The "classic" pattern is round or ovoid cells with little cytoplasm in a single-file infiltrating pattern, sometimes concentrically giving a targetoid pattern.
Sheets of classical-appearing cells with little intervening stroma.
Alveolar
5%
Aggregates of classical-appearing cells
Tubulolobular
5%
Cells form microtubules in >90% of tumor (smaller than in tubular carcinoma)
Pleomorphic
Classical-appearing but with pleomorphic cells. It may include signet-ring cells, or plasmacytoid cells (pictured) which have abundant cytoplasm and eccentric nuclei.
In invasive lobular carcinoma, malignant cells have penetrated the basement membrane, in contrast to lobular carcinoma in situ.
Invasive ductal carcinoma typically has duct-forming tumor cells rather than single files of tumor cells. In uncertain cases, stain for E-cadherin and p120:
p120 has cytoplasmic staining in invasive lobular carcinoma (shown), but has membranous staining in invasive ductal carcinoma
Staging
Stage by the TNM system as follows in sections below.
Also, look for any angiolymphatic invasion. If present, check whether it reaches outside the tumor, and if so, how far.[4] Give greatest dimension (,or 3 dimensions, generally by adding up the estimated thicknesses of involved slices)).[4]
Primary Tumor (T)
Tumor – Depends on the tumor at the primary site of origin, as follows:[5]
T4d: Inflammatory breast cancer, a clinical circumstance where typical skin changes involve at least a third of the breast.
Regional Lymph Nodes (N)
Lymph Node: When sentinel lymph nodes are submitted together with a biopsy or excision of a suspected or previously confirmed invasive lobular carcinoma, and you don't see any involvement on the H&E stain, order immunostain for CK AE1/AE3 in order to visualize otherwise occult lymph node involvement.[6] However, this is not mandatory for invasive carcinoma with lobular features, or non-sentinel lymph nodes.
The lymph node values depend on the number, size and location of breast cancer cell deposits in various regional lymph nodes, such as the armpit (axillary lymph nodes), the collar area (supraclavicular lymph nodes), and inside the chest (internal mammary lymph nodes.)[7][8] Each stage is as follows:[5]
N0: There is some nuance to the official definitions for N0 disease, which includes:
N0(i+) : Isolated Tumor Cell clusters (ITC),[4] which are small clusters of cells not greater than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section, whether detected by routine histology or immunohistochemistry;
N0(mol-): regional lymph nodes have no metastases histologically, but have positive molecular findings (RT-PCR).
N1: Mobile ipsilateral axillary nodes. Lymph node clusters 0.2 - 2.0 mm can be called "micrometastasis". At least one carcinoma focus over 2.0 mm is called "Lymph node metastasis". If one node qualifies as metastasis, count all other nodes even with smaller foci as metastases as well.[4]
Critical numbers of involved nodes: 1-3, 4-9, and 10 and over. Note any extranodal extension.[4]
N2: Fixed/matted ipsilateral axillary nodes.
N3
N3a – Ipsilateral infraclavicular nodes
N3b – Ipsilateral internal mammary nodes
N3c – Ipsilateral supraclavicular nodes
Distant Metastases (M)
M0: No clinical or radiographic evidence of distant metastases
M0(i+): Molecularly or microscopically detected tumor cells in circulating blood, bone marrow or non-regional nodal tissue, no larger than 0.2 mm, and without clinical or radiographic evidence or symptoms or signs of metastases, and which, perhaps counter-intuitively, does not change the stage grouping, as staging for in M0(i+) is done according to the T and N values
M1: Distant detectable metastases as determined by classic clinical and radiographic means, and/or metastasis that are histologically larger than 0.2 mm.
The Nottingham system[9] is recommended for breast cancer grading.[10] The Nottingham system is also called the Bloom–Richardson–Elston system (BRE)[11], or the Elston-Ellis modification[12] of the Scarff-Bloom-Richardson grading system.[13][14] It grades breast carcinomas by adding up scores for tubule formation, nuclear pleomorphism, and mitotic count, each of which is given 1 to 3 points. The scores for each of these three criteria are then added together to give an overall final score and corresponding grade as follows.
Look at local protocols for what immunohistochemistry tests and other biomarker test need to be tested for each case of invasive breast cancer, or what needs to be retested for subsequent excisions at the primary site or at metastatic sites.[note 2]
Ki-67 index is mainly relevant in those with stage T1-T2, N0-N1, to determine if chemotherapy is needed (if Ki67 is >30% rather than <5%).[16]
Ki-67 index is most feasibly quantified by a hot spot method,[note 3] Hot spots are areas in which Ki-67 staining is particularly higher relative to the adjacent tumor areas.[17] Usually, the invasive edge of a tumor is a hot spot.[17] When a tumor had several hot spots, the “hottest” spot is selected.[17] Aim to count at least 500 cells in each case, but this is not always possible in cases with low tumor cell density and small tumor size.[17] Also aim to include at least three high-power (×40 objective) fields. Count a nucleus as “positive” if there is any definite brown staining in the nucleus of an invasive breast cancer cell, above the surrounding background in the cytoplasm and extracellular matrix.[18] If a comparisons must be made between core biopsies and sections from an excision, evaluation of the latter should be across the whole tumor.[16] Only nuclear staining counts. Staining intensity of a positive nucleus is not relevant.[16]
HER2
HER2 can initially be evaluated by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). If IHC is performed first and is borderline/equivocal, then FISH is recommended.[19] If FISH is performed first and indicates that further workup is required, then IHC may be the performed as per established algorithms.[note 4]
HER2 immunohistochemistry
Look at different parts of the tumor, and evaluate the area(s) with most staining. When negative of faint staining is seen, evaluate at high magnification.
HER2 FISH usually uses chromosome enumeration probe 17 (CEP17) to count the amount of chromosomes. Hence, the HER2/CEP17 ratio reflects any amplification of HER2 as compared to the number of chromosomes.
To prepare a slide for HER2 testing, you may need to choose a paraffin-embedded and mark the resulting slide so that you or whoever interprets it knows where to look for the target tumor cells. When there are multiple blocks of the same case, choose the the one with most tumor. (If a block has undergone sectioning for immunohistochemistry (such as ER, PR and/or Ki67) make sure that you have a new H&E slide at a level next to the one to be used for FISH, so that they will correlate better.) In cases of both invasive and in situ carcinoma in the same specimen, mark all invasive carcinoma (also for crushed tissue or with other artifacts) but not the in situ carcinoma. Also mark a small area of normal tissue as an internal control. If possible, it should be a bit away from the tumor, even if only consisting of fatty tissue.
To interpret a HER2 FISH study, first perform a quality control check of the slide as per manufacturer and/or local protocol (generally including checking for proper signals from a control specimen). In cases of both invasive and in situ carcinoma in the same specimen, only score the invasive cells. The signals of 20 cells are usually counted. Also focus up and down on each nucleus to find all signals therein.
A yellow signal cunts as one red and one green (which are overlapping)
If a cytotechnologist has already performed a count, you do not have to recount, but make sure the count is reasonable regarding what you see. In any case, also look around for any obvious tumor heterogeneity in HER2 signals.
Algorithm for the evaluation of HER2 on fluorescence in situ hybridization (FISH).[24] See source article in cases where additional workup is indicated.[note 4]
If the HER2/CEP17 ratio is borderline (1.8-2.2), count an additional 20 nuclei and recalculate a ratio for the total of 40 nuclei.
Classification of HER2 by fluorescence in situ hybridization (FISH)[note 4]
If the initial HER2 result is negative for a needle biopsy of a primary breast cancer, a new HER2 test may be performed on the subsequent breast excision.[note 4]
Margins of resection,[4] as closest distance from carcinoma to margin in mm or cm or "tumor on ink"/"carcinoma is present on margin". ((If applicable, also specify as "close margins" (no tumor on ink but <2 mm), or "negative margins" (≥2 mm).))[25]
Results of any immunohistochemistry and other tests[4]
HER2 as a score or status.
Ki-67, preferably as labeling index
Example:
Breast excision with 70 x 55 x 18 mm ductal invasive breast cancer. Nottingham grade II. Estrogen receptor positive, progesterone receptor negative, HER2 receptor score 0, Ki-67 index 17%, T1b. Radically removed.
1 point: 0-9 mitotic counts per 10 fields under X25 objective using the Leitz Ortholux microscope, 0-5 mitotic counts per 10 fields under X40 objective using the Nikon Labophot microscope, or 0-11 mitotic counts per 10 fields under X40 objective using the Leitz Daiplan microscope
2 points: 10-19 mitotic counts per 10 fields under X25 objective using the Leitz Ortholux microscope, 6-10 mitotic counts per 10 fields under X40 objective using the Nikon Labophot microscope, or 12-22 mitotic counts per 10 fields under X40 objective using the Leitz Daiplan microscope
3 points: Over 19 mitotic counts per 10 fields under X25 objective using the Leitz Ortholux microscope, over 10 mitotic counts per 10 fields under X40 objective using the Nikon Labophot microscope, or over 22 mitotic counts per 10 fields under X40 objective using the Leitz Daiplan microscope
↑For a full list of contributors, see article history. Creators of images are attributed at the image description pages, seen by clicking on the images. See Patholines:Authorship for details.
↑If the previous biopsy was negative for ER and PR receptors, and the patient has undergone neoadjuvant chemotherapy before excision, then generally retest ER/PR on the excision. Retesting ER/PR on any excision with previously negative ER/PR on biopsy on a patient having received neoadjuvant therapy has no scientific support nor opposition. - William M Sikov, MD, FACP, FNCBCJudy C Boughey, MD, FACSZahraa Al-Hilli, MD, FACS, FRCSI. General principles of neoadjuvant management of breast cancer. UpToDate.
In breast cancer metastases, generally retest estrogen and progesterone receptors, and HER2 in the following circumstances:
If the status of the primary tumor is unknown or negative for ER/PR and/or HER2
If the primary tumor is heterogeneous for ER/PR expression
If the metastatic progression is unusual for the tumor characteristics
If the relapse is unexpectedly early or late
If unusual metastasis location
If the initial test was performed more than 10 years ago
If the testing turnaround time are relatively short (to reduce potential delays in patient management by retesting)
↑Besides from a hot spot method of Ki67 counting, there is also a IKWG global average method which is more comprehensive. However, the inter-observer difference between the hot spot method and the 'IKWG global average is not statistically significant, and has not shown any significant difference in clinical outcome (theoretically, the area of highest Ki-67 proliferative index is probably most likely to correlate with malignant transformation and risk of metastasis, making the hot spot both more straightforward and clinically relevant than a global average). - Reference and instructions for the IKWG global average method: Dowsett, M.; Nielsen, T. O.; A'Hern, R.; Bartlett, J.; Coombes, R. C.; Cuzick, J.; Ellis, M.; Henry, N. L.; et al. (2011). "Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group
". JNCI Journal of the National Cancer Institute103 (22): 1656–1664. doi:10.1093/jnci/djr393. ISSN0027-8874.
↑"Synchronous bilateral invasive lobular breast cancer presenting as carcinomatosis in a male
". Am. J. Surg. Pathol.33 (3): 470–4. March 2009. doi:10.1097/PAS.0b013e318190d10d. PMID 19092630.
↑Fletcher's diagnostic histopathology of tumors. 3rd Ed. p. 931-932.
↑"Internal mammary lymphadenopathy in breast carcinoma: CT appraisal of anatomic distribution
". Radiology167 (1): 89–91. April 1988. doi:10.1148/radiology.167.1.3347753. PMID 3347753.
↑"Internal mammary lymphadenopathy: imaging of a vital lymphatic pathway in breast cancer
". Radiographics10 (5): 857–70. September 1990. doi:10.1148/radiographics.10.5.2217975. PMID 2217975.
↑Elston, CW; Ellis, IO (1991). "Pathologic prognostic factors in breast cancer. I. The value of histological grades in breast cancer. Experience from a large study with long-term follow-up
". Histopathology19 (5): 403–10. doi:10.1111/j.1365-2559.1991.tb00229.x. PMID 1757079. "Republished
". Histopathology41: 154–161. 2002. doi:10.1046/j.1365-2559.2002.14892.x.
↑Al-Kuraya, Khawla; Schraml, Peter (2004). "Prognostic relevance of gene amplifications and coamplifications in breast cancer
". Cancer Research64 (23): 8534–8540.
↑Elston CW, Ellis IO. Pathologic prognostic factors in breast cancer. I. The value of histological grades in breast cancer. Experience from a large study with long-term follow-up. Histopathology 1991, 19:403-410.
↑Genestie, C.; Zafrani, B.; Asselain, B.; Fourquet, A.; Rozan, S.; Validire, P.; Vincent-Salomon, A.; Sastre-Garau, X. (1998). "Comparison of the prognostic value of Scarff-Bloom-Richardson and Nottingham histological grades in a series of 825 cases of breast cancer: Major importance of the mitotic count as a component of both grading systems
". Anticancer Research18 (1B): 571–6. PMID 9568179.
↑Pujani, Mukta; Sharma, KiranLata; Srivastava, AN; Singh, US; Bansal, Cherry (2014). "Grading systems in the cytological diagnosis of breast cancer: A review
". Journal of Cancer Research and Therapeutics10 (4): 839. doi:10.4103/0973-1482.140979. ISSN0973-1482.
↑ 16.016.116.2Dowsett, M.; Nielsen, T. O.; A'Hern, R.; Bartlett, J.; Coombes, R. C.; Cuzick, J.; Ellis, M.; Henry, N. L.; et al. (2011). "Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group
". JNCI Journal of the National Cancer Institute103 (22): 1656–1664. doi:10.1093/jnci/djr393. ISSN0027-8874.
↑ 17.017.117.217.3Coleman, William B.; Jang, Min Hye; Kim, Hyun Jung; Chung, Yul Ri; Lee, Yangkyu; Park, So Yeon (2017). "A comparison of Ki-67 counting methods in luminal Breast Cancer: The Average Method vs. the Hot Spot Method
". PLOS ONE12 (2): e0172031. doi:10.1371/journal.pone.0172031. ISSN1932-6203.
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