Breast Cancer Pathology - Phase I

Robbins and Cotran Pathologic basis of disease is a great text for this (and other) sections.

Natural History and Patterns of Spread

Adenocarcinoma

Ductal Carcinoma

Adenocarcinomas typically grow locally before metastasising. If the primary breast lesion is palpable, there is a 50% risk of regional lymphatic involvement. Distant metastasis in the absence of lymph node involvement is rare, but may occur in cases of self neglect, high grade tumours with lymphovascular or perineural invasion, or in women with large or dense breasts. Screening may detect tumours before they are palpable, reducing the likelihood of axillary node invovlement. Metastasis typically occurs to the lung, bones and the brain. The most commonly involved regional nodes are in the axilla.
The natural history of adenocarcinoma is closely related to its stage at diagnosis and the histological grade. Spread of tumour to regional nodes increases the risks of distant relapse significantly, as does grade III disease.

Lobular Carcinoma

Lobular carcinoma has a different natural history to ductal carcinoma of no special type. It may often metastasise to the peritoneum or retroperitoneum, the female genital tract or the brain (leptomeninges).

Metaplastic carcinomas

Metaplastic carcinomas frequently metastasise earlier than standard adenocarcinoma and have a poorer prognosis.

Pre-invasive lesions

DCIS is usually detected mammographically. It may transform into invasive carcinoma at the rate of 1% per year.

Clinical Presentation

Symptoms

Breast cancer localised within the breast is usually asymptomatic, although it can cause localised pain. Women may notice a lump in the breast incidentally. Tumours beneath the areola may cause discharge or inflammation around the nipple (Paget's disease due to growth of tumour out of the ducts into the skin). Some malignancies may cause inflammatory breast cancer, associated with oedema and inflammation of the overlying breast. Neglected cases may ulcerate through the skin or invade the underlying pectoralis muscles and ribs, causing pain.
Spread to lymph nodes may be asymptomatic or may cause pain in the axilla, with or without mobilisation of the shoulder. Advanced cases in the axilla may ulcerate through the skin.
Metastatic disease can present in several ways.

• Pain due to bony metastases, often occuring the mid thoracic spine.
• Rash, itch and jaundice due to liver metastases
• Confusion or neurological signs due to brain metastases, hypercalcaemia or liver failure.

Signs

On examination of the breast, a typical ductal carcinoma feels firm and irregular and may be attached to the overlying skin or underlying deep fascia. Central tumours may cause inversion of the nipple. Discolouration and inflammation of the areola suggests infiltration of the skin by tumour.
Lobular carcinoma is often difficult to palpate as it may infiltrate diffusely and not form a firm mass.
Inflammatory breast cancer is often associated with oedema of the skin (classically called peau d'orange, 'skin of an orange' due to similarities with the fruit). Patients may have a large, swollen and tender breast, similar to mastitis.
Signs of nodal involvement may include palpable lymphadenopathy in the axilla or supraclavicular fossa. The mobility of the nodes is important in clinical staging - freely mobile nodes are staged as cN₁ whereas fixed axillary nodes are cN₂ with poorer prognosis.
Metastatic disease may present in several ways.

• Invasion of bone may lead to tenderness over affected sites, or neurological signs if the spinal column is badly affected
• Liver lesions may cause enlargement of the liver, which may have an irregular shape
• Lung lesions may cause collapse of a lobe and increased sounds on auscultation. Pleural effusion may be caused by metastatic breast cancer.
• Cerebral lesions may cause local or general neurological signs.
• Cancer cachexia may result from advanced disease, with weight loss and loss of energy.
• Hypercalcaemia can lead to confusion and changes in reflexes.

Screening

Screening for breast cancer has become very common, with the Australian government funding a screening program for women aged 50 - 70. This has increased the rate of detection of pre-invasive and early stage disease (such as small tubular carcinomas and DCIS), with the aim of treatment beginning before the tumour has spread to local nodes.

Pathological Features

Adenocarcinoma of the breast

Ductal Carcinoma of No Special Type

Macroscopic Features

Ductal carcinoma is usually firm and hard. They usually are pale to tan in colour and infiltrate surrounding breast tissue. Occasionally multifocal lesions may be present.

Microscopic Features

Ductal adenocarcinoma may show varying degrees of tubule formation, from well formed glands (well differentiated) to sheets of cells (poorly differentiated). Well formed glands lack the deep layer of myoepithelial cells which allows them to be distinguished from normal glands. There is usually some degree of cellular and nuclear polymorphism. The number of mitoses also has an impact on final grading.

Subtypes of 'No Special Type'

More recent studies into carcinomas of no special type have demonstrated that, on special tests, they can be subdivided into several categories.

• Luminal A carcinomas (about 50%) have positive hormone receptors and no amplification of ERBB2. They respond well to hormonal treatments but poorly to chemotherapy.
• Luminal B carcinomas (about 20%) have positive hormone receptors as well as amplification of ERBB2 (triple positive). They are often higher grade and metastasise to nodes. They respond well to all treatments.
• Normal breast type carcinoma (under 10%) show positive hormone receptors and lack ERBB2 amplification.
• Basal like carcinoma (about 15%) are triple negative and respond poorly to hormonal treatment. They have a poor prognosis. They are common tumours in women who lack the BRCA1 gene.
• ERBB2 Positive carcinomas have amplification of HER2 and no hormonal receptors.

Tubular and Cribriform Carcinomas

These carcinomas are always low grade and show extensive tubule formation and few mitoses. They lack the myoepithelial cell layer which allows them to be differentiated from benign conditions (such as ductal hyperplasia). Macroscopically the lesions are small. With immunohistochemistry, the tumour cells are nearly always positive for oestrogen/progesterone receptors. In Situ Hybridisation techniques show no evidence of ERBB2 overexpression.

Lobular carcinoma

Macroscopic Features

Lobular carcinoma may be less firm than ductal adenocarcinoma.

Microscopic Features

Lobular carcinoma has a typical 'single file' appearance of its malignant cells. This is due to loss of the e-cadherin molecule on the cell surface, decreasing the cells connectivity with each other. The cells are usually rounded and show no tubule formation.

Medullary Carcinoma

Macroscopic features

This variant of adenocarcinoma is usually soft and 'fleshy'. It often separates easily from surrounding tissues.

Microscopic features

Medullary carcinomas always show poorly differentiated features. The nuclei are characteristically vesicular and polymorphic with frequent mitoses. There is a prominent infiltrate of immune cells. Importantly, the border of the tumour is pushing and not infiltrative like the other breast carcinomas. There is no evidence of oestrogen, progesterone or ERBB2 receptors on special tests.

Other malignancies of the breast

Other breast malignancies show unique features related to their type. Small cell carcinomas often show neuroendocrine growth patterns and (obviously) small cells. Sarcomas have distinct patterns related to their subtype. Metaplastic carcinomas may show features of squamous differentiation.

Staging

Breast cancer is usually staged with the TNM system developed by the AJCC, which gives a final stage of disease.

Tumour Stage (T)

Tumour stage is important in determining the risk of local relapse or distant disease. The stages include:

• T₀ - No primary tumour evident
• T_is - Carcinoma in situ (either DCIS / LCIS)
• T₁ - Tumour < 2 cm in size
• T₂ - Tumour 2 - 5 cm in size
• T₃ - Tumour > 5 cm in size
• T₄ - Invasion of chest wall or skin (including inflammatory carcinoma)

Nodal Stage (N)

The presence and number of nodes are an important prognostic feature for both local relapse in the breast and for distant disease.

• N₀ - No lymph node involvement
• N₁ - Clinically, mobile nodes in the axilla. Pathologically, 1 - 3 lymph nodes involved with cancer.
• N₂ - Clinically, fixed nodes in the axilla. Pathologically, 4 - 9 nodes in the axilla or involvement of interior thoracic nodes with no axillary involvement
• N₃ - Clinically, nodes in the supraclavicular fossa or interior thoracic chain. Pathologically, over 9 nodes, or nodes in the supraclavicular fossa or interior thoracic chain with axillary involvement.

Metastates (M)

The presence of metastasis typically makes a patient incurable and the worst stage.

• M₀ - No metastases
• M₁ - Metastases to other nodal groups or elsewhere within the body

Final TNM Staging

• In situ disease has a 5 year survival of 92%.
• Stage I disease includes T₁ tumours with or without micrometastasis to 1-3 axillary nodes. 5 year survival 87%.
• Stage II disease includes T₂ tumours with stage N₁ nodal disease, or T₃ tumours with no nodal involvement. 5 year survival approaches 75%.
• Stage III disease includes all other stages of disease except M₁. 5 year survival is still 43%
• Stage IV disease is metastatic. 5 year survival is about 13%.

Important pathological indicators

Kumar divides these into two groups, major and minor factors. Radiotherapy is always required after wide local excision. Following mastectomy, it is sometimes recommended based on the number of major and minor risk factors present.

Major Factors

• Lymph node metastases are of critical importance. Radiotherapy to the supraclavicular fossa or to the chest wall is frequently recommended if 4 or more nodes are involved with cancer. Radiotherapy to the axilla is controversial as it increases the risk of lymphoedema.
  • If no nodes are involved, 10 year disease free survival is about 80%
  • With 1 - 3 nodes 10 year survival falls to 45%
  • If over 10 nodes are involved there is a 10-15% 10 year survival.
• Tumour size is related to risk of nodal metastases and death. Tumours under 1 cm have a 90% ten year survival. Tumours over 2 cm have a 75% 10 year survival. Tumours over 5 cm resected with mastectomy have a higher than usual risk of recurrence in the chest wall.
• T₄ disease is a poor prognostic feature. Local invasion of the skin or skeletal muscle is difficult to resect. Inflammatory carcinoma has a 3 year survival of under 10%.
• In situ disease has a particularly good prognosis.
• Metastatic disease has a particularly poor prognosis for somewhat obvious reasons. It may be treated with hormonal therapy in women with positive oestrogen/progesterone receptors; or with trastuzumab in women with ERBB2 amplification.

Minor factors

• Tumour grade is of some importance, increases the risk of distant failure and local recurrence after surgery. When combined with other factors it is an indication for chest wall radiotherapy.
• Tumour type impacts on survival. In general, the 'special types' are better than those of no special type.
• Hormone receptors are a good prognostic feature if present.
• ERBB2 overexpression is a poor prognostic feature.
• Lymphovascular invasion indicates a poorer prognosis, but by itself is not an indication for post-mastectomy radiotherapy.