Case Report
 

By Dr. Naciri Sarah , Dr. Meriem Glaoui , Dr. Youssef Bensouda , Dr. Mohamed Mesmoudi , Dr. Hassan Errihani
Corresponding Author Dr. Naciri Sarah
Medical Oncology Department, National Institut of Oncology, Rabat, Morocco, Medical Oncology Department. National Institute of Oncology- University Mohamed V- University Hospital. Rabat, Morocco - Morocco 10000
Submitting Author Dr. Naciri Sarah
Other Authors Dr. Meriem Glaoui
Medical Oncology Department. National Institute of Oncology- University Mohamed V- University Hospit, Medical Oncology Department. National Institute of Oncology- University Mohamed V- University Hospital. Rabat, Morocco - Morocco 10000

Dr. Youssef Bensouda
Medical Oncology Department. National Institute of Oncology- University Mohamed V- University Hospit, Medical Oncology Department. National Institute of Oncology- University Mohamed V- University Hospital. Rabat, Morocco - Morocco 10000

Dr. Mohamed Mesmoudi
Medical Oncology Department. National Institute of Oncology- University Mohamed V- University Hospit, Medical Oncology Department. National Institute of Oncology- University Mohamed V- University Hospital. Rabat, Morocco - Morocco 10000

Dr. Hassan Errihani
Medical Oncology Department. National Institute of Oncology- University Mohamed V- University Hospit, Medical Oncology Department. National Institute of Oncology- University Mohamed V- University Hospital. Rabat, Morocco - Morocco 10000

CANCER

Invasive Lobular Carcinoma, Breast cancer, Her2

Sarah N, Glaoui M, Bensouda Y, Mesmoudi M, Errihani H. A Rare Case of Invasive Breast Lobular Carcinoma Overexpressing Her2. WebmedCentral CANCER 2011;2(9):WMC002257
doi: 10.9754/journal.wmc.2011.002257
No
Submitted on: 24 Sep 2011 06:02:26 PM GMT
Published on: 25 Sep 2011 03:35:47 PM GMT

Abstract


Invasive lobular carcinoma (ILC) appears to have distinctive clinical and biologic characteristics compared with Invasive ductal carcinoma (IDC), as the overexpression of HER2.

The association of HER2 positive phenotype with classical ILC is very rare, therefore we present an atypical case of classical ILC overexpressing HER2 in immunohistochemical study (Hercept test HER2 3+).

We describe the case, and propose a literature review of HER2 phenotype positive in ILC breast cancer.

Introduction


Lobular carcinoma of the breast was first described by Foote and Stewart in 1941[1-2]; invasive lobular carcinoma (ILC) comprises approximately 10% of breast cancers, the variation in reported incidence (0.6-20%) [3-4] is most probably due to different histopathological criteria used to define ILC rather than a real variation in incidence. Classical ILC, by definition, is a low-grade tumour with little or no nuclear atypia and a low mitotic rate.
Because it is less common than Infiltrating ductal carcinoma (IDC), knowledge about the clinical outcome of lobular carcinoma has been based on studies including relatively small numbers of patients. In the few reported data, ILC appears to have distinctive clinical and biologic characteristics compared with IDC; one of those differences is the epidermal growth factor receptor HER2.
HER2neu is a proto-oncogene located on the long arm of chromosome 17 [5], low levels of the protein expressed by this gene are normally present in many adult tissues including breast, endometrium, prostate and ovary. Amplification of this gene and increased levels of the protein product have been found in between 10 and 35% of invasive breast carcinomas [6-8].
Studies have shown that HER2 positive (overexpression or amplification) is a poor prognostic factor for patients with both axillary lymph node-negative and positive breast cancer [9-11].Therefore determining HER2 status is primordial of patients to precise the prognostic.
Assay results independently guide therapeutic decisions regarding the suitability of Trastuzumab treatment for both metastatic and adjuvant setting [12].
Trials demonstrated that the addition of Trastuzumab, administered with chemotherapy resulted in a significant increase of overall survival when compared with chemotherapy alone for patients with HER2 positive, reducing the risk of recurrence and mortality by one half and one third, respectively for early-stage breast cancers [13-14].

Case Report


We report a clinical observation of patient, 36 years old, female sex, she’s still menstruated. A right mammary nodule has been discovered in October 2009, and has been constantly increasing in size without any associated inflammatory signs, or clinical lymph nodes invasion.
A bilateral mammography was done and chirurgical exerese has been preformed two month later revealing an invasive lobular carcinoma (ILC), measuring 6,5 cm, Scarff Bloom Richardson (SBR) grading was II with nuclear mitosis grade 2.
The tumorectomy was subsequently completed by a mastectomy associated to an axillary lymph node dissection. The pathology does not find any residual tumour but revealed infiltrating lymph node in 15 lymph nodes of the 16 preleved with an ILC, SBR II
The search for hormonal receptors (HR) revealed a positive status (RE 30%; RP 70%), HER2 was found also positive (HER2 3+) in IHC study (Hercept Test - Dako) with an intensive and total marquage in 50% of the tumoral cells.
A workup for searching metastatic localisation has been performed, comprising Thoraco-Abdominal CT-Scan and bone scintigraphy, displayed metastatic localisations in bone and one hepatic localisation measuring 20mm. The tumoral marker CA15-3 was elevated (38 UI/ml).
It was decided to use a sequential combination chemotherapy with 3 cycles of AC-60 (Doxorubicine 60mg/m2-Day1, Cyclophopshamide 600mg/m2-Day1) and 3 cycles of Docetaxel 100mg/m2 associated with Trastuzumab, The evaluation after 6 cycles objective a complete response in the hepatic localisation and partial response in the bone with normalisation of CA15-3; therefore the trastuzumab was prolonged with hormonoal therapy; the patient still well controlled.
This case was re-examined by a second pathologist revealing that is a classical type of ILC, eliminating a variant ILC like a pleomorphic subtype, and confirming the overexpression of Her2 with new IHC study.

Discussion


To confirm the originality of our case, we carried out a literature review by using the Pubmed database, with the following key words: breast cancer, ILC, HER2
We present here the results concerning breast cancers ILC subtypes associated with HER2 positive phenotype. Those findings will be discussed thereafter.
Results of ILC – HER2 positive
Lobular carcinomas were less likely than ductal carcinomas to have HER2neu amplification or overexpression, the positive phenotype of this gene has been found in less than 1% of classical ILC.
Hoff has found only 1 case with HER2neu amplification of 67 ILC studied (1.5%), but this case was re-examined revealing a pleomorphic variant of lobular carcinoma, with a nuclear grade 3. Another case was taken initially as ILC with HER2neu amplification, determined to represent not an ILC but rather an invasive ductal carcinoma (SBR grade 2) after re-examination by 3 pathologists [15].
Bilous reported also only 1 case with HER2 overexpression (scored as 3+HER2 positive) of 124 ILC (0.8%) and similary to Hoff, this was a grade 3 pleomorphic type[16].
In others studies published but with small effectif of classical ILC (range, 13-50), HER2 overexpression was absent in all cases [17-19].
In contrast with these studies objectiving the rarity of this association (ILC with positive HER2), others authors reported a variable incidence (range 6%, 43%) [20-25].
In a large cohort of 263 ILC tested, Arpino found 28 ILC with HER2 overexpression (10,7%), the author conclude that may not be the classic ILC subtype but possibly a variant pleomorphic or mixed ILC–IDC categories [23].
ILC subtypes have been reported to have different biologic characteristics and clinical behaviour as compared with the classical ILC, especially for HER2 according to the high rate of HER2 positivity among cases of pleomorphic variant of ILC reported on few studies; Middleton found HER2 overexpression (IHC, HER2 2+/3+) in 81% of pleomorphic ILC [26], Frolik reported a rate of 53% in SBR grade 3 pleomorphic ILC [27].
ILC and IDC have distinctive biologic characteristic, especially for HER2 expression, However, Rosen in a study of HER2 expression and tumour phenotype, reported HER2neu amplification in ductal and lobular carcinomas, and they found almost equal rates of amplification in these groups: 49% and 43% respectively. But the low cut off used of immunohistochemical test and the possible inclusion of pleomorphic variant may have been due to overinterpretation of the results with false positives cases included [25].
The discrepancy in the reported rates of HER2 positivity in ILC may be accounted by variation in histological type of ILC or antibody sensitivity and specificity in IHC.
The presence of HER2neu amplification or overexpression in pleomorphic lobular carcinoma (PLC) is not surprising, given its high nuclear grade, and to the fact that the genomic profile of PLC is similar to high-grade IDC according to the recent studies published [28,29]; therefore an HER2 positive in classical ILC should prompt reevaluation of the tumour to exclude the possibility of misclassification.
Molecular characterization of ILC has shown that they have a higher incidence of loss of chromosome 17q than ductal carcinomas, also a low incidence of 17q22–24 amplification, gene location of HER2neu, than their ductal counterparts.[29,30]
Testing for HER2 positivity is primordial in the management of patients with breast cancer, either at the time of diagnosis or at the time of disease recurrence. Trastuzumab has shown to have clinical benefit in adjuvant and metastatic disease, the international guidelines recommend the introduction of Trastuzumab with chemotherapy independently on the histological subtype of breast cancer. Management decisions should be based on individual patient and tumour biologic characteristics, and not on lobular histology.
Despite the fact that the biologic phenotype of ILC is quite favourable, Rosenthal found an adverse outcome if HER2neu gene amplification is associated, the amplification can predict disease-related death in lobular cases independently (p=0.003) [21].
Because of the low probability of HER2 positivity in classical ILC, some authors suggest that it may not be necessary to test for HER2 in this subgroup breast cancer[16]. But due to the current benefice in overall survival of Trastuzumab in the adjuvant setting, and to the fact that diagnostic of classical ILC may be confused with the pleomorphic variant, we think and recommend that all the breast cancer should be test for HER2.

Conclusion


We report an atypique case of classical ILC overexpressing HER2 that reexamined by two different pathologists.
The literature review showed a rarity of typical ILC associated to HER2 positive phenotype, but the studies include small cohorts and report variable incidences due to the possible inclusion of ILC variant such a pleomorphic type. Large data including only a confirmed classical ILC are needed to confirm the rarity of this finding.
We suggest reexamination of tumours diagnosed as lobular carcinomas if the lesion displays HER2 positivity to assure the exclusion of missed ductal components.

References


1. Stewart FW, Foote FW. Lobular carcinoma in situ : a rare form of mammary cancer. Am J Pathol 1941;17:491–496.
2. Foote FW, Stewart FW. A histological classification of carcinoma of the breast. Surgery 1946;19:74–99.
3. Martinez V, Azzopardi JG. Invasive lobular carcinoma of the breast: incidence and variants. Histopathology 1979;3:467–488.
4. Tavassoli FA, Devilee P. Pathology and Genetics of Tumours of the Breast and Female Genital Organs World Health Organisation of Classification of Tumours. IARC Press: Lyon, 2003.
5. Schechter AL, Hung MC, Vaidyanathan L, et al. The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science 1985;229:976–978.
6. Ross J S, Fletcher J A. The HER-2/neu (c-erbB-2) gene and protein in breast cancer. Am J Clin Pathol 1999; 112 (Suppl. 1): 553–567.
7. Birner P, Oberhuber G, Stani J et al. Evaluation of the United States Food and Drug Administration-approved scoring and test system of HER-2 protein expression in breast cancer. Clin Cancer Res 2001; 7: 1669–1675.
8. Bartlett J M, Going J, Mallon E A et al. Evaluating HER2 amplification and overexpression in breast cancer. J Pathol 2001; 195: 422–488.
9. Slamon D J, Clark G M, Wong S G et al. Human breast cancer: correlation of relapse and survival with amplification of the HER- 2/neu proto-oncogene. Science 1987; 235: 177–182.
10. Paik S, Hazan R, Fisher ER, et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 1990;8:103–112.
11. Ross J, Fletcher J A. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells 1998; 16: 413–428.
12. Ross JS, Fletcher JA, Linette GP, et al. The HER-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 2003;8:307–25.
13. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001
14. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007 Jan 1;25(1):118-45.
15. Hoff ER, Tubbs RR, Myles JL, et al. HER2/neu amplification in breast cancer: stratification by tumor type and grade. Am J Clin Pathol 2002 Jun;117(6):916-21
16. Bilous M, Ades C, Armes J, et al. Predicting the HER2 status of breast cancer from basic histo more recent pathology data, an analysis of 1500 breast cancers as part of the HER2000 International Study. The Breast 2003; 12, 92–98.
17. Porter PL, Garcia R, Moe R, et al. C-erbB-2 oncogene protein  in situ and invasive lobular breast neoplasia. Cancer 1991;68:331–334.
18. Bane AL, Tjan S, Parkes RK, et al. Invasive lobular carcinoma: to grade or not to grade. Modern Pathology (2005) 18, 621–628.
19. Reis-Filho JS, Simpson PT, Turner NC, et al. FGFR1 Emerges as a Potential Therapeutic Target for Lobular Breast Carcinomas. Clin Cancer Res 2006;12(22) November 15, 2006
20. Gonzalez-Angulo AM, Sahin A, Krishnamurthy S, et al. Biologic markers in axillary node-negative breast cancer: differential expression in invasive ductal carcinoma versus invasive lobular carcinoma. Clin Breast Cancer 2006 Dec;7(5):396-400.
21. Rosenthal SI, Depowski PL, Sheehan CE, et al. Comparison of HER-2/neu oncogene amplification detected by fluorescence in situ hybridization in lobular and ductal breast cancer. Appl Immunohistochem Mol Morphol 2002 Mar;10(1):40-6.
22. Ariga R, Zarif A, Korasick J, et al. Correlation of her-2/neu gene amplification with other prognostic and predictive factors in female breast carcinoma. Breast J 2005 Jul-Aug;11(4):278-80.
23. Arpino G, Bardou VJ, Clark GM, et al. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res 2004, 6:R149-R156
24. Turashvili G, Bouchalova K, Bouchal J, et al. Expression of E-cadherin and c-erbB-2/HER-2/neu oncoprotein in high-grade breast cancer. Cesk Patol 2007 Jul;43(3):87-92.
25. Rosen PP, Lesser ML, Arroyo CD, et al. Immunohistochemical detection of HER2/neu in patients with axillary lymph node negative breast carcinoma. A study of epidemiologic risk factors, histologic features, and prognosis. Cancer 1995, 75:1320-1326.
26. Middleton L P, Palacios D M, Bryant B R et al. Pleomorphic lobular carcinoma: morphology, immunohistochemistry, and molecular analysis. Am J Surg Pathol 2000; 24: 1650–1656.
27. Frolik D, Caduff R, Varga Z. Pleomorphic lobular carcinoma of the breast: its cell kinetics, expression of oncogenes and tumour suppressor genes compared with invasive ductal carcinomas and classical infiltrating lobular carcinomas. Histopathology 2001; 39:503–513.
28. Reis-Filho JS, Simpson PT, Jones C, et al. Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity. J Pathol 2005; 207:1–13.
29. Yoder BJ, Wilkinson EJ, Massoll NA, et al. Molecular and Morphologic Distinctions between Infiltrating Ductal and Lobular Carcinoma of the Breast. The Breast Journal, Vol 13 N 2, 2007 172–179.
30. Gunther K, Merkelbach-Bruse S, Amo-Takyi BK, et al. Differences in genetic alterations between primary lobular and ductal breast cancers detected by comparative genomic hybridization. J Pathol 2001;193: 40–47.

Source(s) of Funding


The authors declare not having any funding resource.

Competing Interests


The authors declare having no competing interests

Disclaimer


This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

Comments
0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.

 

Author Comments
0 comments posted so far

 

What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
Where
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)