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Histology of Breast Cancer

Proliferative changes in the breast

Premalignant lesions are recognized microscopically by abnormal proliferative activity in the ductal system (ductal) or in the glands (lobular), Without signs that the epithelial cells penetrating the basal membrane. If  penetration of the basal membrane is noted, it is an infiltrating carcinoma and it should be treated accordingly. 

Normally, the glands have two cell layers. Three or more cell layers are a sign of abnormal proliferative activity.

The lesions can be classified according to proliferation, cellular atypia and tissue architecture as shown below: 

  • Lobular and ductal epithelial hyperplasia without atypia
  • Lobular and ductal epithelial hyperplasia with atypia
  • Lobular carcinoma in situ (LCIS)
  • Ductal carcinoma in situ (DCIS) grade 1-3 (van Nuys grading) (2)

There is a gradual transition between the different types; therefore the classification is subjective and inter-observer variation must be considered.

Columnar cell lesions and Flat epitelial atypia (FEA)

The interest for these lesions has increased because they are seen more frequently in screening samples. Lesions with columnar epithelial cell in the terminal ductolobular entities may be divided into the following 3 types:

  • columnar cell change
  • columnar cell hyperplasia
  • flat epitelial atypia  

Columnar cell change  (CCC) and columnar cell hyperplasia  (CCH)

Lesions with enlarged ducto-lobular units with columnar epithelial without atypia covered with columnar epithelium without atypia including 1-2 layers of columnar epithelium (CCC) or  > 2 layers of cells (CCH). These entities are described under different names in the literature as for instance columnar metaplasia and blunt adenosis.)

Flat epitelial atypia (FEA)

Lesions with enlarged terminal ducto-lobular units with one or more layers of cubical or columnar epithelium of low grade celluar atypia. (This type is in the literature also called  clinging carcinoma (monomorphic type), atypical columnar cell lesion, columnar cell change with atypia, columnar cell hyperplasia with atypia).

There is a very low risk of recurrence or progression to cancer when these lesions present as isolated lesions. Since FEA most frequently is seen combined with other lesions the prognosis is difficult to predict. The WHO working group (2011) consider that the risk for cancer development is lower for FEA than for ADH and ALH.

When FEA is found in needle biopsies more sections should be taken to look for associated lesions. The need for routinely resection of  lesions with FEA is not clear. WHO working group 2011 recommends individual evaluation and possibly performing a wire located biopsy to exclude a more advanced lesion.

Lobular carcinoma in situ (LCIS)

LCIS is characterized by the overfilling of the terminal-duct lobular units with atypical epithelial cells, which have not penetrated the basal membrane. The proliferating cells are most frequently negative for the immunohistochemical marker E-cadherin. Based on the morphological appearance LCIS is divided into : classical, pleomorphic and florid type with comedo necrosis.

a) Classic LCIS has high-grade nuclei and are practically always discovered incidentally in a mammary resection specimen or a biopsy performed for a different histological type. The absolute risk for cancer development is around 10% at 10 years, 20% at 20 years and at life-long observation close to 30%. Infiltrating carcinoma in patients with LCIS will most frequently be of the ductal type.

The risk for developing invasive cancer is quite high in the contralateral breast as well as in the biopsied breast. Unilateral ablation therefore only reduces the risk by half. In the absence of a particularly heavy genealogy it is agreed that adequate follow-up care after proven classig LCIS is a yearly control includin mammography.

b) Morphologically, pleomorphic LCIS shows tumor cells with marked nuclear atypia comparable to that seen in high grade DICS. However, in contrast to DCIS, pleomorphic LCIS lacks E-cadherin expression. Since the histological subtype is newly recognized, the risk for subsequent development of invasive carcinoma is not clear. The risk is considered to be higher than classic LCIS and probably not similar to DCIS. This should be taken into account in the patient management.

c) Florid LCIS with comedo necrosis is characterized by distension of terminal-duct lobular unit by cohesive tumor cells with low-grade nuclei, often with central necrosis and calcification. This tumor is often detected by mammography. Morphologically, it resembles low-grade DCIS and it is recommended to manage as DCIS. (Ad therapy: it is also referred to WHO classification where the starting point is treatment of b and c (for instance render 2 mm), but that care/reflection is taken by more aggresive therapy, such as ablation).

Ductal carcinoma in situ (DCIS)

DCIS, also known as intraductal carcinoma, should not be confused with invasive carcinoma of the ductal type. In DCIS the milk ducts are filled with carcinoma cells which do not infiltratet the basal membrane encircling the duct. The cells ar most often positive for E-cadherin.

Previously, DCIS was a rare condition and constituted only between 1.4 and 5.3% of all newly diagnosed breast cancer cases. After the use of screening mammography, suspicion of such changes  has become more frequent (5-10%). In areas with established breast cancer screening DCIS will constitute 25-30% of new cancer cases in the first screening round, in later screening the frequency will be 10-20%.

Lobular carcinoma in situ (LCIS).
Click to enlarge the image.
Ductal carcinoma in situ (DCIS). Click to enlarge the image.

The main problem with DCIS is that the risk for local recurrence in the breast after resection alone is much greater than with other pre-malignant lesions in breast tissue.

Risk for recurrence is dependent on multiple factors, and is greater for:

  • Palpable than for nonpalpable DCIS tumors (3)
  • DCIS grade 3 than for DCIS grade 1 and 2 (3,4)
  • Diffuse spreading than for microfocal
  • Younger women (5)

It has been shown that the risk for recurrence increases with the size of the lesion. It has though, been difficult achieve good data on this correlation because it can be difficult to estimate the excact dimensions of the lesion, due to often several consecutive resections as well as heterogeneous classification and treatment.

Most recurrences are local and in close proximity to the primary scar. It is agreed in the literature that the resection margins should be microscopically free but the length in millimeters of the margin is discussed. NBCG has recommended at least 2 mm from the microscopic DCIS to the resection margin. This is due to the uncertainty of the histopathological  estimation of the resection margin. With such short free resection margin the histopathological examination must be very careful.

Invasive Carcinomas

 

Ablation specimen with tumor. Click to enlarge the image.

Seventy to 80% of invasive breast carcinomas are histologically of the infiltrating ductal type. Ten to 20% are of the infiltrating lobular type while other types constitute the rest. Some of these types have better than average prognosis for example tubular carcinoma, medullary carcinoma, mucinous carcinoma, and adenoid cystic carcinoma. Other types (without particularly good prognosis) are papillary, secretory, and apocrine carcinoma. Paget’s disease of the nipple is almost always connected with an underlying ductal carcinoma.

The pathology group of NBCG has distributed well defined criteria for histological grading of breast carsinomas to all pathology laboratories in Norway. All invasive carsinomas shall be graded after the same criterias. DCIS are graded after Van Nuys grading. In addition Her2 examination should be performed (by means of immunohistochemistry and/or FISH/CISH/SISH) and immunohistochemical examination of Ki67 (quantified according to a defined schedule). The IHC kits are standardized for histological specimens but may also be used on cellblocks from cytological material.

In addition, Her2 analysis should be performed (with the help of immunohistochemistry and/or FISH/CISH).

Infiltrating ductal carcinoma grade I. Click to enlarge the image. Infiltrating ductal carcinoma grade III. Click to enlarge the image.

 

Infiltrating lobular carcinoma. Click to enlarge the image. Infiltrating mucinous carcinoma. Click to enlarge the image.

 

The pathological/anatomical investigation should include information about:

  • Tumor localization, (possibel multifocality)
  • Tumor dimensions (in millimeter) tumor area in case of diffuse growth (typical for lobular carsinoma). and one or several tumofoci should be stated.
  • Histological type 
  • Histological grading 
  • Tumor extension, localization, and grade of DCIS in an invasive carcinoma 
  • Tumor’s relation to resection margins (given in mm), also possibly to the skin and to the breast wall 
  • Number of lymph nodes with metastases and total number of  investigated lymph nodes 
  • Size of the largest proven lymph node metastasis 
  • Perinodal tumor infiltration, including description of whether this is macro- or only microscopical, and description of possible islands of tumorcells in the fat. Hormone receptor analysis based on immunohistochemistry or  -cytology 
  • HER2 status 
  • Ki67 status

Immunohistochemistry. Negative ER. Click to enlarge the image.

Immunohistochemistry. Positive ER. Click to enlarge the image.

 

HER2 immunohistochemistry. Score 1+ Negative. Weak brown staining around the cells. Click to enlarge the image. HER2 immunohistochemistry. Score 2+Non-conclusive. No membrane staining around all cells. Click to enlarge the image. HER2 immunohistochemistry. Score 3+ Positive. Strong brown staining around all cells. Click to enlarge the image.

Immunohistochemistry is performed to determine HER2 amplification in the tumor. The result is graded from 0–3+, where 0 and 1+ are clearly negative and 3 is clinically positive. For a score of 2+, and additional FISH test is performed to confirm HER2 amplification. 

 

Negative FISH. Positive FISH.

FISH test to determine HER2 amplification. An excess of red dots (picture to the right) indicates HER2 amplification in the tumor (positive FISH). A balance between red and green (picture to the left) dots indicates no HER2 amplification (negative FISH).

In addition other tumor markers exist (oncogenes, proliferation markers, ploidity examination) which can be examined on both histological and cytological tumor material to present some additional information for special patient groups. At present there is no general consensus for inclusion of these analyses in routine pathology in Norway. 

Sarcomatoid tumors

Sarcomatoid carcinomas

Sarcomatoid carcinomas are tumors with malignant epithelial and heterologic elements. These tumors constitute less than 1% of malignant tumors in breast cancer. Clinically, there are small differences from the regular carcinomas. Microscopically, there is a varying degree of epithelial differentiation, either in the form of DCIS and/or epithelial differentiation of the invasive component. Sometimes, the epithelial differentiation can only be identified by means of the immunohistochemical analyses with epithelial markers or electron microscopy. The sarcomatoid component appears most often as variations of a high-grade malignant sarcoma. The tumors metastasize most often hematogenously.

Phyllodes tumors

WHO defines a phyllodes tumor as "a more or less well-defined lesion consisting of connective tissue and epithelial elements, as in fibroadenomas, but with larger cell density and varying degrees of atypia in the stromal component." Phyllodes tumors consists of a broad spectrum of fibroepithelial lesions and are classified as benign, borderline, or malignant. A benign phyllodes tumor can be difficult to differentiate from a fibroadenoma. It is usually larger and the shear section has a furcate appearance. It is important to differentiate a phyllodes tumor from a fibroadenoma, as a phyllodes tumor has a pronounced tendency to relapse. In middle-aged and older patients, phyllodes tumors occur more often than fibroadenomas. The relapse tendency pertains to both the benign and the malignant phyllodes tumors. One must be aware that apparent benign phyllodes tumors can be heterogeneous, with malignant areas. A malignant relapse after previous removal of a benign phyllodes tumor can on rare occasions occur. A malignant phyllodes tumor can further dedifferentiate to a higher grade malignant sarcoma. Metastases occur hematogenously.

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