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Breast malignant, males, children

Superpage - Breast cancer

Revised: 12 December 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 November 2012, last major update March 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Epidemiology
=========================================================================

● Most common invasive malignancy in US women after skin cancer
● Estimated 227K new cases of invasive carcinoma in US women in 2012, 2K in men (American Cancer Society)
● Estimated 63K new cases of in situ carcinoma in US women in 2012
● Occurs in 1 of 8 to 9 women in US (1 of 232 at age 30-39 years, 1 of 29 at age 70-79)
● Similar incidence in other Western countries, but much lower incidence in Japan (Cancer Research UK)
● Sharp decrease in incidence in US women 50-69 years old may reflect reduced use of hormone replacement therapy (Breast Cancer Res 2007;9:R28)

Clinical description
=========================================================================

● 50% occur in upper outer quadrant, 17% central (subareolar), 5-15% other quadrants, 13% involve more than one quadrant (3% diffuse)
● Tumors in outer quadrant are more likely to have axillary nodes than those in inner quadrant
● Common symptoms are breast lumps and nipple abnormalities, sometimes discomfort
● Tumors presenting between mammographic screenings (interval tumors) are more aggressive

Synchronous
=========================================================================

● Second tumor discovered within 2 months of initial primary tumor
● Molecular studies can determine if synchronous tumors are two primaries or one primary with metastases (Mod Pathol 2008;21:1200)

Clinical examination
=========================================================================

● For breast, palpation is less sensitive/specific than mammography; mammographic abnormality is often presenting sign
● For axillary nodes, 40% of clinically negative nodes have tumor and 15% of clinically positive nodes lack tumor

Mammography
=========================================================================

● Can detect tumors as small as 1-2 mm via microcalcifications
● Microcalcifications are present in 50% of carcinomas vs. 20% of benign breast disease
● Suspicious mammographic features are opacity with irregular, spiculated margins, variable calcifications
● Also clusters of fine calcifications and asymmetry
● Only 20% of “suspicious” microcalcifications are actually malignant
● Up to 30% of tumors are not detectable by mammography due to poor resolution from surrounding fibrous breast (generally younger women)

MRI
=========================================================================

● Detects increased tumor vascularity and increased tumor uptake of contrast agents
● Usually no gross findings so must examine entire specimen (Hum Pathol 2007;38:1754)

Ultrasound
=========================================================================

● Can distinguish solid versus cystic lesions (latter are generally benign)

Needle biopsy
=========================================================================

● Radiologist marks microcalcifications with needle, surgeon removes area around needle, specimen is Xrayed to verify specimen includes microcalcifications of interest
● Pathologist should verify presence of microcalcifications (note: calcium oxalate crystals are easily missed by pathologists – must look for birefringence under polarized light)

Case reports
=========================================================================

● Recurrence in myocutaneous flaps (Arch Pathol Lab Med 2004;128:1157)
● Massive thyroid tumoral emboli (Arch Pathol Lab Med 2004;128:804)

Treatment and prognosis
=========================================================================

● Five year relative survival overall has improved from 63% in early 1960s to 89% in 2009 (US National Cancer Institute)
● Five year survival rate is 98% for localized breast cancer, dropping to 27% if distant metastases
● Death rate is 27 per 100,000 women (40,000 deaths per year in US), slowly falling since 1990 in North America, Western Europe and Australia
● #2 cause of US cancer deaths in women after lung cancer
● Main treatment is surgical excision (usually lumpectomy or modified radical mastectomy, sampling lumpectomy cavity margins may reduce need for re-excision, Am J Surg Pathol 2005;29:1625)
● Radiation therapy if positive margins or to control locally recurrent disease (44% recur without radiation if close/non-involved margins for DCIS versus 94% recurrence if margins are extensively positive, Mod Pathol 2004;17:81)
● Anti-estrogen drugs (tamoxifen and others to reduce risk of recurrence in same or opposite breast, particularly for ER+ tumors)
● Combination chemotherapy (for metastatic disease, to reduce the risk of contralateral breast carcinoma)
● Preoperative (neoadjuvant) chemotherapy shrinks large tumors to allow surgery or more conservative surgery

Clinical images
=========================================================================


Mass and retracted nipple

Micro description
=========================================================================

● Invasive if stromal invasion present
● Most tumors are adenocarcinomas arising from terminal duct lobular unit
● In situ carcinoma is present to variable extent (“extensive” if > 25% of tumor volume seen inside and outside of invasive tumor field)

Additional references
=========================================================================

Wikipedia, eMedicine



Axillary lymph node examination


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 November 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

See also Sentinel Nodes

Terminology
=========================================================================

● Macrometastases: >2mm
● Micrometastases: 2 mm or less
● Isolated tumor cells: 0.2 mm or less

Clinical description
=========================================================================

● Presence of axillary lymph node metastases is the most important prognostic factor for disease-free and overall survival, and important for determining treatment
● Presurgical staging of axillary nodes (ultrasound with FNA) is increasingly popular (Cancer 2008;114:89)
● Axillary nodal dissection may not be indicated if negative sentinel node examination, even if false-negative (Breast Cancer 2010;17:9, Eur J Cancer 2009;45:1381)
● Occult metastases (identified retrospectively by step-sectioning and immunohistochemical staining) are an independent predictor of disease-free survival, but not overall survival, in node-negative patients, particularly if > 0.5 mm (Am J Surg Pathol 2002;26:1286); recent study reports no prognostic significance of occult metastasis in early stage breast cancer (Cancer 2011 Aug 25 [Epub ahead of print])
● Significance of micrometastases is controversial (Arch Pathol Lab Med 2009;133:869)
● Clearing solutions, such as ethanol, diethyl ether, Carnoy’s solution (Chin Med J (Engl) 2007;120:1762), glacial acetic acid and formalin may identify additional lymph nodes (Am J Surg Pathol 1997;21:1387, Arch Pathol Lab Med 2001;125:642)
● Neoadjuvant chemotherapy may be associated with identification of fewer lymph nodes (J Am Coll Surg 2008;206:704), but see Am J Surg 2009;198:46
● Regional lymph nodes are:
    (1) Axillary (ipsilateral), subdivided as follows (image):
             ● Level I (low axilla): lateral to the lateral border of pectoralis minor muscle
             ● Level II (mid axilla): between medial and lateral borders of pectoralis minor muscle, plus the interpectoral (Rotter’s) lymph nodes
             ● Level III (apical axilla): medial to the medial margin of the pectoralis minor muscle, including those designated as apical, excluding those designated as subclavicular or infraclavicular
    (2) Infraclavicular (subclavicular, ipsilateral)
    (3) Internal mammary (ipsilateral): lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia
    (4) Supraclavicular (ipsilateral)

● Side effects of axillary nodal dissection include lymphedema, shoulder restriction, numbness, weakness and pain syndromes (Cancer J 2008;14:216)
● Dissection of the brachial, acromiothoracic, humeral, Rotter's and scapular lymph nodes is recommended for proper staging (J Egypt Natl Canc Inst 2011;23:25)

Case reports
=========================================================================

● 52 year old woman with submental lymph node metastasis from invasive ductal breast cancer (Arch Gynecol Obstet 2011 Sep 9 [Epub ahead of print])
● 55 year old woman with DCIS arising in intraductal papilloma in axillary lymph node (Arch Pathol Lab Med 2008;132:1940)
● 58 year old woman with melanoma and breast ductal carcinoma metastasizing to same node (Int Semin Surg Oncol 2006;3:32)
● 82 year old woman with sclerosing adenosis in axillary lymph node (Arch Pathol Lab Med 2008;132:1439)

Micro images
=========================================================================



Axillary nodal metastases


Metastatic breast carcinoma and melanoma

   
Subcapsular metastasis: H&E and keratin


Metastatic tumor (A) with adjacent histiocytes (B)

   
Various images


Metastatic carcinoma, benign inclusions and nevus cells

False positives (i.e. not metastatic breast carcinoma):

Intramammary lymph node


Metastatic ovarian serous papillary adenocarcinoma

   
DCIS arising in intraductal papilloma


Sclerosing adenosis


Benign epithelial inclusions - Fig 1: CK 5/6+; Fig 2: p63+

   
Left: heterotopic glands with structure of mammary lobule
Right: myoepithelial cells (arrows) and basement membrane are present



Lactational histiocytosis


Histiocytes (FNA)

       
Clusters of nevus cells have indistinct cell borders and small uniform nuclei,
and are S100+ (as are histiocytes)


   
Hemangioma


Tattoo pigment


Lipogranulomatosis due to triglyceride-filled breast implant

Features of chronic lymphedema of arm:

Hyperkeratosis, thickened dermis with edema, elastosis, fibrosis,
congested capillaries (arrow) and lymphocytes



Pseudoepitheliomatous hyperplasia, hyperkeratosis, dilated dermal vascular channels


Dilated dermal vascular channels with prominent endothelial cells

Cytology images
=========================================================================


Various images

Videos
=========================================================================


Axillary nodal metastases #1; #2

Differential diagnosis
=========================================================================

● Benign transport after prior breast biopsy (Am J Clin Pathol 2000;113:259)
● Ectopic breast tissue (Breast Cancer 2007;14:425)
● Mullerian-type epithelial inclusions: have myoepithelial cells which are p63+ and smooth muscle myosin+ (Arch Pathol Lab Med 2004;128:361, Arch Pathol Lab Med 1995;119:841, Am J Clin Pathol 2008;130:21)
● Muciphages: resemble signet-ring carcinoma, associated with prior surgery or lactation, Alcian blue+, CD68+, Mac387+, keratin- (Am J Surg Pathol 1998;22:545)
● Nevus cells (Am J Clin Pathol 1994;102:102, Am J Surg Pathol 2003;27:673, Arch Pathol Lab Med 1985;109:1044)



Epidermal Growth Factor Receptor (EGFR)


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 11 December 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Terminology
=========================================================================

● Also called HER1; related to HER2

Clinical description
=========================================================================

EGFR expression is associated with these breast cancers:
● Basal-like (BMC Genomics 2007;8:258)
● Metaplastic (76%, Breast Cancer Res 2005;7:R1028), carcinomas with squamous differentiation (87%, Int J Surg Pathol 2005;13:319)
● ER negative tumors (Pathol Res Pract 1988;183:25, Breast Cancer Res 2008;10:R49)
● Phyllodes tumors (all types-19%, malignant-75%, Lab Invest 2006;86:54)
● Sarcoma NOS (5 of 7, Am J Surg Pathol 2006;30:450)

● 6% of breast carcinomas show moderate to low level EGFR amplification associated with protein overexpression, and may be responsive to anti-EGFR therapy (Mod Pathol 2005;18:1027), currently used for lung cancer patients
● EGFR expression is more common in breast tumors in younger and black women
● EGFR expression associated with lower hormone receptor levels, higher proliferation, genomic instability, HER2 overexpression, higher risk of relapse (Cancer 2010;116:1234), poor survival (J Clin Oncol 2007;25:4405)

Micro images
=========================================================================



Metaplastic carcinoma: H&E, EGFR and EGFR-CISH


Phyllodes tumors


Spindle cell carcinoma: EGFR and HER2 overexpression

Contributed by Dr. Semir Vranic:

Invasive breast carcinoma with squamous features: H&E, EGFR

IHC and CISH

Molecular images
=========================================================================



Malignant phyllodes tumor and EGFR amplification



HER2 (c-erbB2)


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 11 December 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● HER2 gene encodes transmembrane growth factor receptor (p185)
● Cytoplasmic tyrosine kinase is constitutively active when overexpressed due to homo/heterodimerization (diagram)
● “3+” protein staining is associated with HER2 gene amplification at 17q21
● The biologic impact of HER2 gene amplification is not due to (a) mere chromosome 17 polysomy without HER2 gene amplification (Am J Surg Pathol 2005;29:1221) or (b) chromosome 17 aneusomy [aneusomy means other than 2 copies of chromosome] (Mod Pathol 2002;15:137)

Terminology
=========================================================================

● Also called Human Epidermal growth factor Receptor 2, c-erbB2, neu, ERBB2, CD340

HER2 gene amplification
=========================================================================

● Present in 18-25% of breast tumors
● Associated with comedocarcinoma and aggressive invasive tumors
● Detectable by FISH; defined as increased ratio of HER2 gene to chromosome 17 (count > 2.2)
● Weak/moderate immunohistochemical staining is common without gene amplification
● Usually appears first in ADH or DCIS (Mod Pathol 2002;15:116)
● Also seen in nonbreast cancers (Mod Pathol 2007;20:192)
● Anti-HER2 therapy (trastuzumab/Herceptin) plus chemotherapy reduces recurrence, metastases and mortality in HER2 gene amplified breast cancer patients (Int Semin Surg Oncol 2008;5:9, Acta Oncol 2008;47:1564); Lapatinib (Tykerb) has a similar effect (Biologics 2009;3:289)
● Anti-HER2 therapy may improve survival in metastatic disease (Am J Clin Oncol 2008;31:250, N Engl J Med 2007;357:1496, but is associated with cardiac toxicity (BMC Cancer 2007 Aug 8;7:153)

Detection of HER2 gene amplification
=========================================================================

● Predominantly determined using immunohistochemistry/IHC as screening test
● 3+ staining (see below) is highly correlated with gene amplification (FISH is more sensitive but more expensive, and it is difficult to distinguish in situ from invasive lesions because a fluorescent microscope must be used, which makes it difficult to assess histologic features (Mod Pathol 2000;13:1238, Hum Pathol 2005;36:250 [quality assurance])
● Can also detect with chromogenic in situ hybridization (CISH, Mod Pathol 2002;15:657, Mod Pathol 2005;18:1015, Mod Pathol 2006;19:481, Breast Cancer Res 2007;9:R68) and silver enhanced in situ hybridization (SISH, Am J Clin Pathol 2009;132:514)
● CISH is comparable to FISH using ASCO/CAP criteria (Am J Clin Pathol 2009;131:490), even in cases with polysomy 17 and equivocal HercepTest results (Am J Clin Pathol 2009;132:228)
● CISH and SISH use a peroxidase enzyme labeled probe with chromogenic detection, allowing results to be visualized with standard bright-field microscopy, so histologic features and HER2 status can be evaluated in parallel; signals do not decay over time, unlike FISH (Am J Clin Pathol 2009;132:539)
● Can also use quantitative reverse transcription-polymerase chain reaction (Am J Clin Pathol 2008;129:563)
● FISH may be an appropriate screening test (instead of immunohistochemistry) under some conditions (Oncol Rep 2008;19:1271)
● Use of FISH cutpoint of 1.5 instead of 2.2 (signifies intermediate outcome between amplification negative and positive) has been suggested (Breast Cancer Res Treat 2008;112:453)
● For IHC, should compare intensity of patient sample to 3+ control slide with negative normal epithelium
● For node negative patients, FISH and IHC results are generally similar with some discrepant cases (Arch Pathol Lab Med 2001;125:746)
● Equivocal IHC and borderline FISH cases are difficult to interpret, even for highly experienced and validated laboratories (Mod Pathol 2007;20:584)
● External quality assurance is important (Am J Clin Pathol 2009;131:106)
● HER2 overexpression by IHC is associated with high Ki-67 index and negative ER/PR
● Note: even low level HER2 expression, without amplification, may be an adverse prognostic factor (Am J Surg Pathol 2009;33:759)

ASCO/CAP recommendations
=========================================================================

(a) Determine HER2 by IHC for all invasive breast cancer cases
(b) Specific procedures are recommended to reduce assay variation
(c) Define HER2 amplification as either 3+ IHC staining (uniform, intense stain of >30% of tumor cells), FISH of > 6 HER2 gene copies/nucleus or FISH ration > 2.2
(d) Define negative tests as 0 or 1+ IHC, FISH <4.0 or FISH ratio < 1.8
(e) Classify other results as equivocal, and perform additional testing
(f) Labs should show 95% concordance with another validated test (Arch Pathol Lab Med 2007;131:18, Mod Pathol 2008;21 Suppl 2:S8); similar recommendations in UK (J Clin Pathol 2008;61:818)

● FDA and ASCO/CAP schemes for HER2 evaluation select patients differently, with major discordances for low-grade, borderline HER2 amplification (Am J Clin Pathol 2008;129:907); high concordance between FISH and ISH requires modification of FDA scoring system (Mod Pathol 2008;21:1271)
● Standardized formalin fixation (minimum of 6 hours for core biopsies) is also important for IHC / FISH concordance (Arch Pathol Lab Med 2009;133:775), as is not delaying formalin fixation by more than one hour (Mod Pathol 2009;22:1457)
● Guidelines for evaluating genetic heterogeneity in HER2 testing have been produced (Arch Pathol Lab Med 2009;133:611)

Staining pattern
=========================================================================

● 0 (negative) - no staining or membrane staining in <30% of tumor cells
● 1+ (negative) - faint membrane staining in > 30% of tumor cells; only part of membrane is stained
● 2+ (weak positive) - weak/moderate complete membrane staining in >30% of tumor cells
● 3+ (strong positive) - strong complete membrane staining in >30% of tumor cells
● Note: 30% threshold is from ASCO/CAP scheme in 2008, prior threshold was 10%
● IHC stain scores of 0/1+ (negative/weak) or 3+ (strong) are predictive of FISH results (negative and positive amplification respectively)
● 2+ is not predictive and has significant interobserver variability (Mod Pathol 2001;14:1079)
● Suggested to perform FISH or PCR for 2+ tests (Am J Clin Pathol 2005;123:766)
● For equivocal HER2 results by FISH or PCR on breast core biopsies, recommended to evaluate on larger tumor sample (Am J Clin Pathol 2008;129:383)
● Normalization of IHC markedly improves concordance between IHC and FISH (Mod Pathol 2008;21:1271)
● Serum HER2 levels may predict histopathologic response to chemotherapy (Am J Clin Pathol 2007;128:630), and presence of HER2 mRNA-positive circulating tumor cells is independent prognostic factor in women with early breast cancer (Breast Cancer Res Treat 2009;117:525)
● HER2 gene status remains highly conserved as breast cancers metastasize; the discrepancies present are often due to interpretational difficulties and heterogeneity of HER2 amplification (Breast Cancer Res 2007;9:R31)

Testing algorithm
=========================================================================




Other images: HER2/neu testing algorithm

Case reports
=========================================================================

● Overgrowth of HER2 negative cells after anti-HER2 antibody therapy (Hum Pathol 2004;35:379)

Micro images
=========================================================================


Immunohistochemistry:
           
3+: IHC


3+: IHC, CISH and FISH

2+: IHC


1+: IHC

Various images:
   
Strong versus weak staining


Heterogeneous staining

FISH, CISH:
           
FISH amplification


IHC and FISH


FISH: amplified and not amplified


Not amplified - CISH and FISH

   
CISH amplification: clusters and single signals


CISH - not amplified, amplified, borderline amplification, equivocal signals


CISH and IHC

Other images: Figure 2, Figure 1, 3+: IHC, 2+: IHC, 1+: IHC, DCIS with ER and HER2 double immunostaining, Ductal hyperplasia, ADH, DCIS, and invasive carcinoma, Not amplified - FISH, CISH amplification: clusters and single signals

Additional references
=========================================================================

Wikipedia, eMedicine



Histologic grading


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 November 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Grading system
=========================================================================

● Most commonly used system is Elston/Nottingham modification of Bloom-Richardson system, based on (a) tumor tubule formation, (b) number of mitotic figures in most active areas, and (c) nuclear pleomorphism (Br J Cancer 1957;11:359, Histopathology 1991;19:403)
● Tumor should be graded based on representative portion of tumor, not the least differentiated part (Arch Pathol Lab Med 1983;107:411)

Tumor tubule formation:
1 point: > 75% of tumor
2 points: 10-75% of tumor
3 points: < 10% of tumor

Note: the overall appearance of the tumor must be taken into consideration in scoring tubule formation
Note: tubules must have clear central lumina to be counted

Number of mitotic figures in most active area, counting 10 high power fields:
               (a)     (b)     (c)
1 point:   0-5     0-9    0-11
2 points: 6-11   10-19 12-22
3 points: 11+    20+    23+

(a) Nikon or Labophot 40x objective or comparable with field diameter of 0.44 mm
(b) Leitz or Ortholux 25x objective or comparable with field diameter of 0.59 mm
(c) Leitz or Diaplan 40x objective or comparable with field diameter of 0.63 mm

Notes:
(a) count mitotic figures at periphery of tumor in most mitotically active area; count 10 high power fields in the same area, but not necessarily contiguous; select fields with as much tumor as possible; avoid poorly preserved areas; ignore cells with hyperchromatic and pyknotic nuclei, which may be undergoing apoptosis
(b) quick scan mitotic impression is less accurate (Hum Pathol 2008;39:584)

Nuclear pleomorphism:
1 point: minimal nuclear variation in size and shape; small regular uniform cells
2 points: moderate nuclear variation in size and shape
3 points: marked nuclear variation in size and shape

Note: evaluate areas with greatest atypia
Note: for infiltrating lobular carcinoma, two tiered grading system for nuclear pleomorphism is recommended (Ann Diagn Pathol 2009;13:223)

Scoring
3-5 points: well differentiated (grade I)
6-7 points; moderately differentiated (grade II)
8-9 points: poorly differentiated (grade III)

Criticisms of Nottingham Bloom Richardson grading system
=========================================================================

● Grading has been criticized for low reproducibility (Mod Pathol 2005;18:1067, Virchows Arch 2007;450:627)
● The concept of a moderately differentiated category has been criticized (Pathobiology 2008;75:104, J Natl Cancer Inst 2006;98:262)
● Tumors with 3+3+1 pattern (i.e. <10% tubules, marked nuclear pleomorphism but few mitotic figures) may have low mitotic count due to failure to fix tumor immediately after excision, which allows tumor cells to complete cell division and leads to reduction in observed mitotic figures; Ki-67 may serve as surrogate for mitotic figure counting in these cases (Oncologist 2008;13:477)

Clinical description
=========================================================================

● Histologic grade is a strong predictor of survival (J Clin Oncol 2008;26:3153)
● In US, blacks overall have higher grade tumors than whites (Cancer 2003;98:908)

Micro images
=========================================================================


Tubule formation (AFIP Fascicle Third Series)
            
1 point (>75% tubules)     3 points (<10% tubules)

Nuclear pleomorphism
       
Mild                            Moderate                 Marked

Overall histologic grades
               
Low grade

   
Intermediate grade


Possibly high grade - see caption

           
High grade

Other images: high grade #1; #2; #3



Hormone receptors


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 11 December 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Estrogen receptors (ER) have alpha and beta subtypes
● ER-alpha: “classic” functions of ER; may render breast epithelium susceptible to proliferative stimulation of estrogen; expressed in breast and endometrium; immunostains not specifically classified as ER-alpha or ER-beta are usually ER-alpha
● ER-beta: provides “housekeeping” functions; expressed in normal ovary and granulosa cells, carcinoma of breast, colon, prostate; values differ from ER-alpha in BRCA1 associated breast carcinoma (BMC Cancer 2008;8:100)

Features
=========================================================================

● Presence of estrogen (type alpha) and progesterone receptors correlates best with response to anti-estrogen treatment (tamoxifen or others) or chemotherapy
● Expression of ER-beta in ER-alpha negative breast cancer patients is an independent marker for favorable prognosis after adjuvant tamoxifen treatment (Clin Cancer Res 2007;13:1987, Hum Pathol 2001;32:113); may have prognostic value in ER+/PR+ patients (APMIS 2009;117:644)
● Otherwise, hormone expression correlates only weakly with prognosis; presence is associated with older age
● Endocrine therapy responsiveness is observed even with low expression of ER (1-5%)
● ER gene profiling (BMC Genomics 2008;9:239) or ER-beta mRNA (BMC Cancer 2007;7:131) may predict the 30-40% of ER+ tumors that will NOT respond to tamoxifen
● Immunostaining is done on paraffin fixed tissue (previously required fresh tissue)
● Recommended to fix tissue within 1 hour of receipt (Mod Pathol 2009;22:1457), and for at least 6 hours (for HER2, Arch Pathol Lab Med 2009;133:775)
● ER antibodies SP1 and 1D5 give similar results (Am J Clin Pathol 2009;132:396)
● Report % of tumor nuclei stained and intensity of staining (none, weak, moderate, strong)
● Note: tumor staining may be heterogeneous
● Note: must validate tumor protocols in each lab; SP2 antibody for PR may be less reliable (Am J Clin Pathol 2008;129:398)
● Compared to ER, PR staining adds only a limited amount of additional predictive information for response to hormonal therapy (Mod Pathol 2004;17:1545)
● Antigen retrieval techniques are required for ER if glyoxal fixative is used (Hum Pathol 2004;35:1058)
● Metastases to skin are often positive for androgen receptor, even if ER- and PR- (Mod Pathol 2000;13:119)
● ASCO/CAP recommendations for immunohistochemistry testing (Arch Pathol Lab Med 2010;134:930)

ER/PR positive tumors
=========================================================================

● Includes most colloid carcinomas, most well differentiated tumors, bcl2+ tumors
● ER+ tumors have lower microvessel density (Int Semin Surg Oncol 2007;4:22)

Micro images
=========================================================================


   
ER+ (strong)


ER alpha+


ER beta+


ER+ (weak)


ER negative tumors have high microvessel density (CD34 staining)


PR+ tumor


PR+ in only a few cells


PR cytoplasmic staining is considered negative, Fig. B


PR membranous staining is considered negative, Fig. B

Contributed by Leica Microsystems, Biosystems Division:

Invasive ductal carcinoma - ER (6F11) with intense nuclear staining


Strong nuclear staining for PR

Other images: DCIS with ER and HER2 double immunostaining

Additional references
=========================================================================

Wikipedia (ER), Wikipedia (PR), US National Cancer Institute - Tutorial


ER/PR negative tumors

Clinical description
=========================================================================

● Tumors are usually moderate/poorly differentiated with axillary nodal metastases and poor prognosis (Arch Pathol Lab Med 2002;126:325)
● Includes metaplastic, adenoid cystic, apocrine and acinic cell carcinomas; also comedocarcinoma, medullary carcinoma and basal-like carcinoma (which are typically triple negative [ER, PR, HER2])
● Often occurs in premenopausal women
● 30% of primary operable breast cancers are ER negative; of these, 94% are high grade, 85% are invasive ductal NOS (Mod Pathol 2005;18:26)
● Amongst breast cancer subtypes, triple negative tumors have the worst overall survival and the worst disease free survival (Clin Med Res 2009;7:4)
● BRCA1 pathway dysfunction is found in a substantial proportion of basal-like and triple negative breast cancers and can be exploited therapeutically (e.g., inhibitors of the PARP enzyme and cross-linking agents, link)

Gross images
=========================================================================


   
Various images

Micro description for triple negative tumors (basal-like morphology)
=========================================================================

● Poorly differentiated with central fibrosis / necrosis
● Usually lymphoid stroma, pushing margin

Micro images
=========================================================================



CD10+ invasive ductal carcinoma (also ER-)

   
Various images


Image

Positive stains
=========================================================================

● More likely p53+, HER2+, EGFR+ than ER+ tumors (Mod Pathol 2005;18:26)
● Basal-like tumors (triple negative) are intensely CK5/6 positive (see image)
● Express one or more myoepithelial markers (CD10, S100, smooth muscle actin) more frequently than ER- tumors (47% vs. 8%, Mod Pathol 2004;17:646)



Microinvasive carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 11 December 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition of microinvasion
=========================================================================

● Dominant lesion is not invasive, but there are 1+ separate small, microscopic foci of infiltration, each 1 mm or less in size

Terminology
=========================================================================

● “Minimal breast carcinoma” includes microinvasive carcinoma and DCIS
● Can confirm using myoepithelial stains (myoepithelial layer is not intact) and keratin (to observe infiltrative growth)
● Diagnosis requires certainty of invasion; if doubt remains after recuts and immunostains, call DCIS or suspicious

Epidemiology
=========================================================================

● Mean age 61 years

Clinical description
=========================================================================

● Less than 1% of all breast cancers
● Usually detected by mammography due to abnormal calcifications in associated DCIS
● 72% associated with comedo DCIS, 89% with high nuclear grade and 89% with necrosis
● Sentinel lymph node dissection may be appropriate, although axillary nodal metastases occur in less than 10% (Breast J 2008;14:335, Breast 2008;17:395); controversial whether to perform complete axillary dissection if positive sentinel node (yes - Breast 2007;16:146, no - Am J Surg 2007;194:845)
● Commonly misdiagnosed, as true diagnosis is usually DCIS or T1a carcinoma (Cancer 2000;88:1403)
● In breast core needle biopsies, invasive carcinomas 1 mm or less are rare, are associated with DCIS and ADH, and often with large invasive foci at excision (Arch Pathol Lab Med 2004;128:996)
● Report number of foci of invasion, size of largest focus

Treatment and prognosis
=========================================================================

● Cure rate is close to 100% with surgical excision (Ann Oncol 2004;15:1633)
● Prognosis may depend on features of DCIS (Am J Surg Pathol 2000;24:422)
● Natural history closely resembles that of DCIS; thus, microinvasion alone should not be the sole criterion for more aggressive treatment (Int J Radiat Oncol Biol Phys 2012;82:7)

Micro description
=========================================================================

● Usually ductal, rarely tubular or lobular morphology
● Nodules of invading neoplastic cells in periductal or perilobular stroma, none exceeding 1.0 mm
● Usually arises in background of high grade DCIS; stromal microinvasion typically associated with fibroblast proliferation, collagenization and focal inflammation
False positives: lobular cancerization, radial scar, sclerosing adenosis (Arch Pathol Lab Med 2001;125:1259)
False negatives: masking of invasion by inflammatory cells or histiocytes; use cytokeratin to highlight tumor cells

Micro images
=========================================================================


           
With high grade DCIS


Examples from core biopsies

   
Tumor breaches basement membrane


Fig A: false negative due to inflammatory cells
Fig B: false negative due to mistaking tumor cells for histiocytes
Fig C: AE1-3 distinguishes tumor cells (+) from inflammatory cells (-)
Fig D: smooth muscle actin highlights myoepithelial cells in benign but not malignant lesions



Invasive carcinoma (arrow) < 1 mm, surrounded by DCIS


High grade DCIS with foci of microinvasion

Other images: Figures 1 and 2; Figure 3; Figure 1; Figure A

Negative stains
=========================================================================

● Myoepithelial layer is not intact in invasive component (detected with smooth muscle myosin heavy chain, smooth muscle actin, calponin, p63)

Additional references
=========================================================================

Hum Pathol 1998;29:1412



Pregnancy related carcinoma


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 12 November 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Clinical description
=========================================================================

● Estimated incidence of 1 case per 3,000 pregnancies
● Increasing incidence due to delay of childbearing (Obstet Gynecol 2009;114:568)
● Associated with higher stage and larger primary tumors than non-pregnancy associated tumors (Obstet Gynecol 2008;112:71)
● Similar features as breast carcinoma in other young women, and clinical course may not be as aggressive as initially reported (Cancer 2003;98:1055)
● Mammogram is less sensitive during pregnancy due to increased parenchymal density; ultrasound is best technique for evaluation of breast masses during pregnancy or lactation
● Diagnosis may be delayed (Cancer 2009;115:1174)
● Tumors usually contain rare fetal cells (Breast Cancer Res 2008;10:R14)

Treatment and prognosis
=========================================================================

● Sentinel lymph node mapping can be performed safely (Breast J 2008;14:250, Ann Surg Oncol 2007;14:218)
● Wait until second trimester to use chemotherapy (Cancer 2006;106:237, Eur J Surg Oncol 2009;35:215), which should be anthracycline based
● Delay until after delivery use of anti-folate (methotrexate) and anti-estrogen drugs (tamoxifen, Expert Opin Pharmacother 2009;10:2259), radiotherapy and Herceptin / trastuzumab (associated with anhydramnios, Ann Oncol 2008;19:607)

Micro description/grading
=========================================================================

● 80% high grade
● Cancerization of lobules in 79%

Micro images
=========================================================================


   
Extensive cancerization of lobules

   
Lactation associated colloid carcinoma is MUC2+

Other images: Figures 1 and 2

Positive stains
=========================================================================

● MUC2 (if during lactation)
● Variable HER2 (Virchows Arch 2003;443:44)

Negative stains
=========================================================================

● Usually ER, PR, although these markers may underestimate tumor hormone dependence (Anticancer Res 2008;28:2447)

Molecular images
=========================================================================



FISH shows cells from male fetuses within tumor

Additional references
=========================================================================

Arch Pathol Lab Med 2000;124:1053, National Cancer Institute (US)



Risk factors for breast cancer


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 November 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Primarily genetic, hormonal or environmental
● After menopause, about 40% of risk is modifiable (Am J Epidemiol 2008;168:404)

Genetic risk factors
=========================================================================

● (a) First degree relatives with breast cancer; having one first degree relative (mother, sister, daughter) creates a relative risk of 2-3x, higher if relative is affected before age 50 or had bilateral disease (Int J Cancer 1997;71:800); relative risk with two first degree relatives is 4-6x
● b) Li-Fraumeni syndrome (germline p53 mutations) - 25% of patients develop breast cancer
● (c) Mutations of BRCA1 and BRCA2 genes are associated with familial breast cancer at an early age, account for 20-60% of familial breast cancer, but only 5% of all cases
● (d) Cowden's disease (multiple hamartoma syndrome) - autosomal dominant, due to 10q mutation: 30-50% risk of breast cancer (DCIS or invasive ductal carcinoma) by age 50; also benign skin tumors (Hum Pathol 1998;29:47)
● (e) Heterozygous carriers for ataxia-telangiectasia have an 11% risk of breast cancer by age 50
● (f) Blacks (compared to whites) have more frequent breast cancers in women < age 40; present with higher stage tumors with higher nuclear grade that are more likely ER/PR negative, have higher mortality rate
● (g) Women have 100x risk of breast cancer compared to men

Hormone-related risk factors
=========================================================================

● (a) Early menarche
● (b) Late menopause
● (c) Nulliparity
● (d) Having first child after age 30
● (e) Postmenopausal women with obesity (BJOG 2006;113:1160) or estrogen producing ovarian tumors
● (f) Women using combined hormone replacement therapy with progestins, or estrogens alone (Int J Cancer 2007;121:645)
● (g) Risk with oral contraceptives is controversial, but see Mayo Clin Proc 2006;81:1290
● Proposed mechanism of hormonal related risk factors is strong or prolonged estrogen stimulation, which may allow secretion of growth promoters

Factors associated with reduced risk of breast cancer:
● (a) Oophorectomy before age 35 or first child before age 18
● (b) Obesity prior to age 40 - due to anovulatory cycles and lower progesterone levels in late cycle

Environmental risk factors
=========================================================================

● Rates in US > Japan / Taiwan (5:1), also high in Northern Europe, low in Asia/Africa; may be due to known risks of obesity/high fat diet (Nutr Cancer 2008;60:492) and heavy alcohol use (Am J Epidemiol 2000;152:950)
● Differences diminish with immigration
● Breast cancer is not associated with smoking
● In Nigeria, breast cancers are high-grade, high-stage and high-proliferating, and occur at a younger age than in Western countries (Mod Pathol 2002;15:783)
● Physical activity has a protective effect (J Natl Cancer Inst 2008;100:728, Breast Cancer Res Treat 2010;120:235)
● Adult dietary soy foods (Am J Clin Nutr 2009;89:1920) and carotenoids (Int J Cancer 2009;124:2929) have protective effect

Other risk factors
=========================================================================

● (a) Older age
● (b) Proliferative breast disease (see individual topics in Breast-nonmalignant chapter), particularly in situ carcinoma, and possibly concurrent multiple nonproliferative or proliferative benign breast lesions at biopsy (Clin Cancer Res 2007;13:5474)
● (c) Carcinoma of opposite breast or endometrium
● (d) Radiation exposure in young women, including women < age 30 with supradiaphragmatic radiation for Hodgkin's lymphoma (Int J Radiat Oncol Biol Phys 2009;73:69); reduced risk if also have irradiation of ovaries > 5 Gy (J Clin Oncol 2009;27:3901)
● (e) Mammographic density (J Br Menopause Soc 2006;12:186) is a highly heritable risk (Breast Cancer Res 2011;13:R132)
● (f) Birth weight > 3000 g (for cancers arising at age 50 years or less, Cancer Epidemiol Biomarkers Prev 2009;18:2447)
● (g) Previous breast biopsy (Rev Med Inst Mex Seguro Soc 2011;49:655)

Additional references
=========================================================================

American Cancer Society website



Sentinel lymph nodes


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 11 December 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Sentinel node is first node to which lymphatic drainage and metastasis from breast cancer occurs
● Usually an axillary node in central group of level I, but may be at level II (behind the pectoralis minor muscle), level III (infraclavicular) or be intramammary, interpectoral (Rotter's) or internal mammary node (Eur J Surg Oncol 2009;35:252)
● Tumor is more likely at inflow junction of afferent lymphatic vessel (Am J Surg Pathol 2003;27:385)

Clinical
=========================================================================

● Sentinel node may have characteristics that prevent further tumor spread up the lymphatic chain (Int Semin Surg Oncol 2006;3:39)
Procedure: surgeon injects blue dye or radioactive colloid around tumor, which travels to and identifies the first draining sentinel lymph node; extensive pathologic examination is performed of sentinel node (see below) to look for micrometastases
● If sentinel node(s) is negative, other nodes are negative in >95% of cases; axillary recurrence rate is only 0.3% at median 34 months (Eur J Surg Oncol 2008;34:1277)
● Considered a suitable replacement for axillary dissection for staging/diagnosis in T1 and T2 tumors, with reduced patient morbidity because fewer lymph nodes are removed (Ann Surg OncolM 2008;15:1996); may have a role in microinvasive disease (Breast J 2008;14:335)
● Intraoperative frozen section (World J Surg Oncol 2008;6:69), intraoperative imprint cytology (Eur J Surg Oncol 2009;35:16) or molecular assays may be useful (J Clin Oncol 2008;26:3338)
● Frozen section had 60% sensitivity and 100% specificity in one study, with “atypical” cases usually negative on permanent sections (Mod Pathol 2005;18:58); concentrated smear technique is more sensitive than direct smears (Am J Clin Pathol 2004;122:944)
● High risk (60%) of tumor in nonsentinel nodes if sentinel node has macroscopic tumor (2 mm or more) versus low risk (3%) if microscopic tumor (0.2 to 2 mm, Mod Pathol 2005;18:762)
● Micrometastases may not affect survival (Ann Oncol 2009;20:41, J Clin Oncol 2009;27:4679) but see J Am Coll Surg. 2009;208:333
● In addition, cohesive cluster of malignant cells, 0.2 mm to 2.0 mm, may indicate significant axillary disease; smaller clusters are highly unlikely to be associated with significant residual metastasis or poor prognosis
● May be useful even after neoadjuvant [preoperative] chemotherapy (Acad Radiol 2009;16:551)
● In transit metastasis - metastases in lymph nodes other than sentinel node, that are associated with afferent lymph vessels to the sentinel node but not are typically removed during sentinel node procedure (J Clin Pathol 2008;61:1314)
● Memorial Sloan-Kettering Cancer Center nomogram is useful to surgeons to predict likelihood of non-sentinel lymph node axillary metastases (Ann Surg Oncol 2003;10:1140, J Am Coll Surg 2009;208:229)
● Recommendations for handling radioactive specimens at: Am J Surg Pathol 2000;24:1549
● Pre-operative axillary ultrasound and fine needle aspirate cytology (FNAC) are routine at many breast units, with a sensitivity of 56% (confidence interval: 47-64%) and specificity of 90% (84-93%) for ultrasound alone, and 76% (61-87%) and 100% (65-100%) combined with FNAC (Breast. 2011 Oct 5. [Epub ahead of print]); its use before sentinel lymph node biopsy significantly increases the identification rate and decreases the false negative rate (J BUON 2011;16:454)

Isolated tumor cells
=========================================================================

● Single cells in lymph nodes interpreted as malignant; clinical significance has not yet been demonstrated
● Primary tumors associated with sentinel nodes with isolated tumor cells have more lymphovascular invasion and higher proliferative rate than primaries without nodal involvement, but less lymphovascular invasion, lower proliferative rate and smaller tumor size than primary tumors with micro- or macrometastases (Surgery 2008;144:518)
● May represent benign epithelium or degenerated malignant cells (Am J Surg Pathol 2009;33:106, Hum Pathol 2009;40:778)

Consensus recommendations
=========================================================================

References: Hum Pathol 2002;33:579
● Submit entire node unless gross tumor
● Slice large nodes into 3-4 mm thick sections and submit all

● Other possible protocols if examination of initial H & E stained section does not reveal metastases:
(1) Obtain 2 additional hematoxylin and eosin-stained sections and one pancytokeratin (AE1-AE3) stained section (Am J Surg Pathol 2002;26:377)
(2) Obtain 3 additional H & E stained sections (no immunohistochemistry since occult metastases have minimal predictive value, Mod Pathol 2002;15:641), or:
(3) Cut into 2 mm slices, obtain 5 levels for each slice - 2 H&E, 3 AE1-AE3 (Arch Pathol Lab Med 2003;127:701, Arch Pathol Lab Med 2009;133:1437)
(4) Complete sectioning through block detects additional micrometastases, but raises cost effectiveness concerns (Am J Surg Pathol 2009;33:1583)

Note: AE1-AE3 is better than CAM 5.2 since less staining of reticulum cells (Arch Pathol Lab Med 2000;124:1310)

False positives with cytokeratin
=========================================================================

● Benign epithelial cells are associated with pre-sentinel biopsy breast massage (Am J Surg Pathol 2004;28:1641)
● Benign glandular inclusions (Am J Clin Pathol 2008;130:21)
● Ectopic breast tissue (Am J Surg Pathol 2003;27:513)
● Megakaryocytes (Arch Pathol Lab Med 2002;126:618, image)
● Mesothelial cell inclusions
● Nevus cells (Eur J Dermatol 2008;18:586)
● Reticulum cells may be AE3+ (Arch Pathol Lab Med 2002;126:248, image), less of a problem with AE1-AE3)
● Sclerosing adenosis (Arch Pathol Lab Med 2008;132:1439)
● Wrong antibody (Arch Pathol Lab Med 2001;125:1497)

Case reports
=========================================================================

● 45 year old woman with distinct populations of infiltrating ductal carcinoma and lobular carcinoma in both breast and sentinel lymph node (Arch Pathol Lab Med 2004;128:365)
● Level III sentinel node (World J Surg Oncol 2006;4:31)

Clinical images
=========================================================================



Blue stained axillary node

Other images: Blue stained axillary node

Micro images
=========================================================================



Fig 1: micrometastases-H&E
Fig 2: micrometastasis-AE1/AE3+



Isolated tumor cells are AE1/AE3+


Fig 1: negative H&E
Fig 2: AE1/AE3 demonstrates micrometastasis



Isolated tumor cells and micrometastasis


False positive cases


Erroneous use of lamda light chain, which
stains plasma cells, instead of AE1/AE3



Sclerosing adenosis, not tumor

Other images: Micrometastases: H&E and keratin, Clusters and single cells highlighted with pan-keratin antibody

Additional references
=========================================================================

Am J Surg Pathol 2002;26:383 (other recommendations), Am J Surg Pathol 2003;27:842 (which micrometastases are significant), Wikipedia, eMedicineHealth



Spread and metastases


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 November 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Local spread
=========================================================================

● To skin or chest wall
● Nipple invasion more common if tumors are within 2.5 cm of nipple
● Local recurrence after surgery appears as nodules, often near old scar, but can be simulated clinically by post-surgical granulomas

Nodal metastases
=========================================================================

● Axilla is most common site of nodal metastases
● Also supraclavicular and internal mammary region

Distant metastases
=========================================================================

● Common sites are adrenal gland, bone (desmoplasia may cause dry taps in bone marrow), central nervous system (more often basal-like phenotype - high grade, CK 5/6+, EGFR+, ER negative, Am J Surg Pathol 2006;30:1097), liver, lung/pleura (often mammaglobin+, Mod Pathol 2007;20:208), ovary (60-80% are bilateral, are GCDFP15+)
● Lobular carcinoma tends to metastasize to abdominal/pelvic cavities including GI tract, ovaries and serosal surfaces

Occult primary
=========================================================================

● If enlarged axillary node contains carcinoma, but no breast mass or other tumor is detected clinically or radiologically, usually a primary breast carcinoma will eventually be found in adjacent breast, although it may be very small (usually < 2 cm)
● Radiation therapy may be adequate therapy for patients with occult primary (Oncology 2006;71:456)
● Melanomas may also present with occult primary
● Metastatic breast carcinomas to GI tract are usually positive for GCDFP15 (78%), ER (72%), CK5/6 (61%); also PR (33%), androgen receptors and HER2; negative for CDX2 and CK20 (Arch Pathol Lab Med 2005;129:338)
● Androgen receptor nuclear staining suggests breast or ovarian primary (Diagn Pathol 2006;1:34)

Case reports of metastatic sites
=========================================================================

● Colonic polyp (Arch Pathol Lab Med 1984;108:318)
● Endometrial polyp (Case of the Week #125)
● Liver (Arch Pathol Lab Med 2004;128:1418)
● Lung causing cor pulmonale (Arch Pathol Lab Med 1986;110:1197)
● Ovarian granulosa cell tumor (Hum Pathol 2002;33:445)
● Stomach #1 (Arch Pathol Lab Med 2001;125:567), #2 (World J Surg Oncol 2007;5:75)
● Thyroid follicular adenoma (Arch Pathol Lab Med 1994;118:551)

Gross images
=========================================================================



Liver-hepar lobatum (irregular nodularity, usually due to either
tertiary syphilis or metastatic tumor)


Micro images
=========================================================================


Breast cancer metastases:
       
To cervix

       
To endometrial polyp

       
To endometrial polyp (left to right): ER, PR, GCDFP15


To jaw - mandible

           
To liver

   
To lung

   
To oral cavity

   
To skin; tumor is p63 negative

       

       
To stomach


To thyroid


To thyroid: lobular carcinoma and entrapped thyroid follicles


To thyroid: ER stains breast tumor but not papillary thyroid carcinoma (AFIP)


To thyroid: false positive thyroglobulin stain due to diffusion from trapped follicles and nonspecific absorption (AFIP)

Other images:

Androgen receptor+ ductal, lobular and ovarian carcinoma


Androgen receptor stains nuclei

Virtual slides
=========================================================================



Metastatic to heart and pericardium

Positive stains in unknown primary
=========================================================================

● GCDFP15, lactalbumin, ER and PR staining are relatively specific for breast primary
● Breast carcinoma is usually CK7+/CK20- (also carcinomas of lung and ovary, but GI, pancreaticobiliary and some ovarian tumors are CK20+)
● Mammaglobulin in more sensitive but less specific than GCDFP15 (Am J Clin Pathol 2007;127:103)

Markers to distinguish specific primaries
=========================================================================

Breast vs. lung: GCDFP15 (breast) and TTF-1 (lung)
Breast vs. ovary: GCDFP15 (breast) and WT1 (ovary) (Am J Surg Pathol 2004;28:1076), although breast mucinous carcinomas may also be WT1+ (Mod Pathol 2008;21:1217)

Differential diagnosis
=========================================================================

● Sarcoidosis may mimic metastatic breast cancer (Clin Breast Cancer 2007;7:804)



Suspicious for microinvasion


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 November 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Clinical description
=========================================================================

● In one study, 90% of core biopsies that were suspicious for invasion had definitive invasive disease at excision (Ann Surg Oncol 2007;14:704)

Micro description
=========================================================================

● Periductal or perilobular stroma contains either isolated individual neoplastic cells or rare clusters of cells thought to be neoplastic, but review of multiple levels fails to demonstrate continuity of cells/groups with adjacent in situ neoplasm or underlying residual epithelial structures

Micro images
=========================================================================



Various images (fig B, C, D)

Positive stains
=========================================================================

Myoepithelial cells (favor noninvasive process) - p63 (sensitive and specific), smooth muscle actin (also stains myofibroblasts), calponin, smooth muscle myosin heavy chain
Basement membrane - type IV collagen, laminin

Additional references
=========================================================================

Mod Pathol 2002;15:95 (core biopsies), Am J Surg Pathol 2004;28:1076 (immunostains), Am J Surg Pathol 2003;27:82 (immunostains)



WHO histological classification of tumors of the breast


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 November 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Background
=========================================================================

● Reflects views of Working Groups that convened in Lyon, France in January and March 2002
● Publication: Tavassoli: Tumours of the Breast and Female Genital Organs (WHO, 2003)
● Also listed below are ICD-O (morphology code) and behavior code: /0 for benign, /1 for borderline or uncertain, /2 for in situ and grade 3 intraepithelial neoplasia, /3 for malignant

Epithelial tumors
=========================================================================

● Invasive ductal carcinoma, not otherwise specified (NOS) - 8500/3
     ● Mixed type carcinoma
     ● Pleomorphic carcinoma - 8022/3
     ● Carcinoma with osteoclastic giant cells - 8035/3
     ● Carcinoma with choriocarcinomatous features
     ● Carcinoma with melanotic features
● Invasive lobular carcinoma - 8520/3
● Tubular carcinoma - 8211/3
● Invasive cribriform carcinoma - 8201/3
● Medullary carcinoma - 8510/3
● Mucinous carcinoma and other tumours with abundant mucin
     ● Mucinous carcinoma - 8480/3
     ● Cystadenocarcinoma and columnar cell mucinous carcinoma - 8480/3
     ● Signet ring cell carcinoma - 8490/3
● Neuroendocrine tumours
     ● Solid neuroendocrine carcinoma
     ● Atypical carcinoid tumour - 8249/3
     ● Small cell / oat cell carcinoma - 8041/3
     ● Large cell neuroendocrine carcinoma - 8013/3
● Invasive papillary carcinoma - 8503/3
● Invasive micropapillary carcinoma - 8507/3
● Apocrine carcinoma - 8401/3
● Metaplastic carcinomas - 8575/3
     ● Pure epithelial metaplastic carcinomas - 8575/3
     ● Squamous cell carcinoma - 8070/3
     ● Adenocarcinoma with spindle cell metaplasia - 8572/3
     ● Adenosquamous carcinoma - 8560/3
     ● Mucoepidermoid carcinoma - 8430/3
     ● Mixed epithelial/mesenchymal metaplastic carcinomas - 8575/3
● Lipid-rich carcinoma - 8314/3
● Secretory carcinoma - 8502/3
● Oncocytic carcinoma - 8290/3
● Adenoid cystic carcinoma - 8200/3
● Acinic cell carcinoma - 8550/3
● Glycogen-rich clear cell carcinoma - 8315/3
● Sebaceous carcinoma - 8410/3
● Inflammatory carcinoma - 8530/3
● Lobular neoplasia
     ● Lobular carcinoma in situ - 8520/2
● Intraductal proliferative lesions
     ● Usual ductal hyperplasia
     ● Flat epithelial atypia
     ● Atypical ductal hyperplasia
     ● Ductal carcinoma in situ - 8500/2
● Microinvasive carcinoma
● Intraductal papillary neoplasms
     ● Central papilloma - 8503/0
     ● Peripheral papilloma - 8503/0
     ● Atypical papilloma
     ● Intraductal papillary carcinoma - 8503/2
     ● Intracystic papillary carcinoma - 8504/2
● Benign epithelial proliferations
     ● Adenosis including variants: sclerosing adenosis, apocrine adenosis, blunt duct adenosis, microglandular adenosis, adenomyoepithelial adenosis
     ● Radial scar / complex sclerosing lesion
     ● Adenomas
          ● Tubular adenoma - 8211/0
          ● Lactating adenoma - 8204/0
          ● Apocrine adenoma - 8401/0
          ● Pleomorphic adenoma - 8940/0
          ● Ductal adenoma - 8503/0

Myoepithelial lesions
=========================================================================

● Myoepitheliosis
● Adenomyoepithelial adenosis
● Adenomyoepithelioma - 8983/0
● Malignant myoepithelioma - 8982/3

Mesenchymal Tumors
=========================================================================

● Hemangioma - 9120/0
● Angiomatosis
● Haemangiopericytoma - 9150/1
● Pseudoangiomatous stromal hyperplasia
● Myofibroblastoma - 8825/0
● Fibromatosis (aggressive) - 8821/1
● Inflammatory myofibroblastic tumour - 8825/1
● Lipoma - 8850/0
     ● Angiolipoma - 8861/0
● Granular cell tumour - 9580/0
● Neurofibroma - 9540/0
● Schwannoma - 9560/0
● Angiosarcoma - 9120/3
● Liposarcoma - 8850/3
● Rhabdomyosarcoma - 8900/3
● Osteosarcoma - 9180/3
● Leiomyoma - 8890/0
● Leiomyosarcoma - 8890/3

Fibroepithelial Tumors
=========================================================================

● Fibroadenoma - 9010/0
● Phyllodes tumour - 9020/1
     ● Benign - 9020/0
     ● Borderline - 9020/1
     ● Malignant - 9020/3
● Periductal stromal sarcoma, low grade - 9020/3
● Mammary hamartoma

Tumors of the nipple
=========================================================================

● Nipple adenoma - 8506/0
● Syringomatous adenoma - 8407/0
● Paget disease of the nipple - 8540/3

Malignant lymphoma
=========================================================================

● Diffuse large B cell lymphoma - 9680/3
● Burkitt lymphoma - 9687/3
● Extranodal marginal-zone B-cell lymphoma of MALT type - 9699/3
● Follicular lymphoma - 9690/3

Metastatic tumors - Tumors of the male breast
=========================================================================

● Gynaecomastia
● Carcinoma
     ● Invasive - 8500/3
     ● In situ - 8500/2



Prognostic factors - General


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 November 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Prognostic factors
=========================================================================

● Assess future outcome, such as survival
● See also prognostic factors for particular tumor subtypes

Negative prognostic factors
=========================================================================

Classic factors:
● High stage (defined by tumor size, nodal and distant metastases, including possibly nodal micrometastases, Ann Surg Oncol 2007;14:3378)
● High histologic grade (J Clin Oncol 2008;26:3153, Histopathology 1991;19:403)
● Younger age
● Skin invasion
● Nipple invasion
Angiolymphatic invasion
Fibrotic focus
● HER2 (cERBB2) expression
● Value of traditional prognostic factors persists for assessing survival at 10+ years (Breast Cancer Res Treat 2008;107:309)

Negative prognostic factors that are less commonly accepted/used:
● Matrix metalloproteinase-1 (MMP1) expression in tumor and stromal cells (BMC Cancer 2011 Aug 11;11:348)
● Increased Ki-67 positivity
● Retraction artifact mimicking angiolymphatic invasion (Am J Surg Pathol 2007;31:129)
● Infiltrative margins versus pushing margins
● Local recurrence
● bcl2 negativity (Clin Cancer Res 2006;12:2468, BMC Cancer 2008;8:153)
● p53 mutation or HER2+ (Acta Oncol 2008;47:618)
● Phosphohistone H3 >=13 (Mod Pathol 2007;20:1307)
● Disseminated tumor cells to bone marrow (Clin Cancer Res 2008;14:3306)
● Tumor detection by symptoms versus screening (Cancer Epidemiol Biomarkers Prev 2008;17:1096)
● In women with metastatic disease: age at initial diagnosis, hormonal receptor status and site of metastasis (Ann Oncol 2008;19:2012)
● S phase fraction may have prognostic value for fine needle aspirates (Cytopathology 2008;19:294); otherwise ploidy and S phase fraction appear to NOT have prognostic value (Arch Pathol Lab Med 2001;125:364)

Favorable histology types
=========================================================================

● Tubular, cribriform, medullary, colloid, papillary, adenoid cystic and secretory/juvenile
● Unfavorable types are signet ring, basal-like and inflammatory

Nottingham Prognostic Index
=========================================================================

● Based on tumor size, stage and grade (Breast Cancer Res Treat 1992;22:207, Pathol Oncol Res 2008;14:113, table 1, table 2)

Predictive factors
=========================================================================

● Assess response to treatment, such as ER and PR (response to anti-estrogens) or HER2 (response to anti-HER2 treatment)



Prognostic factors - Angiolymphatic invasion


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 11 December 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Features
=========================================================================

● Prognostic significance particularly for lymphatic invasion (Am J Surg Pathol 2007;31:1825, Am J Surg Pathol 1977;1:25) and D2-40 microvessel density (Am J Clin Pathol 2008;129:578)
● Note that D2-40 is not specific for lymphatic endothelium because it also stains breast myoepithelium (Hum Pathol 2008;39:175, Appl Immunohistochem Mol Morphol 2009;17:425)
● Lymphatic invasion occurs primarily at invasive front of tumor
● Related variables - presence of 6+ apoptotic figures in tumor emboli in patients without nodal metastases and 4+ mitotic figures in tumor emboli of patients with nodal metastases (Mod Pathol 2002;15:904, Hum Pathol 2008;39:427)
● Lymph vessel tumor emboli in stroma invasive tumor area (by H&E or D2-40) predicts high risk of tumor recurrence or death (Hum Pathol 2007;38:247, Mod Pathol 2007;20:183)
● Lymphatic invasion may be particularly important in node negative patients (Ann Oncol 2007;18:1632)
● Although they should be distinguished, lymphatic invasion is associated with extensive retraction artifact (Am J Surg Pathol 2007;31:129)
● Correlates with more positive lymph nodes (sentinel and non-sentinel) and size of largest metastatic deposits (Am Surg 2011;77:874)

Micro images
=========================================================================


               
Various images

   
Cuff of lymphatic invasion around a small vein in a vascular bundle

Contributed by Dr. Semir Vranic, University of Sarajevo, Bosnia:
         
Tumor in vessel wall     Post-chemotherapy

   
CD31 and D2-40


Not angiolymphatic invasion


Not angiolymphatic invasion, but shrinkage artifact with partly necrotic tumor
in space created by shrinkage; no endothelial cells are present, elastic stain
highlights elastic tissue in walls of vessels (AFIP)


Other images: retraction artifact, Blood vessel versus lymphatic vascular invasion, D2-40 stains endothelium of lymphatic but not artery or vein, D2-40+ lymphatics without tumor emboli at advancing front of tumor, D2-40+ lymphatics containing tumor emboli, Tumor emboli within tumor



Prognostic factors - Fibrotic focus


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 11 December 2012, last major update February 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Mixture of fibroblasts and collagen fibers that may occupy almost the entire center of an invasive ductal carcinoma, replacing the necrotic central area (see also central acellular subtype)
● May be due to intratumoral hypoxia (Histopathology 2007;51:440), leading to clonal heterogeneity of tumor cells (Mod Pathol 2001;14:325)
● Invasive ductal carcinomas with fibrotic focus have poorer survival than those without (Mod Pathol 2002;15:502, Jpn J Cancer Res 1997;88:590)
● Associated with basal-like subtype, activated wound-healing signature and a poor prognosis 76-gene signature (Clin Cancer Res 2008;14:2944)
● Fibrotic focus diameter greater than 8 mm and fibrotic focus fibrosis grade 1 predict distant organ metastasis and bone metastasis in patients with invasive ductal carcinoma who did not receive adjuvant therapy (Hum Pathol 2008;39:681)

Micro images
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Various images


Low power

Other images: MIB1+ fibroblasts, Figure 3



Prognostic factors - Multigene products


Reviewer: Monika Roychowdhury, M.D. (see Reviewers page)
Revised: 10 November 2012, last major update March 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Multigene prognostic products

Features
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● Gene expression profiles are associated with overall survival for several tumor types, including breast (N Engl J Med 2007;356:217)
● Several multigene prognostic products are commercially successful, including oncotype DX™ and MammaPrint® (Oncologist 2008;13:477, Adv Anat Pathol 2009;16:204)
● US Food and Drug Administration has in vitro diagnostic multivariate index assay (IVDMIA) classification for these tests (link)
● For all tests, the relationship of predicted to observed risk in different populations and their incremental contribution over conventional predictors, optimal implementation, and relevance to patients receiving current therapies need further study (Ann Intern Med 2008;148:358, Ann Oncol 2007;18 Suppl 6:vi58, Genet Med 2009;11:66)
● Testing most valuable for ER+ HER2- patients (Breast 2011;20:S87)

MammaPrint®
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● Prognostic test for women under age of 61 years with lymph node-negative breast cancer (ER positive or negative)
● Requires freshly prepared tissue collected in RNA preservative solution
● The assay is comprised of 70 genes focused on proliferation, invasion, metastasis, stromal integrity and angiogenesis

Mammostrat®
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● Uses five immunohistochemical markers (p53, HTF9C, CEACAM5, NDRG1 and SLC7A5) on paraffin fixed tissue to stratify patients on tamoxifen therapy into risk groups to inform treatment decisions
● Increased scores were significantly associated with reduced survival in ER+ positive breast cancer (Breast Cancer Res 2010;12:R47)

Oncotype DX™
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● First available in January 2004
● Measures changes in 21 genes on paraffin fixed tissue to predict likelihood of disease recurrence and which patients are most likely to respond to chemotherapy (Breast Cancer Res 2006;8:R25)
● Recurrence score is used for some patients with ER+, node negative breast cancer
● Recurrence score is associated with real world decision changes (Am J Surg 2008;196:527, J Surg Oncol 2009;99:319); use is increasing, reduces adjuvant chemotherapy utilization (Ann Surg Oncol 2011;18:3399)

End of Breast malignant, males, children > Superpage > Breast cancer


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