Gene Summary

Gene:SLC4A3; solute carrier family 4 (anion exchanger), member 3
Aliases: AE3, SLC2C
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:anion exchange protein 3
Source:NCBIAccessed: 06 August, 2015


What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Anion Exchange Protein 1, Erythrocyte
  • Carrier Proteins
  • Down-Regulation
  • Promoter Regions
  • Gene Deletion
  • Protein Transport
  • Transcriptional Activation
  • Polymerase Chain Reaction
  • Antiporters
  • Up-Regulation
  • Intestinal Mucosa
  • Signal Transduction
  • Immunohistochemistry
  • Chlorides
  • Membrane Proteins
  • Tumor Suppressor Gene
  • Colonic Neoplasms
  • Messenger RNA
  • Base Sequence
  • Chloride-Bicarbonate Antiporters
  • VHL
  • Transcription Factors
  • Tissue Distribution
  • Proteins
  • SLC4A Proteins
  • p53 Protein
  • Colorectal Cancer
  • Chromosome 2
  • Hydrogen-Ion Concentration
  • Transfection
  • Diarrhea
  • Cancer Gene Expression Regulation
  • Sodium-Hydrogen Antiporter
  • Tumor Markers
  • Cancer DNA
  • Anion Transport Proteins
  • Transplantation Chimera
  • Molecular Sequence Data
  • ras Proteins
  • Adenoma
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SLC4A3 (cancer-related)

Hayes M, Peckova K, Martinek P, et al.
Molecular-genetic analysis is essential for accurate classification of renal carcinoma resembling Xp11.2 translocation carcinoma.
Virchows Arch. 2015; 466(3):313-22 [PubMed] Related Publications
Xp11.2-translocation renal carcinoma (TRCC) is suspected when a renal carcinoma occurs in young patients, patients with a prior history of exposure to chemotherapy and when the neoplasm has morphological features suggestive of that entity. We retrieved 20 renal tumours (from 17,500 archival cases) of which morphology arose suspicion for TRCC. In nine cases, TFE3 translocation was confirmed by fluorescence in situ hybridisation analysis. In 9 of the remaining 11 TRCC-like cases (7 male, 4 female, aged 22-84 years), material was available for further study. The morphological spectrum was diverse. Six tumours showed a mixture of cells with eosinophilic or clear cytoplasm in tubular, acinar and papillary architecture. One case was high grade with epithelioid, spindle cell and sarcomatoid areas. Another showed tubular, solid, and papillary areas and foci containing spindle cells reminiscent of mucinous tubular and spindle cell carcinoma. The third showed dyscohesive nests of large epithelioid and histiocytoid cells in a background of dense lymphoplasmacytic infiltrate. By immunohistochemistry, keratin AE1/AE3 was diffusely positive in three tumours, while CK7 strongly stained one tumour and another focally and weakly. CD10 and Pax8 were expressed by eight, AMACR and vimentin by seven, CA-IX by four and TFE3 and cathepsin K by two tumours. Of the two TFE3-positive tumours, one showed polysomy of chromosome 7 and the other of 17; they were VHL normal and diagnosed as unclassifiable RCC. Of the seven TFE3-negative tumours, three showed polysomy of 7/17 and VHL abnormality and were diagnosed as combined clear cell RCC/papillary RCC. One TFE3-negative tumour with normal 7/17 but LOH 3p (VHL abnormality) was diagnosed as clear cell RCC. One TFE3-negative tumour with polysomy 7/17 but normal VHL was diagnosed as papillary RCC, and two with normal chromosomes 7/17 and VHL gene were considered unclassifiable. As morphological features and IHC are heterogeneous, TRCC-like renal tumours can only be sub-classified accurately by multi-parameter molecular-genetic analysis.

García JJ, Jin L, Jackson SB, et al.
Primary pulmonary hyalinizing clear cell carcinoma of bronchial submucosal gland origin.
Hum Pathol. 2015; 46(3):471-5 [PubMed] Related Publications
Hyalinizing clear cell carcinoma (HCCC) has only been described in salivary glands of the head and neck. We report a 38-year-old man with a 2.6-cm lung tumor that was growing in a peribronchial location and had morphologic features of HCCC. The tumor cells expressed cytokeratin 7 and keratin AE1/AE3, and the vast majority of tumor cells marked also with p63 and p40. They were negative for cytokeratin 20, S-100, smooth muscle actin, napsin A, and thyroid transcription factor-1. Fluorescence in situ hybridization revealed Ewing Sarcoma Breakpoint Region 1 (EWSR1) rearrangement, and reverse-transcription polymerase chain reaction confirmed the presence of the EWSR1-Activating Transcription Factor 1 (ATF1) fusion transcript, which was subsequently sequenced. The morphologic, immunophenotypic, cytogenetic, and molecular findings together with the patient's history and location of the tumor support a diagnosis of primary pulmonary HCCC of bronchial submucosal gland origin. It is our understanding that this is the first report of HCCC arising as a primary tumor outside the head and neck region.

Muller KE, Tafe LJ, de Abreu FB, et al.
Benign phyllodes tumor of the breast recurring as a malignant phyllodes tumor and spindle cell metaplastic carcinoma.
Hum Pathol. 2015; 46(2):327-33 [PubMed] Related Publications
We report a unique case of a 59-year-old woman diagnosed with a benign phyllodes tumor (PT), which recurred twice in the same location over a 7-year period: first as a malignant PT and then as a malignant PT with coexisting spindle cell metaplastic breast carcinoma (MBC). The MBC was differentiated from the malignant PT by expression of cytokeratins (CKs) AE1/AE3, CK MNF-116, CK 5/6, and p63. Somatic mutation analysis using a next-generation sequencing platform revealed a shared mutation in F-box and WD repeat domain containing 7, a tumor suppressor gene that encodes a ubiquitin ligase-associated protein, in the original benign PT and the first recurrent malignant PT. Chromosomal microarray analysis showed shared genetic gains and losses between the malignant PT and MBC. This case highlights the utility of immunohistochemistry to differentiate malignant PT from spindle cell MBC, describes a novel mutation in PT, and demonstrates a biologic relationship between these 2 entities.

Sullivan HC, Edgar MA, Cohen C, et al.
The utility of ERG, CD31 and CD34 in the cytological diagnosis of angiosarcoma: an analysis of 25 cases.
J Clin Pathol. 2015; 68(1):44-50 [PubMed] Related Publications
AIMS: Erythroblast transformation specific related gene (ERG), a proto-oncogene member of the erythroblast transformation specific transcription factor family, is a sensitive marker of endothelial differentiation and is expressed in vascular tumours, including angiosarcomas (AS). Immunohistochemistry is necessary for the diagnosis of AS in fine needle aspirates where low cellularity and lack of preserved tissue architecture impedes diagnosis. The aim of this study was to assess the utility of an ERG-enriched immunohistochemistry panel in the cytological diagnosis of AS.
METHODS: 25 AS diagnosed on fine needle aspirates were stained for ERG, CD31, CD34, and AE1/AE3. Staining intensity and percentage tumour cell positivity were evaluated. Spearman's correlation was assessed for significant correlations between antibodies.
RESULTS: Sensitivities for ERG, CD31, CD34 and AE1/AE3 were 100%, 100%, 60% and 21%, respectively. Spearman's analysis revealed that ERG and CD31 staining correlated significantly; there was no significant correlation between CD31 and CD34 staining.
CONCLUSIONS: With equal sensitivity to, and strong correlation with CD31, ERG staining is highly suitable for the cytological diagnosis of AS. ERG and CD31 are more sensitive vascular markers than CD34. ERG, a nuclear stain, complements the cytoplasmic/membranous staining of CD31. Used in conjunction with CD31, ERG can corroborate the diagnosis of AS.

Sing Y, Ramdial PK, Ramburan A, Sewram V
Cytokeratin expression in gastrointestinal stromal tumors: morphology, meaning, and mimicry.
Indian J Pathol Microbiol. 2014 Apr-Jun; 57(2):209-16 [PubMed] Related Publications
BACKGROUND: Gastrointestinal stromal tumors (GISTs) are biologically distinctive neoplasms harboring KIT and PDGFRA mutations. Cytokeratin expression in GISTs is an under-recognized diagnostic pitfall, especially in high grade GISTs with limited biopsy material and from metastatic sites.
MATERIALS AND METHODS: We evaluated the histomorphology and expression of four 'broad-spectrum' cytokeratin markers, AE1-AE3, CAM 5.2, MNF-116, and 34βE12 in 64 GISTs diagnosed over a 68-month period. Individual cytokeratins 5, 6, 7, 8, 14, 17, 18, 19, and 20 were investigated in the 'broad-spectrum' cytokeratin-positive GISTs.
RESULTS: Of 64 GISTs, 10 (15%) demonstrated cytokeratin immunopositivity. All 10, considered high risk by the National Institutes of Health consensus approach, were immunopositive for CAM 5.2 and MNF-116. Seven were AE1-AE3 immunopositive. Cytokeratins 8 and 18 were confirmed in 10 and 9 GISTs, respectively. One GIST demonstrated biphasic morphology with cytokeratin immunonegativity in low-grade spindle and immunopositivity in high-grade epithelioid foci. KIT and PDGFRA mutational analysis, undertaken in 5/10 cytokeratin-positive GISTs, harbored KIT exon 11 mutations.
CONCLUSION: We hypothesize that cytokeratin expression exclusively in high risk GISTs is a consequence of tumor progression. Given the increasing number of commercially available broad-spectrum cytokeratin immunomarkers, including those reacting with cytokeratins 8 and 18, cytokeratin-positive GISTs must be differentiated from carcinomas, melanomas, and a range of cytokeratin-positive sarcomas to ensure optimal patient management and prognostication.

Wang L, Huang J, Jiang M, et al.
CAMK1 phosphoinositide signal-mediated protein sorting and transport network in human hepatocellular carcinoma (HCC) by biocomputation.
Cell Biochem Biophys. 2014; 70(2):1011-6 [PubMed] Related Publications
We data-analyzed and constructed the high-expression CAMK1 phosphoinositide signal-mediated protein sorting and transport network in human hepatocellular carcinoma (HCC) compared with low-expression (fold change ≥ 2) no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) in GEO data set, using integration of gene regulatory network inference method with gene ontology (GO). Our result showed that CAMK1 transport subnetwork upstream KCNQ3, LCN2, NKX2_5, NUP62, SORT1, STX1A activated CAMK1, and downstream CAMK1-activated AFP, ENAH, KPNA2, SLC4A3; CAMK1 signal subnetwork upstream BRCA1, DKK1, GPSM2, LEF1, NR5A1, NUP62, SORT1, SSTR5, TBL3 activated CAMK1, and downstream CAMK1-activated MAP2K6, SFRP4, SSTR5, TSHB, UBE2C in HCC. We proposed that CAMK1 activated network enhanced endosome to lysosome transport, endosome transport via multivesicular body sorting pathway, Golgi to endosome transport, intracellular protein transmembrane transport, intracellular protein transport, ion transport, mRNA transport, plasma membrane to endosome transport, potassium ion transport, protein transport, vesicle-mediated transport, anion transport, intracellular transport, androgen receptor signaling pathway, cell surface receptor-linked signal transduction, hormone-mediated signaling, induction of apoptosis by extracellular signals, signal transduction by p53 class mediator resulting in transcription of p21 class mediator, signal transduction resulting in induction of apoptosis, phosphoinositide-mediated signaling, Wnt receptor signaling pathway, as a result of inducing phosphoinositide signal-mediated protein sorting, and transport in HCC. Our hypothesis was verified by CAMK1 functional regulation subnetwork containing positive regulation of calcium ion transport via voltage gated calcium channel, cell proliferation, DNA repair, exocytosis, I-kappaB kinase/NF-kappaB cascade, immunoglobulin-mediated immune response, mast cell activation, natural killer cell-mediated cytotoxicity directed against tumor cell target, protein ubiquitination, sodium ion transport, survival gene product activity, T cell-mediated cytotoxicity, transcription, transcription from RNA polymerase II promoter, transcription initiation from RNA polymerase II promoter, transcription via serum response element binding, exit from mitosis, ubiquitin ligase activity during mitotic cell cycle, regulation of angiogenesis, apoptosis, cell growth, cell proliferation, cyclin-dependent protein kinase activity, gene expression, insulin secretion, steroid biosynthesis, transcription from RNA polymerase II promoter, transcription from RNA polymerase III promoter, cell cycle, cell migration, DNA recombination, and protein metabolism; also by CAMK1 negative functional regulation subnetwork including negative regulation of apoptosis, cell proliferation, centriole replication, fatty acid biosynthesis, lipoprotein lipase activity, MAPK activity, progression through cell cycle, transcription, transcription from RNA polymerase II promoter, cell growth, phosphorylation, and ubiquitin ligase activity during mitotic cell cycle in HCC.

Suzuki S, Kurabe N, Minato H, et al.
A rare Japanese case with a NUT midline carcinoma in the nasal cavity: a case report with immunohistochemical and genetic analyses.
Pathol Res Pract. 2014; 210(6):383-8 [PubMed] Related Publications
BACKGROUND: NUT (nuclear protein in testis) midline carcinoma (NMC) is a recently described aggressive malignancy that is genetically defined by rearrangements of the NUT locus at 15q14. In approximately two-thirds of cases, the characteristic t(15;19) results in the fusion oncogene BRD4-NUT. Only 10 sinonasal NMCs have been documented, none of which were Japanese cases.
CASE PRESENTATION: An 18-year-old woman was admitted because of a rapidly progressing tumor in the nasal cavity. A biopsy revealed an undifferentiated neoplasm without squamous differentiation. The tumor cells had round to oval nuclei with vesicular chromatin, prominent nucleoli, and scant cytoplasm. Immunohistochemical staining demonstrated a strong positivity for vimentin and NUT, with focal CD138 and only spotty EMA and cytokeratin AE1/AE3 staining. Cytogenetic and fluorescence in situ hybridization analyses revealed a t(15;19) and BRD4-NUT gene rearrangement. Direct sequencing identified the in-frame fusion of exon11 of BRD4 with exon2 of NUT. The patient was transferred to another hospital for chemoradiotherapy.
CONCLUSION: We herein describe the first Japanese case with an NMC of the sinonasal cavity, providing detailed and unambiguous cyto- and molecular genetic information on BRD4-NUT-rearrangement. The accumulation of cases with well-documented genetic data should provide clues to the treatment of this tumor entity.

Ceballos Sáenz C, Argyris PP, Manivel JC, et al.
Nasopharyngeal hyalinizing clear cell carcinoma: report of the histopathologic features of a case showing EWSR1 rearrangements by FISH and literature review.
Int J Surg Pathol. 2014; 22(7):667-72 [PubMed] Related Publications
BACKGROUND: Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade malignant tumor affecting the minor salivary glands; nasopharyngeal involvement is uncommon.
METHODS AND RESULTS: A 38-year-old male patient presented with a 3.2 × 4.5 × 4.4 cm expansile mass obliterating the lumen of the nasopharynx and extending into the left nasal cavity. Histopathologically, the tumor was characterized by clear round to polygonal epithelial cells arranged in anastomosing trabeculae and solid nests. The stroma consisted of fibromyxoid connective tissue with areas of intense hyalinization and desmoplasia. Immunohistochemically, strong and diffuse reactivity for AE1/AE3, CK5/6, and p63 was observed. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization. The diagnosis of nasopharyngeal HCCC was rendered. Surgical excision was performed along with adjuvant radiotherapy and chemotherapy.
CONCLUSIONS: HCCC generally demonstrates good prognosis with low metastatic potential. Identification of EWSR1 gene disruption is usefulin discerning HCCC from other neoplasms with overlapping microscopic features.

Nakazawa T, Cameselle-Teijeiro J, Vinagre J, et al.
C-cell-derived calcitonin-free neuroendocrine carcinoma of the thyroid: the diagnostic importance of CGRP immunoreactivity.
Int J Surg Pathol. 2014; 22(6):530-5 [PubMed] Related Publications
In the thyroid, primary neuroendocrine tumors encompass medullary thyroid carcinoma (MTC) and, rarely, other tumors such as paragangliomas. MTCs are derived from C-cells and express calcitonin and neuroendocrine markers. Besides classic MTC, some reports have documented thyroid neuroendocrine tumors, which show no calcitonin expression and raise difficult diagnostic problems. A 76-year-old man presented with a mass in the left thyroid with neither serological calcitonin elevation nor familial history. A thorough clinico-laboratorial study did not disclose any other mass elsewhere. A left hemithyroidectomy was performed, and the histological examination revealed a neuroendocrine carcinoma resembling a paraganglioma-like MTC displaying unequivocal signs of vascular invasion. Immunohistochemically, the tumor cells showed reactivity for chromogranin A, synaptophysin, thyroid transcription factor-1 (TTF-1), paired box gene 8 (PAX8), cytokeratins (AE1/AE3 and CK8/18), and calcitonin gene-related peptide (CGRP) and negativity for calcitonin, carcinoembryonic antigen, TTF-2, thyroperoxidase, and thyroglobulin. In situ hybridization showed that the tumor cells lacked expression for calcitonin and thyroglobulin mRNA. Genetic analysis did not disclose any RET mutation. A diagnosis of C-cell-derived primary neuroendocrine carcinoma of the thyroid without calcitonin expression was made, and the patient remains free of metastasis or recurrence 18 months after surgery.

Hes O, de Souza TG, Pivovarcikova K, et al.
Distinctive renal cell tumor simulating atrophic kidney with 2 types of microcalcifications. Report of 3 cases.
Ann Diagn Pathol. 2014; 18(2):82-8 [PubMed] Related Publications
We report 3 cases of primary renal cell tumor simulating atrophic kidney with distinct gross, morphologic, immunohistochemical, and molecular genetic features. The tumors were retrieved out of more than 17 000 renal tumors from the Plzen Tumor Registry. Tissues for light microscopy had been fixed, embedded, and stained with hematoxylin and eosin using routine procedures. The tumors were further analyzed using immunohistochemistry, array comparative genomic hybridization, and human androgen receptor. Analyses of VHL gene and loss of heterozygosity (LOH) 3p were also performed. The patients were 2 women and 1 man, with ages ranging from 29 to 35 years (mean, 31.3 years). Grossly, the neoplasms were encapsulated and round with largest diameter of 3.5 cm (mean, 3.2 cm). Follow-up available for all patients ranged from 2 to 14 years (mean, 8 years). No aggressive behavior was noted. Histologically, akin to atrophic (postpyelonephritic) kidney parenchyma, the tumors were composed of follicles of varying sizes that were filled by eosinophilic secretion. Rare areas contained collapsed follicles. Each follicle was endowed with a small capillary. The stroma was loose, inconspicuous, and focally fibrotic. Two types of calcifications were noted: typical psammoma bodies and amorphous dark-blue stained calcified deposits. Immunohistochemically, tumors were strongly positive for cytokeratins (OSCAR), CD10, and vimentin, with weak immunopositivity for CAM5.2 and AE1-AE3. WT1 and cathepsin K were weakly to moderately focally to diffusely positive. Tumors were negative for cytokeratin 20, carbonic anhydrase IX, parvalbumin, HMB45, TTF1, TFE3, chromogranin A, thyroglobulin, PAX8, and ALK. Only 1 case was suitable for molecular genetic analyses. No mutations were found in the VHL gene; no methylation of VHL promoter was noted. No numerical aberrations were found by array comparative genomic hybridization analysis. LOH for chromosome 3p was not detected. Analysis of clonality (human androgen receptor) revealed the monoclonal nature of the tumor. We describe an unknown tumor of the kidney that (1) resembles renal atrophic kidney or nodular goiter of thyroidal gland; (2) contains a leiomyomatous capsule and 2 types of calcifications; (3) lacks mitoses, atypias, necroses, and hemorrhages and nearly lack Ki-67 positivity; and (4) so far showed benign biological behavior.

Zustin J, Reske D, Zrnc TA, et al.
Pseudoepitheliomatous hyperplasia associated with bisphosphonate-related osteonecrosis of the jaw.
In Vivo. 2014 Jan-Feb; 28(1):125-31 [PubMed] Related Publications
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-characterized oral complication of systemic therapy with bisphosphonates. Pseudoepitheliomatous hyperplasia was observed in some of the lesions. Because podoplanin expression has been linked to malignant lesions of the oral mucosa, we aimed to investigate podoplanin expression in the pseudoepitheliomatous hyperplasia. We analyzed archival paraffin- and plastic-embedded specimens from BRONJ using both conventional and immunohistochemical (AE1/AE3, D2-40) staining methods. Eleven out of seventeen BRONJ cases showed pseudoepitheliomatous hyperplasia. All these cases were positive for AE1/AE3 and pseudoepitheliomatous hyperplasia displayed a strong basal and parabasal reaction against podoplanin. The podoplanin expression in pseudoepitheliomatous hyperplasia in BRONJ specimens should not be considered a sign of malignancy. We discuss the current and possible future roles of surgical pathologists in diagnosing morphological changes associated with the development and therapy of BRONJ lesions.

Lee SE, Park HY, Kim S, et al.
Epithelioid hemangioendothelioma with extensive cystic change and CAMTA1 rearrangement.
Pathol Int. 2013; 63(10):502-5 [PubMed] Related Publications
Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm that has the ability to recur locally and metastasize. Thus, it is important to distinguish this tumor from other epithelioid vascular neoplasms. A 47-year-old man presented to our hospital with a pelvic mass with severe ischialgia and weight loss. Surgical resection was performed, and the mass was found to have dark red multiloculated cysts with hemorrhage and calcification. The histopathologic examination showed a central sclerotic, hypocellular zone and a peripheral cellular zone. Only the peripheral portion of the wall revealed nested tumor cells in light blue myxoid stroma. These tumors are typically composed of short strands or cords of bland epithelioid cells with occasional intracytoplasmic lumens embedded in a myxohyalinized stroma. The tumor cells were positive for CD31 and CD34 and negative for factor VIII-related antigen, CK (AE1/AE3) and S-100. The tumor nuclei showed distinct break-apart signals with individual green and/or red signals, indicating the presence of CAMTA1 rearrangement. In this study, we report a case of EHE that was difficult to diagnose based on histology alone. Therefore, we also performed fluorescence in situ hybridization, and found that the tumor harbored a CAMTA1 gene rearrangement, which confirmed the diagnosis.

Cummings MC, Simpson PT, Reid LE, et al.
Metastatic progression of breast cancer: insights from 50 years of autopsies.
J Pathol. 2014; 232(1):23-31 [PubMed] Free Access to Full Article Related Publications
There remain no clear guidelines for the optimal management of patients with metastatic breast cancer. To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer. We reviewed clinical, treatment and pathological aspects of all cases and, additionally, pathological features and biomarker expression (ER, PgR, HER2, EGFR, p53, Ki67, c-Kit, CK AE1/AE3) were assessed in detail for the primary tumour and matched metastases for 55 of the cases. Genomes of the primary tumour and multiple metastases were analysed by array-based comparative genomic hybridization for six cases(##) . 945 metastatic deposits were identified, with a median of four/patient. The most common organs involved were lung/pleura (80%), bone (74%), liver (71%) and non-axillary lymph nodes (55%). Major findings included: (a) patients with CNS metastases were more likely to have bone metastases (p < 0.013); (b) younger age was associated with metastasis to the liver (≤ 49 years; p < 0.001) and to gynaecological organs (≤ 49 years; p = 0.001); (c) surgical excision of the primary tumour was associated with metastasis to the liver (p = 0.002); and (d) ER and PgR showed down-regulation during progression in a non-random manner, particularly in lung/pleura (ER; p < 0.001), liver and bone metastases. Genomic analysis revealed DNA copy number variation between the primary tumour and metastases (e.g. amplification of 2q11.2-q12.1 and 10q22.2-q22.3) but little variation between metastases from the same patient. In summary, the association of CNS and bone metastases, liver and gynaecological metastases in young women and the risk of liver metastases following surgery have important implications for the management of patients with breast cancer. Clonal heterogeneity of the primary tumour is important in developing metastatic propensity and the change in tumour phenotype during progression/colonization highlights the importance of sampling metastatic disease for optimal treatment strategies.

Gupta A, Sheridan RM, Towbin A, et al.
Multifocal hepatic neoplasia in 3 children with APC gene mutation.
Am J Surg Pathol. 2013; 37(7):1058-66 [PubMed] Related Publications
Hepatoblastoma (HB), the most common hepatic neoplasm in children is associated with germline mutations in adenomatous polyposis coli tumor-suppressor gene that cause familial adenomatous polyposis syndrome. Individuals with familial adenomatous polyposis have a 750 to 7500× the risk of developing HB. We report 3 children with APC gene mutation, who underwent resection or liver transplant for HB. In addition to HB, all 3 patients had multiple independent adenoma-like nodules lacking qualities of intrahepatic metastases. Twenty-five nodules were subjected to immunohistochemical analysis using a panel of antibodies including glypican-3 (GPC3), β-catenin, cytokeratin AE1/AE3, CD34, Ki-67, glutamine synthetase (GS), and fatty acid binding protein. The nodules were round, ranged in size from 0.2 to 1.5 cm, and paler than the background liver. All lacked the chemotherapy effect. The nodules were circumscribed but nonencapsulated and composed of well-differentiated hepatocytes with occasional minor atypical features and absent or rare portal tracts. One lesion displayed a "nodule-within-nodule" pattern. The nodules demonstrated diffuse GS overexpression. Nine (36%) nodules were focally reactive for GPC3, and 1 (4%) displayed focal nuclear β-catenin expression. The associated HB showed diffuse expression of GS, GPC3, and β-catenin nuclear staining. We interpret these nodules as neoplastic with most being adenomas (GPC3 negative) that show features of independent origin and represent early stages of carcinogenesis, implying potential to progress to HB or hepatocellular carcinoma. To our knowledge, this is the first report of multifocal neoplasms in patients with HB and APC gene mutation.

Shelekhova KV, Calonje E, Grossmann P, et al.
Superficial soft tissue biphasic synovial sarcoma with apocrine differentiation in the glandular component: a report of two cases.
Am J Dermatopathol. 2014; 36(10):847-52 [PubMed] Related Publications
: The authors present 2 cases of a subcutaneous biphasic synovial sarcoma with marked apocrine differentiation that potentially may be confused with cutaneous epithelial neoplasms, including malignant apocrine mixed tumor or metaplastic carcinoma with an apocrine glandular component. Microscopically, both neoplasms had a biphasic architecture with the epithelial and spindle cell components. The epithelial component was prominent and consisted of simple glands with round lumina and complex glandular structures with intraluminal bridges forming cribriform areas. The glands were lined by cuboidal to columnar cells with eosinophilic or clear cytoplasm manifesting apical apocrine-like and intraluminal eosinophilic secretions. The spindle cell component was less prominent and was composed of relatively uniform or slightly atypical spindle sells surrounding and merging focally with the glandular structures. Immunohistochemically, the tumor cells in both components were positive for vimentin, AE1/AE3, CK7, and epithelial membrane antigen. Desmin, smooth muscle actin, muscle-specific actin, CD34, and S-100 protein were all negative. SYT-SSX1 gene fusion using fluorescence in situ hybridization and RT-PCR methods was detected in both cases.

de Ronde JJ, Lips EH, Mulder L, et al.
SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer.
Breast Cancer Res Treat. 2013; 137(1):213-23 [PubMed] Related Publications
Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicin and cyclophosphamide). We collected, gene expression-profiled, and analyzed 178 HER2-negative breast tumor biopsies ("NKI dataset"). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings in three external datasets, totaling 456 HER2-negative samples. Since these external sets included patients who received differing treatment regimens, the validated markers represent markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p value overlap < 1 × 10(-6)). These five genes identified resistant tumors that could not have been identified by merely taking ER status or proliferation into account. The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival.

Wang T, Zhao L, Yang Y, et al.
EGR1 is critical for gastrin-dependent upregulation of anion exchanger 2 in gastric cancer cells.
FEBS J. 2013; 280(1):174-83 [PubMed] Related Publications
The essential anion exchanger (AE) involved in bicarbonate secretion is AE2/SLC4A2, a membrane protein recognized to be relevant for the regulation of the intracellular pH in several cell types. Here we report that gastrin, a major gastrointestinal hormone, upregulates the expression of AE2 mRNA and protein in a cholecystokinin B receptor dependent manner in gastric cancer cells. The upregulated species of AE2 mRNA originates from the classical upstream promoter of the AE2 gene (here referred to as AE2a1) which provides the binding site for transcription factors early growth response 1 (EGR1) and SP1. EGR1 upregulated the AE2 expression that can be competitively inhibited by SP1 in co-transfection experiments. This competitive inhibition was avoided in cells because the SP1 expression was time-staggered to EGR1 in response to gastrin. Overexpression or knockdown of EGR1 consistently increased or decreased the expression of AE2. Our data linked a novel signal pathway involved in gastrin-stimulated AE2 expression.

Mosakhani N, Lahti L, Borze I, et al.
MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF.
Cancer Genet. 2012; 205(11):545-51 [PubMed] Related Publications
Anti-EGFR monoclonal antibodies (anti-EGFRmAb) serve in the treatment of metastatic colorectal cancer (mCRC), but patients with a mutation in KRAS/BRAF and nearly one-half of those without the mutation fail to respond. We performed microRNA (miRNA) analysis to find miRNAs predicting anti-EGFRmAb efficacy. Of the 99 mCRC patients, we studied differential miRNA expression by microarrays from primary tumors of 33 patients who had wild-type KRAS/BRAF and third- to sixth-line anti-EGFRmAb treatment, with/without irinotecan. We tested the association of each miRNA with overall survival (OS) by the Cox proportional hazards regression model. Significant miR-31* up-regulation and miR-592 down-regulation appeared in progressive disease versus disease control. miR-31* expression and down-regulation of its target genes SLC26A3 and ATN1 were verified by quantitative reverse transcriptase polymerase chain reaction. Clustering of patients based on miRNA expression revealed a significant difference in OS between patient clusters. Members of the let-7 family showed significant up-regulation in the patient cluster with poor OS. Additionally, miR-140-5p up-regulation and miR-1224-5p down-regulation were significantly associated with poor OS in both cluster analysis and the Cox proportional hazards regression model. In mCRC patients with wild-type KRAS/BRAF, miRNA profiling can efficiently predict the benefits of anti-EGFRmAb treatment. Larger series of patients are necessary for application of these miRNAs as predictive/prognostic markers.

Rekhi B, Sable M, Jambhekar NA
Histopathological, immunohistochemical and molecular spectrum of myoepithelial tumours of soft tissues.
Virchows Arch. 2012; 461(6):687-97 [PubMed] Related Publications
Primary soft tissue myoepithelial tumours (METs) are rare. Recent studies have shown EWSR1 rearrangement in certain METs. We present clinicopathological, immunohistochemical and molecular features of 14 primary soft tissue METs. Fourteen tumours, five benign and nine malignant, occurred in 12 men and two women, with an age range of 18-60 years (mean, 39.2); in upper extremities, four (29 %); chest wall, three (21 %); paraspinal region, three (21 %); pelvis, two (14 %) and lower extremities, two (14 %). Tumour size varied from 2 to 21.6 cm (mean, 8.7). Microscopically, most tumours were at least focally circumscribed. Morphological heterogeneity was noted, commonest patterns being cord-like and diffuse arrangement of polygonal cells in a myxoid stroma. By immunohistochemistry, tumours were positive for epithelial membrane antigen (EMA) (10/12, 83 %), cytokeratin (CK)/MNF116 (3/12, 25 %), p63 (7/10, 70 %), CD10 (4/6, 67 %), calponin (6/6, 100 %), S-100P (11/13, 85 %), glial fibrillary acidic protein (GFAP) (6/12, 50 %), smooth muscle actin (SMA) (3/9, 33 %), INI1/SMARCB1 (6/10, 60 %), brachyury (0/11), CD34 (0/5) and vimentin (4/4, 100 %), implying 93 % positivity for at least one epithelial marker. EWSR1 gene rearrangement was detected in 3/6 (50 %) METs (one benign and two malignant) and in an eccrine porocarcinoma which was included for reasons of comparison. Outcome details were available for six patients all surgically treated; three tumours (two malignant and one benign) resected with unknown marginal status recurred; two patients died and a single patient with myoepithelial carcinoma, who underwent a wide excision, is disease-free. This study illustrates the wide morphological spectrum of soft tissue METs, including benign and malignant subtypes. EMA and S-100P are optimal markers that should be supplemented with broad spectrum keratins, such as AE1/AE3, along with p63, GFAP and calponin in case of need but the results must be correlated with morphological features. Brachyury is useful in separating parachordoma/myoepithelioma from chordoma. EWSR1 rearrangement mostly occurs in METs that are deep-seated, irrespective of benign or malignant behaviour. Most malignant METs are INI1 negative.

Takahashi RH, Matsubayashi J, Yokotsuka M, et al.
An intrapelvic extraintestinal gastrointestinal stromal tumor of undetermined origin: diagnosis by prostate needle biopsy.
Pathol Res Pract. 2012; 208(12):736-40 [PubMed] Related Publications
We herein report a case of intrapelvic gastrointestinal stromal tumor (GIST) of undetermined origin in a 48-year-old male who presented with dysuria. An enlarged tumor was detected on digital rectal examination. Imaging studies showed a solid and lobular homogenous tumor of 7.0 cm in diameter. The tumor was attached to the right dorsal aspect of the prostate with compression of the seminal vesicles and rectum. It was considered that the tumor had arisen from the prostate, although the patient's serum prostate-specific antigen level was low (0.436 ng/mL). The histological diagnosis by prostate needle biopsy was a spindle cell tumor. At cystoprostatectomy, the tumor was confirmed to be separated from the prostate by a fibrous band, and showed spindle cells with a fascicular growth pattern, but without necrotic areas. Mitotic figures were noted in 12 of 50 high-power fields. The tumor cells were immunoreactive for the KIT protein (CD117), CD34, Discovered on GIST-1 (DOG-1), and vimentin. In contrast, they were negative for desmin, α-smooth muscle actin, pancytokeratin (AE1/AE3), and S100 protein. The Ki-67 labeling index was 5%. The genetic analyses targeting the c-kit gene revealed a point mutation at codon 559 (GTT→GAT). The diagnosis of GIST was confirmed on the basis of the morphological features, immunoprofile, and results of the molecular analyses. Since extraintestinal GIST can resemble a prostatic tumor clinically, KIT (CD117) and DOG-1 should be considered for inclusion in the immunohistochemical panel for spindle cell tumors obtained by prostate needle biopsy.

Petersson F, Bulimbasic S, Hes O, et al.
Biphasic alveolosquamoid renal carcinoma: a histomorphological, immunohistochemical, molecular genetic, and ultrastructural study of a distinctive morphologic variant of renal cell carcinoma.
Ann Diagn Pathol. 2012; 16(6):459-69 [PubMed] Related Publications
Only a few cases of sarcomatoid renal cell carcinomas (RCCs) with squamous differentiation have been published. We present 2 RCCs exhibiting a hitherto not reported biphasic neoplastic cell population exhibiting a predominantly alveolar architecture where squamoid differentiation was identified in one of the neoplastic cell populations. None of the tumors showed chromophobe features or any evidence of sarcomatoid transformation. The tumors arose in 2 adult patients and were characterized by routine histology, immunohistochemistry, ultrastructure, array comparative genomic hybridization, confirmatory fluorescent in situ hybridization, and loss of heterozygosity analysis. Tumors measured 3 and 4 cm and were located within the renal parenchyma and had no pelvicalyceal connection. Both tumors were composed of a distinctly dual-cell population. The larger tumor cells displayed squamoid features and formed round well-demarcated solid alveolated islands that, in large parts, were surrounded by a smaller neoplastic cell component. The squamoid cells were immunoreactive for cytokeratins (CKs) (AE1-AE3, Cam 5.2, CK5/6, CK7, and CK20), epithelial membrane antigen, racemase/AMACR, and carboanhydrase IX (in 1 case focally). The small cell population was positive for CK7, epithelial membrane antigen, and racemase/AMACR, whereas CK20, AE1-3, and carboanhydrase IX were negative. CD10 was focally positive in the large squamoid cells in 1 case. Cathepsin K, E-cadherin, and CD117 displayed focal positivity in 1 case. Vimentin, RCC marker, parvalbumin, S100 protein, S100 A1, p63, p53, CDX2, uroplakin III, HMB45, TFE3, WT1, synaptophysin, chromogranin A, thyroglobulin, and TTF1 were negative. The proliferative activity (Ki-67) was low (1%) in the small cell component in both cases, whereas the large neoplastic tumor cells displayed a significantly higher proliferation (20%-35%). Ultrastructurally, desmosomes and tonofilaments were identified in the large tumor cells, confirming squamoid differentiation in a subset of tumor cells. Array comparative genomic hybridization of 1 analyzable case (confirmed with fluorescent in situ hybridization and loss of heterozygosity analysis) revealed partial or complete losses of chromosomes 2, 5, 6, 9, 12, 15, 16, 17, 18 and 22, (including biallelic loss of CDKN2A locus) and partial gains of chromosomes 1, 5, 11, 12 and 13. Follow-up at 6 years showed no recurrence or metastasis in 1 patient. The other (male) patients had a subcutaneous metastasis at presentation, but during a 1-year follow-up no evidence of recurrence or further metastatic events have been documented. Our data indicate that biphasic alveolosquamoid renal carcinoma is a unique and distinctive tumor. The large squamoid and small tumor cells have overlapping but still distinctive immunohistochemical patterns of protein expression. Multiple chromosomal aberrations were identified, some of them located in regions with known tumor suppressor genes and oncogenes.

Kubouchi Y, Taniguchi Y, Matsuoka Y, et al.
Radiation-induced synovial sarcoma of the lung diagnosed by gene analysis after the surgical resection of chondrosarcoma arising from the scapula.
Ann Thorac Cardiovasc Surg. 2013; 19(2):144-7 [PubMed] Related Publications
The patient was a 62-year-old male who underwent wide resection and radiotherapy for right scapular chondrosarcoma 12 years ago. An abnormal shadow was detected in the right upper lung field included in the irradiated field on chest X-ray. Since the nodule tended to enlarge, a malignant lung tumor was suspected, and surgery was performed. On histological examination, spindle cells densely proliferated in a bundle pattern. Vimentin, bcl-2 protein, and CD99 were positive, and CD34, cytokeratin, AE1/AE3, and EMA were partially positive on immunohistochemical staining. The SYT-SSX (synaptotagmin- synovial sarcoma X) fusion gene was detected employing RT-PCR, based on which primary synovial sarcoma of the lung was diagnosed. The findings also matched the diagnostic criteria of radiation-induced sarcoma, suggesting radiation-induced primary synovial sarcoma of the lung. Primary synovial sarcoma of the lung is a rare tumor. It is difficult to diagnose based on cellular findings, and immunohistochemical and genetic investigations are essential. Radiation-induced sarcoma may develop through a long-term course, as seen in this patient, for which long-term follow-up after radiotherapy is important.

Martinez EF, Napimoga MH, Montalli VA, et al.
In vitro cytokine expression in in situ-like areas of malignant neoplasia.
Arch Oral Biol. 2013; 58(5):552-7 [PubMed] Related Publications
OBJECTIVES: The myoepithelial cells exert important effects regulating the transition of an in situ to an invasive carcinoma. This cell has been associated with a tumour suppressor phenotype due to its ability to inhibit tumour growth as well as its immunomodulatory role in cancer behaviour.
DESIGN: In order to correlate the cancer cell growth and the role of cytokines in regulating the neoplastic process, we have attempted to simulate an in vitro model of tumorigenesis, which mimics a situation where in situ neoplastic cells of carcinoma are surrounded by benign myoepithelial cells from pleomorphic adenoma. To certify the formation of in situ-like neoplasic areas, the cells were immunostained with vimentin and AE1/AE3, markers for tumoral benign myoepithelial cells and squamous cell carcinoma lineage, respectively. We investigated the correlation of the cancer cell growth with the releasing of IL-4, IL-6 and IL-10 associated with the immune response. The cytokines levels were evaluated using ELISA.
RESULTS: In in situ neoplastic areas, IL-6 amounts were higher released when compared with IL-4 and IL-10, in all studied periods. Interestingly, the peak of IL-6 release fits with the predominance of malignant cells in the culture.
CONCLUSIONS: The present results demonstrated that, in this in vitro condition, the myoepithelial cells were not able to suppress the tumour cell proliferation even with high secretion of IL-4 by benign myoepithelial cells which at the beginning is supposed to act as an anti-tumour agent. In addition, these cells favoured the tumour growth by excessive production of IL-6 and IL-10.

Lv SQ, Song YC, Xu JP, et al.
A novel TP53 somatic mutation involved in the pathogenesis of pediatric choroid plexus carcinoma.
Med Sci Monit. 2012; 18(5):CS37-41 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Choroid plexus carcinoma (CPC) is an uncommon, aggressive, malignant, central nervous system neoplasm that typically occurs in children, presenting with the signs and symptoms of intracranial hypertension and cerebrospinal fluid obstruction.
CASE REPORT: We report the case of a 2.5-year-old girl with CPC. The tumor was subtotally removed by microsurgery, followed by gamma knife radiosurgery for the residual lesion. H&E staining indicated that this was a rare case of CPC. Neuropathological studies, assayed by immunohistochemical staining, showed that the tumor sample was positive to antibodies against S-100, CgA, AE1/AE3 (cytokeratin), Ki-67, INI1 and TP53, and was negative to antibodies against Nestin, GFAP, CD133, EMA and AFP. Moreover, stainings for transthyretin and vimentin were focally positive. Interestingly, direct DNA sequencing of the paraffin-embedded tumor sample identified a novel R248Q mutation in the TP53 gene. In contrast to previous reports suggesting that TP53 germline mutations were associated with the pathogenesis of CPC, here we provide a rare case of CPC with TP53 somatic mutation, as evidence that the peritumoral tissue possesses the non-mutant TP53 allele.
CONCLUSIONS: Our finding suggests that TP53 somatic mutations, in addition to its germline mutations, may also be involved in the pathogenesis of pediatric CPC.

Griscelli F, Féraud O, Oudrhiri N, et al.
Malignant germ cell-like tumors, expressing Ki-1 antigen (CD30), are revealed during in vivo differentiation of partially reprogrammed human-induced pluripotent stem cells.
Am J Pathol. 2012; 180(5):2084-96 [PubMed] Related Publications
Because many of the genes used to produce induced pluripotent stem cells (iPSCs) from somatic cells are either outright established oncogenes, such as c-myc and Klf4, or potentially related to tumorigenesis in various cancers, both the safety and the risks of tumorigenesis linked to iPSC generation require evaluation. In this work, we generated, by lentivirus-mediated gene transfer of Oct4, Sox2, Nanog, and Lin28, two types of iPSCs from human mesenchymal stem cells and human amniotic fluid-derived cells: fully reprogrammed iPSCs with silencing of the four transgenes and partially reprogrammed iPSCs that still express one or several transgenes. We assessed the behavior of these cells during both their differentiation and proliferation using in vivo teratoma assays in nonobese diabetic mice with severe combined immunodeficiency. In contrast to fully reprogrammed iPSCs, 43% of partially reprogrammed iPSC cases (6 of 14 teratomas) generated major dysplasia and malignant tumors, with yolk sac tumors and embryonal carcinomas positive for α-fetoprotein, cytokeratin AE1/AE3, and CD30. This correlated with the expression of one or several transgenes used for the reprogramming, down-regulation of CDK 1A mRNA (p21/CDKN1A), and up-regulation of antiapoptotic Bcl-2 mRNA. Therefore, the oncogenicity of therapeutically valuable patient-specific iPSC-derived cells should be scrupulously evaluated before they are used for any clinical applications.

Gatta LB, Incardona P, Cadei M, et al.
Simultaneous fluorescence immunophenotyping and Her-2/neu genotyping (FICTION) in breast carcinoma candidates to target therapy.
Appl Immunohistochem Mol Morphol. 2012; 20(4):413-20 [PubMed] Related Publications
The study of proto-oncogene Her-2/neu using the fluorescence in situ hybridization (FISH) technique in routinely paraffin-embedded formalin-fixed tissue has become commonplace over the past decade and mandatory among invasive breast cancer expressing a score 2+ by immunohistochemical analysis of c-erbB2 protein. The patient's eligibility for treatment with the biological drug trastuzumab/herceptin is based on the evidence of a Her-2/neu proto-oncogene amplification (ratio Her-2/neu/CEP-17>2.2). However, although the exclusion is declared in the absence of Her-2/neu gene amplification (ratio Her-2/neu/CEP-17 <1.8) according to the American Society of Clinical Oncology/College of American Pathologists recommendations, there are borderline cases (1.82.2) that need to be investigated (eg, ductal carcinoma in situ with microinvasion, metastatic breast cancer). In such cases with Her-2/neu genetic heterogeneity it is difficult to count the nuclear signals in the areas of invasive tumor using fluorescence. The availability of a Fluorescence Immunophenotyping and Interphase Cytogenetics as a Tool for Investigation of Neoplasms technique, based on the simultaneous evaluation of immunostaining with anticytokeratins (CKAE1/AE3 and CK19), together with FISH for Her-2/neu gene status [it is therefore useful and of current applicability in breast cancer blocks (formalin-fixed and paraffin-embedded)], permits a more easy identification of even single neoplastic cells by immunofluorescence and then a better evaluation of Her-2/neu status gene by the FISH technique, as shown in our study.

Durkes A, Garner M, Juan-Sallés C, Ramos-Vara J
Immunohistochemical characterization of nonhuman primate ovarian sex cord-stromal tumors.
Vet Pathol. 2012; 49(5):834-8 [PubMed] Related Publications
This study evaluates the immunoreactivity of 12 sex cord-stromal tumors of nonhuman primates (11 granulosa cell tumors and 1 luteoma). The markers selected are used in the characterization of gonadal tumors in dogs and other species, including cytokeratins AE1/AE3, GATA-4, inhibin-α, neuron-specific enolase, protein gene product 9.5, and vimentin. A normal nonhuman primate ovary was used as a control and to optimize immunolabeling. Staining was graded as follows: 0 (nonstaining), 1+ (< 10% positive cells), 2+ (10%-50% positive cells), and 3+ (> 50% positive cells). Calretinin, GATA-4, neuron-specific enolase, and vimentin were the most consistently expressed markers (12 of 12). Cytokeratins AE1/AE3 were also consistently expressed (11 of 12). Inhibin-α and protein gene product 9.5 were expressed in 8 and 10 sex cord-stromal tumors, respectively. Results indicate that immunoreactivity of nonhuman primate sex cord-stromal tumors is similar to that observed in other species and that calretinin, GATA-4, and neuron-specific enolase are the most consistently expressed markers in nonhuman primate sex cord-stromal tumors.

Joosse SA, Hannemann J, Spötter J, et al.
Changes in keratin expression during metastatic progression of breast cancer: impact on the detection of circulating tumor cells.
Clin Cancer Res. 2012; 18(4):993-1003 [PubMed] Related Publications
PURPOSE: Circulating tumor cells (CTC) might function as early markers for breast cancer metastasis or monitoring therapy efficacy. Enrichment and identification of CTCs are based on epithelial markers that might be modulated during epithelial-mesenchymal transition. Little is known about the expression of keratins in CTCs and whether all CTCs can be detected with antibodies directed against a limited panel of keratins.
EXPERIMENTAL DESIGN: Protein expression of keratin 2, 4-10, 13-16, 18, and 19 were assessed by a cocktail of antibodies (C11, AE1, AE3, and K7) and keratin antibodies C11 and A45-B/B3 alone in 11 breast cancer cell lines and 50 primary breast carcinomas and their lymph node metastases. Furthermore, CTCs were assessed in blood of 70 metastatic breast cancer patients.
RESULTS: Claudin-low cell lines did not show expression of normal breast epithelial keratins but were positive for K14 and K16, detected by the cocktail only. Primary breast carcinomas showed changes in keratin expression during metastatic progression to the lymph nodes. In 35 of 70 patients CTCs were identified, of which 83%, 40%, and 57% were identified by the cocktail, C11 and A45-B/B3, respectively. Identification of CTCs by the cocktail was associated with shorter survival (P < 0.01). In silico analyses revealed association between KRT16 expression and shorter relapse-free survival in metastatic breast cancer.
CONCLUSION: Breast cancer cells show a complex pattern of keratin expression with potential biologic relevance. Individual keratin antibodies recognizing only a limited set of keratins inherit the risk to miss biologically relevant CTCs in cancer patients, and antibody cocktails including these keratins are therefore recommended.

Lopes LF, Bacchi CE
Cytokeratin expression in gastrointestinal stromal tumor: a clinicopathologic and immunohistochemical study of 687 cases.
Appl Immunohistochem Mol Morphol. 2012; 20(1):8-12 [PubMed] Related Publications
Gastrointestinal stromal tumor is the most common clinically significant mesenchymal neoplasm of the gastrointestinal tract. The expression of the intermediate filament cytokeratin in gastrointestinal stromal tumor is not frequently reported in the literature. The aim of this study was to investigate the immunohistochemical expression of several types of cytokeratin in a large number of cases (n=687), including a pan-cytokeratin marker (AE1/AE3 cocktail antibodies), high-molecular weight cytokeratins (34ßE12 antibody), and individual cytokeratins 8 (35ßH11 and CAM5.2 antibodies), 7, 14, and 20. Ki-67 antigen was used for the determination of cell proliferation index, and the correlation between Ki-67 and cytokeratin expression was evaluated. Cytokeratin expression was also correlated with several clinicopathologic parameters. The expression of pan-cytokeratin was observed in 24 (3.5%) cases, with variable intensity. Only 1 of 687 (0.1%) cases showed cytokeratin 14 expression. All 687 cases revealed no expression of high-molecular weight cytokeratins, cytokeratins 7, 8, and 20. No significant statistical association was found between AE1/AE3 immunoreactivity and several clinicopathologic parameters, including sex, tumor location and size, cell morphology, mitotic count, risk of aggressive behavior, and Ki-67 antigen cell proliferation index. However, statistical correlation between AE1/AE3 immunoreactivity and a higher age at diagnosis was detected. These results show that cytokeratin expression is not frequent in gastrointestinal stromal tumor, but caution is necessary to avoid erroneous diagnoses.

Kontic M, Stevic R, Stojsic J, et al.
Synchronous primary lung cancers: a multidisciplinary approach in diagnosis.
Tumori. 2011 Jul-Aug; 97(4):e16-9 [PubMed] Related Publications
UNLABELLED: BACKGROUND. For patients with two or more primary cancers a correct diagnosis is critically important because prognosis and treatment vary considerably between multiple primary cancers and metastatic disease.
CASE REPORT: Two bilateral synchronous primary lung malignancies of different histological types were diagnosed and immunohistochemically confirmed in a 60-year-old woman. In biopsy specimens of the right lung pure squamous cell carcinoma was detected (stage IIIa). The tumor expressed AE1/AE3, cytokeratin 5 and 34βE12. In biopsy specimens of the left lung small cell carcinoma was detected (stage IIIa). The small cells expressed synaptophysin, chromogranin A and CD56. DNA was extracted from paraffin-embedded tissue of both tumors. Exons 5-9 of the TP53 gene were examined for genetic mutations by polymerase chain reaction and DNA sequencing analysis. Direct sequencing of DNA isolated from the small cell carcinoma revealed a TGC to TTC mutation at codon 404 of TP53 exon 5. In DNA isolated from the squamous cell carcinoma no TP53 mutation was found. The tumors' different response to chemotherapy also suggested that they belonged to different histological types. The patient lived 24 months after the diagnosis, which is more typical for stage III than for stage IV lung carcinoma.
CONCLUSION: Discrimination of synchronous primary lung cancers from intrapulmonary metastases based only on clinical findings can be very difficult. Multidisciplinary diagnostic evaluation is therefore very helpful in cases like this, because a correct diagnosis will determine the best treatment for the patient and consequently a better prognosis.

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