Invasive lobular carcinoma

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Author: Mikael Häggström [note 1]
Invasive lobular carcinoma (ILC):

Gross examination

As per:

or mastectomy.

Microscopic evaluation

Invasive lobular carcinoma.

Characteristics

The "classic" pattern is round or ovoid cells with little cytoplasm in a single-file infiltrating pattern, sometimes concentrically giving a targetoid pattern.

Subtyping

The histologic patterns mainly include:[1][2][3]

Type Prevalence Description Image
Classical 40% Round or ovoid cells with little cytoplasm in a single-file infiltrating pattern, sometimes concentrically giving a targetoid pattern Classic Invasive Lobular Carcinoma of the Breast (6813147194).jpg
Mixed 40% No dominant pattern
Solid 10% 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.
Histopathology of pleomorphic lobular carcinoma with plasmacytoid cells.jpg

Differential diagnosis

  • 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:

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]

Measurements can be made by marking the tumor on microscopy, and then measuring between the markings, which may overlap between multiple slides as shown.
  • T1: Less than 2 cm
  • T1a: 0.1 to 0.5 cm
  • T1b: 0.5 to 1.0 cm
  • T1c: 1.0 to 2.0 cm
  • T2: 2 to 5 cm
  • T3: Larger than 5 cm
  • T4
  • T4a: Chest wall involvement
  • T4b: Skin involvement
  • T4c: Both 4a and 4b
  • 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.

Overall stage

A combination of T, N and M, as follows:[5]

  • Stage 0: Tis
  • Stage I: T1N0
  • Stage II: T2N0, T3N0 T0N1, T1N1, or T2N1
  • Stage III: Invasion into skin and/or ribs, matted lymph nodes, T3N1, T0N2, T1N2, T2N2, T3N2, AnyT N3, T4 any N, locally advanced breast cancer
  • Stage IV: M1, advanced breast cancer
Further information: Evaluation of tumors

Grading

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.

Tubule formation

By definition, tubule formation in classic invasive lobular carcinoma is scored as 3.[15]

Nuclear pleomorphism

Such as nuclei being larger, darker, or irregular/pleomorphic. Note: The cancer areas having cells with the greatest atypia should be evaluated.

  • 1 point: nuclei with minimal or mild variation in size and shape
  • 2 points: nuclei with moderate variation in size and shape
  • 3 points: nuclei with marked variation in size and shape

Mitotic count

Mitosis appearances in breast cancer

Mitotic figures are counted only at the periphery of the tumor, and counting should begin in the most mitotically active areas.

  • 1 point: Between 0-5 and 0-11 mitotic counts per 10 high-power fields (HPFs), depending on type of microscope used.[note 2]
  • 2 points: Between 6-10 and 12-22 mitotic counts per 10 HPFs.[note 2]
  • 3 points: Over 10 to 22 mitotic counts per 10 HPFs.[note 2]

Overall grade

The scores for each of these three criteria are added together to give a final overall score and a corresponding grade as follows:

  • 3-5 Grade 1 tumor (well-differentiated). Best prognosis.
  • 6-7 Grade 2 tumor (moderately differentiated). Medium prognosis.
  • 8-9 Grade 3 tumor (poorly differentiated). Worst prognosis.

Immunohistochemistry

Ki-67 index

Ki-67 in an invasive breast cancer: cancer nuclei are stained (brown). There is tumor cell positivity in 70% of the cells (Ki-67 labelling index = 70%).
To count as positive, a nucleus should:
- Not be located in stroma.
- Be at least half within the field of view.
- Be large enough.
Otherwise, even weakly positive nuclei count as positive.

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

Score[19] Status[19]
0 to 1+ HER2 negative
(not present)
2+ Borderline
3+ HER2 positive

Biomarker retesting

((If the previous biopsy was negative for ER and PR receptors, and the patient has undergone neoadjuvant chemotherapy before excision, then retest ER/PR on the excision.))[note 4]

In breast cancer metastases, retest estrogen and progesterone receptors, and HER2 in the following circumstances:[20]

  • 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)

Estrogen and progesterone receptors

Generally perform immunohistochemistry for estrogen and progesterone receptors and calculate the percentage of positive tumor cells.

Neoadjuvant cases

edit
In neoadjuvant cases (patient has received chemotherapy, endocrine therapy and/or radiotherapy before the excision), perform:

  • Measurement of the tumor bed which generally manifests as a fibroelastic area.
  • Classification of residual cancer, for which there are multiple systems, mainly Residual Cancer Burden (RCB)[note 5] and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC).[21]
Further information: Evaluation of tumors

Report

Breast excision

  • Tumor size, if not already given from gross report.[4] Give 3 dimensions or greatest dimension.[4]
  • Histopathologic subtype if apparent, but "invasive carcinoma" is acceptable.
  • Stage[4]
  • Grade, preferably by overall BRE grade. Optionally, give scores for the components thereof.[4]
  • Extent of any angiolymphatic invasion.[4]
  • Margins of resection,[4] either as minimal distance to margin, or as radical vs. not radical excision.
  • 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.

Needle or core biopsy

  • Histopathologic subtype if apparent, but "invasive carcinoma" is acceptable.
  • Results of any immunohistochemistry and other tests, as per excision[4]
  • Presence of absence of angiolymphatic invasion[4]
  • Optionally: Provisional grading. Grading can alternatively be deferred to excision.[4]
  • State if studies are deferred for a later excision sample[4]

For cancers, generally include a synoptic report, such as per College of American Pathologists (CAP) protocols at cap.org/protocols-and-guidelines.

synoptic report example
Tumor type:  invasive ductal carcinoma with micropapillary pattern
Tumor size:  greatest microscopic measurement of invasive carcinoma in positive core(s)):  0.7 cm
In-situ component: no
Microscopic grading (Nottingham modification of the Bloom-Richardson system):
  • Only applies to infiltrating ductal and lobular carcinoma:  
Tubule formation: Little or none (score =3)
Nuclear pleomorphism: Marked variation in size, nucleoli, chromatin clumping, etc. (score =3)
Mitotic count : Less than 6 mitoses per 10 hpf (score =1)
Composite score: 7 points  (applies to infiltrating ductal and lobular carcinoma only)
Histologic grade: Grade II: 6-7  points
Nuclear grade: grade 3
Microcalcifications of non-neoplastic breast glands.
Microcalcifications: Present in non-neoplastic tissue
Lymphocytic host response: absent
Necrosis:  absent
Blood vessel invasion: absent
Lymphatic permeation: indeterminate
Skin involvement: not applicable
Results of immunohistochemical stains for prognostic markers (as per original report):
Estrogen Receptor (ER) Status:  Positive (greater than 10% of cells demonstrate nuclear positivity)
Percentage of Cells with Nuclear Positivity:  91-100%
Average Intensity of Staining:  Strong
Progesterone Receptor (PgR) Status:  Positive
Percentage of Cells with Nuclear Positivity:  51-60%
Average Intensity of Staining:  Strong, moderate and weak
HER-2 by IHC:  2+ / Equivocal
REFLEX HER-2 FISH TEST:  Nonamplificed (ratio 1.5;  3.5 Her-2 signals/cell)
Ki-67:
Percentage of Cells with Nuclear Positivity: 43%
Primary Antibody: MIB1
Cold Ischemia and Fixation Times: 3 minutes
Fixation Time (hours): 14 hours and 33 minutes
Fixative:  formalin

Notes

  1. 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.
  2. 2.0 2.1 2.2 Mitotic count:
    • 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
  3. 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 Institute 103 (22): 1656–1664. doi:10.1093/jnci/djr393. ISSN 0027-8874. 
  4. 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.
  5. A calculator and explanations for calculating RCB is found at: http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3

Main page

References

  1. "Association of Infiltrating Lobular Carcinoma With Positive Surgical Margins After Breast-Conservation Therapy ". Ann. Surg. 231 (6): 877–82. June 2000. doi:10.1097/00000658-200006000-00012. PMID 10816631. 
  2. "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. 
  3. Fletcher's diagnostic histopathology of tumors. 3rd Ed. p. 931-932.
  4. 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 . Infiltrating Ductal Carcinoma of the Breast (Carcinoma of No Special Type). Stanford Medical School. Retrieved on 2019-10-02.
  5. 5.0 5.1 5.2 Originally copied from Fadi M. Alkabban; Troy Ferguson. Cancer, Breast. National Center for Biotechnology Information. Last Update: June 4, 2019. Creative Commons Attribution 4.0 International License
  6. Chandler IP, Oommen R, Lawson CW (2003). "Invasive lobular carcinoma and cytokeratin immunohistochemistry: an audit. ". J Clin Pathol 56 (3): 240. doi:10.1136/jcp.56.3.240. PMID 12610108. PMC: 1769908. Archived from the original. . 
  7. "Internal mammary lymphadenopathy in breast carcinoma: CT appraisal of anatomic distribution ". Radiology 167 (1): 89–91. April 1988. doi:10.1148/radiology.167.1.3347753. PMID 3347753. 
  8. "Internal mammary lymphadenopathy: imaging of a vital lymphatic pathway in breast cancer ". Radiographics 10 (5): 857–70. September 1990. doi:10.1148/radiographics.10.5.2217975. PMID 2217975. 
  9. 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 ". Histopathology 19 (5): 403–10. doi:10.1111/j.1365-2559.1991.tb00229.x. PMID 1757079.  "Republished ". Histopathology 41: 154–161. 2002. doi:10.1046/j.1365-2559.2002.14892.x. 
  10. Oudai Hassan. What is the Nottingham combined histologic grade (modified Scarff-Bloom-Richardson grade) system for breast tumors?. Medscape. Updated: Mar 20, 2019
  11. Al-Kuraya, Khawla; Schraml, Peter (2004). "Prognostic relevance of gene amplifications and coamplifications in breast cancer ". Cancer Research 64 (23): 8534–8540. 
  12. 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.
  13. Bloom, H.J.; Richardson, W.W. (1957). "Histological grading and prognosis in breast cancer; A study of 1409 cases of which 359 have been followed for 15 years ". British Journal of Cancer 11 (3): 359–77. doi:10.1038/bjc.1957.43. PMID 13499785. 
  14. 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 Research 18 (1B): 571–6. PMID 9568179. 
  15. . Infiltrating Lobular Carcinoma of the Breast. Stanford Medicine. Retrieved on 2021-01-06.
  16. 16.0 16.1 16.2 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 Institute 103 (22): 1656–1664. doi:10.1093/jnci/djr393. ISSN 0027-8874. 
  17. 17.0 17.1 17.2 17.3 Coleman, 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 ONE 12 (2): e0172031. doi:10.1371/journal.pone.0172031. ISSN 1932-6203. 
  18. . Ki67-QC international working group: whole section scoring protocol (global method). International Ki67 in Breast Cancer Working Group (2018-11-29).
  19. 19.0 19.1 . IHC Tests (ImmunoHistoChemistry). Breastcancer.org. Retrieved on 2019-10-04. Last modified on October 23, 2015
  20. Penault-Llorca F, Coudry RA, Hanna WM, Osamura RY, Rüschoff J, Viale G (2013). "Experts' opinion: Recommendations for retesting breast cancer metastases for HER2 and hormone receptor status. ". Breast 22 (2): 200-202. doi:10.1016/j.breast.2012.12.004. PMID 23352656. Archived from the original. . 
  21. Campbell JI, Yau C, Krass P, Moore D, Carey LA, Au A (2017). "Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). ". Breast Cancer Res Treat 165 (1): 181-191. doi:10.1007/s10549-017-4303-8. PMID 28577078. PMC: 5653207. Archived from the original. . 

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