Pathology: Preparation for Oral Exam, Breast Carcinoma and Diagnosis

Giulia Amoia Pathology Overview

Giulia Amoia
Pathology
(preparation for oral exam)
Second semester, fourth year (2022/2023)
Giulia Amoia
Info from Robbins'
"Pathology, basis of
disease" and lectures
1Giulia Amoia
2Giulia Amoia

Breast Anatomy and Conditions

Breast Nodule Epidemiology

1. Breast
3Giulia Amoia
4Giulia Amoia
The breast

1) Epidemiology of a breast nodule
Nearly every woman develops or feels a nodule in her breast during the course of her lifetime.
Though only 1 out of 10 women will actually develop a cancer. Indeed:

• only in 10% of cases these nodules are malignancies, whereas in:
• 30%: they are not disease at all, and they are due to hormonal changes taking place during
  the menstrual cycle;
• 40%: they are caused by fibrocystic changes;
• 20%: they are miscellaneous benign lesions, of which 7% is represented by
  fibroadenoma.

Fibrocystic
changes
40%
No disease
30%
13%
Miscellaneou
benign
7%
10%
Cancer
Fibroadenoma

Age is another key factor to take into account when evaluating a breast nodule; indeed, a
nodule in a 20-year-old is in 99% of cases a benign condition; whereas in women 60yo or
older is most likely a cancer.

Cancer
Benign
nodularity
Incidence
Cyst.
Fibroadenoma
20
30
40
50
60
Age in years

Another important factor in determining the nature of the nodule is its location, as nodules
closer to the nipple are most likely benign conditions (such as papilloma), whereas nodules
deep in the parenchyma, fixed and perhaps anchored to the muscle are most likely malignant.

NORMAL
LESION
Terminal duct
Lobular unit
Cyst
Sclerosing adenosis
Small duct papilloma
Hyperplasia
Atypical hyperplasia
Carcinoma
Lobular stroma
Fibroadenoma
Phyllodes tumor
Nipple and areola:
Smooth muscle
Large ducts and
lactiferous sinuses
Duct ectasia
Recurrent subareolar
abscess
Solitary ductal papilloma
Paget's disease
Interlobular stroma
Fat necrosis
Lipoma
Fibrous tumor
PASH
Fibromatosis
Sarcoma
Pectoralis muscle
Chest wall and ribs
5Giulia Amoia

Breast Anatomy and Histology

2) Anatomy of the breast
The breast is an exocrine gland made by two major structures (ducts and lobules), two types
of epithelial cells (luminal and myoepithelial) and two types of stroma (interlobular and
intralobular).

6 to 10 major ducts extend down from the nipple and brunch into multiple smaller ducts and
finally terminate in lobules. The initial part of the major duct is lined by keratinized squamous
epithelium that then abruptly transition into a double-layer epithelium, which lines the
remaining smaller ducts and lobules; the double layer ep. is composed by:

• Inner layer: made by luminal cells, which are involved in the production of milk;
• Outer layer: made by myoepithelial cells, which have contractile functions able to
  squeeze milk out and feed the baby.

o Myoepithelial cells have specific marker (p63 and calponin - the most specific
ones, and smooth muscle actin - not as specific as the others), which are important
to determine infiltration and the state of invasions of a tumor.
o In fact, the concept of infiltration for a breast cancer is related both to myoepithelial
cells and basal membrane (I guess which surround myoep cells). An infiltrative
carcinoma is indeed defined as a malignant epithelial tumor that has infiltrated
the basal membrane. To document the basal infiltration, it's possible to use
immunohistochemistry markers for myoepithelial cells. If myoepithelial cells are
present, it means that it's either a benign condition or a malignant condition in situ
(so, without infiltration).

As a general rule, the ductal or luminal cells are columnar; whereas the basal cells are
cuboidal.

Breast anatomy and histology
Eric Wong
Clin Obstet Gynecol. 2011 Mar;54(1):91-5.

The breast is composed of glandular and stromal tissue. Glandular tissue includes the ducts and lobules.
Stroma comprises area between lobes.

1
Breast
Lumen
Pectoralis
muscle
Chest wall
and ribs
Nipple
Ducts
Stroma
Each lobe drains into a major
lactiferous duct that dilates into
a lactiferous sinus beneath the
areola opening onto the nipple
Each terminal duct lobular
unit is composed of branched
tubuloalveolar glands
organized into lobes
Inner layer of
myoepithelial cells
provide structural
support to the
lobules and assist in
milk ejection during
lactation
Outer layer of lobular
luminal epithelial
cells produce milk
during lactation

The breast also undergoes changes according to the different periods of life of a woman:

• Puberty: duct system expands and proliferate, giving rise to numerous duct lobular units.
  Menstrual cycle:
• o
  Estrogenic/proliferative phase: lobules are relative quiescent.
  o
  Ovulation
  o
  Progestinic/secretory phase: influence of estrogen and rising progesterone levels
  make so that cell proliferation increases, as does the number of acini per lobule.
  Menstruation: the fall in hormone levels induces regression of the lobules.
  o
• Pregnancy: lobules increase in size and number. By the end of pregnancy, the breast is
  composed basically only by lobules separated by scant stroma.
• After parturition: lobules initially produce colostrum (high in proteins), changing to milk
  (high in fat and calories) over the next 10 days as progesterone levels drop.
  6Giulia Amoia
• Cessation of lactation: epithelial cells undergo apoptosis and lobules regress, but only
  partially.
  o The permanent changes produced after pregnancy make women that get pregnant
  young less likely to develop malignancies in the future.

After the third decade (long before menopause): lobules and their specialized stroma
start to involute, and the interlobular stroma is converted from radiodense fibrous tissue
to radiolucent fibrous tissue.

Nipple-
Luminal cells (blue)
Myoepithelial cells (black)
Intralobular stroma (green)
Interlobular stroma (red)
Papilloma
DCIS
Epithelial
hyperplasia
Fibroadenoma
Phyllodes
tumor
Invasive
carcinoma
Hemangioma
Angiosarcoma
NORMAL
BENIGN
MALIGNANT
Figure 23.1 The normal cells and structures of the breast, including epithelial cells and myoepithelial cells, intralobular stromal cells and interlobular
stromal cells, and large ducts and terminal duct lobular units, can give rise to both benign and malignant tumors. DCIS, Ductal carcinoma in situ.

Fibrocystic Disease: Pathology and Clinical Features

3) Define the pathological (cytology, histology and gross findings) and clinical features of fibrocystic
disease
Case: 22yo woman presenting with a tender palpable nodule.
Diagnosi: Parenchima mammario caratterizzato da dotti ectasici, bordati da epitelio in
metaplasia apocrina, adenosi, adenosi sclerosante e fibrosi stromale. Reperto riferibile a
malattia fibrocistica della mammella.
Considerations: given the age of the patient and the nature of the nodule upon palpation, this
is most likely to be a benign condition, like fibrocystic changes (as confirmed by the
diagnosis) or fibroadenoma.
Pathology findings: Cytology revealed macrophages and epithelial cells without any atypia,
while the biopsy showed ectasia of the ducts, some adenosis and some fibrosis, but nothing
malignant, suggesting the presence of breast fibro-cystic changes (malattia fibrocistica della
mammella).
Fibrocystic changes are a benign epithelial lesion. They are classified as non-proliferative
changes, proliferative breast disease (with or without atypia).
They are defined as "lumpy-bumpy" lesions at palpation by the clinician, radio-dense by the
radiologist, and as benign histological findings from the pathologist.
7Giulia Amoia

Fibrocystic changes are characterized by the hyperplastic overgrowth of components of the
mammary unit:

• Epithelial overgrowth: of lobules and ducts -> resulting in adenosis and epitheliosis;
• Fibrous overgrowth: of specialized hormone-responsive lobule-supporting stroma.

It is the most frequent disorder of the female breast and it seems to be associated to hormonal
changes occurring during the menstrual cycle.
It's asymptomatic in 40% of cases and, instead, it might present with symptoms in 10% of
patients.

o
Typical symptom: palpable thickening and nodularity of breast tissue or single breast
lumps - lumpy with midcycle tenderness.
o
As a general rule, the clinical presentation (so, symptoms) of a breast disease can potentially
include:

§
Pain, nipple discharge, inflammation, palpable mass, lumpiness or other symptoms.
It's common in the breast of mature women, more often as menopause nears, and it's rare
after menopause or before adolescence.
In a smaller number of cases, it can transform into carcinoma (differential diagnosis to be
distinguished from malignant conditions).
Regarding gross features, it is usually bilateral, it has an increased consistency and a poorly
0 defined area (sometimes nodular). In a normal breast specimen, the parenchyma appears
typically yellow, as it is constituted by fat. Instead, in fibrocystic changes, it might appear
both:

• Whitish: the whitish tissue is connective tissue, so fibrosis;
• Bluish: the bluish tissue is constituted by cysts.

Breast lesions
Benign
(fibrocystic changes)
malignant
non-proliferative breast changes
proliferative breast disease
Radial scar
cysts
microcalcifications
hyperplasia
Sclerosing adenosis
apocrine metaplasia
atypical hyperplasia
fibrosis
adenosis

The main types of non-proliferative breast changes are the followings (still, all 4 can also be
detected in normal breast):

• Cysts: they are the dilation of lobules of different size (they start as small cysts formed
  by the dilation of lobules, and in turn they may coalesce to form larger cysts). They contain
  turbid, semitranslucent fluid, but they are also filled with macrophages - this explains
  their tender consistency. They can be lined by either flat epithelial cells or by apocrine
  cells (which have abundant granular eosinophilic cytoplasm and closely resemble the
  normal apocrine epithelium of sweat glands). Calcifications are common.
• Apocrine metaplasia: they are constituted by luminal cells with an abundant granular
  eosinophilic cytoplasm. It's characterized by hyperchromatic nuclei with prominent
  nucleoli, growing into micro-papillae.
• Stromal fibrosis: it's the result of inflammation derived from cysts rupture with
  consequent release of secretory material in the adjacent stroma. The resulting chronic
  inflammation and fibrosis explains the increased consistency and nodularity upon
  palpation.
• Microcalcification: they are chemical structures characterized by the deposition of salt in
  the nucleus or in necrotic cells. They are not per se diagnostic of malignancies, as they
  can also be appreciated in benign conditions. They can be seen during mammography.
  8