgical revisions: As discussed earlier positive margins should be revised, though with use of the liberal SSO-ASTRO definition of a positive margin such revision surgeries are reducing. The patient, tumor, and treatment variables influence the decision for re-excision of positive margins. Likewise, in DCIS with <2 mm margin decision is individualized based on several factors such as the volume of disease near a margin, the patient's age, the tumor's size and grade, and the patient's tolerance of risk.[33] Also a false negative SLN or LAS in frozen section will mean revised axillary surgery for patients with high-risk disease and this decision is based on nodal disease burden as captured in the histopathology report.

Use of histology in radiation treatment planning: Whole breast irradiation (WBI) is given following breast conservation.[62] It consists of two phases: whole breast followed by boost to tumor bed. It is imperative to get full pathologic information especially the tumor size, margin width both for invasive as well as pre-invasive component and presence of LVI and EIC. In case of multifocal or multi-centric tumors it is important to know the status of the intervening breast tissue. This is required for planning boost radiation after WBI as it is very effective in reducing local recurrences around the tumor bed. As recent guidelines suggest anisotropic margins around the tumor bed (2 cm minus each margin width), reporting of width of each margin and not just closest cut margin is highly recommended. This ensures that the subclinical disease will be covered adequately in all directions. Similarly, it will also be useful to get information on the number of positive LNs and the levels involved as the inclusion of regional nodes depends upon this information. Although even patients with N1 disease are increasingly offered regional nodal irradiation, certain proportion of patients with favorable tumor biology may be spared of this. Accelerated partial breast irradiation (APBI) involves irradiation of the tumor bed alone instead of WBI in highly select cases of early breast cancer. The success of APBI depends a lot on the case selection and pathology is the backbone of this. Various pathologic factors such as tumor size, margin width, presence of EIC and LVI, nodal status, and hormone receptor status constitute important selection criteria for APBI given by various professional bodies.[63],[64] Excellent outcome has been reported with the approach when optimal case selection criteria are used. APBI is generally considered when tumor size is up to 3 cm, margin width ≥2 mm, absence of EIC and LVI, hormone positive, and negative nodes. Post mastectomy radiotherapy (PMRT) requires detailed information on node status.[65] Hence, not only is the number of positive nodes important but the LN ratio also seems to have a prognostic importance especially in high-risk node-negative disease as well as in 1–3 LN positive cohort.[65] In this early-stage disease, LVI also serves as an important prognostic factor that is frequently considered while deciding indication for PMRT especially when multiple risk factors such as high tumor grade, large tumor size, and non-luminal subtype are also present

Use of histology in adjuvant systemic treatment planning

The recommendations for adjuvant therapies are based on classic anatomic and pathologic factors, such as tumor size, tumor grade, and LN status, hormone, and HER 2-receptor status.[66] Although there has been significant development in genomic profiling techniques and the identification of tumor subtypes based on molecular expression patterns,[67],[68] but these tests are not yet routinely performed and also not freely available worldwide, Immunohistochemistry is still considered standard for planning adjuvant treatment and evaluating risk of relapse. Routine good histology is of paramount importance in deciding the need for adjuvant. A summary of risk stratification for adjuvant systemic therapies is given in [Table 2].
Table 2: Systemic adjuvant therapy options for patients stratified by risk of relapse

Click here to view


To conclude, the essentials in a histopathology report must include tumor size, type, grade, EIC, LVI, node status, ENE, and extent of nodal burden. In special situations such as DCIS or post-NACT, grossing should be done meticulously the first time as that's the best time to capture the predictive power of a histopathology report. Awareness of do's and don'ts will help us manage our patients better.

Acknowledgement

We thank Dr Prarthana Shah for the photographs of the specimens.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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

  [Table 1], [Table 2]



 

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