The Histopathology of Breast Cancer- Part A

Although this article has been written with medical professionals in mind, we have left ample opportunity for the concerned patient/caregiver to know more about a specific histopathological diagnosis, especially by incorporating prognosis (the outcome) and clinical features to expect in a certain tumor.

The normal breast is made up of the lobules (which are the sacs where milk is produced), and ducts (which are the tubes that carry the milk towards the nipple). Cancer starts in the cells lining the ducts or lobules. 

As long as the carcinoma cells are still confined to the breast ducts or lobules, without breaking out and growing into surrounding tissue, it is considered in-situ carcinoma (or carcinoma in situ).

Image result for terminal ductal lobular unit
ITD-interlobular terminal ductule
ETD-extralobular terminal ductule
Image result for breast lobes

Most breast cancers arise from the epithelial cells of terminal epithelial ductal units(TDLU). Invasive/infiltrative carcinomas refer to a proliferation and penetration through the basement membrane of ducts and lobular units into the breast stroma.

Even though breast carcinoma is discussed as a single disease, it actually involves a diverse group of lesions that involves different types of clinical presentation, clinical behaviour, imaging and histological features. 

In this article we will focus mostly on the histological features of invasive breast tumours, covering them through the WHO Classification System.

Classification

According to WHO breast tumours can be classified into 21 different types

  • Invasive ductal carcinoma
  • Invasive lobular carcinoma
  • Tubular carcinoma
  • Invasive cribriform carcinoma
  • Mucinous carcinoma
  • Carcinoma with medullary features
  • Carcinoma with apocrine differentiation
  • Carcinoma with signet ring cell differentiation
  • Invasive micropapillary carcinoma
  • Metaplastic carcinoma
  • Carcinoma with neuroendocrine features
  • Secretory carcinoma
  • Invasive papillary carcinoma
  • Acinic cell carcinoma
  • Mucoepidermoid carcinoma
  • Polymorphous carcinoma
  • Oncocytic carcinoma
  • Lipid-rich carcinoma
  • Glycogen rich clear cell carcinoma
  • Sebaceous carcinoma
  • Salivary gland/skin adnexal type tumours

Infiltrating ductal carcinoma

Definition

Infiltrating or invasive ductal carcinomas are those tumours with histological features that belong to no special type. The diagnosis of this type is based on the exclusion of other types of breast cancers.

Epidemiology

45-75 % of all breast carcinomas belong to invasive ductal carcinomas. Invasive ductal carcinomas may show a mixed type of growth pattern in combination with other histologic subtypes. It is most common in in the fifth and sixth decades of life and the incidence decreases after 80.

Clinical features

A painless palpable lump is the most common present ation. Skin changes, nipple discharge, skin fixation maybe seen in advanced cases. These changes are described in the article on Diagnosis.

Imaging features

On mammography the mass appears as irregular and lobulated. Margins of the mass are irregular and spiculated.(Spiculated borders correspond to an invasive growth pattern).

Microcalcifications are more associated with the in situ component of the tumour,  although the stroma or necrosis within the invasive carcinomas can also show microcalcification. Ultrasound reveals an irregular mass, with indistinct margins and inhomogeneous echotexture with acoustic shadowing. These findings are described in the article on Mammography.

Pathologic features


Pathologic features are divided into gross and microscopic:

Gross features

Most invasive ductal carcinomas have the following gross features-

  • Ill defined margins with infiltrative edges
  • Round and circumscribed with pushing margins
  • Mixture of the two

Consistency and colour depend on the amount of stromal component of the tumour. Tumors with abundant stromal component are greyish white in colour and firm in consistency.Tumours with less strom are tan yellow in colour and are softer. Some tumours may appear red brown because of dense cellularity, papillary growth pattern and intratumoral haemorrhage. In contrast to benign tumours which have a convex cut surface, these tumours have a concave cut surface. Tumour necrosis may result in cystic change.

Whitish appearance of tumour due to increased stromal component
Tan yellow appearance indicating less stroma
Ill defined margins with ill defined edges

Microscopic features

The microscopic appearance of ductal carcinoma is highly variable.The degree of atypia, cellularity, growth pattern, mitotic activity,necrosis, amount of stroma, lymphocytic infiltration  all vary between different tumours or may even vary within the same tumour.

Tumour cells may show varying degrees of gland formation, may form nests cords, sheets, or trabeculae. Necrosis may be extensive leading to pseudocyst formation.

The appearance of malignant cells vary. Some tumours have minimal atypia and pleomorphism, and are small and uniform similar to cells of normal ductal epithelium. There can be marked atypia and pleomorphism with tumour cells that have enlarged hyperchromatic nuclei. Intracellular and extracellular can sometimes be seen.

Marked nuclear atypia

The stroma may display marked variation in its amount, composition and distribution.Some tumours have large amounts of stroma resulting in a firm consistency , termed scirrhous carcinoma. Stromal distribution throughout the tumour is also variable.

Calcifications maybe detected in more than half of the cases.

Lymphoplasmacytic infiltrate within the tumour varies considerably, from marked to none. It has been suggested that the amount of lymphoplasmacytic infiltrate may have a prognostic value, particularly in triple negative and c-erbB-2 overexpressing breast cancer.

Lymphoplasmacytic infiltration

Osteoclast like giant cells may also be seen in the stroma.

The presence of lymphovascular invasion should be evaluated in invasive ductal carcinomas, especially at the periphery of the tumour.

Perineural invasion maybe seen but this finding is not of prognostic significance.

Grading of invasive ductal carcinoma

Grading of invasive ductal carcinoma helps in determining the clinical outcome. The most widely used grading system is the Nottingham histologic grading.This grading system is based on three characteristics of the tumour

  • Tubule formation
  • Nuclear pleomorphism
  • Mitotic count

Each characteristic is assessed and given a score of 1-3 and is added to reach a final score of 3-9.

Image result for nottingham histologic score

One of the main concerns while determining the grade of a tumour is tumour heterogeneity.

Immunohistochemistry features

Invasive ductal carcinomas are mostly positive for cytokeratin 7. Cytokeratins are keratin proteins found in the intracytoplasmic cytoskeleton of epithelial tissue.Cytokeratins are important structural proteins of benign and malignant epithelial cells.

Luminal type cytokeratins are positive in most tumours(cytokeratin 7,8,18 and 19). Basal cytokeratins (cytokeratins 5,6 and 14) are positive in only a small subset.

Nearly all invasive ductal carcinomas are negative for cytokeratin 20, and they are positive for epithelial membrane antigen and E-cadherin. Epithelial membrane antigen (EMA), is a family of glycoproteins and is expressed by a variety of epithelia and their neoplasms.E-cadherin is an important molecule in cell-cell adhesion in epithelial tissues.

Gross cystic disease fluid protein 15 (GCDFP-15) and mammaglobin are reported to be positive in 50-70% invasive ductal carcinomas. 

Two thirds of invasive ductal carcinomas are positive for estrogen and progesterone receptors.About 15-20% of invasive ductal carcinomas show HER2 protein overexpression or gene amplification, correlating with high grade carcinomas.

Invasive Lobular Carcinoma

Definition

Type of invasive breast malignancy that begins in the lobules(milk producing glands). The cancer cells have ‘escaped’ the lobules and invades the surrounding breast tissue and beyond.

Epidemiology

Second most common type of infiltrating breast cancer. Incidence is rising more than that of ductal carcinoma in the united states, possibly due to postmenopausal hormonal therapy. Invasive breast cancers cause an area of thickening in the breast. They are less likely than other breast cancers to form a distinct breast lump due to lack of desmoplastic response(growth of fibrous or connective tissue). These tumours are more likely to be multicentric and multifocal and 10-20% are bilateral. Metastasize to bone marrow, cerebrospinal fluid, leptomeninges, GI tract, ovary, uterus and retroperitoneum.

  • Has better prognosis than invasive ductal carcinoma.
  • Has better survival at 6 years and worse survival at 10 years.
  • It has been shown that local relapse free survival at 12 years was 89%, the predictors of relapse being positive margins, age >50 years and contralateral breast cancer.

Imaging

Often multicentric and bilateral (10-15%). The detection of invasive lobular carcinoma on mammogram is between 57-81%. Because of this limitation sonography and MRI is being used in suspicious masses to assess the extent of the disease.

Image result for Lobular carcinoma gross
Mammographic findings include spiculated mass lesion (most common), asymmetrical densities, opacities or architectural distortion, microcalcifications, 16 % are occult or benign on mammogram.

Pathology

Gross

Mass with ill defined margins, often no mass is seen because of diffuse growth pattern. Some infiltrating lobular carcinomas may have similar macroscopic appearance to that of infiltrating ductal carcinomas. In many cases no obvious mass is evident and the excised breast may have either normal or slightly firm in consistency. The microscopic size may be significantly greater than that measured grossly.

Microscopy

Microscopically the tumour cells invade the stoma and adipose tissue in a single file like pattern, growing in a target like pattern around normal breast ducts, inducing only a minimal fibrous reaction.

The tumour cells are small, round, uniform and lack pleomorphism. These cells are not very mitotically active and are of intermediate histologic grade(Nottingham grade 2).




Single file like pattern

Metastatic lobular carcinoma is seen mostly outside the lymph node capsule with only 

Associated lobular carcinoma in situ(LCIS) is present in two thirds of the case, DCIS may also be present. The cells have a loss of E-cadherin adhesion protein in 85% of the cases.

Cells may be seen encircling normal ducts- onion skin pattern.

Dense lymphoid infiltrate may be seen at the periphery. 

Metastatic cells are very unusual and require immunohistochemical studies for identification.

Lymph node mets may appear as lymphocytes.

Bone marrow mets- may appear as signet ring cells, histiocyte like cells accompanied with fibrosis.

There is an association between e cadherin(CDH1) and invasive lobular carcinomas. Seen in families with hereditary diffuse gastric carcinoma with mutations in the CDH1 gene. E-cadherin mutations are seen in around half of the patients and the other half have PIK3CA, PTEN, and AKT1 .

Lymphocyte like cells in lobular carcinoma lymph node metastasis

Tubular carcinoma

Definition

Tubular carcinoma is a type of invasive breast carcinoma, which consists of tubules occupying most of the tumour. These tubules are lined by low grade tubular cells.

Incidence

(10-20 % invasive ca breast)- incidence is higher in mammography screened populations. Seen in a slightly older age group than invasive ductal carcinoma with an average age of 60 years.

Imaging

Tubular carcinomas present either with a palpable mass or mammographic abnormality. Tubular carcinomas on mammography appear as irregular masses with spiculated margins, with the spicules being greater in length than the diameter of the central lesion. The lesion is very small in majority of the cases(<1cm) in diameter.

Amorphous microcalcifications may be seen in 10-15% of the cases.

On sonography the lesions are hypoechoic with posterior acoustic shadowing.

Pathologic features

Gross findings

Most tubular carcinomas are less than 2 cm and form stellate nodules. They are poorly circumscribed and are hard on consistency.

Image result for tUBULAR CARCINOMA GROSS

Microscopic features

Characterised by tubular or glandular structures, infiltrating the stroma. The tubules are elongated in shape and are composed of columnar to cuboidal cells. The tumour cells are low grade and is associated with low grade DCIS in three fourths of the cases. These tumours have desmoplastic stroma and may form trabecular bars. There is minimal pleomorphism,

These lesions have a favourable prognosis. Infiltration of tubules into peripheral fatty tissue is an important diagnostic clue. Microcalcifications may be present. WHO criteria says that greater than 90% of tubules is required for diagnosis of tubular carcinoma, 50-90% tubular differentiation are classified as mixed tumours, and those with less than 50% tubules are classified as invasive ductal carcinoma. Majority of tumours are ER/PR positive and have a negative expression of HER2 receptors.Show E-cadherin positivity.

Tubular carcinoma

Prognosis

Tubular cell carcinomas have low incidence of axillary metastasis and have a favourable prognosis. In most cases even if there are axillary metastasis only 3-4 axillary lymph nodes may be involved and are mostly micrometastasis. It is treated by resection of the tumour, sentinel lymph node dissection, followed by radiation, and endocrine therapy since most tumours are positive for hormone receptors.

Invasive Cribriform Carcinoma

Definition

Invasive cribriform carcinoma is a well differentiated carcinoma, with a cribriform growth pattern, similar to cribriform pattern of ductal carcinoma in situ. These tumours may have <50% component of tubular carcinoma.

Epidemiology

These tumours are around 0-3.5 % of all invasive breast cancers. This tumour is associated with tubular carcinomas, both types have excellent prognosis.

If an invasive carcinoma consists of both patterns, the final diagnosis will depend on which pattern predominates. Average age is around 50 years. Nodal metastasis are present in 14%.

Epidemiology

These tumours are around 0-3.5 % of all invasive breast cancers. This tumour is associated with tubular carcinomas, both types have excellent prognosis.

If an invasive carcinoma consists of both patterns, the final diagnosis will depend on which pattern predominates. Average age is around 50 years. Nodal metastasis are present in 14%.

Pathology

Gross

These tumours form stellate masses with infiltrative margins.

Microscopy

These tumours consists of nests of cells which have a cribriform pattern. They have irregular borders, but the in situ carcinomas are well rounded and have myoepithelial cells which are absent in invasive pattern.

Tumour cells are small, with apical snouts, mild/moderate pleomorphism.

Stroma invasion by islands of cells is present.

Pure pattern/classical type if >90 % cribriform pattern is present.






Invasive cribriform carcinoma- nests of cells invading the stroma

The tumour cells are usually columnar or cuboidal and are of low grade. These tumours are commonly associated with osteoclast like giant cells. They are mostly ER/PR positive and HER2 negative. 

Prognosis

If diagnosis is restricted to classical pattern it means excellent prognosis even with nodal metastasis.


Mucinous

Definition

Clusters of small uniform cells floating in lakes of extracellular mucin. Mucin accumulation maybe towards the base of cell rather than luminal border.

Defined as pure mucinous if more than 90 % is mucinous and mixed if 75-90% is mucinous with another variant.

Epidemiology

Accounts for 2% of all breast cancer especially in women above 55 years of age.

Imaging features

Dense mass on mammography, ill- defined borders, maybe partially circumscribed, and shows posterior enhancement on ultrasound.

Pathology

Gross

Consists of a mucinous or gelatinous mass, and may demonstrate haemorrhage and lobulated contours.

Microscopy

Well defined, low grade tumour cells floating in large amounts of mucin, tumour cells may be solid, acinar or detached, and surrounded by connective tissue bands. It is recommended that at least one third of the tumour consists of mucin. There are no mitotic figures seen. They are usually hormone receptor positive and HER2 negative. Classified as Type A(with neuroendocrine differentiation), type B(no neuroendocrine differentiation) and type AB(intermediate form).

IHC- ER/PR positive in less than 70%, NSE and chromogranin in 15-50%
Stains with PAS, alcian blue and mucicarmine.

Prognosis

Pure mucinous carcinoma has an excellent prognosis with 10 year survival exceeding 80%.

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