00019606-201212000-00004ReportDiagnostic Molecular PathologyDiagnostic Molecular Pathology© 2012 Lippincott Williams & Wilkins, Inc.21December 2012
p 221–224Biphasic Papillary and Lobular Breast Carcinoma With PIK3CA and
IDH1 MutationsCase ReportAng, Daphne MD*,†; VanSandt, Amanda M. MD*; Beadling, Carol PhD†; Warrick, Andrea BS†; West, Robert B. MD, PhD‡; Corless, Christopher L. MD, PhD*,†; Troxell, Megan L. MD, PhD*,†*Department of Pathology†Knight Cancer Institute, Oregon Health & Science University, Portland, OR‡Department of Pathology, Stanford University, Stanford, CAM.L.T. is currently receiving a grant from Susan G. Komen for the Cure, KG100112, and R.B.W. from California Breast Cancer Research Program, 17IB-0038. The remaining authors declare no conflict of interest.Reprints: Megan L. Troxell, MD, PhD, Department of Pathology, Oregon Health & Science University, L471, 3181 SW Sam Jackson Park Rd., Portland, OR 97239 (e-mail:
[email protected]).AbstractMorphologic “special types” of breast carcinomas have been recognized for many years, and their molecular and genetic properties have not been specifically studied until recently. Lobular carcinoma lacks functional E-cadherin expression but shares molecular similarities with low-grade invasive ductal carcinomas. Papillary carcinoma is relatively rare, and molecular features are just being elucidated. We report a case of concurrent invasive lobular and papillary carcinoma, the latter with extensive nodal involvement. Multiplex screening for activating point mutations identified different point mutations in the distinct morphologic components: lobular PIK3CA H1047R, papillary; PIK3CA Q546P, and
IDH1 R132H. These molecular data favor coincidental “collision tumors” over clonal evolution. The
IDH1 R132H point mutation is common in gliomas and acute myelogenous leukemia, but this has not been previously reported in breast carcinoma. The characterization of activating point mutations in morphologic special types of breast carcinoma may suggest avenues amenable to targeted therapy.Breast cancer is traditionally characterized morphologically, with the majority of cancers representing invasive ductal carcinoma and the minority of cases representing special types with distinctive morphologic features.1,2 However, more recently, breast cancers have been characterized and classified on the basis of protein expression (hormone receptors), mRNA [expression microarray, quantitative polymerase chain reaction (PCR) analysis, etc.], and genetic features (karyotype, comparative genomic hybridization, point mutation analysis, promoter methylation analysis, whole-genome sequencing, etc.).3–5 These studies have revealed new groupings of breast tumors and have informed breast cancer therapy. However, the classic and many ongoing microarray, genetic, genomic, and proteomic studies of breast cancer focused primarily on invasive ductal and/or lobular carcinoma.3–5 The known morphologic “special types” of breast cancer have only recently been studied with these techniques.2,6 We report a case encompassing 2 morphologic special types of breast cancer with different activating point mutations, including a mutation in a metabolic enzyme that has not previously been reported in breast carcinoma.MATERIALS AND METHODSMolecular AnalysisLesional tissue from the areas of invasive lobular carcinoma and papillary carcinoma in the breast, as well as papillary carcinoma metastatic to the lymph node, were separately isolated by punching the paraffin tissue block. DNA was extracted using standard methods and screened for activating point mutations using a multiplexed PCR-mass spectroscopy–based technique encompassing 643 point mutations in 53 genes (Sequenom MassArray), as previously described.7,8 In brief, the updated mutation panel covers point mutations in AKT1/2/3, ALK, BRAF, CDK4, CSF1R, CTNNB1, EGFR, ERBB2, ERCC6, FBX4, FBXW7, FES, FGFR1/2/3/4, FOXL2, GNA11, GNAQ, GNAS, HRAS,
IDH1/2, IGF1R, KDR, KIT, KRAS, MAPK2K1/2/7, MET, MYC, NEK9, NRAS, NTRK1/2/3, PDGFRA, PIK3CA, PIK3R1/4/5, PKHD1, PRKCB1, RAF1, RET, SMO, SOS1, STAT1, TEC, and TP53.7,8 The panel includes 41 substitutions in 23 codons of the PIK3CA gene. Mutations were confirmed by Sanger sequencing or with an
IDH1 mutation–specific antibody (see below).ImmunohistochemistryImmunohistochemical staining was performed with an antibody specific to the R132H mutant isoform of
IDH1 (Dianova, distributed by HistoBioTec LLC, Miami Beach, FL; catalog #DIA H09). Staining was performed on Benchmark XT instruments (Ventana, Tucson AZ) after cc1-standard antigen retrieval, with a primary antibody dilution of 1:25, and Ultraview polymer-based detection (Ventana). In addition, this antibody was used to screen a breast carcinoma tissue microarray for additional
IDH1 R132H–mutated breast carcinomas.9Immunohistochemical staining for the myoepithelial markers p63 (4A4; Biocare, Concord, CA), smooth muscle myosin heavy chain (SMMS-1; Ventana) and cell-to-cell adhesion protein E-cadherin (36B5 Leica; Novocastra, Buffalo Grove, IL) was performed using standard techniques, also on Benchmark XT instruments. Analysis of the breast hormone receptors and Her-2/neu was performed using FDA-cleared kits according to the manufacturer’s instructions (estrogen receptor: SP1; progesterone receptor: 1E2; Her-2/neu: 4B5, all from Ventana). Her-2/neu fluorescence in situ hybridization studies were performed using the FDA-approved PathVysion kit according to the manufacturer’s protocol (Abbott Molecular, Abbott Park, IL).RESULTSClinical HistoryThe patient is a 75-year-old woman with a complex medical history including invasive colonic adenocarcinoma status post colectomy 10 years prior, bilateral stable adrenal adenomas, persistent amegakaryocytic thrombocytopenia, a collection of orthopedic complaints, and persistent bloody nipple discharge. The patient had received a 5-flourouracil and a leucovorin therapy for colon cancer, a trial of cyclosporine for amegakaryocytic thrombocytopenia, and was on hormone replacement therapy for nearly 20 years. Her family history included numerous cancers, including an aunt with breast cancer.The patient first reported bloody nipple discharge of the left breast 3 years prior, while undergoing therapy for profound and persistent amegakaryocytic thrombocytopenia. A thorough workup of the nipple discharge was negative, and the patient proceeded to duct ligation once the thrombocytopenia improved. Interval mammograms and ultrasounds were essentially unremarkable, with the findings of amorphous calcifications of the upper outer quadrant of the left breast, read as BIRADS 1 or 2. During this interval, the patient experienced symptoms of breast abscess and had 2 benign left breast biopsies; however, nipple discharge persisted intermittently without an associated mass lesion.The patient subsequently represented with a palpable mass in the upper outer quadrant of the left breast. A fine-needle aspiration biopsy was performed and yielded a markedly cellular aspirate with features of papilloma, although cytologic features were low grade. The mammogram and ultrasound studies 2 months prior had demonstrated a complex pattern of fibroglandular tissue in the upper outer quadrant of the left breast, BIRADS 3. Subsequently an incisional biopsy was performed, followed by a mastectomy.Histopathologic FindingsThe excisional biopsy demonstrated invasive lobular, as well as apparently intracystic papillary carcinoma, prompting a mastectomy and a sentinel lymph node biopsy, followed by an immediate axillary lymph node dissection based on positive frozen section. The sections of the mastectomy specimen again demonstrated an invasive lobular carcinoma, with infiltrative single cells or cords of cells of variable density. Focally, the invasive lobular carcinoma formed a densely cellular mass, whereas in most areas, it was present as dispersed collections of cells in stroma or admixed with papillary carcinoma (Fig. 1). There was no lobular carcinoma in situ. Overall, the invasive lobular carcinoma spanned 10.8 cm and was negative for E-cadherin, strongly-diffusely positive for estrogen and progesterone receptors, but negative for Her-2/neu (1+ immunohistochemistry, nonamplified by fluorescence in situ hybridization; Her-2/CEP-17 ratio=1.09).JOURNAL/dimp/04.03/00019606-201212000-00004/figure1-4/v/2021-02-17T200047Z/r/image-jpegHistologic and molecular characterization of biphasic breast carcinoma. A, Papillary carcinoma (left) and invasive lobular carcinoma (right) in close association. B, Papillary component is extensively metastatic to axillary lymph nodes, with extracapsular extension. C, Mutation-specific antibody (
IDH1 R132H) stains papillary tumor strongly (upper, positive), whereas invasive lobular carcinoma is negative (lower). D, Polymerase chain reaction–mass spectroscopy assay (PCR-MS) of lobular carcinoma demonstrates a PIK3CA H1047R mutant (*) peak, along with a larger wild-type (WT) peak. The H1047R mutation was confirmed by Sanger sequencing (data not shown). E, PCR-MS of papillary carcinoma demonstrates a PIK3CA Q546P mutant (*) peak along with a WT peak. The Q546P mutation was confirmed by Sanger sequencing (data not shown). F, PCR-MS of papillary carcinoma also demonstrates an
IDH1 R132H mutation (*), along with a WT peak. (The large peaks in the middle of the PCR-MS tracings represent WT peaks from an unrelated, multiplexed assay).In addition, there was admixed papillary carcinoma with strikingly different cytologic and architectural features, with circumscribed small cystic spaces, filled with papillary projections lined by atypical cells (Fig. 1). This component spanned 9 cm. Immunohistochemical staining for the myoepithelial proteins p63 and smooth muscle myosin heavy chain demonstrated the presence of myoepithelial cells along papillae and surrounding the cysts, although in diminished numbers (not shown). Despite the presence of myoepithelial cells, the papillary component was metastatic to 5 of the 35 axillary lymph nodes, with extensive extracapsular extension. The metastatic papillary carcinoma lacked myoepithelial cells, was strongly-diffusely positive for estrogen and progesterone receptors, and negative for Her-2/neu (0 immunohistochemistry). Only a microscopic focus of invasive lobular carcinoma was seen in adipose tissue in the sentinel lymph node specimen (not shown).Molecular AnalysisThe different morphologic components of the primary breast lesions and the papillary lymph node metastasis were separately isolated and screened for point mutations using a multiplexed PCR-mass spectroscopy methodology.7,8 A PIK3CA exon 20 H1047R mutation was discovered in the invasive lobular carcinoma (Fig. 1). The papillary carcinoma had a distinct mutational profile including a PIK3CA exon 9 Q546P mutation, along with an
IDH1 R132H mutation (Fig. 1); these mutations were common to the primary breast papillary carcinoma and metastatic nodal papillary carcinoma. Immunohistochemical staining with an antibody specific to the R132H mutant isoform of
IDH1 demonstrated strong cytoplasmic staining in the papillary carcinoma, but not in the invasive lobular carcinoma, paralleling the molecular results (Fig. 1). A tissue microarray containing 194 scorable cases of invasive breast carcinoma was also stained with this mutation-specific
IDH1 antibody.9 No additional mutation-positive cases were identified (0/194).DISCUSSIONWe present a unique case of biphasic breast carcinoma, including invasive lobular and papillary carcinoma components, with distinct morphologies and different genotypes. Mutations in the lipid kinase phosphotidylinositol-3-kinase catalytic subunit (PIK3CA) are quite common in breast cancer, found in >25% of carcinomas.10–13PIK3CA mutations are concentrated in “hotspots” in the helical (exon 9, most commonly codons E542, E545) and kinase (exon 20, codon H1047) domains.10–13 Our group and Duprez and colleagues have surveyed papillary carcinomas and found the PIK3CA mutational profile to be similar to that of low-grade invasive ductal carcinoma.14,15 However, some groups have found and even greater frequency of PIK3CA mutations in the lobular carcinomas.13,16 The invasive lobular carcinoma reported here harbored a PIK3CA H1047R mutation; in contrast, the papillary carcinoma lacked the H107R mutation, but, instead had both a PIK3CA exon 9 mutation (Q546P) and an
IDH1 R132H mutation. These molecular studies suggest the coincidence of 2 independent carcinomas (eg, “collision tumor”), rather than the progression from a common precursor.The
IDH1 mutation identified in this study is a well-characterized mutation in gliomas, secondary glioblastomas, and leukemia.17–19 We report for the first time, a breast carcinoma with
IDH1 R132H mutation. In 404 cases of breast carcinoma previously tested, this mutation had not been identified.17–19IDH1 encodes the enzyme isocitrate dehydrogenase 1, which normally catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate to produce NADPH. This enzyme is thought to play a role in the cellular control of oxidative damage, glucose sensing, and other metabolic processes.19–22 The R132H mutation inactivates the normal enzymatic activity of
IDH1, and, in contrast, the mutant isoform catalyzes the NADPH-dependent reduction of α-ketoglutarate to 2-hydroxyglutarate, which accumulates to levels 100-fold normal and may be amenable to imaging in vitro.20–22 Although the molecular mechanisms of
IDH1 R132H in malignancy are not yet understood, dysfunctional
IDH1 is a potential target of directed therapy: for example, small molecules that “reprogram” cellular metabolism.23 Further, a study in gliomas suggests that
IDH1 mutation may alter sensitivity to targeted VEGFR and EGFR inhibitors.24 Although the
IDH1 mutation is rare in breast cancer, this case illustrates that molecular profiling can reveal unanticipated potential targets for individualized cancer therapy.In summary, we present a unique case of breast cancer with divergent morphologies and genotypes, including an
IDH1 mutation identified for the first time in breast carcinoma.ACKNOWLEDGMENTSKelli Montgomery provided expert technical assistance, and Erin Popelka and Eileen Maisen provided excellent administrative assistance. The authors thank Alex Bolinder for expert assistance with graphics.REFERENCES1. van Bogaert LJ. Recent progress in the histological typing of human breast tumours. Diagn Histopathol. 1981;4:349–353[Context Link][Medline Link]2. Weigelt B, Reis-Filho JS. Histological and molecular types of breast cancer: is there a unifying taxonomy? Nat Rev Clin Oncol. 2009;6:718–730[Context Link]3. Sørlie T. Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer. 2004;40:2667–2675[Context Link][CrossRef][Medline Link]4. Rakha EA, Ellis IO. Modern classification of breast cancer: should we stick with morphology or convert to molecular profile characteristics. Adv Anat Pathol. 2011;18:255–267[Context Link][Full Text][CrossRef][Medline Link]5. Reis-Filho JS, Pusztai L. Gene expression profiling in breast cancer: classification, prognostication, and prediction. Lancet. 2011;378:1812–1823[Context Link][CrossRef][Medline Link]6. Weigelt B, Horlings HM, Kreike B, et al. Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol. 2008;216:141–150[Context Link][Full Text][CrossRef][Medline Link]7. Beadling C, Heinrich MC, Warrick A, et al. Multiplex mutation screening by mass spectrometry evaluation of 820 cases from a personalized cancer medicine registry. J Mol Diagn. 2011;13:504–513[Context Link][CrossRef][Medline Link]8. Troxell ML, Brunner AL, Neff T, et al. Phosphatidylinositol-3-kinase pathway mutations are common in breast columnar cell lesions. Mod Pathol. 2012;25:930–937[Context Link][CrossRef][Medline Link]9. Webster JA, Beck AH, Sharma M, et al. Variations in stromal signatures in breast and colorectal cancer metastases. J Pathol. 2010;222:158–165[Context Link][Full Text][CrossRef][Medline Link]10. Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. Br J Cancer. 2006;94:455–459[Context Link][CrossRef][Medline Link]11. Castaneda CA, Cortes-Funes H, Gomez HL, et al. The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer. Cancer Metastasis Rev. 2010;29:751–759[Context Link][CrossRef][Medline Link]12. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550–562[Context Link][CrossRef][Medline Link]13. Troxell ML. PIK3CA/AKT1 mutations in breast carcinoma: a comprehensive review of experimental and clinical studies. J Clin Exp Pathol. 2012 In press. doi:10.4172/2161-0681.S1-002[Context Link]14. Troxell ML, Levine J, Beadling C, et al. High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast. Mod Pathol. 2010;23:27–37[Context Link][CrossRef][Medline Link]15. Duprez R, Wilkerson PM, Lacroix-Triki M, et al. Immunophenotypic and genomic characterization of papillary carcinomas of the breast. J Pathol. 2012;226:427–441[Context Link][Full Text][CrossRef][Medline Link]16. Buttitta F, Felicioni L, Barassi F, et al. PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma. J Pathol. 2006;208:350–355[Context Link][Full Text][CrossRef][Medline Link]17. Yan H, Parsons DW, Jin G, et al.
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A, Papillary carcinoma (left) and invasive lobular carcinoma (right) in close association. B, Papillary component is extensively metastatic to axillary lymph nodes, with extracapsular extension. C, Mutation-specific antibody (
IDH1 R132H) stains papillary tumor strongly (upper, positive), whereas invasive lobular carcinoma is negative (lower). D, Polymerase chain reaction–mass spectroscopy assay (PCR-MS) of lobular carcinoma demonstrates a PIK3CA H1047R mutant (*) peak, along with a larger wild-type (WT) peak. The H1047R mutation was confirmed by Sanger sequencing (data not shown). E, PCR-MS of papillary carcinoma demonstrates a PIK3CA Q546P mutant (*) peak along with a WT peak. The Q546P mutation was confirmed by Sanger sequencing (data not shown). F, PCR-MS of papillary carcinoma also demonstrates an
IDH1 R132H mutation (*), along with a WT peak. (The large peaks in the middle of the PCR-MS tracings represent WT peaks from an unrelated, multiplexed assay).Biphasic Papillary and Lobular Breast Carcinoma With <em xmlns:mrws="http://webservices.ovid.com/mrws/1.0">PIK3CA</em> and <em xmlns:mrws="http://webservices.ovid.com/mrws/1.0">
IDH1</em> MutationsAng Daphne MD; VanSandt, Amanda M. MD; Beadling, Carol PhD; Warrick, Andrea BS; West, Robert B. MD, PhD; Corless, Christopher L. MD, PhD; Troxell, Megan L. MD, PhDCase ReportCase Report421p 221-224
