Invasive Carcinoma of No Special Type (NST)

“Invasive Ductal Carcinoma”

Ductal NST

Invasive Carcinoma, NOS

Infiltrating ductal carcinoma

Epidemiology and Etiology:

• 40-75% of invasive carcinoma of the breast
• Hormone exposure
• Gender
• Earlier age at menarche
• Later age at menopause
• Nulliparity or first birth > 35 y
• Breast-feeding
• The longer, the more protective
• Exogenous estrogens
• Hormone replacement therapy
• Not oral contraceptives
• Oophorectomy (decreased risk)
• Age
• Mean age 64 y
• Family history
• Prior biopsies with lesions that increase risk
• Proliferative disease without atypia (RR 1.5 - 2.0, both breasts)
• Moderate or florid hyperplasia
• Sclerosing adenosis
• Papilloma
• Complex sclerosing lesion (radial scar)
• Fibroadenoma with complex features
• Proliferative disease with atypia (RR 4 – 5, both breasts)
• Atypical ductal hyperplasia
• Atypical lobular hyperplasia
• Carcinoma in situ (RR 8 – 10)
• LCIS (both breasts)
• DCIS (low-grade, ipsilateral breast)
• ethnicity
• Caucasian highest rates
• Black women present more advanced, higher grade, more frequent lack hormone receptors
• Radiation exposure
• History of endometrial cancer (or breast cancer)
• Geographic
• Higher incidence in US and Europe (environmental factors unidentified as of yet)
• Alcohol
• Obesity
• Protective in women younger than 40
• Increased risk in post-menopausal women
• Exercise (some studies reduced risk)

Common sites:

Gross features:

• firm to hard
• irregular border
• small foci or streaks of chalky white elastotic stroma in the centre
• characteristic grating sound on cutting (like cutting a waterchestnut)

Histologic features:

• > 50% of non-specialized pattern in representative sections
• If 10-49% is non-specialized, it falls in one of the mixed groups:
• Mixed invasive NST and special type
• Mixed invasive NST and lobular carcinoma
• If up to 50% of specialized pattern is present, you can say:
• Invasive carcinoma NST with xxxxx features
• wide spectrum of appearances
• lack of myoepithelial layer
• marked desmoplastic stromal reaction
• well-differentiated:
• tubules lined by minimally atypical cells
• poorly-differentiated:
• anastomosing sheets of pleomorphic cells
• accompanied by varying amounts of DCIS
• Extensive intraductal component (EIC) defined if one of these two are true:
• >= 25% of area within the invasive carcinoma is DCIS AND DCIS is present outside the invasive carcinoma
• DCIS associated with a small (<= 10 mm) invasive carcinoma(s)
• If there is a lot of DCIS outside of the invasive carcinoma, it is best to provide measurements even if EIC criteria is not met

Immunophenotype:

Marker:	Sensitivity:	Specificity:
ER/PR	More likely in well-differentiated tumours
HER2/neu	More likely in poorly-differentiated tumours

• Neuroendocrine differentiation by IHC in up to 30% of NST and other special types, particularly mucinous carcinomas, and solid papillary carcinomas
• Interpreting immunostains and FISH/CISH:
• ER/PR (nuclear):
• >10% of cells is interpreted as positive
• 5-10% of cells is borderline
• <5% is negative

Molecular features:

• Sporadic:
• P53 mutations (19-57%)
• BRCA1 defects
• Mutations only rarely
• Decreased or absent expression (50%)
• LOH
• Methylation of promoter (13%)
• PTEN LOH (11-41%)
• Mutations rare
• PIK3CA mutation
• FGFR1 amplification (12.5 % of invasive, 6.0% of in situ) (FGFR1 > 6.0, or ratio > 2.2)
• Most common in luminal B subtype (20%) than luminal A (10%) and basal-like (12.5%) and TNNB (0/18)
• Significantly associated with poor disease-free survival (multivariate)
• Grade 1:
• Diploid or near diploid
• Deletions
• 16q (>85%)
• Gains
• 1q (60%)
• 16p (40%)
• Unbalanced translocation involving chromosomes 1 and 16 (up to 40%)
• Grade 3:
• Heterogeneous
• Aneuploidy
• Deletions:
• 16q (30%) (50% of ER positive)
• Gains:
• 1q (ER positive)
• 16p (ER positive)
• Amplifications:
• 8q24
• 17q12
• 20q13
• “mutator phenotype” (ER-negative/HER2-negative more frequently)
• Multiple tandem duplications
• Familial (not specific to NST cancers):
• At least 2/3 of familial risk remains unexplained
• 25% of familial cases involve BRCA1 and BRCA2
• BRCA1:
• Tumour suppressor
• Autosomal dominant inheritance
• 17q21
• role in DNA repair
• 60-80% risk of breast cancer
• greater incidence of medullary carcinomas, poorly differentiated carcinomas, ER, PR, and Her2/neu-negative carcinomas, and p53 mutations
• also 20-40% risk of ovarian CA
• other related tumours: prostate, colon, pancreas
• BRCA2:
• Tumour suppressor
• Autosomal dominant inheritance
• 13q12.3
• role in DNA repair
• 60-80% risk of breast cancer
• types of breast cancer similar to sporadic
• also 10-20% risk of ovarian CA
• also increases risk of male breast cancer
• other related tumours: prostate, pancreas, stomach, melanoma, colon
• CHEK2 mutations (5% of familial)
• Cell-cycle check-point kinase
• Li-Fraumeni syndrome
• P53 germline mutation
• 18-fold higher risk of developing breast CA before age 45
• Cowden syndrome ("multiple hamartoma syndrome")
• PTEN mutation
• Chromosome 10q
• 25-50% lifetime risk of breast cancer
• Peutz-Jehgers syndrome
• Truncating mutations in LKBI gene

Other features:

•  Important Pathologic Findings for Clinical Management:
• Neoadjuvant Specimens:
• Response (ex. Residual Cancer Burden)
• pathological complete response (excellent prognostic indicator, some disagreement on how it should be defined)
• absence of disease in both breast and lymph nodes
• no residual LVI
• no isolated tumour cells in nodes
• whether the previous tumour site is identified should be documented
• whether residual DCIS should be included is contentious
• presence / absence of chemotherapy effect in breast and lymph nodes
• CAP protocol:

· minor response: little or no change in size

· greater degrees of response:

· decreased cellularity

· multiple foci of invasion scattered over a larger tumour bed

· measurements:

· number of foci of invasive carcinoma

· number of blocks with invasive carcinoma

· The CAP synoptic has the minimum recommended grading of response for both primary tumour and lymph nodes

· Number of lymph nodes with evidence of treatment response but no tumour cells should be documented

• Lesion size including all cell clusters and intervening fibrous tissue correlates with survival
• (size of the largest contiguous area of invasive carcinoma has not been correlated with outcome)
• Residual tumour cellularity (%, and as compared to pretreatment)
• Mitotic rate reduction by treatment (better DFS and OS)
• ER/PR/HER2 should be repeated, if negative prior to treatment
• Significant changes may occur in a subset of carcinomas
• Insufficient data on the independent prognostic significance of LVI or extensive LVI in neoadjuvant specimens

References:

•  Jang et al. Breast Cancer Research 2012, 14:R115
• WHO Classification of Tumours of the Breast (2012)
• Provenzano E et al. Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group. Modern Pathology (2015) 28;1185-1201.