BREAST PATHOLOGY 2
(OPACITIES)

FIBROADENOMA

very common also in young women, completely benign (B2 or C2) and diagnosed preoperatively

clinically, it presents as a mobile lump,
slipping between fingers, hard and painless

cysts are lumps and elastic,
but they are not slippery or hard

at US, they show circumscribed margins, a roundish or oval appearance and they are hypoechoic

calcifications may be present or not

if they are present, they usually refer to an old fibroadenoma, typical of older women

coarse popcorn calcification appearance

due to regression of fibroadenoma

they do not need surgery
(unless it is growing too much)

cause: HYPERESTROGENISM

the fibroadenoma acts into the stroma on the cells that are present between the acini in the TDLU (mantle stroma), which have estrogen receptors

estrogen receptors can be alpha or beta

generally, tumors are rich in ERalpha; however, the cells of the mantle stroma of the lobules are rich in ERbeta

the growing part is the mantle/intralobular stroma

usually associated with some collagen deposition
--> hard consistency

PHYLLOIDES TUMOR

rarer than fibroadenoma, typical of older
women, more frequent after menopause

the main difference from fibroadenoma is that at radiology PT does not appear completely hypoechoic, it has something inside of it; moreover, at mammography, PT borders are not so roundish

most important clinical sign:
RAPID GROWTH

based on the diagnosis coming from core
biopsy, surgery will be more or less aggressive
(but it is needed mandatorily)

criteria for PT classification

  • proliferation of the stroma, which becomes very rich in cells
  • it is important to evaluate pleomorphism of the nuclei, then mitotic and necrotic indices

subtypes

  • benign (B3)
  • malignant (B5)
  • borderline (B3, B4)

BENIGN: the stroma proliferates crushing the epithelium cavities, which are elongated and contain histiocytes; no mitosis and atypia

BORDERLINE: aome atypia and
mitosis are observed in the stroma

MALIGNANT: rapid growing lump,
necrosis, numerous mitoses, atypia

since it is a sarcoma, metastases can move through blood

analysis of the sentinel lymph node and its dissection are not recommended

remember that analysis of the lymph node would instead be recommended in carcinomas, which generally metastasize through the lymphatic system

it is important to perdoem a PET scan before surgery

margins of resection must be clear
(even benign cells can transform into
malignant ones)

RADIAL SCAR

usually classsified R3, R4

not malignant, but at risk of transformation

if these lesions are found, a core biopsy has to be performed to be sure of the nature of the lesion

radiological distortion

the lesion is not roundish and there is something that is stretching the profile of the gland

stellate lesion

histologically, it appears like a branching pattern with a central core

the central core is elastic and it has some
collagen deposition (fibroelastic core);
small tubules are also observed (made of epithelial and myoepithelial cells)

around the core, hyperplasia can be found together within situ carcinoma (ductal or lobular)

they are not invasive cancers, but around them there might be some lesions that may evolve into an invasive carcinoma (RISK OF PROGRESSION)

classified as either B3 or C3
(indicative for surgery)

DD

tubular carcinoma, an invasive cancer that presents a similar aspect to radial scars (radiologically and histologically)

myoepithelial cells present in radial scars are absent in the tubular carcinoma

INVASIVE CARCINOMA

cancer that grows by invading the stroma and likely to metastasize by invasion of blood and lymphatic vessels

not confined within the cortex of the gland: it goes through the cortex, the basal membrane and the stroma

it generally arises from an in situ carcinoma that, by growing, induces the breakage of the basal membrane and the neoplastic cells may move from inside the gland into the stroma

if vessels are present, cells may enter in them
and five rise to metastases around the body

standard parameters

morphological

  1. tumor extent
  2. tumor size
  3. lymph node status
  4. histotype
  5. grade
  6. vascular invasion
  7. TILs

immunophenotypic

  1. steroid receptor status
  2. HER2
  3. Ki67

TUMOR EXTENT: determining the involvement of the breast by the tumor

it can be unifocal (one single nodule), multiple (more nodules) or diffuse (breast is completely involved by the tumor)

TNM: "T" refers to tumor size ("M" is added if there are more lesions and you measure the largest one)

also consider the presence of microinvasion: if the lesion is microinvasive, the prognosis is very good

typical macroscopic feature: peau d'orange sign

CT is started before surgery, even without biopsy

lymph node metastasis

tumor emboli may enter into the lymphatic system and arrive at the first lymph node of the axillary lesion (SENTINEL LN)

this LN is removed by surgeons in order to examine it to look for the presence of metastases

the pathologist has to measure the volume of metastases inside the sentinel LN, on the basis of which categories can be defined

  • completely free LN
  • some new isolated cells
  • micrometastases
  • large metastases

if the metastatic content is greater than 2 mm then all the lymph nodes have to be taken away

histotype

it correlates with the aspect of the mammogram

  • not special types (NTS): 83%
  • lobular
  • tubular: appearing like a distortion (stellate lesion)
  • medullary: roundish, low frequency (2%)
  • mucinous: roundish, low frequency (2%)
  • mixed

NTS

it correlates with spiculated lesions, with histological variation from a lot of ducts to a solid growth with no lumen

the pathologist must look for the presence of tubular structures with a lumen, all devoid of myoepithelial cells

tubular carcinoma

characterized by a distorted stellate lesion (DD: radial scar), which in this case does not have myoepithelial cells around the tubules

also look for markers for myoepithelial cells, e.g. p53 which stains the nuclei of the basal cells (to be found in the case of radial scars)

it has a very good prognosis

lobular carcinoma

it may arise from a lobular in situ carcinoma, which is generally not seen on mammogram; it may be bilateral, multifocal and it needs surgery (not mastectomy)

only part of the gland where the biopsy is done is removed, then the patient might receive hormonal therapy, blocking the growth of other lobular carcinoma foci

the diagnosis is very complex

it grows as single cells not producing collagen deposits, but rather growing in the stroma of the breast, following a natural way of progression

cells may frequently have vacuoles inside the cytoplasm and they have a low pleomorphism

they may invade the whole breast
(SPIDER-WEB INVASION PATTERN)

look for CDH1 mutation (+++) and e-cadherin mutation (---)

e-cadherin absence is an indication for the likelihood of cellular invasion of the stroma

moreover, e-cadherin mutation is indicative for the risk of both breast and gastric cancers

medullary-like carcinoma

chronic inflammation in the stroma, where a lot of lymphocytes are found; association with BRCA1

roundish shape at microscope, cluster of atypical cells, with a lot of mitosis within a stroma rich in lymphocytes

the presence of lymphocytes ameliorates the prognosis

immunotherapy can be used as a treatment if patients show metastases

no estrogen-progesterone receptor expression, HER2 negativity

TRIPLE NEGATIVE CANCER

not all triple neg cancers have a good prognosis, but th presence of a surrounding inflammation indicates a better condition

grading
(Elston and Ellis)

important in any histotype, but most of all in NST

parameters

presence of tubules with a lumen

if a lot of structures with a lumen are present, it will be more similar to a normal mammary gland

the greater the presence of tubules, the lower the score assigned to the tumor

  1. a lot of tubules (>70%)
  2. some tubules (10-70%
  3. just a few tubules (<10%)

pleomorphism (look at nuclei)

  1. low pleomorphism
  2. in between
  3. high pleomorphism

number of mitoses

  1. few mitoses
  2. in between
  3. numerous mitoses

the sum of these data gives a final score

  • G1: 3-5
  • G2: 6-7
  • G3: 8-9

vascular invasion

remember that both blood and lymphatic vessels invasion must be assessed, but in this case lymphatic vessels are more likely to be involved

tumor infiltrating lymphocytes (TILs)

they are conditions in which there is the presence of lymphocytes into the stroma

TILs presence predicts the response to noadjuvant therapy in all molecular subtypes: it is considered a marker of CT response

TIL correlates with the prognosis of the patient: the higher the TIL the better the overall survival

steroid receptor status

in the nucleus of cancer cells there are many steroid receptors (ER, PR, AR), but the most important one from a therapeutic point of view is the estrogen receptor (heterogeneous, found on luminal cells and determining cellular proliferation); also progesterone receptors must be evaluated, as they are important to regulate cellular proliferation as well

prognostic marker: ER/PR presence
is indicative for a better prognosis

prefictive factor: high ER/PR expression is associated with a better response to hormonal therapy

tamoxifen

antagonist of ER, blocking proliferation in breast (but stimulating proliferation in endometrium)

aromatase inhibitors

involved in estrogen synthesis blockage by inhibiting the aromatase enzyme

ER and PR expression also plays a role in recurrence rate determination

if a tumor is ER+/PR- the recurrence is higher than in a ER+/PR+ tumor

the cutoff for PR expression is 20%

HER2

member of the epidermal growth factor receptors, present in all cells

we use FISH to detect its presence on ch17

in the case of true amplification, the number of centromeres does not increase, while the number of genes does; if the ratio between the number of chromosomes and genes is >2, the gene is amplified and the cancer may be considered for specific treatment with HER2 drugs

scores:

  • 3+: very brown staining, found in >10% of cancer cells
  • 2+: staining is around 10%, but cells are not completely stained or the staining is heterogeneous
    --> in this case, FISH is recommended
  • 1+: negative, just a few stainings are observed

tts activation induces cell proliferation, migration, differentiation and apoptosis

activation of HER2 happens upon dimerization

even tumors with very low HER2 expression may respond to double treatment including anti-HER2, e.g. trastuzumab + CT

Ki67 proliferation index

Ki67 is a moAb staining all the cells that are in the mitotic phase and it is both prognostic and predictive

stained nuclei have to be counted to calculate the percentage of positivity: the cutoff is 20%

if there is high proliferation, the tumor is more aggressive, but it also responds better to treatment

molecular classification

ER+

expression of ERs

subtypes

Luminal A

  • good prognosis
  • expression of some specific genes
  • HER2-
  • low proliferation index
  • treated with endocrine therapy

Luminal B

  • more aggressive
  • Luminal B HER2+ (ER+, PR+, HER2+): treated with endocrine therapy, CT, anti-HER2
  • Luminal B HER2- (ER+, PR+, HER2-): high proliferation index, treated with endocrine therapy, CT

ER-

no ERs expression

subtypes

ERBB2+

triple negative (basal-like)

  • only HER2+ (ER-, PR-)
  • treated with CT and anti-HER2
  • ER-, PR-, HER2-
  • treated with CT

metastases mainly tend to spread via blood to lungs, CNS, liver and bones

the tumor size does not impact on prognosis and, if the patient is alive after 5 years, she can be considered cured

after such a diagnosis, the pt must be evaluated to check for the eventual presence of PIK3CA gene mutation

association with ovarian cancer (women), prostate and pancreatic cancer (men)

if the pt is positive for this mutation, Alpelisib can be used for the treatment (good response); this mutation is not responsive to endocrine therapy

also evaluate PD-L1 expression

in particular in women who had breast cancer, were treated with CT and, at the end of the treatment, still showed metastases development

in the case of positivity, Atezolizumab is a treatment option