Breast: Pathogenesis and

histopathological features
of malignant epithelial
tumors
Moderator- Dr. Yogendra Narayan Verma sir
Speaker- Aditi Pal
Lobular carcinoma in situ
• Non invasive, neoplastic proliferation of dyscohesive cells, orginating
in TDLUs, with/without pagetoid involvement of terminal ducts.
• More than half of acini in TDLU are filled and expanded by neoplastic
cells.
• Localization- multicentric in ipsilateral breast-80% patients
• bilateral-30-67%
• Pathogenesis – CDH-1 inactivation leading to loss of E-cadherin
• Variants - classic, pleomorphic, florid
Essential and desirable diagnostic criteria
• Classic LCIS-
• Essential- small dyscohesive cells with uniform
hyperchromatic nuclei(type A) to slightly larger
vesicular nuclei with mild variability(type B), filling
and expanding more than half of acini in TDLU
• Desirable- loss of E- cadherin membrane staining
.

• Pleomorphic LCIS-
• Essential- large dyscohesive cells with marked nuclear
pleomorphism, more than 4 times size of
lymphocytes/ equivalent to cells of high grade DCIS,
with/without apocrine features
• Desirable- loss of E-cadherin membrane staining
.
• Florid LCIS-
• Essential- classic LCIS creating confluent mass like
architecture, little to no intervening stroma between
markedly distended acini of involved TDLUs, and/or
size cut-off point at which an expanded acini/duct fills
an area equivalent to 40-50 cells in diameter
• Desirable- loss of E-cadherin membrane staining
Ductal carcinoma in situ
• Non invasive, proliferation of cohesive neoplastic epithelial
cells confined to mammary duct- lobular system, exhibiting
a range of architectural pattern and nuclear grades.
• Localization- either breast or accessory breast parenchyma
in axillary tail
• Macroscopic appearance- rarely identified macroscopically
as mass.
• Most DCIS detected mammographically.
Histopathology-
• Characteristically unifocal disease limited to single
duct system, but it can extend into lobules.
• DCIS classified according to architectural pattern as-
solid, cribriform, micropapillary or papillary.
• Cytonuclear morphology recommended for
histological grading of DCIS.
• DCIS categorized as low, intermediate and high
nuclear grade
DCIS low nuclear grade
• Composed of small, monomorphic cells, typically
growing in cribriform, micropapillary/solid pattern
involving more than 2 complete spaces/ measuring
more than 2mm.
• Nucleus – uniform size and shape, regular chromatin
and inconspicuous nucleoli. Nuclei 1.5-2 times the size
of erythrocyte.
• Mitoses few or absent.
DCIS intermediate nuclear grade
• Cells show moderate variability size, shape and
polarization.
• Nucleus- variably coarse chromatin and sometimes
prominent nucleoli.
• Mitoses may be present.
• Necrosis may be seen.
• Microcalcification may be present in secretion and/
necrotic material.
DCIS high nuclear grade
• Large, atypical cells, most commonly with solid
architecture
• Nucleus- large and typically pleomorphic, with
irregular contours, coarse chromatin, often prominent
nucleoli.
• Nuclei more than 2.5 times the size of an erythrocyte.
• Mitoses usually conspicuous.
• Central comedo-necrosis bearing microcalcification
often present
Essential and desirable diagnostic
criteria
• Essential- proliferating, cohesive neoplastic epithelial
cells, confined to mammary ductal-lobular system,
exhibiting range of architectural pattern and nuclear
grades.
• Desirable- in difficult cases, pragmatic interpretation
of multiple myoepithelial markers for diagnosis.
Invasive breast carcinoma
• Invasive breast carcinoma refers to large and heterogenous group of
malignant epithelial neoplasm of the glandular elements of breast.
• All IBC are grouped into following biomarker-defined subtypes for
treatment purposes on basis of ER and HER 2 status-
• ER- positive, HER-2 negative
• ER- positive, HER-2 positive
• ER- negative, HER-2 positive
• ER- negative, HER-2 negative
.

• Majority (90%) of breast cancer are unifocal

• Occur in any quadrant of breast, higher frequency in
UOQ
• Synchronous contralateral tumor found approx. 2%
patients
• 0.1% breast cancers present as axillary metastasis
with no clear breast primary
Etiology
• Multifactorial
• High calorie diet rich in animal fat and protein,
combined with lack of physical exercise and obesity
• Early menarche
• Older age at first childbirth
• Decrease duration of lactation
• Germline BRCA1 and BRCA 2 mutation
Pathogenesis
Macroscopic appearance
• Most IBCs visualized/palpated as grossly evident mass with
irregular, stellate outline or nodular configuration
• Tumor edge is poorly defined and lack sharp circumscription
• Firm or even hard on palpation, gritty feel when cut with
knife
• Some IBCs including neo-adjuvant treated cases, may be
grossly inapparent and require careful correlation with
imaging at time of gross examination and tissue sampling.
Histopathology
• Four histological features are described to further
characterize the biology-
• 1. histological subtype based on tumor architecture,
cytonuclear features, and stromal features
• 2. Nottingham grade
• 3. presence or absence of spread in angiolymphatic
spaces
• 4. an associated in situ component
Invasive breast carcinoma of no special
type
• Refers to large heterogenous group of IBCs that cannot be
classified morphologically as any of the special histological
types
• General histological features-
• Tumor margins- from highly infiltrative to continuous pushing
margins with expansive pattern of growth.
• Architecturally- tumor cells arranged in cords, clusters and
trabeculae, some tumor are characterized by a
predominantly solid/syncytial infiltrative pattern with little
associated stroma.
.

• Stromal component variable. May be highly cellular

fibroblastic proliferation, scant element of connective tissue,
or marked hyalinization.
• Special morphological patterns-
• three most common include- medullary pattern invasive
cancer, invasive carcinoma with neuro-endocrine
differentiation, carcinoma with osteoclast like stromal giant
cells
• Rare pattern include pleomorphic, chorio-carcinomatous,
melanotic, oncocytic, lipid-rich, glycogen-rich, clear cell,
sebaceous pattern.
Special histologic types of
invasive carcinoma
.
1. Microinvasive carcinoma

• Refers an invasive breast carcinoma ≤ 1mm in size

• Macroscopic appearance- has gross features of
carcinoma in situ
• Histopathology- periductal stromal desmoplasia and
lymphoid infiltrate, often in context of high grade
DCIS, should prompt a careful examination for small
nests, glands or single cells of microinvasive
carcinoma
Essential and desirable diagnostic
criteria
• Essential- invasive carcinoma ≤ 1mm in size; exclusion
of presence of larger foci by deeper sections to avoid
underdiagnosis and exclude non invasive mimics to
avoid overdiagnosis
• Desirable- pre-existing lesion, most often carcinoma in
situ (usually high grade ductal)
2. Invasive lobular carcinoma
• Composed of dyscohesive cells that are most often individually
dispersed or arranged in single file pattern.
• Macroscopic appearance- irregular and poorly delimited tumor that
can be difficult to define grossly, because of diffuse growth pattern of
cell infiltrate.
• Histopathology- proliferation of small cells that lack cohesion and
appear individually dispersed throughout fibrous connective
tissue/arranged in single file linear cords that invade stroma.
• The neoplastic cells have round or notched ovoid nuclei and a thin rim
of cytoplasm, occasional intracytoplasmic lumen.
Essential and desirable diagnostic criteria
• Classic ILC-
• Essential- an IBC composed of dispersed or linear
dyscohesive cells with low to intermediate nuclear grade
morphology and low mitotic count; ER immunoreactivity is
high and HER2 is negative/ non-amplified
• Desirable- coexisting lobular neoplasia; E-cadherin loss may
be useful
.
• Pleomorphic ILC-
• Essential- intermediate-high/ high nuclear grade/
pleomorphism
3. Tubular carcinoma
• Low grade invasive carcinoma composed of well formed
tubules with open lumina lined by single layer of neoplastic
cells.
• Macroscopic appearance- poorly defined spiculated tumor
that are firm to hard in consistency and pale grey in colour.
• Histopathology- diagnosis requires > 90% of tumor
composed of tubules and glands lined by single layer of
neoplastic epithelium.
• Tumor with 10-90% TC are classified as mixed tumor.
.

• Low power, TC has stellate outline and invades adjacent

normal breast parenchyma.
• TC composed of small, round to ovoid/ angular glands and
tubules with open lumina set within fibrous/fibroelastotic
desmoplastic stroma.
• Cuboidal to columnar neoplastic cells have relatively uniform
nuclei of small/intermediate size.
• Tubules in TC have no surrounding myoepithelium, useful in
differentiating them from benign conditions as sclerosing
adenosis and radial scar.
Essential and desirable criteria
• Essential- an IBC with >90% tumor consisting of round
to ovoid/angular tubules with open lumina, lined by
single layer of epithelial cells with low-grade nuclei
and sparse mitosis (grade 1); ER- positive and HER2
negative
4.Cribriform carcinoma
• Low grade invasive carcinoma composed of islands of tumor
cells with well defined cribriform spaces.
• Macroscopic appearance- no specific macroscopic feature
• Usually consist of firm/hard spiculated mass
• Histopathology- invasive epithelial islands containing well
defined, rounded spaces similar in appearance to cribriform
type DCIS.
• Island have ovoid/angular outline and set within
desmoplastic stroma.
.

• Comprise multilayered epithelial cells of small to

intermediate size forming secondary glandular structures
lined by cuboidal to columnar cells.
Essential and desirable criteria
• IBC with >90% of the tumor composed of cribriform
islands of epithelial cells with low grade nuclei and
sparse mitosis (grade 1); ER- positive and HER2
negative
5.Mucinous carcinoma
• IBC characterize by clusters of epithelial tumor cells
suspended in pools of extracellular mucin.
• Macroscopic appearance- glistening and gelatinous
nodule with pushing margins and soft, viscous
consistency.
• Histopathology- clusters/sheets of neoplastic cells
suspended in abundant extracellular mucin,
partitioned by delicate fibrous septa containing
capillary blood vessels.
Essential and desirable diagnostic criteria
• Pure mucinous carcinoma characterize by >90%
mucinous component, with clusters of epithelial
tumor cells of low to intermediate nuclear grade,
suspended in pools of extracellular mucin; usually
ER/PR- positive and HER2 negative
6.Mucinous cystadenocarcinoma
• IBC characterized by cystic structures lined by tall columnar
cells with abundant intracytoplasmic mucin, resembling
pancreatobiliary pr ovarian mucinous cystadenocarcinoma.
• Macroscopic appearance- well circumscribed solid and cystic
mass. Cystic spaces usually contain gelatinous material.
• Histopathology- cystic spaces lined by tall columnar cells with
stratification, tufting and papillary formation.
• Neoplastic cells have basally located nuclei and contain
abundant intracytoplasmic mucin.
Essential and desirable diagnostic criteria
• Essential- IBC with large cystic spaces containing
mucin and lined by atypical columnar cells with
intracytoplasmic mucin
• Desirable- ER negative and PR negative (typically);
adjacent DCIS
7.Invasive micropapillary carcinoma
• IBC composed of small, hollow, or morula like clusters of
malignant cells, surrounded by clear spaces with an inside-
out growth pattern.
• Macroscopic appearance- not clinically relevant
• Histopathology- >90% of tumor consist of hollow or morula
like aggregates of cuboidal to columnar neoplastic cells.
• These are devoid of fibrovascular core and are immersed in
spongy stroma characterized by clear and empty spaced
around the cell clusters and a delicate stromal framework
composed of fibroblasts and connective tissue.
Essential and desirable diagnostic criteria
• Essential- invasive tumor clusters with micropapillary
architecture with reversed cell polarity, set in clear
spaces in >90% of the tumor
• Desirable- clean staining for EMA (MUC1) lining the
stroma facing border of the cell clusters.
8.Carcinoma with apocrine
differentiation
• Invasive carcinoma characterized by large cell with abundant
eosinophilic granular cytoplasm and enlarged nuclei with
prominent nucleoli, resembling apocrine sweat glands.
• Macroscopic appearance- nonspecific and similar to IBC-NST
• Histopathology- cells have abundant eosinophilic/vacuolated
cytoplasm with distinct cell borders. The nuclei are enlarged
and round to oval, with marked/moderate atypia and
prominent nucleoli
• Predominant growth pattern is solid, but any architectural
pattern may be observed
Essential and desirable diagnostic criteria
• Essential- apocrine morphology in >90% of tumor
• Desirable- ER- negative, PR- negative and AR- positive
9.Metaplastic carcinoma
• Heterogenous group of invasive breast carcinoma
characterized by differentiation of neoplastic epithelium
towards squamous cells and/or mesenchymal looking
elements, including but not restricted to spindle, chondroid,
and osseus cells.
• Macroscopic appearance- either well circumscribed or
display indistinct, irregular borders.
• Pearly white to greyish, and glistening cut surface in areas of
squamous and chondroid metaplasia, whereas cut surface of
osseus metaplasia can be gritty and hard.
Essential and desirable diagnostic criteria
• Essential- IBC with atypical squamous, spindle cell,
and/or mesenchymal/matrix producing
differentiation; in metaplastic carcinomas lacking
DCIS/ conventional type mammary carcinoma
components, direct evidence of epithelial
differentiation by IHC, based or unequivocal
expression of HMWCK and/or p53
10. Rare and salivary gland type tumor
• Breast and salivary gland tissues share tubuloacinar
morphology, composed of luminal epithelial cells
surrounded by a myoepithelial cell layer
a. Acinic cell carcinoma
• Malignant epithelial neoplasm composed of clear and
granular epithelial cells, some of which contain
intracytoplasmic zymogen granules, arranged in
micro-glandular and solid pattern
b. Adenoid cystic carcinoma
• Invasive carcinoma composed of epithelial and
myoepithelial neoplastic cells arranged in tubular,
cribriform, and solid pattern associated with
basophilic matrix and reduplicated basement
membrane material, frequently associated with MYB-
NFIB fusion
c. Secretory carcinoma
• Invasive carcinoma composed of epithelial cells with
intracytoplasmic secretory vacuoles and extracellular
eosinophilic bubbly secretions, arranged in a variable
architecture and frequently associated with ETV6-
NTRK3 fusion
d. Mucoepidermoid carcinoma

• Invasive carcinoma composed of mixed mucinous,

intermediate (transitional), and squamoid neoplastic
cells arranged in solid and cystic pattern.
e. Polymorphous adenocarcinoma
• Infiltrative malignant epithelial neoplasm with
histological features similar to those of polymorphous
adenocarcinoma of salivary glands, composed of a
proliferation of monotonous neoplastic cells
demonstrating architectural diversity, arranged in
variety of patterns including large nests surrounded
by cords and single files
f. Tall cell carcinoma with reversed
polarity
• Invasive carcinoma characterize by tall columnar cells
with reversed nuclear polarity, arranged in solid and
solid papillary pattern, most commonly associated
with IDH2pArg 172 hotspot mutation
11. Neuroendocrine carcinoma
• Invasive carcinoma characterized by high-grade neuro-
endocrine morphology (small cell or large cell),
supported by the presence of neurosecretory granules
and a diffuse, uniform immunoreactivity for
neuroendocrine markers
.

Thank you