Lymphoepithelioma-like Carcinomas Research Articles

Neoadjuvant immunotherapy in patients with pulmonary lymphoepithelioma-like carcinoma

ObjectivesNeoadjuvant immunotherapy can be used to treat early-stage non-small-cell lung cancer; however, their effects on pulmonary lymphoepithelioma-like carcinomas (LELC) remain unclear. Materials and methodsThirty-nine patients with stages I–III LELC were treated with chemotherapy (Chemo) or neoadjuvant immune-checkpoint inhibitors (ICIs) with or without chemo (IO) before radical-intent surgery. Short-term outcomes included objective response rate (ORR), major pathologic response (MPR), pathologic complete response (PCR), and event-free survival. For comparison, we used IO to treat 63 patients with pulmonary squamous cell carcinomas (SQC) and 47 with adenocarcinomas (ADC). Propensity score matching was analyzed to minimize bias. ResultsORRs of the LELC-IO and LELC-Chemo groups were 62.5% and 42.9%, respectively (odds ratio, 2.2, 95% confidence interval, 0.423–11.678, p = 0.346). Seven (21.9%) and zero patients in LELC-IO and LELC-Chemo groups, respectively, reached PCR. MPR was identified in five (15.6%) of the 32 patients with LELC-IO. The 1-year progression-free survival rates were 96.9% and 71.4% in IO and Chemo groups, respectively (p > 0.05). However, no difference was observed in ORR, PCR, and MPR between LELC and SQC groups (ORR, 63.2% vs. 68.4%, p > 0.05; PCR, 21.1% vs. 47.4, p > 0.05; MPR, 42.1% vs. 57.9%, p > 0.05) and LELC and ADC groups (ORR, 58.8% vs. 41.2%, p > 0.05; PCR, 17.6% vs. 23.5%, p = 0.672; MPR, 29.4% vs. 47.1%, p > 0.05). The plasma Epstein–Barr virus (EBV) DNA level in a patient was altered posttreatment. ConclusionPatients with LELC could be benefit from neoadjuvant immunotherapy. Distinct histological subtypes demonstrated comparable efficacy with respect to neoadjuvant immunotherapy.

Lymphoepithelioma-like hepatocellular carcinoma, case report of a rare indolent subtype of hepatic cancer

Background: Lymphoepithelioma - Like Carcinomas (LELC) of the liver are tumors of poorly differentiated epithelial cells with prominent lymphoid cell infiltration of the stroma. Unlike common primary liver cancers, LELC is a rare subtype of primary liver cancer with notably better prognosis. Unfortunately, available data and understanding of this unique cancer type is limited. Case report: A 72-year-old Hispanic female with compensated cirrhosis due to treatment-naïve hepatitis C and Primary Biliary Cirrhosis (PBC) presented with chronic abdominal pain. Computed Tomography scan (CT) of her abdomen at that time showed nodular liver with a mass measuring 4.6 x 3.7 cm in the right hepatic lobe with heterogeneous enhancement on arterial phase associated with mild venous washout, concerning for Hepatocellular Carcinoma (HCC). She was lost to follow up but re-presented 4 years later with an interval increase in the liver mass to 6.4 x 4.8 cm. Staging work up was unremarkable and patient underwent resection of the mass. Histopathologic examination showed moderately differentiated HCC with massive lymphocytic infiltration within the tumor with lymphocyte outnumbering tumor cells and diagnosed as lymphoepithelial-like carcinoma-HCC. The patient remained asymptomatic with no tumor recurrence at 16 months post resection. Conclusion: This report of an indolent course of untreated EBV positive LELC-hepatocellular carcinoma provides valuable insight about this rare tumor type

Lymphoepithelioma-like carcinoma of the upper urinary tract: A systematic review of case reports.

BACKGROUNDLymphoepithelioma-like carcinomas (LELCs) are rare, malignant epithelial tumors, generally considered a subtype of squamous cell carcinoma. LELCs are undifferentiated and can occur in multiple tissues, although LELCs in the urinary tract are extremely rare. As such, evidence does not provide clinicians with guidelines for the best practices. Even though this is a rare disease, it is associated with high morbidity and mortality. Therefore, we must learn to differentiate LELC types and identify risk factors for early identification.AIMTo develop an evidence base to guide clinicians treating primary LELCs of the upper urinary tract (UUT-LELC).METHODSWe performed a systematic review of all reports on UUT-LELC from the first published case in 1998 until October 2019, according to the PRISMA. A database was then developed by extracting data from previously published reports in order to analyze interactions between clinical characteristics, pathological features, interventions and outcomes. Survival was analyzed using Kaplan–Meier estimates, which were compared using log rank tests.RESULTSA total of 28 previously published cases were identified for inclusion. The median age was 72 years with a male to female ratio of 4:3. Pure type LELCs were most common with 48.3% (n = 14), followed by 37.9% (n = 11) predominant LELCs and 3.4% (n = 1) focal LELCs. Epstein-Barr virus testing was negative in all cases. Fourteen patients received radical nephroureterectomy (RNU)-based intervention. Twenty-three patients survived with no evidence of further metastasis, although six died before the median 18 mo follow-up point. Survival analysis suggests pure histological subtypes, and patients who receive complete tumor resection have more favorable prognoses. As always in cancer care, early identification generally increases the probability of interventional success.CONCLUSIONThe most effective treatment for UUT-LELC is RNU-based therapy. Since cases are few in number, case reporting must be enhanced and publishing encouraged to both save and prolong lives.

Epstein-Barr Virus-Induced Epigenetic Pathogenesis of Viral-Associated Lymphoepithelioma-Like Carcinomas and Natural Killer/T-Cell Lymphomas.

Cancer genome studies of Epstein-Barr virus (EBV)-associated tumors, including lymphoepithelioma-like carcinomas (LELC) of nasopharyngeal (NPC), gastric (EBVaGC) and lung tissues, and natural killer (NK)/T-cell lymphoma (NKTCL), reveal a unique feature of genomic alterations with fewer gene mutations detected than other common cancers. It is known now that epigenetic alterations play a critical role in the pathogenesis of EBV-associated tumors. As an oncogenic virus, EBV establishes its latent and lytic infections in B-lymphoid and epithelial cells, utilizing hijacked cellular epigenetic machinery. EBV-encoded oncoproteins modulate cellular epigenetic machinery to reprogram viral and host epigenomes, especially in the early stage of infection, using host epigenetic regulators. The genome-wide epigenetic alterations further inactivate a series of tumor suppressor genes (TSG) and disrupt key cellular signaling pathways, contributing to EBV-associated cancer initiation and progression. Profiling of genome-wide CpG methylation changes (CpG methylome) have revealed a unique epigenotype of global high-grade methylation of TSGs in EBV-associated tumors. Here, we have summarized recent advances of epigenetic alterations in EBV-associated tumors (LELCs and NKTCL), highlighting the importance of epigenetic etiology in EBV-associated tumorigenesis. Epigenetic study of these EBV-associated tumors will discover valuable biomarkers for their early detection and prognosis prediction, and also develop effective epigenetic therapeutics for these cancers.

Medullary Carcinoma of the Penis: A Distinctive HPV-related Neoplasm: A Report of 12 Cases.

A third to half of penile invasive squamous cell carcinomas are human papillomavirus (HPV) related. Warty (condylomatous), warty-basaloid, and basaloid carcinomas are the most common subtypes associated with HPV. Less frequent are clear cell and lymphoepithelioma-like carcinomas. Here we report a novel penile tumor associated with HPV. Twelve cases were selected from 1010 penile carcinomas, part of an international HPV detection study conducted at the Institut Català d'Oncologia, Barcelona, Spain. Immunostaining with p16 was performed on all cases, and HPV-mRNA detection was also performed. En bloc full tumor staining was the utilized criteria for positivity of p16. For HPV-DNA detection, whole-tissue section polymerase chain reaction analysis was performed by SPF10-DEIA-LiPA25 (version 1). The patients' ages ranged from 42 to 92 years (average, 71 y). The tumor was most commonly located in the glans. A characteristic microscopic finding was the presence of a moderate to dense tumor-associated inflammatory cell infiltrate composed of neutrophils, lymphocytes, plasma cells, or eosinophils. Tumors grew in large solid sheets, nests, or had a trabecular pattern. Cells were large and poorly differentiated or anaplastic. Keratinization was minimal or absent. Nuclei were large with prominent nucleoli. Mitoses were numerous. Tumor necrosis was common. Deep invasion of the corpora cavernosa was frequent. p16 and HPV-DNA were positive in all cases, whereas mRNA detection was positive in 9 cases only. The prevalent genotype was HPV16 (9 cases, 75%). Other genotypes were HPVs 58, 33, and 66. Medullary carcinomas of the penis are morphologically distinctive HPV-related high-grade neoplasms affecting older individuals. More studies are necessary to delineate the epidemiological, clinical, and molecular features of this unusual penile neoplasm.

Berberine inhibits the proliferation of human nasopharyngeal carcinoma cells via an Epstein-Barr virus nuclear antigen1-dependent mechanism.

Nasopharyngeal carcinoma(NPC) is a malignancy derived from the epithelial cells of the nasopharynx cavity, and is closely associated with Epstein-Barr virus(EBV) infection. In addition to NPC, EBV causes various human malignancies, such as gastric cancer, hematological tumors and lymphoepithelioma-like carcinomas. Epstein-Barr nuclear antigen1(EBNA1) encoded by EBV is indispensable for replication, partition, transcription and maintenance of viral genomes. Berberine, a naturally occurring isoquinoline alkaloid, shows anti-inflammatory, anticholinergic, antioxidative, and anticancer activities. In the present study, the antitumor effect of berberine was studied. Cell Counting Kit-8(CCK-8) assays were performed to demonstrate whether the proliferation of EBV-positive NPC cells was inhibited by berberine. Flow cytometric results revealed that berberine induced cellcycle arrest and apoptosis. Quantitative-PCR and western blotting results indicated that berberine decreased the expression of EBNA1 at both the mRNA and protein levels in the EBV-positive NPC cells. The function of EBNA1 promoter Qp which is to drive EBNA1 transcription in typeⅡ latent infection was strongly suppressed by berberine. Overexpression of EBNA1 attenuated this inhibitory effect. Berberine also suppressed the activity of signal transducer and activator of transcription3 which is a new therapeutic target in a series of malignancies, including NPC. Viral titer experiments demonstrated that berberine decreased the production of virions in HONE1 and HK1-EBV cells. In a mouse xenograft model of NPC induced by HONE1 cells, berberine significantly inhibited tumor formation. Altogether, these results indicate that berberine decreases the expression of EBNA1 and exhibits an antitumor effect against NPC both invitro and invivo.

Specific types of bladder cancer

Bladder cancer shows rare variants and special subtypes with diverse prognostic importance and therefore may necessitate different therapeutic approaches. For pathologists it is important to histologically diagnose and specify such variants. Nested variants of urothelial carcinoma with inconspicuous, well-formed tumor cell nests present with an aggressive course. The plasmacytoid variant, which morphologically resembles plasma cells is associated with a shorter survival time and a high frequency of peritoneal metastasis. Micropapillary urothelial carcinoma with small papillary tumor cell islands within artificial tissue retraction spaces and frequent lymphovascular invasion also has a poor prognosis. Other important rare differential variants listed in the World Health Organization (WHO) classification are microcystic, lymphoepithelioma-like, sarcomatoid, giant cell and undifferentiated urothelial carcinomas. Additionally, there are three special types of bladder cancer: squamous cell carcinoma, adenocarcinoma and small cell neuroendocrine carcinoma of the bladder. These tumors are characterized by pure squamous cell or glandular differentiation and are sometimes less responsive to adjuvant (chemo)therapy. Small cell carcinoma of the bladder mimics the neuroendocrine features of its pulmonary counterpart, shows an aggressive course but is sensitive to (neo-)adjuvant chemotherapy. The morphology and histology of the most important variants and special types are discussed in this review.

Lymphoepithelioma-Like Hepatocellular Carcinoma: Report of Three Cases and Review of Literature

Lymphoepithelioma-like carcinomas (LELCs) are carcinomas which show histologic similarities to lymphoepithelioma (AKA nasopharyngeal carcinoma) and prominently feature a lymphoid-rich stroma with tumor-infiltrating lymphocytes. LELCs have been described in a number of different organ systems, are often associated with Epstein-Barr virus (EBV) infection, and have been reported to carry favorable prognoses when compared to classic carcinomas of these organ systems. LELCs of the liver are exceedingly rare. Here, we report three cases of lymphoepithelioma-like hepatocellular carcinoma (HCC) in one female and two male patients. All three carcinomas were composed of a population of malignant cells with focal to diffuse positivity for HepPar-1, as well as a prominent lymphoplasmacytic infiltrate intimately associated with the malignant cells. In two cases investigated by immunohistochemistry, the lymphoid population contained a prominent CD3 + T-cell population which consisted of CD4 + lymphocytes and CD8 + cytotoxic T cells, which also showed staining for T-cell intracellular antigen-1 (TIA-1). Chromogenic in situ hybridization for EBV-encoded RNA (EBER CISH) was negative in both the malignant cells and the lymphoid population in all three cases. Two patients who underwent surgical resection are alive without recurrence at 38 and 26 months after surgery. The third patient treated by chemoembolization died 31 months after the diagnosis. J Med Cases. 2015;6(7):297-303 doi: http://dx.doi.org/10.14740/jmc2106w

FDG PET/CT in Primary Pulmonary Lymphoepithelioma-like Carcinoma

Primary pulmonary lymphoepithelioma-like carcinomas are extremely rare tumors with better prognosis than other types of non-small cell lung cancer. An 83-year-old man presented with cough and hemoptysis for 2 weeks. Chest CT images showed a cylinder-shaped lesion in the right upper lung. F-FDG PET/CT showed strong FDG uptake (SUVmax, 34.5) of the tumor with ipsilateral hilar lymph node metastases. Video-assisted thoracoscopic lobectomy was performed. Histopathologically, the tumor was composed of epithelial tumor cells with high proliferation index (80%) and abundant lymphoplasmacytic cells, consistent with lymphoepithelioma-like carcinoma.

Lymphoepithelioma-Like Hepatocellular Carcinoma: Report of Three Cases and Review of Literature

Lymphoepithelioma-like carcinomas (LELCs) are carcinomas which show histologic similarities to lymphoepithelioma (AKA nasopharyngeal carcinoma) and prominently feature a lymphoid-rich stroma with tumor-infiltrating lymphocytes. LELCs have been described in a number of different organ systems, are often associated with Epstein-Barr virus (EBV) infection, and have been reported to carry favorable prognoses when compared to classic carcinomas of these organ systems. LELCs of the liver are exceedingly rare. Here, we report three cases of lymphoepithelioma-like hepatocellular carcinoma (HCC) in one female and two male patients. All three carcinomas were composed of a population of malignant cells with focal to diffuse positivity for HepPar-1, as well as a prominent lymphoplasmacytic infiltrate intimately associated with the malignant cells. In two cases investigated by immunohistochemistry, the lymphoid population contained a prominent CD3 + T-cell population which consisted of CD4 + lymphocytes and CD8 + cytotoxic T cells, which also showed staining for T-cell intracellular antigen-1 (TIA-1). Chromogenic in situ hybridization for EBV-encoded RNA (EBER CISH) was negative in both the malignant cells and the lymphoid population in all three cases. Two patients who underwent surgical resection are alive without recurrence at 38 and 26 months after surgery. The third patient treated by chemoembolization died 31 months after the diagnosis. J Med Cases. 2015;6(7):297-303 doi: http://dx.doi.org/10.14740/jmc2106w

Lymphoepithelioma-Like Carcinoma of Parapharyngeal Space—A Case Report with Review of Literature

Extra-nasopharyngeal lymphoepithelioma-like carcinomas (LELC) are uncommon epithelial tumors. A few isolated case reports and series are available in literature involving the larynx, pharynx, salivary gland, lung etc., but involvement in the parapharyngeal space has not yet been reported. We aim to highlight one such case that has a clinical and radiological characteristic of a benign lesion whilst the histopathology reveals an infiltrating neoplasm. The typical clinical aggressiveness of a classical LELC of extra-nasopharyngeal lesion as described in literature is not present in our case. Also seen is an uncommon finding of abnormal branching of left external carotid artery. There is no standard treatment protocol for such a tumor; however, wide excision of this tumor in the parapharyngeal space via trans-cervical, trans-mandibular, trans-palatal approach has shown good and satisfactory tumor control of the primary site so far.

Lessons from rare tumors: hepatic lymphoepithelioma-like carcinomas.

In this review we focus on lymphoepithelioma-like hepatocellular carcinomas (LEL-HCC) and lymphoepithelioma-like cholangiocarcinomas (LEL-ICC). Despite their rarity, these tumors are of general interest because of their epidemiological and clinical features, and because they represent a distinct model of interaction between the immune system and neoplastic cells. Approximately half of LEL-HCC arise in the context of chronic hepatitis C virus (HCV) infection and have been described both in Eastern and Western patients. By contrast, LEL-ICC is associated in almost all cases with Epstein-Barr virus (EBV) infection and exhibits the same epidemiological features of EBV related malignancies. Compared with classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma of corresponding stage, both LEL-HCC and LEL-ICC are characterized by lower rates of recurrence after surgery and better overall survival. How this behavior is related to distinct genetic alterations and tumor microenvironment is unclear. The pathophysiological mechanisms of lymphoid infiltrations seem to be different among the two groups of tumors. In fact, LEL-HCC frequently arises in the context of inflammatory changes driven by HCV infection, and has been recognized as a variant of classical hepatocellular carcinoma. At variance, lymphocyte recruitment of LEL-ICC is similar to that described in nasopharyngeal carcinoma and gastric LEL, and possibly depends on the expression pattern of latent EBV infection.

Impact of histological variants on the outcomes of nonmuscle invasive bladder cancer after transurethral resection.

The scoring system used after transurethral resection of the bladder (TURB) to guide clinical decision-making regarding nonmuscle invasive bladder cancer (NMIBC) largely assumes that NMIBCs are pure urothelial carcinomas and does not take into account the role of variant histology. This review outlines pathological and clinical characteristics of major histological variants to determine their potential impact in therapeutic strategies for the management of NMIBC. Assessing the presence of histological variants in NMIBCs after TURB currently remains challenging because of limited tissue sample sizes. However, the presence of these variants often indicates poor prognosis with increased risk for recurrence and progression. Among them, only the following histological variants are indications for Bacillus Calmette-Guerin intravesical instillations: squamous or glandular differentiations and deceptively benign or lymphoepithelioma-like carcinomas. However, patients diagnosed with any other variants should be promptly considered for early radical cystectomy, and only those with small cell carcinoma might benefit from neoadjuvant chemotherapy with a neuroendocrine-specific regimen. Based on the available literature (e.g., small case studies and retrospective studies), the existence of histological variants after TURB appears to massively impact NMIBC outcomes.

Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up

Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up

Considerations on the Link Between Merkel Cell Polyomavirus And Lung Cancer

Smoking is well known to be a predominant risk factor for the development of lung cancer, but lung cancers occurring in never smokers has increased in recent times [1]. It is also shown that the increase in the incidence of lung cancer in never smokers is higher in east Asia than the US or European countries [1]. These findings suggest that factors other than smoking may be etiological and risk factors for lung cancer. Some environmental agents, such as radon, asbestos and cooking fumes, have also been implicated in its development [1,2]. However, to date, a large fraction of lung cancers have not been definitively associated with such environmental risk factors, highlighting the need for a dditional epidemiological research. Infectious agents including oncogenic viruses have been proposed to be associated with the pathogenesis of lung cancer. Many studies suggest that human papillomavirus (HPV) is detectable in cases of lung cancer worldwide [3]. However, the prevalence rate of HPV infection in patients with lung cancer varies across different countries. A higher incidence of HPV in lung cancers has been reported in Asian cohorts [4]. Another human tumor virus, Epstein–Barr virus, is found in lung cancers, especially in lymphoepithelioma-like carcinomas, predominantly in Asian patients [5]. Recently, the presence of murine mammary tumor virus-like sequence was identified in 18% of the lung cancer from Mexican patients [6]. Thus, the prevalence of viral infections in lung cancers appears to depend on geographic location. In 2008, a new human tumor virus, designated Merkel cell polyomavirus (MCPyV), was reported in Merkel cell carcinoma (MCC), a neuroendocrine carcinoma of the skin [7]. Although the route of MCPyV transmission has not been established, MCPyV genome is detected in lower respiratory tract secretions [8]. It is conceivable that long-standing exposure of the respiratory tract to this oncogenic virus may lead to development of cancer in this region.

Epstein-Barr virus-associated lymphoepithelioma-like early gastric carcinomas and endoscopic submucosal dissection: Case series

Epstein-Barr virus (EBV)-associated lymphoepithelioma-like gastric carcinoma (LELC) is characterized by a lower lymph node (LN) metastasis rate and a higher survival rate than other forms of gastric cancer. Although current prognosis for LELC is favorable, the most common approach is radical gastrectomy involving an extensive D2 lymph node dissection. Here, we report four cases of EBV-associated early LELC that were treated by an alternative approach, endoscopic submucosal dissection (ESD). The long-term outcome of this procedure is discussed. All patients were treated by ESD en bloc, and all ESD specimens showed tumor-free lateral resection margins. None of the lesions showed lymphovascular invasion. A pathological examination of ESD specimens revealed submucosal invasion of more than 500 μm in all four cases. One patient underwent additional radical surgery post-ESD; no residual tumor or LN metastasis was noted in the surgical specimen. The other three patients did not undergo additional surgery, either because of severe comorbidity or their refusal to undergo operation, but were subjected to medical follow-up. None of the ESD-treated patients reported local recurrence or distant metastases during the 27-32 mo of follow-up after ESD.

Large cell carcinoma of the lung: clinically oriented classification integrating immunohistochemistry and molecular biology

This study aimed at challenging pulmonary large cell carcinoma (LLC) as tumor entity and defining different subgroups according to immunohistochemical and molecular features. Expression of markers specific for glandular (TTF-1, napsin A, cytokeratin 7), squamous cell (p40, p63, cytokeratins 5/6, desmocollin-3), and neuroendocrine (chromogranin, synaptophysin, CD56) differentiation was studied in 121 LCC across their entire histological spectrum also using direct sequencing for epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and FISH analysis for ALK gene translocation. Survival was not investigated. All 47 large cell neuroendocrine carcinomas demonstrated a true neuroendocrine cell lineage, whereas all 24 basaloid and both 2 lymphoepithelioma-like carcinomas showed squamous cell markers. Eighteen out of 22 clear cell carcinomas had glandular differentiation, with KRAS mutations being present in 39 % of cases, whereas squamous cell differentiation was present in four cases. Eighteen out of 20 large cell carcinomas, not otherwise specified, had glandular differentiation upon immunohistochemistry, with an exon 21 L858R EGFR mutation in one (5 %) tumor, an exon 2 KRAS mutation in eight (40 %) tumors, and an ALK translocation in one (5 %) tumor, whereas two tumors positive for CK7 and CK5/6 and negative for all other markers were considered adenocarcinoma. All six LCC of rhabdoid type expressed TTF-1 and/or CK7, three of which also harbored KRAS mutations. When positive and negative immunohistochemical staining for these markers was combined, three subsets of LCC emerged exhibiting glandular, squamous, and neuroendocrine differentiation. Molecular alterations were restricted to tumors classified as adenocarcinoma. Stratifying LCC into specific categories using immunohistochemistry and molecular analysis may significantly impact on the choice of therapy.

Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

To investigate human epidermal growth factor receptor 2 (HER2)-phosphatidylinositol 3-kinase (PI3K)-v-Akt murine thymoma viral oncogene homolog signaling pathway. We analyzed 231 formalin-fixed, paraffin-embedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment. The patients' age, sex, tumor location, depth of invasion, pathological type, lymph node metastasis, and pathological stage were determined by a review of the medical records. Expression of HER2 was analyzed by immunohistochemistry (IHC) using the HercepTest(TM) kit. Standard criteria for HER2 positivity (0, 1+, 2+, and 3+) were used. Tumors that scored 3+ were considered HER2-positive. Expression of phospho Akt (pAkt) was also analyzed by IHC. Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more. PI3K, catalytic, alpha polypeptide (PIK3CA) mutations in exons 1, 9 and 20 were analyzed by pyrosequencing. Epstein-Barr virus (EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA (EBER) with an EBER-RNA probe. Microsatellite instability (MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26. HER2 expression levels of 0, 1+, 2+ and 3+ were found in 167 (72%), 32 (14%), 12 (5%) and 20 (8.7%) samples, respectively. HER2 overexpression (IHC 3+) significantly correlated with intestinal histological type (15/20 vs 98 /205, P = 0.05). PIK3CA mutations were present in 20 cases (8.7%) and significantly correlated with MSI (10/20 vs 9/211, P < 0.01). The mutation frequency was high (21%) in T4 cancers and very low (6%) in T2 cancers. Mutations in exons 1, 9 and 20 were detected in 5 (2%), 9 (4%) and 7 (3%) cases, respectively. Two new types of PIK3CA mutation, R88Q and R108H, were found in exon1. All PIK3CA mutations were heterozygous missense single-base substitutions, the most common being H1047R (6/20, 30%) in exon20. Eighteen cancers (8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type (13/18 vs 93/198, P = 0.04). There were 7 cases of lymphoepithelioma-like carcinomas (LELC) and 6 of those cases were EBV-positive (percent/EBV: 6/18, 33%; percent/all LELC: 6/7, 86%). pAkt expression was positive in 119 (53%) cases but showed no correlation with clinicopathological characteristics. pAkt expression was significantly correlated with HER2 overexpression (16/20 vs 103/211, P < 0.01) but not with PIK3CA mutations (12/20 vs 107/211, P = 0.37) or EBV infection (8/18 vs 103/211, P = 0.69). The frequency of pAkt expression was higher in cancers with exon20 mutations (100%) than in those with exon1 (40%) or exon9 (56%) mutations. One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection. However, no cases showed both PIK3CA mutations and HER2 overexpression. One EBV-positive cancer with PIK3CA mutation (H1047R) was MSI-positive. Three of these 4 cases were positive for pAkt expression. In survival analysis, pAkt expression significantly correlated with a poor prognosis (hazard ratio 1.75; 95%CI: 1.12-2.80, P = 0.02). HER2 expression, PIK3CA mutations and EBV infection in gastric cancer were characterized. pAkt expression significantly correlates with HER2 expression and with a poor prognosis.

Cytological features of lung adenocarcinoma with massive lymphocyte infiltration

Adenocarcinoma with massive lymphocyte infiltration is a rare pulmonary neoplasm with few reported cases. It seems to have a better outcome than conventional adenocarcinomas, but it is still not clear if it constitutes a specific clinicopathological entity. We report a case in which cytological studies were available. The small size of the tumor, abundant lymphocyte population, well-differentiated morphology of the neoplasm and scarcity of atypical cells resulted in a difficult cytological diagnosis. This entity should be considered when evaluating pulmonary lesions with abundant lymphocytes. Not all carcinomas with prominent lymphoid stroma show the high-grade, pleomorphic morphology of lymphoepithelioma-like carcinomas.

Histological variants of prostatic carcinoma and their significance

The vast majority of prostatic cancers are acinar adenocarcinomas. Histological variants of prostatic carcinoma have been variably defined. One approach is to consider two groups of variants. The first group comprises histological variants of acinar adenocarcinoma and the second group non-acinar carcinoma variants or types. Variants of usual acinar adenocarcinoma defined in 2004 by the World Health Organization (WHO) include atrophic, pseudohyperplastic, foamy, colloid, signet ring, oncocytic and lymphoepithelioma-like carcinomas. The second group of non-acinar carcinoma histological variants or types of prostatic carcinoma accounts for about 5-10% of carcinomas that originate in the prostate. These include sarcomatoid carcinoma, ductal adenocarcinoma, urothelial carcinoma, squamous and adenosquamous carcinoma, basal cell carcinoma, and neuroendocrine tumours, specifically small-cell carcinoma. Recently characterized variants not present in the 2004 WHO classification, including microcystic adenocarcinoma, prostatic intraepithelial neoplasia-like adenocarcinoma, large-cell neuroendocrine carcinoma, and pleomorphic giant cell carcinoma, are also described. The aims of this review are to present the essential histomorphological diagnostic attributes of these variants, and to emphasize the clinical signficance of the variants, when different from usual acinar adenocarcinoma, including clinical presentation and outcome.