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Hindawi Journal of Oncology Volume 2019, Article ID 5836821, 11 pages https://doi.org/10.1155/2019/5836821 Research Article Gastrointestinal Carcinoma with Plasmacytoid Morphology: Positivity for c-MET, Arylsulfatase, and Markers of Epithelial-Mesenchymal Transition, as Indicators of Aggressivity 1 1,2,3 4 2 Zsolt Kovacs, Simona Gurzu , Calin Molnar, Mihaela Sincu, 1 2 1 Laura Banias, Catalin Satala, and Ioan Jung Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology, Tirgu-Mures, Romania Department of Pathology, Clinical County Emergency Hospital, Tirgu-Mures, Romania Department of Pathology, Research Center (CCAMF), Tirgu-Mures, Romania Department of Surgery, University of Medicine, Pharmacy, Sciences and Technology, Tirgu-Mures, Romania Correspondence should be addressed to Simona Gurzu; email@example.com Received 3 February 2019; Revised 6 March 2019; Accepted 18 March 2019; Published 8 May 2019 Guest Editor: Daniele Vergara Copyright © 2019 Zsolt Kovacs et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Plasmacytoid urothelial carcinoma is a rare and aggressive histologic variant of high-grade carcinoma of the urinary bladder. Few than 250 cases have been reported in the urinary bladder till January 2019. In this paper, a case series of unusual gastrointestinal carcinomas with plasmacytoid morphology was included. Only one similar case of the stomach was previously published and no such cases were found in colon. Methods. We present the complex immunoprofile, using a panel of 39 biomarkers, of the largest group of primary gastrointestinal carcinomas with plasmacytoid morphology reported in literature (one from upper rectum and six from stomach). Results. All of the seven cases showed lymph node metastases and only one survived over 25 weeks aer ft surgical excision. eTh indicators of aggressivity were age (over 60), advanced stage (from IIIA to IV), E-cadherin negativity, and vimentin positivity. eTh immunoprofile indicated unfavorable prognosis for mesenchymal-type carcinomas (negativity for E- cadherin and positivity for vimentin, with membrane to nuclear translocation or negativity of𝛽 -catenin). eTh survivor showed an “epithelial-type adenocarcinoma with plasmacytoid dedieff rentiation”, with membrane positivity for E-cadherin and 𝛽 -catenin and vimentin negativity. All of the cases expressed c-MET and were negative for HER-2. Conclusions.Primary carcinoma with plasmacytoid morphology is a dedifferentiated variant of adenocarcinoma or poorly cohesive carcinomas. Vimentin positive dedieff rentiated-poorly cohesive carcinomas should be considered as mesenchymal-type highly malignant carcinomas. This rare histologic variant of gastrointestinal cancer might respond to anti-c-MET tyrosine kinases. 1. Introduction the age of 69 (range 46–87 years) [4, 6]. Due to their rare occurrence, few data are known about these carcinomas. Plasmacytoid urothelial carcinoma (PUC) is a rare and Although PUCs proved chemosensitive to cisplatin , aggressive histologic variant of high-grade carcinoma of the they are usually diagnosed in late stages (pT3, pT4) , with urinary bladder [1–4] whose diagnosis is difficult to make. metastases in 60% of the patients . The median overall The PUC variant was described in the urinary bladder in survival is 19-23 months (range: one week-43 months) [1– 1991  but was recognized by the World Health Organiza- 4, 6]. tion (WHO) in 2004 [3, 5]. Except the urinary bladder, carcinomas with plasmacy- About1-3%ofall UCsare diagnosed asPUCs. 61cases toid morphology were also described involving other organs. have been reported in the English literature till 2012 , less Although CD138 may infrequently mark gastrointestinal than 100 cases till 2017 , and less than 250 till January carcinoma cells, only one case of primary gastric PC was 2019. They occur more frequently in males (M:F=3:1), around reported in 2012 . Another duodenal carcinoma with 2 Journal of Oncology (a) (b) (c) (d) Figure 1: Representative aspect of carcinoma with plasmacytoid morphology, with discohesive round to ovoid cells with eccentrically located nuclei (a-left, b–d), sometimes with nuclear pleomorphism (c). eTh mucinous adenocarcinoma can be associated (a-right). plasmacytoid morphology was reported in 2017 but n fi ally 2. Material and Methods proved to be metastatic tumors from a PUC and not a primary 2.1. Case Selection. We have retrospectively evaluated seven carcinoma . WHO has not yet recognized this entity as consecutive cases of primary gastrointestinal PCs (one of histological subtype of gastric or colorectal carcinomas . the colon and 6 of the stomach), diagnosed by our team in Independently from the localization, carcinoma with the last four years. No synchronous urothelial carcinoma or plasmacytoid morphology is characterized by diffuse prolif- lobular carcinoma of the breast was associated with any of the eration of discohesive cells with plasmacytoid morphology, included cases. No preoperative therapy was done. with eccentrically located nuclei, indistinct nucleoli, and The signed informed consent was obtained from all of the eosinophilic cytoplasm that express cytokeratin (CK) and patients for publication of clinicopathological data. the transmembrane heparan sulfate proteoglycan CD138 We reviewed the Hematoxylin and Eosin- (HE-) stained (Syndecan-1) in over 50% of tumor cells [3–5]. The tumor cells slides to confirm diagnosis and quantify the percentage and can show solid sheet-like architecture or are arranged in cords microscopic subtype of adenocarcinoma versus carcinoma and small nests . with plasmacytoid morphology component. All cases pre- In this paper, we present a comprehensive immunoprofile sented at least 80% plasmacytoid component (Table 1). It was of 7 primary carcinomas with plasmacytoid morphology of evaluated based on the presence of round to ovoid discohesive the gastrointestinal tract: one from colon and 6 cases with cells, with eccentrically located nuclei (Figure 1). gastric localization. The aim of the study was to identify the The 8th edition of AJCC staging system  was used for immunoprofile of the tumor cells, as a possible therapeutic establishing the pTNM stage. The Dukes-MAC stage was also target of this rare histologic variant of gastrointestinal carci- appreciated based on new literature proposal . noma. To have a complex immunohistochemical (IHC) picture of these tumors, we assessed the expression of a panel of 39 2.2. Immunohistochemistry. In all of the cases, a complex biomarkers that includes markers for diagnosis, epithelial- immunoprofile of the tumor cells was done to perform mesenchymal transition (EMT), adhesion molecules, mark- differential diagnosis of a primary versus metastatic tumor ers of angiogenesis, and predictive markers. The obtained (Table 2). The diagnosis of carcinoma with plasmacytoid data were correlated with those obtained after a complex morphology was suspected in HE and conrfi med by double review of literature. positivity for CD138 and cytokeratins (CK AE1/AE3 and CK7 Journal of Oncology 3 Th Table 1: e clinicopathological features of patients with gastrointestinal carcinomas with plasmacytoid morphology ( ∗ means upon 9, and∗∗ means 8). Microscopy – Microscopy – Angio- Dukes-MAC Case Age Tumor adenocarcinoma pT pN WHO’s Gender Macroscopy plasmacytoid lymphatic pM stage (Dukes-MAC OS no (years) localization type and part stage stage stage∗∗ part (%) invasion like∗)stage (%) 10% - mucinous adenocarcinoma N2 Died at 3 1 M 62 Upper rectum Ulceroinfiltrative and 10% - signet 80% 4a L1V1 M0 D IIIC (13/13) weeks ring cells component 10% G3 Small curvature adenocarcinoma N2 Alive at 25 2M 52 –proximal Ulceroinfiltrative and 10% poorly 80% 4a L1V0 M0 D IIIA (4/30) weeks stomach cohesive carcinoma 10% - Poorly Small curvature N3b Died at 20 3M 70 Polypoid-ulcerated cohesive 90% 4b L1V0 M0 D IIIC – Distal stomach (19/22) weeks carcinoma Greater 10% - Poorly curvature – Linitis plastica N3a Died at 23 90% 4b L1V1 M0 D IIIC 4M 67 cohesive Proximal and (Infiltrative) (14/55) weeks carcinoma distal stomach Small curvature 10% - Signet M1 Linitis plastica N3a Died at 4 5F 83 –Proximaland ring cell 90% 4a L1V1 (abdominal DIV (Infiltrative) (13/46) weeks distal stomach carcinoma carcinomatosis) 10% G2 adenocarcinoma N3b Died at 4 6 M 82 Antrum Ulceroinfiltrative and 10% poorly 80% 2 L1V1 M0 B2 IIIB (25/26) weeks cohesive carcinoma M1 Small curvature 10% - Poorly N3b (metastases in Died at 15 7F 77 –proximal Ulceroinfiltrative cohesive 90% 3 L1V1 DIV pericaval lymph weeks (18/39) stomach carcinoma nodes) 4 Journal of Oncology ff ff ff ff ff ff ff ff ff ff ff ff ff Th fi Th Th Th Table 2: e immunohistochemical markers used in the study. Marker Supplier Clone Dilution Scoring CD138 Dako, Glostrup, Denmark MI 15 RTU ≥50% cytoplasmic or membrane staining CDX2 Dako DAK-CDX2 RTU ≥1% nuclear staining CEA ermo Scientific, San Diego, CA, USA Ab3 1:200 ≥1% cytoplasmic staining CK AE1/AE3 Dako AE1/AE3 1:100 ≥1% cytoplasmic or membrane staining CK20 Thermo Scientific Q6 1:100 ≥1% cytoplasmic or membrane staining CK7 ermo Scientific OV-TL 12/30 1:100 ≥1% cytoplasmic or membrane staining MLH-1 Leica ESO5 1:50 ≥1% nuclear staining MSH-2 Leica 25D12 1:50 ≥1% nuclear staining PMS-2 Leica Monoclonal 1:50 ≥1% nuclear staining MSH-6 Leica Monoclonal 1:50 ≥1% nuclear staining SLUG Santa Cruz Polyclonal 1:100 Cytoplasmic positivity – 1% cut-off E-cadherin Dako NCH-38 1:50 Membrane positivity – 5% cut-o -catenin Leica 17 C2 1:50 Membrane, cytoplasmic or nuclear positivity – 5% cut-o N-cadherin Dako 6G11 1:100 Membrane or cytoplasmic positivity – 1% cut-o Vimentin Dako V9 1:800 Cytoplasmic positivity – 10% cut-o c-met Abcam, Cambridge, UK Monoclonal 1:2000 Cytoplasmic positivity – 5% cut-o VSIG Sigma Aldrich Polyclonal 1:2500 Cytoplasmic or membrane positivity – 5% cut-off S100 ermo Scientic Polyclonal 1:8000 Cytoplasmic positivity – 5% cut-off SMA Dako 1A4 RTU Cytoplasmic positivity – 1% cut-o CD44 Leica DF1485 1:50 Cytoplasmic or membrane positivity – 10% cut-o Maspin Santa Cruz H-130 1:25 Cytoplasmic or nuclear positivity – 5% cut-o VEGF-A Novocastra VG1 1:50 Cytoplasmic positivity – 5% cut-o Synaptophysin Dako DAK-SYNAP RTU Cytoplasmic or membrane positivity – 5% cut-o Chromogranin Dako DAK A3 RTU Cytoplasmic or membrane positivity – 5% cut-off NSE Dako M0873 1:100 Cytoplasmic or membrane positivity – 5% cut-o ER Dako 1D5 RTU Nuclear positivity - 1% cut-off PR Dako PgR636 RTU Nuclear positivity - 1% cut-o HER-2 Dako Polyclonal 1:200 Membrane positivity – HercepTestTM guidelines Melan A Dako A103 RTU Cytoplasmic positivity – 1% cut-o HMB45 Cell Marque Monoclonal RTU Cytoplasmic positivity – 1% cut-off Journal of Oncology 5 (a) (b) (c) (d) Figure 2: eTh diagnosis of primary gastrointestinal carcinoma with plasmacytoid morphology is based on positivity for cytokeratin 20 (a) or cytokeratin 7 (b) and simultaneous positivity for CD138 (c, d). or CK20) (Table 3 and Figure 2). As we have mentioned 3. Results before, at least 80% plasmacytoid component was identified 3.1. Clinicopathological Data. In our university hospital, there in all of the cases. CD138 marked the plasmacytoid compo- are about 60 gastric carcinomas and 150 colorectal carcino- nent only, without positivity in the adenocarcinoma/poorly cohesive carcinoma (including signet ring cells) component. mas diagnosed every year. The 7 primary carcinomas with plasmacytoid morphology (one from upper rectum and 6 No stromal positivity was noted. from stomach) represented about 0.16% of all colorectal The EMT was analyzed using the IHC markers of the carcinomas and 2.5% of all gastric carcinomas diagnosed in Wnt pathway E-cadherin,𝛽 -catenin, N-cadherin, vimentin, our department of pathology during 2016-2019. They were andarylsulfatase A and B (ARSA,ARSB).CD44 was used identified in patients with a median age of 70.43 ±11.24 years to explore the stemness features of the tumor cells. Those (range: 52 to 83 years) and a report of M:F=2.5:1. cases showing loss of E-cadherin with membrane to nuclear translocation of𝛽 -catenin, or negativity for𝛽 -catenin, were All of the patients were diagnosed in metastatic stages, with invasion in lymphatic (L1) and/or blood vessels (V1) and considered as showing EMT. Positivity for N-cadherin and extremely short overall survival (Table 1). All of the tumors vimentin was also checked for identification of mesenchymal were removed with free resection margins (R0). Only one features. As the adhesion molecule V-set and immunoglob- ulin (VSIG) and SLUG were positive in all of the cases and patient (the youngest one: 52 years old) is alive at 25 weeks N-cadherin and smooth muscle actin (SMA) was negative, aer ft surgery (case 3). As the tumor cells did not express the tumors were classified as epithelial-type carcinomas HER-2, classic chemotherapy was administrated. The other 6 patients died between 3 and 23 weeks (below six months) (positive for E-cadherin, with membrane expression of 𝛽 - catenin and negativity for vimentin) or mesenchymal-type after surgery (Table 1). carcinomas (negative for E-cadherin, with nuclear expression of𝛽 -catenin or positivity for vimentin). The other cases were 3.2. Histological Diagnosis. The diagnosis of a primary car- considered as having a hybrid EMT phenotype (Table 3 and cinoma was histologically based on the origin of tumor cells Figure 3). within gastric or colorectal mucosa. 6 Journal of Oncology (a) (b) (c) (d) (e) (f) Figure 3: Epithelial-mesenchymal transition (EMT) of gastrointesti nal carcinoma with plasmacytoid morphology. eTh “epithelial-type carcinoma with plasmacytoid morphology” is characterized by membrane positivity for E-cadherin (a) and 𝛽 -catenin (b). In the “mesenchymal-type carcinoma with plasmacytoid morphology”, loss of E-cadherin (c-right) and𝛽 -catenin (d-right) or nuclear translocation of𝛽 -catenin (e) can be seen. Vimentin positivity (f) is also characteristics of carcinomas with EMT transition. In carcinoma with plasmacytoid morphology of the 3.3. Immunohistochemistry upper rectum (Case 1, Table 1), it was about a mucinous ade- 3.3.1. Primary versus Metastatic Tumor. The colonic origin nocarcinoma with signet ring cell component, with plasma was proved by positivity of tumor cells for CK20 and cells-like discohesive cells, in the invasion front (Figure 1). inconstant positivity for CDX2. Gastric origin was revealed As the surgical intervention was made in emergency, due by inconstant positivity for CK7 and/or CK20 (Figure 2). to mechanical ileus, no preoperative chemoradiotherapy was Lymphoma was excluded based on negativity for Leukocyte done. Common Antigen (LCA), CD20, and CD3, and three neu- All of the six gastric carcinomas were of poorly cohesive- roendocrine markers (chromogranin, synaptophysin, neuron type, with/without signet ring cell component, with 10% specific enolase [NSE]) were used to exclude a neuroen- component of adenocarcinoma, in cases 2 and 6 (Table 1). docrine carcinoma (Table 3). Journal of Oncology 7 Table 3: Immunohistochemical profile of gastrointestinal carcinoma with plasmacytoid morphology included in the study. Case number Biomarker group Biomarker name Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Plasmacytoid CD138 Positive Positive Positive Positive Positive Positive Positive differentiation CD38 Focal positive Focal positive Negative Focal positive Positive Positive Positive CK AE1/AE3 Positive Positive Positive Positive Positive Positive Positive CK7 Negative Positive Negative Positive Positive Positive Positive Epithelial origin CK20 Positive Negative Negative Negative Negative Negative Negative CDX2 Positive Negative Negative Negative Negative Negative Negative CEA Positive Negative Negative Negative Negative Negative Negative MLH-1 Positive Positive Positive Positive Positive Positive Positive MSH-2 Positive Positive Positive Positive Positive Positive Positive Microsatellite status PMS-2 Positive Positive Positive Positive Positive Positive Positive MSH-6 Positive Positive Positive Positive Positive Positive Positive SLUG Positive Positive Positive Positive Positive Positive Positive E-cadherin Negative Positive Negative Negative Negative Negative Negative N-cadherin Negative Negative Negative Negative Negative Negative Negative -catenin Positive - Nuclear Positive - membrane Negative Negative Positive -membrane Negative Negative Epithelial- Vimentin Negative Negative Positive Positive Positive Negative Negative mesenchymal VSIG Focal positive Positive Positive - cytoplasm Positive Positive - membrane Positive - cytoplasm Positive transition (EMT) CD44 Positive>25% Negative Positive>50% Positive>50% Positive>50% Negative Negative Arylsulfatase A Positive Positive Positive Positive Positive Positive Negative Arylsulfatase B Positive Positive Positive Negative Positive Positive Positive SMA Negative Negative Negative Negative Negative Negative Negative EMT subtype Mesenchymal Epithelial Mesenchymal Mesenchymal Mesenchymal Hybrid Mesenchymal Angiogenesis Maspin Negative Negative Negative Negative Negative Negative Nuclear VEGF-A Negative Negative Negative Negative Negative Negative Negative Differential diagnosis Chromogranin, Neuroendocrine NSE, Negative Negative Negative Negative Negative Negative Negative markers synaptophysin Lymphoid CD20, CD3, Negative Negative Negative Negative Negative Negative Negative differentiation LCA, CD15 Mammaglobin, Breast origin Negative Negative Negative Negative Negative Negative Negative GATA3 Melanoma origin S100, HMB45 Negative Negative Negative Negative Negative Negative Negative c-MET Positive Positive Positive Positive Positive Positive Positive HER-2 Negative Negative Negative Negative Negative Negative Negative Predictive markers C-KIT Negative Negative Negative Negative Negative Negative Negative NGAL Negative Negative Negative Negative Negative Negative Negative CD10 Negative Negative Negative Negative Negative Negative Negative 8 Journal of Oncology (a) (b) (c) (d) Figure 4: Predictive markers of carcinoma with plasmacytoid morphology c-MET (a, b) and CD44 (c, d) are expressed in the tumor cells cytoplasm (a, c) or membrane (b, d). Metastases from a PUC were excluded based on positiv- 3.3.4. Angiogenesis. All of the cases showed negativity for ity for CK20 and/or CDX2 and carcinoembryonic antigen Vascular Endothelial Growth Factor A (VEGF-A), as expres- (CEA) and negativity for GATA3. Metastases from a lobular sion of lack of angiogenic immunophenotype. Negativity for carcinoma of the breast were based on negativity for Estrogen maspin was an indicator of high risk for distant metastases. and Progesteron receptors (ER, PgR) and also negativity for mammaglobin, endothelial transcription factor 3 (GATA 3), 3.3.5. Predictive Markers. No positivity for HER-2, c-KIT, and gross cystic disease uid fl protein 15 (GCDFP-15). S100 and NGAL,orCD10was observed butall of the cases diffusely HMB45 negativity excluded a metastatic melanoma (Tables 3 expressed c-MET protein (Figure 4). and 4). 4. Discussion 3.3.2. Microsatellite Status. The microsatellite status was IHC To differentiate a primary carcinoma with plasmacytoid assessed using the markers MLH-1, MSH-2, PMS-2, and morphology of gastrointestinal tract from a metastatic tumor, MSH-6. As all of the markers were positive (Table 3), especially from PUC or breast lobular carcinoma, a complex all tumors were considered proficient for mismatch repair immunoprolfi e is necessary (Table 4). Primary lymphomas, proteins (MMR-proficient), respectively, microsatellite stable as plasma cell lymphoma, and carcinoma variants should also (MSS) carcinomas. be excluded . Although carcinoma with plasmacytoid morphology 3.3.3. Epithelial-Mesenchymal Transition. From 6 gastric car- expresses CD138, the diagnosis is based on simultaneous cinomas with plasmacytoid morphology, 4 cases were clas- positivity for pan-cytokeratin (CK AE1/AE3) and epithe- sified as mesenchymal-type carcinomas, one as epithelial lial membrane antigen (EMA) [3, 5]. In contrast with type, and one as having a hybrid phenotype (positivity lymphomas, Leukocyte Antigen (LCA), multiple myeloma for VSIG and SLUG only), the same as the mesenchymal- 1/interferon regulatory factor 4, and k and l light chains are type carcinoma with plasmacytoid morphology of the upper negative in PCs [4, 5]. rectum (Table 3). The longer survival (over 25 weeks) was seen for the epithelial-type carcinoma (case 2) (Tables 1 and 3 CK AE1/AE3 marks 97% of carcinomas with plasma- and Figure 3). cytoid morphology , independently of their localization. Journal of Oncology 9 Th Table 4: e immunoprofile of primary carcinoma with plasmacytoid morphology versus metastatic tumors in the gastrointestinal tract (adapted upon 1, 2, 3, 5, 7, 12-16). Invasive lobular carcinoma of the BIOMARKER Gastric PC Colorectal PC Urothelial PC breast ∼90% positivity in metastatic CD138 100% positivity 100% positivity ∼78% positivity cases, in epithelium and/or stroma CK AE1/AE3 97% positivity 100% positivity ∼97% positivity Usually positive CK7 Usually positive Sporadic positive ∼77.4% positivity Usually positive CK20 Negative or focally positive ∼97% positivity ∼72% focal positivity Usually negative CDX2 Usually negative Usually positive ∼18% positivity Negative CEA Usually negative Positive ∼49% positivity Negative Uroplakin II Negative Negative ∼33% positivity Negative ER Usually negative Usually negative Negative ∼95% positivity PR Negative Negative ∼13% positivity ∼76-83% positivity Mammaglobin Negative Negative Negative Usually positive GCPDFP-15 Negative Negative ∼24% positivity Usually negative ≥90% positivity (only 22% in GATA 3 Negative or weak and sporadic Negative ∼70-88% positivity triple negative tumors) MLH-1 Usually positive, usually MSS Usually positive, usually MSS No data in PubMed cited papers Usually positive, usually MSS MSH-2 Usually positive Usually positive No data in PubMed cited papers Usually positive PMS-2 Usually positive Usually positive No data in PubMed cited papers No data in PubMed cited papers MSH-6 Usually positive Usually positive No data in PubMed cited papers No data in PubMed cited papers ∼25% positivity, 75% diminished ∼10-25% membrane or aberrant E-cadherin Usually negative Usually negative or negative nuclear positivity 22.5% negative, 17% nuclear ∼90% reduction or complete loss -catenin Negative or membrane positivity Nuclear positivity positivity, 60.5% membrane of positivity, 8-10% membrane or positivity cytoplasmic positivity Vimentin Usually positive Negative Usually negative ∼14% positivity N-cadherin Usually negative Usually negative No data in PubMed cited papers ∼4% positivity VSIG1 Usually positive Usually positive No data in PubMed cited papers Usually negative SLUG Usually positive Usually positive No data in PubMed cited papers ∼2-4% positivity Positive in metastatic or CD44 Positive or negative Positive or negative No data in PubMed cited papers multidrug resistant cases Maspin Negative Negative or nuclear positivity No data in PubMed cited papers ∼7% cytoplasmic positivity S100 Negative Negative Negative ∼57% positivity VEGF-A Negative Negative No data in PubMed cited papers Negative or positive HER-2 Negative Negative Usually negative Positive in triple negative c-MET Usually positive Usually positive No data in PubMed cited papers metastatic cases 10 Journal of Oncology Regarding the CK variants, CK20 is usually positive for col- [8,9,15]:age over 50,advanced stage (both pTNM and orectal carcinomas but gastric carcinomas with plasmacytoid Dukes-MAC like), angiolymphatic invasion, EMT pheno- morphology and PUCs can also express this marker. The type, and positivity for c-MET and CD44. CD44 is a cancer stem marker that seems to induce chemoresistance . gastrointestinal versus urothelial origin cannot be based on keratin 7. It is positive for urothelial carcinoma but can also As CD138 is an extracellular matrix receptor involved mark the gastric and colorectal carcinomas, especially those in intercellular communication, proliferation, angiogenesis, and metastasis , we consider that it should be considered with microsatellite status or with serrated pathway and BRAF mutations [7, 10]. as an indicator of poorly cohesive carcinoma aggressivity, CDX2 and polyclonal carcinoembryonic antigen (p- independent of the tumor location. It probably interacts with CEA) may mark both colorectal carcinomas with plasma- the Wnt and ARSA/ARSB pathways and is involved in the cytoid morphology and PUCs but uroplakin is positive process of EMT of carcinoma cells. Our case series showed that, in gastrointestinal tract, forPUCsonly [1, 4]. CDX2 israrelypositive ingastric carcinomas, as in our cases. carcinoma with plasmacytoid morphology is an aggres- The suspicion of a metastasis from a lobular carcinoma sive “mesenchymal-type poorly cohesive carcinoma” that expresses c-MET but not HER-2. This immunophenotype of the breast is eliminated based on negativity for specific markers such mammaglobin, ER, PR, and GATA 3 [1, 3, indicates a possibility of the response of these tumors to 11, 12]. However, the poorly cohesive gastric carcinomas can tyrosine kinase inhibitors that target MET signaling, such as imatinib or foretinib, which are currently used in clinical express ER [1, 11, 12] and urothelial carcinoma can be diffusely positive for GCDFP-15  and express nuclear GATA3 [1, trials, in patients with solid tumors. This aspect should be 3]. CD138 can mark the breast lobular carcinoma but its proved in large cohorts. expression is simultaneously seen in tumor and stroma cells . E-cadherin is negative in over 75% of invasive lobular Data Availability carcinoma of the breast, as a result of mutations of the CDH1 gene [13, 14]. Loss of E-cadherin occurs in parallel with The clinicopathological data used to support the findings of decreased𝛽 -catenin expression . GCDFP-15 is commonly this study are available from the corresponding author upon negative in invasive breast lobular carcinoma. Whereas request. HER-2, ER and PR are used as predictive factors, c-MET aberrations (mutations or amplification) are indicators of Conflicts of Interest high-grade invasive breast lobular carcinomas with increased metastatic risk and are commonly identified in triple negative None of the authors have any conifl cts of interest. basal-like cases  that represent below 2% of all invasive lobular carcinomas of the breast . Authors’ Contributions Similar to our study, it was shown that E-cadherin is mostly negative in PUC, as marker of aggressivity and All authors have equally contributed to the paper. activated Wnt pathway [2, 5, 6] but vimentin can be positive or negative . S100, a marker of EMT, was also found Acknowledgments negative in the reported PUCs , as in our cases. PUC shows a predilection for intraperitoneal spread and This work was supported by a grant of the Romanian National carcinomatous ascites [3, 4]. As CA-125, the marker usually Authority for Scientific Research, CNCS–UEFISCDI, project used for diagnosis of ovarian cancer, can rise in the serum number: 20 PCCF/2018, code: PN-III-P4-ID-PCCF-2016- of patients , the differential diagnosis of metastatic carci- noma with plasmacytoid morphology is extremely difficult in females. Similar to colorectal carcinomas, serum CEA References canalso behighinpatients with PUC . CA19-9 and𝛽 - HCG were also reported to be increased . 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