College of American Pathologists

2013 — August Case of the Month

Posted August 6, 2013


CAP Foundation Online Case of the Month

Click Slide Image to View Case with DigitalScope

After reading the summary, try answering the three related multiple-choice questions below.

A 46-year-old woman with negative annual screening mammograms presented to her primary care physician with sense of fullness in the upper outer quadrant of right breast. Although the patient thought she could palpate a specific abnormality, physical examination did not reveal a well-defined mass. A diagnostic mammogram of the right breast showed a group of stable calcifications seen before and what appeared to be a new ill-defined area of minimally increased density and architectural distortion in the upper outer quadrant. A stereotactic core biopsy was followed by a sentinel lymph node biopsy and needle localization lumpectomy.

Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2010, case 23, and is an invasive lobular carcinoma.

Criteria for Diagnosis and Comments:
In most large series, invasive lobular carcinoma accounts for 5-15% of mammary carcinomas, depending on the criteria for classification (pure lobular carcinoma only versus mixed ductal and lobular) and is the second most common histologic type (after ductal). Invasive lobular carcinomas are often multifocal and can be bilateral. Some studies report increased rates of bilaterality while others indicate similar rates of bilaterality when compared to other histologic types of invasive mammary carcinoma. In the vast majority of cases (70-80%), an in-situ component (lobular carcinoma in-situ) is present.

The main difference in the clinical presentation between invasive lobular carcinoma and other histologic types is that lobular carcinoma is more often clinically and mammographically occult. However, some cases do present as palpable and/or mammographic abnormalities. Gross specimens containing invasive lobular carcinomas may show an obvious firm tan-white mass, similar to carcinomas of no special type. However, in many cases, the tumor or the extent of the tumor is not grossly evident. Thorough sampling and microscopic examination are required to determine the extent of the tumor and number of tumor foci.

The distinguishing feature of invasive lobular carcinoma on histologic examination is the diffuse pattern of the infiltration as single cells or in a linear or single-file pattern. This pattern of infiltration may be associated with minimal desmoplastic response with tumor cells infiltrating the septa between adipocytes and the mammary stroma. Linear strands and single cells of invasive lobular carcinoma tend to encircle benign ducts in a “targetoid” pattern. The tumor cells themselves may show intracellular lumina or vacuoles. Lymphoma and metastatic melanoma may mimic the single cell pattern of infiltration of lobular carcinoma. The cellular morphology, clinical history and immunoperoxidase studies aid in correctly identifying these tumors. Intracytoplasmic melanin pigment (when present), prominent single nucleoli, and immunoreactivity for S100, HMB-45 and MART-1 (Melan A) distinguish melanoma from lobular carcinoma. With the notable exception of rare lymphomas with signet ring cell morphology, the intracytoplasmic lumina typical for lobular carcinoma cells are not seen in lymphoma. The vast majority of lymphomas involving the breast are B-cell lymphomas that are positive for CD45 (LCA) and CD20.

Various subtypes of invasive lobular carcinoma have been described. The classical type is characterized by the cellular and infiltrative features described above. The tumor cells contain small often eccentric nuclei with little variation in size, scant nucleoli, and few mitotic figures; intracellular lumina and signet ring morphology occurs in a minority of tumor cells. In the solid and alveolar variants of lobular carcinoma, the tumor cells are grouped together in large sheets and/or aggregates, respectively. The pleomorphic variant shows a similar pattern of infiltration as classical lobular carcinoma but the degree of nuclear atypia is much greater. The tumor cell nuclei are considerably larger and show single or multiple nucleoli. This variant of invasive lobular carcinoma with a higher nuclear grade has been reported to have a poor prognosis. Tumors comprised predominantly of cells with low to intermediate grade nuclei and signet ring cell morphology are sometimes classified as the signet ring cell type of invasive lobular carcinoma. A more unusual variant is histiocytoid carcinoma in which the tumor cells show a histiocyte-like appearance with a large amount of foamy pale eosinophilic cytoplasm.

The classical and solid types of invasive lobular carcinoma are typically ER and PR positive and negative for Her-2/neu protein over-expression and gene amplification. The pleomorphic variant is also usually ER and PR positive and may show Her-2/neu protein over-expression and gene amplification. Pleomorphic lobular carcinomas are also usually positive for gross cystic disease fluid protein (GCDFP-15), consistent with the tumor appearance suggesting apocrine differentiation. One of the more recently characterized distinguishing features of lobular carcinoma is the loss of expression of E-cadherin, a protein involved in calcium-dependent cellular adhesion. Mechanisms of loss of E-cadherin protein include mutations in the gene, which is located on chromosome 16q22.1, loss of heterozygosity of chromosome 16, and silencing of gene expression by promoter methylation. In contrast, ductal carcinomas typically show strong diffuse membranous E-cadherin staining.

In some studies, there are differences in the pattern of metastatic spread between invasive lobular and invasive ductal carcinoma. Invasive lobular carcinoma is associated with metastases to bone, the peritoneum, meninges and GI tract, while pulmonary, hepatic, and brain metastases appear to be less common. Metastatic lobular carcinoma to the stomach may mimic diffusely infiltrating primary gastric carcinoma (linitis plastica). Metastatic lobular tumors in the ovaries may have an appearance similar to a Krukenberg tumor.

Until recently, many pathologists did not assign a complete combined histologic grade to invasive lobular carcinomas. In the 7th Edition of the AJCC/UICC Staging Manual, a combined histologic grade (Nottingham) is now required on all invasive mammary carcinomas. Studies from Nottingham and elsewhere confirmed that the combined histologic grade of invasive lobular tumors has prognostic significance. Classical lobular invasive carcinomas have a low combined histologic grade with no tubule formation (score = 3), low nuclear grade (score = 1), and scant mitoses (score = 1), for a numerical combined histologic grade of 5/9. Pleomorphic lobular carcinomas have at least an intermediate combined histologic grade with a high nuclear grade.

A review of 15 trials from the International Breast Cancer Study Group showed a higher disease-free survival in the first five years after diagnosis for invasive lobular carcinoma as compared to invasive ductal carcinoma and an increased overall survival in the first ten years after diagnosis. However, 6 to 10 years after diagnosis, invasive ductal carcinoma showed a better disease free survival, and after 10 years of follow-up invasive ductal carcinoma showed a better overall survival.

Supplementary Questions:

Question Diagnostic Set
1. The invasive lobular carcinoma variant with poor prognosis is: A. Alveolar
B. Classical
C. Histiocytoid
D. Pleomorphic
E. Solid
2. The most typical immunohistochemical profile for classical invasive lobular carcinoma is: A. ER(+), PR(+), HER2(+), E-cadherin(-)
B. ER(+), PR(+), HER2(-), E-cadherin(-)
C. ER(+), PR(+), HER2(+), E-cadherin(-), GCDFP-15(+)
D. ER(+), PR(-), HER2(+), E-cadherin(+)
E. ER(-), PR(-), HER2(-), E-cadherin(-), GCDFP-15(-)

3. Which of the following statements about the prognosis of invasive lobular carcinomas is true? A. All of the invasive lobular variants have essentially the same prognosis
B. E-cadherin-negative lobular tumors have a worse prognosis than E-cadherin-positive tumors
C. In lobular tumors, only the nuclear grade has prognostic significance
D. The Nottingham combined histologic grade has prognostic significance in invasive lobular tumors
E. With long term follow-up (10 years or more), invasive lobular tumors show a better overall survival than invasive ductal tumors


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Benjamin C. Calhoun, MD, PhD
Surgical Pathology Committee
Carolinas Medical Center
Charlotte, NC