Invasive Cribriform Breast Cancer

Cribriform carcinoma of the breast is characterized by a particular histological architecture or ‘growth pattern‘, which looks like a kind of ‘ripple‘ effect. ‘Cribriform‘ is from the latin root for ‘perforated‘ and it typically refers to a microscopic pattern of glandular epithelial cells growing in a “back to back” pattern without intervening stroma. Within the cribriform breast tumor, there tends to be distinctive ‘holes‘ in between the cancer cells, giving an appearance often described as like ‘Swiss cheese‘.

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Invasive cribriform carcinoma (ICC) is a rare type of invasive breast carcinoma that exhibits this cribriform pattern in the majority of the invasive component, and is usually associated with an excellent prognosis. Invasive cribriform breast carcinoma accounts for around 6% of all invasive breast cancers. Cribriform breast carcinoma, along with tubular breast carcinoma, medullary breast carcinoma, mucinous breast carcinoma, and lobular breast carcinoma, form an informal group of ‘specialized‘ breast cancers, (as opposed to generic infiltrating ductal carcinoma, NOS) which together account for 20%-30% of all invasive breast cancers, and they are generally characterized by low malignant potential and a good prognosis.

It is quite common for cribriform breast carcinomas to have some elements which are still ‘intraductal‘ (DCIS) while other elements are invasive. There are no specific clinical features to invasive cribriform carcinoma of the breast, and it is usually diagnosed histologically following mammography.

Cribriform breast carcinoma does not always present in a ‘pure’ form.

The diagnosis (or labeling really) of invasive cribriform breast carcinoma can be a bit of a grey area because it often presents with components of other types of breast carcinoma.

In a ‘pure‘ or ‘classic‘ form of invasive cribriform breast carcinoma, the cribriform growth pattern should account for nearly 100% of the tumor. Pathologists might then speak of ‘predominant‘ invasive cribriform breast carcinoma, which has a majority of cribriform features and lesser amounts of any other types of breast carcinoma.

One might also encounter the term ‘mixed‘ cribriform breast carcinoma, which generally means that there is a cribriform component, but it accounts for less than 50% of the entire tumor mass.

Other common breast carcinomas which comprise the ‘mixed‘ components of cribriform breast carcinoma tumors include tubular breast carcinoma, and comedo carcinoma. (Usually a diagnosis of tubular carcinoma is reserved for tumors in which almost the entire lesion is of a tubular pattern).

About 20% of invasive cribriform breast carcinomas are pure, about 30% are predominantly cribriform, (more than 50%) and about half contain less than 50% of cribriform cell-growth features. Whether or not the tumor is called ‘mixed‘ or ‘predominant‘ is a matter of subjective opinion, and if the other ‘mixed‘ component is tubular carcinoma, this again is considered a bit differently.

Relative amounts of ‘pure’ vs. ‘mixed’ cribriform cells

The relative amount of cribriform features (pure vs. mixed) is important, however, and can effect the outlook. Even though the prognosis for cribriform breast carcinoma is always very positive, the mixed presentations tend to be more aggressive. “Mixed” cribriform breast cancers tend to occur in a slightly older age group, and tumors also tend to be a little larger in size.

Predominant (greater than 50%, but not pure) invasive cribriform breast carcinomas are quite prone to metastasize, but interestingly, almost never to more than three nodes, while tumors of infiltrating ductal carcinoma NOS with less than 50% cribriform carcinoma can metastasize to the lymph nodes at the average rate.

Histological features typical of invasive cribriform carcinoma of the breast

The invasive portion of a cribriform breast carcinoma is the same of for the intraductal component (cribriform DCIS).

Sharply outlined round or oval glandular spaces are distributed throughout the tumor given a ‘fenestrated‘ appearance. Invasive cribriform breast carcinoma usually presents with rounded and angular masses of uniform, well-differentiated tumor cells, embedded in variable amounts of desmoplastic collagenous stroma.

 
 

About 90% of the tumor cells will be nuclear grade I. Nuclei are usually uniform, and slightly enlarged (about 2-3 times the size of a red blood cell, typically). Nucleoli are inconspicuous, and pleomorphism is typically either minimal or absent completely.

Immunohistological features typical of invasive cribriform carcinoma of the breast

Invasive cribriform breast carcinoma tends to be estrogen receptor positive in almost 100% of cases and progesterone receptor positive in just under 70%. (There seems to be no appreciable difference in hormone receptor status in pure vs. mixed types of cribriform breast carcinoma).

 
 

Myoepithelial cells will typically be absent on immunohistochemical stains, and staining also tends to show that cribriform spaces do not contain basement membrane material. This suggests that cribriform tumor cells tend not to differentiate into basaloid cells or lactating mammary epithelium.

Diagnosis of invasive cribriform breast cancer is sometimes based on negative immunocytochemical staining for laminin, along with ultra structural evidence of luminal differentiation by cells lining the cystic spaces. This is essentially a means of differentiating between invasive cribriform breast carcinoma and adenoid cystic carcinoma of the breast. Negative laminin staining suggests the absence of basal lamina around islands of tumor cells and inside the cyst-like spaces of tumor, and would be in contrast with the strong positive staining observed in adenoid cystic breast cancers.

If immunocytochemical staining reveals the presence of myoepithelial cells, that tends to suggest an ‘in situ‘ nature of the tumor, while absence of myoepithelial cells suggests an invasive context. Protein-based stains such as calponin, p63, and smooth muscle myosin heavy chain are useful markers to determine the presence of myoepithelial cells in cribriform breast carcinomas.

Frequently, the Ki67 labeling index for invasive cribriform carcinomas of the breast is very low (below 3%). This would be expected in a ‘low grade‘ breast cancer such as pure invasive cribriform breast carcinoma. Ki-67 is a nuclear antigen that is related to growth potential in many cancer tumors, and is a proliferation marker expressed only in cycling cells. As a consequence, a quantitative assessment of Ki-67 staining on paraffin-embedded breast tumor sections can give a fairly accurate estimate of the proliferation index of an individual breast cancer tumor.

 
 

Mammographic and Sonographic features of invasive cribriform breast cancer

There is no specific mammographic finding characteristic of invasive cribriform breast carcinoma, but experienced radiologists are still often able to distinguish these tumors from tubular breast carcinoma, which is the closest histological analogue. One will typically find an area of increased density within the breast parenchyma, often with spiculation, which would be regarded as highly suspicious for malignancy. Quite frequently the tumor is hidden (occult) mammographically and might be found on ultrasound instead. On ultrasound, invasive cribriform breast cancer may not appear entirely typical of breast carcinoma.

One usually finds an ill-defined, irregularly shaped hypoechoic, heterogeneous solid mass, but without the distal acoustic attenuation that appears in 60%-95% of other forms of breast carcinoma.

Cribriform breast carcinoma usually shows microcalcifications

Mammographic studies on invasive cribriform breast carcinoma usually report finding microcalcifications, (often punctate) but the histological finding of extensive microcalcification is quite unusual. Most often, the microcalcifications in invasive cribriform carcinomas of the breast tend to be found in only part of the tumor. As a result, the histological extent of the tumor (the degree of malignant cell invasion) is frequently underestimated from mammography alone.

Treatment and Prognosis for invasive cribriform breast cancer

If an adequate surgical excision of the tumor can be performed, breast conservation therapy is feasible. In the absence of axillary nodal metastases, the use of adjuvant therapies such as chemotherapy and radiation therapy is probably not warranted, especially when the tumors are less than 1cm. Generally speaking, there is no recurrent malignant growth in the resection borders of invasive cribriform breast carcinomas.

Long term survival for cribriform breast carcinoma is over 80%

The prognosis for invasive cribriform carcinoma of the breast is generally very good. Even though there are often instances of local recurrences, there tends not to be progression to systemic disease. The long term survival of invasive cribriform breast cancer is been reported to be close to 100% when ‘pure‘ or mixed only with tubular carcinoma. The incidence of axillary lymph node metastasis is a little bit unclear, with reports ranging from 14% up to 40%, and metastasis tends to be associated with grade II nuclei in cancer cells. But even in those instances, close to 100% of patients survive. The five year survival rate for pure and predominantly cribriform invasive breast carcinoma is basically 100%, and about 80% for mixed invasive cribriform breast carcinoma where the cribriform areas account for less than 50% of the tumor. (The five year survival rate for invasive ductal carcinoma NOS is around 78%).

Hey, that paragraph above about survivals is too old. Survivals are improved, and there’s no way I can stay up-to-date, so ask an Oncologist. They know this stuff.

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Everything you need to know about cribriform carcinoma is in the information above. But let’s go over a couple Q&A to refresh your memory…

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References

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9. Velev, V., Matev, A., Stratiev, S. A case of Invasive Mixed Cribriform breast Cancer with areas of intraductal comedocarcinoma.Trakia Journal of Sciences, (2006) Vol. 4, No.1, pp 59-61.
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