The Histopathology of Breast Cancer- Part C

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.

Continuing from The Histopathology of Breast Cancer- Part B

Carcinoma with Neuroendocrine features

Definition

Defined as breast carcinoma with at least 50% neuroendocrine cells. These tumours arise from neuroendocrine cell hyperplasia.

Epidemiology

Accounts for less than 5 % of all breast cancers. Frequency increases with age. Apocrine phenotype is present in elderly women. Similar prognosis as ductal carcinoma.

Pathology

Gross

No distinct gross features. Similar to ductal carcinoma.

Microscopy

Image result for neuroendocrine breast carcinoma

Small low-grade nests, surrounded by fibrous tissue, with no specific histologic pattern such as colloid, papillary. Mitotic figures are rarely seen. These cells are positive for chromogranin. These cells have salt and pepper chromatin which is highly specific for neuroendocrine tumours and high mitotic activity.

Rosette formation of cells and extracellular mucin may also be present.



Nests of cells in neuroendocrine breast cancer

Other markers may be synaptophysin and neuron specific enolase. These tumours may be metastatic from the pulmonary neuroendocrine small cell carcinoma. This can be distinguished from patient history and the presence of TTF-1 which is present in lung tumours and absent in mammary. 

Image result for neuroendocrine breast carcinoma
Nests of cells separated by fibrovascular stroma

Neuroendocrine tumour solid type– Densely cellular nests with trabeculae, separated by a delicate fibrovascular stroma. The cells are polygonal with abundant cytoplasm.

Neuroendocrine tumour large cell– Cells are large with granular chromatin and presence of mitotic figures.

Secretory Carcinoma Breast

Definition

Rare tumour, of low grade associated with translocation, and  microcystic and tubular architecture with vacuolated tumour cells producing intra and extracellular secretions.

Clinical features

The tumour is fairly benign.The size of the tumour, rates of axillary nodal metastasis and stage are all similar to ductal carcinoma. Breast lump is mostly subareolar. These tumours have excellent prognosis with 5 year overall survival rate of 87%. Distant mets have been noted in some cases.

Young women tend to have better survival than older women.

Epidemiology

These tumours accounts for less than 1% of all breast cancers. Although it can be seen in any age group it is the most common paediatric age group cancer. Average age of presentation is around 25 years.

Imaging

Imaging features are not specific. May range from well circumscribed mass to mass with irregular margins and microcalcifications.

Pathology

Gross

Well circumscribed mass

Microscopic

The cells maybe arranged in solid, microcystic or tubular pattern or a mixture of all three. These cells have uniform nuclei and low mitotic rate.

The hallmark of this tumour is the presence of vacuolated tumour cells secreting intra and extracellular mucin which is PAS positive and diastase resistant.

The classic secretory carcinoma has microacini, abundant secretion, and papillary features.

Image result for secretory cell carcinoma breast

Immunohistochemistry

These tumours tend to be positive for cytokeratin, EMA, CEA, alpha lactalbumin and vimentin.

It has been shown that many secretory breast carcinomas are characterised by a balanced translocation t(12:15), creating a fusion gene ETV6-NTRK3.

Acinic cell Carcinoma of Breast

Definition

These tumours are identical to salivary gland counterparts. These tumours show significant infiltrative growth patterns of glandular structures.

Clinical Features

Low grade tumour even if the tumour has high mitotic activity and hormone receptor negativity.

Epidemiology

Extremely rare tumour with less than 20 cases reported.

Pathology

Gross

Well circumscribed, infiltrative, having a haemorrhagic cut surface. These tumours are usually in the size range of 2-5 cm.

Microscopic

Image result for acinic cell carcinoma breast

Cells are weakly eosinophilic or clear, or vacuolated with a central round nucleus and nucleoli. These tumours are sometimes surrounded by a pseudocapsule.

Immunohistochemistry

Positive for CK7 and amylase, E-cadherin and EMA positive. Granules are PAS positive.

When amylase, lysozyme and alpha-1 antichymotrypsin are present it confirms the diagnosis.

Mucoepidermoid Carcinoma

Definition

Rare tumour that has three components– Mucus secreting cells, squamous cells and Intermediate cells. Most common tumour in the salivary glands but is rare in distant sites such as breast.

Mucoepidermoid carcinoma may have a low and high grade variety. Low grade variety grows slowly and has an excellent prognosis. High grade variety is aggressive and shows axillary mets and distant mets

Clinical features

These masses have irregular margins and appear partially or wholly cystic on ultrasound and mammography.

Pathology

These tumours have two types of cells– Cells without mucus in the cytoplasm and cells with mucus in the cytoplasm. These cells are arranged in clusters. These tumors are often surrounded by a fibrous pseudocapsule.

In low grade variety, cells show keratinization and glandular cells forming distinct small Lumina.

In high grade– These tumours show mixtures of glandular, squamous and epithelial cells. There may also be scant intra and extracellular mucin. The tumour shows areas of necrosis and presence of mitoses.

Immunohistochemistry

S-100 protein, E-cadherin and EMA positive. Higher grades of tumour may stain for CEA. High expression of ki-67 indicates aggressiveness.
Tumor is triple negative.

Polymorphous Breast Carcinoma

Definition

Tumour that resembles polymorphous low grade adenocarcinoma of the salivary glands.

Clinical features

Among the cases reported the average tumour size was around 1.5-4 cm and patient age ranging from 37-74 years. Distant metastasis seen.

Epidemiology

Extremely rare tumour.

Pathology

Cell arranged in tubules, alveolae, nests and trabeculae. Nuclei are round to oval.

Moderate mitotic activity is present. Immunohistochemical and architectural features may differ within the same tumour.

Immunohistochemistry

These cells are positive for bcl-2, CK-7, E-cadherin, GFAP and CK-5/6, and are triple negative.

Oncocytic carcinoma

Definition

Also called malignant oncocytoma or malignant epithelial oncocytoma. These tumour can develop in men as well. If the tumour contains more than 60-70% oncocytic cells it will be referred to as oncocytic breast carcinoma. Oncocytic means swollen cells, the swelling being due to accumulation of mitochondria.

Clinical features

These tumours have favourable prognosis. They have shown to be ER and PR positive.

Pathology

Oncocytes are swollen cells with abundant cytoplasm. The histology is same as oncocytic tumours of other organs such as salivary glands and endocrine organs. These carcinomas are mostly solid, without glandular differentiation and not diffusely cribriform.

Image result for oncocytic carcinoma breast
Oncocytes(swollen cells)

GCDFP15 staining is negative for oncocytic carcinoma and positive for antimitochondrial antibody. This helps differentiate these tumours from apocrine tumours of the breast which maybe difficult to differentiate.

Lipid rich carcinoma breast

Definition

More than 90% cells within the tumour have intracytoplasmic neutral lipid.

Clinical features

1-2% of breast carcinomas. 70% show nodal metastasis at presentation and have a poor prognosis. The mass is usually felt in the subareolar region

Imaging

Irregular dense mass, with lobulated borders.

Pathology

Gross

The tumour is lobulated, and firm

Microscopy

The lesion contains nests and cords of polygonal cells filled with vacuolated cytoplasm containing lipid. The nuclei are irregular, with coarse chromatin, moderate atypia and nucleoli.

Image result for lipid rich carcinoma breast
Lipid rich carcinoma breast

Immunohistochemistry

These cells stain with ‘oil red O’ stain. The cells are PR positive with varying immunoreactivity towards ER. E-cadherin is positive. Cytokeratin, vimentin and S-100 also tend to be positive.

HER2 is negative.

Glycogen rich clear cell carcinoma breast

Definition

Rare tumours in which more than 90% cells have abundant clear cytoplasm due to presence of glycogen. It may be a variant of apocrine carcinoma.

Imaging

Glycogen rich CA breast can be misdiagnosed on mammogram as fibroadenoma, due to its lobulated circumscribed appearance. MRI helps in distinguishing the two.

Epidemiology

Accounts for 2-3 % of all breast cancers. These tumours are considered a member of the heterogenous group of breast tumours which include secretory, lipid rich and signet ring breast cancer. These tumours are rare and have a poor prognosis.

Pathology

Solid or papillary patterns of large clear cells containing glycogen, with clear to granular cytoplasm. May have scant mucin intracellularly and do not have cytoplasmic vacuoles.

Image result for glycogen rich carcinoma breast

Necrosis is generally absent. There is often intraductal growth with stromal invasion.
Moderate degree of inflammatory cell infiltration will be seen in the intervening stroma.
Moderate to marked nuclear nuclear pleomorphism containing prominent nucleoli.

Stains positive for PAS.

Immunohistochemistry

Cells are usually ER positive and PR negative. Other positive tests are- Keratins, AE1/AE3, EMA, CK7.

Sebaceous breast carcinoma

Definition

Sebaceous breast cancer is actually a skin cancer, growing on the skin of the breast, characterized by cells with morphological differentiation toward sebaceous epithelium.

The breast cancer cells resemble skin sebaceous glands. This is usually a low grade tumour and can sometimes also develop within an intraductal breast papilloma.

Clinical features

These tumours often present as a small mass, and may be mistaken for a benign lesion. These lesions are often well circumscribed and may be missed on a mammogram.

Epidemiology

These tumours are seen in older age groups around 60-70 years of age, and is very rare. The tumour is often low grade, but sometimes, may be poorly differentiated and have a poor prognosis.

Image result for sebaceous carcinoma breast


Pathology

Microscopy

These tumours have well defined solid sheets or lobules of atypical epithelial cells, including large, pale or clear cells with coarsely vacuolated cytoplasm with abundant lipid droplets (stains with oil red O) and often scalloped nuclei.  

The cells are negative for PAS.

These cells are positive for EMA, Leu M1, human milk fat globules subclass 1, human milk fat globules subclass 2. These glands are also reactive for Cam 5.2 and BRST-1. These help in differentiating sebaceous carcinomas from squamous cell and basal cell carcinomas. ER/PR positivity is seen and negativity for HER2.

With this we conclude with the pathological aspects of breast cancer as per the WHO classification. 

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