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  • Histology of common causes of breast lumps, and correlate the appearances with clinical manifestations. To distinguish between neoplastic and non-neoplastic lesions, and then to distinguish between benign and malignant neoplastic lesions.

Case 1 clinical history

A 45 year old woman presented to her local medical officer with a lump in the right breast. The lesion, which was in the lower outer quadrant of her breast, had been noticed to be enlarging over the last two weeks. There was no change in the size or nature of the lump in relation to her menstrual cycle. On examination there was a 3 cm stony hard lump, which was tethered to the overlying skin. There was dimpling of the overlying skin on contraction of the pectoralis muscle. There were firm, but mobile axillary lymph nodes on the right side.

Fibrocystic change

BreastLump1.png

Presenting

Consider Hx – menopausal status, previous cancers, family history, change in lump with cycle/time Observe for desmoplasia [hardened lump], tethering to skin, dimpling, lymph node enlargement or if biopsy needed.

Aetiology

  • Most common in patients in 30’s and 40’s complicating screening cancer due to microcalcifications also present [50% of women at some point in their lives]
  • Usually bilateral – and for changes during menstrual cycle and ceases upon menopause
  • Most commonly in upper outer quadrants of breast [axilla]
  • Most are smooth, rounded and mobile lumps [if palpable]

Pathology

  • Fibrosis – dense collage distorting and compressing structures and ducts
  • Cyst formation – dilated ducts with serious fluid; more tender before menses and after drinking coffee
  • Adenosis – extra crowded acini; mainly hyperplasia of epithelium and stroma due to estrogen levels
  • Less adiposity than you expect in a normal breast
  • Breast duct - looks slightly cuboidal (normally is bilayered: myoepithelium and luminal cell) with camel humps on top of the cell
    • Known as apocrine metaplasia (like in sweat glands
    • Normal epithelium has undergone pressure atrophy and has been replaced with apocrine metaplasia. This reflects the embryological nature of the breast tissue: an apocrine sweat gland
  • This doesn't agree with the history:
    • the lump in fibrocystic change should increase in size during the luteal/secretory phase (against diagnosis)
    • fibrocystic change is firm, but not 'stoney hard'
    • fibrocystic change isn't indicative of tethering to the overlying skin - it should be free in the breast tissue
  • This lesion is a common variant of normal: no proliferation of breast ductal epithelium. It is not a predisposing condition for breast cancer. Some other benign breast diseases (e.g. atypical ductal hyperplasia) do predispose to breast cancer, but not this lesion

Diagnosis

  • Palpation, mammogram/ultrasound, and fine needle biopsy if needed [aspiration may also drain cysts to relieve symptoms]

Treatment

  • Avoid caffeine, reduce Na, More fruit/veg, pain medications
  • Diuretics, Vit E, B6, Niacin, Apply Heat
  • Surgical removal

Fibroadenoma

BreastLump2.png

Presenting

  • Mostly soft, rubbery and mobile with no tethering
  • Respond to estrogen, increasing in size during pregnancy and receding after menopause

Aetiology

  • Most common form of benign tumour
    • Myoepithelial layer and stroma appear normal (unlike metastatic tumours)
  • Can also be a form of hyperplasia induced by cyclosporin A in renal transplantation
  • All neoplasms are monoclonal
  • Hyperplastic growth is polyclonal

Pathology

  • Benign tumour of breast CT [stroma] and glands [epithelium] growing with changing estrogen levels
  • Well differentiated (all resembles normal-looking fibroblasts, no pleomorphism)
  • Well circumscribed and lobulated and capsulated with no invasion; CT capsule.
    • Slow, expansile pattern of growth (CT pseudocapsule around lesion)
  • Normal stroma with neoplasia; stroma compressing white part (glands).
  • Normal ducts (2 layers) with some proliferation
    • Myoepithelium and luminal cells are hyperplastic
    • Vacuolated layer underneath the epithelium, and luminal cells along the surface of the epithelium: differentiation indicates that it's a polyclonal (not monoclonal). Hence it's not a monoclonal proliferation of epithelial cells - instead it's the proliferation of stromal cells.
      • Name "fibroadenoma" is an historical misnomer. It's actually a fibroma
  • No angiogenesis.
  • Doesn't match the clinical case
    • Fibroadenomas are usually rubbery, not stony hard
    • Fibroadenomas are not tethered - they're mobile
    • Involves dermis
    • Lymph nodes are firm, indicating metastases (but fibroadenomas are benign so there shouldn't be involvement of lymph nodes)
    • Fibroadenomas are slow growing, while the lesion in the case was fast growing

Diagnosis / Treatment

  • Mammogram, Ultrasound, Fine Needle Aspiration
  • May require surgical removal


Ductal carcinoma

BreastLump3.png

Aetiology

  • Accounts for 80% of Breast cancers
  • Risk factors – BRCA genes, radiation, early menarche, late menopause, nulliparity and obesity

Diagnosis / Presenting

  • Palpable mass, nipple discharge, Paget’s Disease of the Nipple
  • Screening – microcalcifications, granular appearance
  • Fine needle aspiration biopsy – shows cytological appearance indicating aneuploidy to differentiate DCIS or invasive
  • Core biopsy – better as shows architecture of breast tissue as well as cell differentiation

Pathology

  • Dysplastic invasive mass – poorly differentiated, forming cord like glands with little tubular structure.
  • Cytological features of malignancy: Cells have high N:C ratio, hyperchromatic, pleomorphic [variable nuclei], prominent nucleoli and loss of structure [clumps → not spindly like mesenchymal tumours], mitotic figures, metaphase bars
  • Ducts have no lumen or structure: proliferation of cells that resemble luminal cells (not polyclonal anymore)
  • Invasive cords into normal breast tissue
  • Desmoplasia (surrounding the tumour) and angiogenesis (in stroma surrounding tumour cells)
    • Stroma is remarkable for its eosinophilic bands of collagen throughout the tumour (desmoplasia: causes the stony hardness)
  • Formation of tubules allows us to do histopathological staging
  • Ductular epithlial cells within the duct occurs in the relatively normal surrounding breast tissue (DCIS; the precursor lesion to invasive ductal carcinoma)

Prognosis

  • Staging – Tumour / Nodes / Metastasis
    • Invasion (blood vessels, lymphatics, surrounding tissues) by looking at advancing edge of the tumour
    • Site of the primary
  • Grading – degree of differentiation / structure
  • Receptors – HER2, Estrogen receptors
    • Cytological markers (e.g. her2:epidermal growth factor, estrogen and progesterone nuclear receptors)


  • Note:
    • Tethering to the skin is a poor prognostic indicator (due to involvement of the skin)
    • No lymphatic invasion (no peau d'orange)
    • Once the breast cancer becomes palpable, there is a 50% chance of involvement of axillary lymph nodes (hence do a sentinel lymph node biopsy)
    • This is an "invasive ductal carcinoma of no special type"
      • Most common, has the worst outcomes (special types have the best outcome)

Metastatic adenocarcinoma, lymph node

  • Loss of follicular appearance
  • Widespread desmoplasia and angiogenesis
  • Highly invasive
  • Replacement of the normal lymph node structures (medulla (germinal centres, follicles) and cortex and sinus) with tissue of glandular differentiation)
    • There is some differentiation: forming glands, but there is no variation between cell types
    • Stromal induction
    • Haemorrhage and necrosis
    • Pleomorphic cells, high N:C ratio, mitotic figures, neoplastic proliferation of glandular tissue that is secreting mucin into the glands. Breast cancer does not secrete mucin (this is a visceral adenocarcinoma that has metastasised to the lymph node).

BreastLump4.png

BreastLump5.png


  • Is the lymph node consistent with case history?
    • Could have been reactive changes: sinus histiocytosis (tumour debris that has been drained). But reactive = tender, painful, enlargement.
    • If it's due to metastases to the lymph nodes, we have hard, matted lymph nodes (due to induction of stroma and invasion through capsule).

Metastatic adenocarcinoma, bone

BreastLump6.png

  • Four months later the patient returned with back pain and right shoulder pain. She had lost 6 kg in weight over the past two months and was anorexic. Examination revealed tenderness over the fifth and sixth thoracic vertebrae and also over the right acromion.
  • What is the likely cause of these symptoms and signs? What investigations would you perform to substantiate your provisional diagnosis?
  • Weight loss, tenderness of 5th/6th thoracic vertebrae indicate unlikely due to back pain from arthritis
  • Likely to be metastatic adenocarcinoma to the bone

Investigations

  • Metastasis to bone is through blood supply (see anatomy). Bone is vascular, with blood running through Haversian canals. Just because tumour cells get somewhere doesn't mean they'll survive and grow. They have to break out of blood vessel, induce stroma (CT, blood vessels) and local microenvironment. Skeletal muscle and spleen have great blood flow but rare mets (due to local microenvironment). Within bone, it is odd that there are so many metastases, except that bone marrow has a great blood supply. Haemapoeitic red marrow is more vascular (and present in epiphyses of long bone, the vertebrae, the pelvis, scapula, ribs, sternum and skull: the axial skeleton). These are the sites of blood-borne metastases from bone.
  • Weight loss is due to anorexia in malignancy. They feel sick due to cachectin (a.k.a. TNF-a; involved in both weight loss in malignancy and in inflammation).
  • Investigations: 1) Bone scan with radio nucleotides (showing vascularity, revealing more than are clinically apparent) 2) Plain x-ray (skeletal survey; not as sensitive as): 3) CT scan
    • Bone scan is more sensitive than both, but its localisation is not as good as the others
  • Biochemistry - increased Ca, P [CaPO4 in bone, released with tissue destruction] and Alkaline Phosphatase [indicates bone turnover; rises in parallel with osteoblast activity]
    • Don't know whether it's a reaction of osteoblastic reaction of the tumour or due to an osteosclerotic metastasis (rather than an osteolytic metastasis)
      • Note that breast carcinoma is one of the forms of cancer that can produce osteosclerotic lesions
  • Macro of spine: multiple lesions and collapsing fractures in the vertebrae
    • Can see grey tissue in the vertebral bodies and collapsed fractures
  • increased Ca can lead to neurological disturbances
  • X Ray – metastatic deposits, darker if lytic, lighter if sclerotic [may be both, mainly lytic]
  • Pathological fractures may be visible

BreastLump7.png

Features of the slide

Start on the right

  • Stuff filling the field is a piece of articular hyaline cartilage (stuck right onto some bone underneath - you can see a wavy line attaching to the bone underneath, which is part of a joint)
    • This could be the epiphyseal end of a long bone or the costochondral cartilage of a rib
  • Calcification seams with osteocytes sitting inside the bone of the trabecula (inside lacunae)
  • Empty lacunae in some bone = necrosis of osteocytes (even though there is vasculature).
  • The space within the trabeculae should be very cellular (red marrow), has no haemapoeitic cells where there should be many (just has stroma)
    • Nearby we note glandular epithelial tumour cells (these are adenocarcinoma cells that are inducing stroma).
  • These cells are also beating up the bone and triggering a response: these are new trabeculae (small and thin, and covered by osteoblasts - this is part of the reactive new bone formation triggered by metastases)

Overall:

  1. Bone destruction
  2. New bone formation
  3. Replacement of the haemapoeitic tissue
  4. Bone death

Sequence of Events

  • Direct spread through blood or through lymphatics → thoracic duct → bloodstream
  • Bone is a favourable site → increased blood, increased growth factors
  • Prostatic and lung cancers frequently metastasise to bone

Causes of Death

Many of the answers are true for all malignancies

  • Massive pulmonary embolism – cachexia, bed confinement, DVT
  • Bronchopneumonia – cachexia, weak cough, increased secretions (or even due to atelectasis from lung mets)
    • decreased respiration due to analgesics, infection, sepsis and hypoxia → death
  • Intracranial herniation syndromes – metastasis to brain (mass effect)
  • Liver failure – metastasis to liver, unlikely, needs 90% loss in function (lots of metastases needed) → hepatic coma

Likely observations at autopsy

Video

  • Axillary tail of breast contain axillary lymph nodes
  • Instead of normal adipose tissue, there are large areas of whitish fibrous tissue (fibrocystic change)
  • From some areas we can extrude yellowish necrotic material along with the ducts (due to cystic change)
  • Greyish stellate scar-like lesion: infiltrating ductal carcinoma of the breast, which is extremely firm and resistant to the tough. Different colour and consistency to surrounding tissue
    • Like cutting through an unripe pear
  • Axillary lymph nodes are assessed for presence of metastases.
    • Lymph node is firm to the touch and hard to cut. Lacks white centre that we'd expect from tumour involvement
  • Frequent: Simultaneous presence of fibrocystic change and tumour (often that what appears to be a malignant lump is due to fibrocystic change (but don't forget about the possibility of both occurring at once)).
  • Mastectomy if left late.
  • Draining lymph nodes were enlarged, without tumour involvement (this is due to sinus histiocytosis).

Adaptive tutorial