Endobronchial spread of adenocarcinoma is a distinct pattern of invasion and associated with inferior clinical outcomes in lung adenocarcinoma.

AIM: The spread of lung adenocarcinoma cells into the bronchi and bronchioles is not well documented. We termed this histological finding "endobronchial spreading of adenocarcinoma" (EBSA) and investigated its prevalence and clinical significance. METHODS AND RESULTS: We reviewed 320 resected specimens from patients diagnosed with invasive adenocarcinoma, and EBSA was observed in 144 patients (45%). EBSA was significantly associated with advanced pathological stage, higher histological grade, larger tumour invasion, lymphovascular infiltration, and spread through air spaces. Patients with EBSA had significantly shorter relapse-free survival (RFS) and cancer-specific survival (CSS) in univariate analysis (P < 0.001). In a subgroup analysis of patient with small-sized (invasion size ≤30 mm) adenocarcinoma in the localized stage, EBSA was an independent inferior prognostic indicator in multivariate analysis. In a subgroup analysis of patients with small-sized Grade 1 nonmucinous adenocarcinoma (n = 61), EBSA was observed in 11 patients, and the presence of EBSA was associated with significantly shorter RFS and CSS (P = 0.026 and P = 0.001, respectively). CONCLUSION: Our results demonstrated that EBSA is a significant risk factor for disease recurrence and cancer-related deaths. EBSA can be regarded as a distinctive pattern of invasion and its recognition can be beneficial in the diagnosis of lung adenocarcinoma.

PTEN loss in intraductal carcinoma of the prostate has low incidence in Japanese patients.

Clinical and genomic features of prostate cancer (PCa) vary considerably between Asian and Western populations. PTEN loss is the most frequent abnormality in intraductal carcinoma of the prostate (IDC-P) in Western populations. However, its prevalence and significance in Asian populations have not yet been well studied. In the present study, we evaluated PTEN expression in IDC-P in a Japanese population and its association with ERG expression. This study included 45 and 59 patients with PCa with and without IDC-P, respectively, who underwent radical prostatectomy. PTEN loss was observed in 10 patients with PCa with IDC-P (22%) and nine patients with PCa without IDC-P (17%). ERG expression was relatively frequent in patients with PCa with PTEN loss, although a significant difference was not observed. The co-occurrence of PTEN loss and ERG expression was observed in four patients with PCa with IDC-P and one without IDC-P. PTEN loss and ERG expression did not affect progression-free survival, regardless of the presence of IDC-P. The frequency of PTEN loss in IDC-P is lower in Asian patients than in Western patients. Our results indicate that mechanisms underlying IDC-P in Asian populations are different from those of Western populations.

Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS.

Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copynumber aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.

Histiocytic and dendritic cell neoplasms: Reappraisal of a Japanese series based on t(14;18) and neoplastic PD-L1 expression.

Histiocytic and dendritic cell (H/DC) neoplasms are heterogeneous, originating from myeloid- or stromal-derived cells. Multiple reports describe the cross-lineage transdifferentiation of neoplastic B cells into H/DC neoplasms. Most such cases are from Western countries, and rarely from Japan or East Asia. Here we report 17 cases of H/DC neoplasms in Japanese patients, with analysis of t(14;18) by fluorescence in situ hybridization, and of neoplastic programmed death-ligand 1 (PD-L1) expression by immunostaining (clones SP142, E1J2J, and 28-8). These 17 cases were diagnosed according to the 2017 World Health Organization (WHO) classification, and included two histiocytic sarcomas (HS), two interdigitating cell (IDC) sarcomas, one Langerhans cell sarcoma, two dendritic cell sarcomas, and 10 follicular dendritic cell (FDC) sarcomas. No case had any past history of follicular lymphoma (FL). Two cases of HS and one IDC sarcoma, all of which were myeloid-driven, were found to exhibit t(14;18). In the latter case, at 30 months after IDC sarcoma diagnosis, FL development was detected. Three (30%) FDC sarcoma cases exhibited neoplastic PD-L1 expression with all the three PD-L1 antibody clones. This is the first report of t(14;18) and neoplastic PD-L1 expression on H/DC neoplasms among Japanese patients, each of which appeared to be associated with HS and FDC sarcoma, respectively.

Enhanced PD-L1 expression on tumor cells in primary cutaneous large T-cell lymphoma with CD30 expression as classic Hodgkin lymphoma mimics: A report of lymph node lesions of two cases.

Neoplastic PD-L1 (nPD-L1, clone SP142) expression remains unclear in cutaneous T-cell lymphoma (CTCL), although it is well-documented in classic Hodgkin lymphoma (CHL). Here, we report two cases of primary cutaneous large T-cell lymphoma (PCLTCL) with CD30 expression that developed secondary nodal lesions morphologically mimicking CHL, and describe their PD-L1 expression. Our two cases (52- and 60-year-old males) had long-standing clinical courses of CTCL. Their PCLTCL with CD30 expression developed nodal lesions, having a nodular growth pattern containing scattered CD30+ Hodgkin and Reed-Sternberg-like and/or lacunar cells that expressed CD15 but did not harbor Epstein-Barr virus. Their differential diagnosis from CHL was challenging. A diagnosis of PCLTCL with secondary nodal involvement featuring CHL mimicry was based on comparison of the primary and secondary lesions. In one case, shared expression of the same T-cell antigen was revealed by immunohistochemistry, and in the other, identical clonal TCR rearrangement was demonstrated by polymerase chain reaction (PCR). Interestingly, nPD-L1 was expressed on more than 50% of the tumor cells in the secondary nodal lesions, but on very few in the primary cutaneous lesions, in both cases. This is the first report of nPD-L1 expression greatly increasing with PCLTCL tumor progression to nodal involvement.

Age-related EBV-associated B-cell lymphoproliferative disorders and other EBV + lymphoproliferative diseases: New insights into immune escape and immunodeficiency through staining with anti-PD-L1 antibody clone SP142.

Epstein-Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age-related EBV-associated B-cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency-associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B-cells often have a Hodgkin/Reed-Sternberg (HRS)-like appearance and are shared beyond the diagnostic categories of mature B-cell neoplasms, mature T-cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency-associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD-L1). Assessing PD-L1 positivity by staining with the anti-PD-L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B-cells harboring EBV.

Diagnostic utility of programmed cell death ligand 1 (clone SP142) in mediastinal composite lymphoma: A report of two cases.

Composite lymphoma is a well-known diagnostic entity exhibiting the synchronous occurrence of two or more distinct types of lymphomas in the same specimen. Here we report two patients, a 14-year-old female (Case 1) and a 45-year-old male (Case 2), with mediastinal composite lymphoma, comprising nodular sclerosis classic Hodgkin lymphoma (NSCHL) and primary mediastinal large B-cell lymphoma (PMBL). Both patients had a mediastinal mass, and manifested two different histologic components in the same biopsy, one characteristic of NSCHL and the other PMBL. The NSCHL areas included Hodgkin and Reed-Sternberg (HRS) cells with typical immunophenotypic features (CD30-positive and CD20-negative), whereas the sheets of large tumor cells characteristic of PMBL were strongly and uniformly CD20-positive. Interestingly, although both cases showed neoplastic PD-L1 (nPD-L1) positivity on the HRS cells of NSCHL, they differed regarding nPD-L1 expression on the PMBL tumor cells. In Case 1, the nPD-L1-negative PMBL component was anatomically situated outside the NSCHL lesion. On the other hand, in Case 2, the nPD-L1-positive PMBL component was characterized by transitional or continuous areas with the NSCHL component. These findings suggested that nPD-L1 expression may define two subtypes of PMBL that are more similar to or distinct from classic Hodgkin lymphoma.

Syncytial variant of classic Hodgkin lymphoma: Four cases diagnosed with the aid of CD274/programmed cell death ligand 1 immunohistochemistry.

Although several reports have highlighted neoplastic PD-L1 (nPD-L1) expression in classic Hodgkin lymphoma (CHL), some have addressed associations between its expression and detailed histopathologic features. Here we describe four cases of syncytial variant of CHL (SV-CHL), with and without Epstein-Barr virus (EBV) association, and highlight the diagnostic utility of PD-L1 (clone SP142) immunohistochemistry. The patients were a 61-year-old male, 45-year-old male, 85-year-old female, and 89-year-old female. All presented with cervical or axillary lymphadenopathy, which on biopsy had the established histopathologic features of SV-CHL with a biphasic pattern of cohesive sheets of large tumor cells and typically scattered distribution of Hodgkin and Reed-Stenberg (HRS) cells. These tumor cells showed identical immunophenotypic findings for CD15, CD30, Fascin, PAX5, OCT2, BOB1 and EBV harboring, regardless of location. The exception was absent or decreased expression of nPD-L1 from tumor cells in the confluent sheets, contrasting with HRS cell positivity in typical areas of CHL. These findings offer the first suggestion of possible downregulation of nPD-L1 expression in association with the histopathologic progression of CHL. The results may be relevant for recognizing 'confluent' sheets in the diagnostic workup for SV-CHL.

EBV-positive mucocutaneous ulcer arising in rheumatoid arthritis patients treated with methotrexate: Single center series of nine cases.

Methotrexate (MTX) is currently used as first-line anchor drug for rheumatoid arthritis (RA). Therefore, the number of MTX-associated lymphoproliferative disorders, including Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU), has increased. Some aspects of MTX-associated EBVMCU (MTX-EBVMCU), particularly clinical behavior and treatment for RA after MTX cessation, have not been well described. Herein, we report nine cases of MTX-EBVMCU with clinical information regarding RA. Seven of nine patients showed spontaneous regression (SR) after immunosuppressive (IS) cessation. The other two required cytotoxic chemotherapy. Eventually, all achieved complete remission. No patients experienced EBVMCU relapse. Eight patients had RA flare after IS cessation. To control the RA activity, rituximab was administered to three patients. The remaining patients were treated by other agents. Regarding the RA activity, all were in the status of low disease activity or clinical remission. In conclusion, MTX-associated EBVMCU has an indolent clinical course and SR after IS cessation can be expected. After the withdrawal of MTX, the majority of patients experience RA flare and required treatment. In our series, RA was well controlled without reinitiating MTX. Therefore, to prevent the EBVMCU relapse, it might be advisable to avoid MTX reintroduction, and rituximab might be the more preferable agent for RA treatment.

Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes.

The molecular biology of primary nodal T- and NK-cell lymphoma and its relationship with extranodal NK/T-cell lymphoma, nasal type is poorly understood. In this study, we assessed the relationship between nodal and extranodal Epstein-Barr virus-positive T/NK-cell lymphomas using gene expression profiling and copy number aberration analyses. We performed gene expression profiling and copy number aberration analysis on 66 cases of Epstein-Barr virus-associated T/NK-cell lymphoma from nodal and extranodal sites, and correlated the molecular signatures with clinicopathological features. Three distinct molecular clusters were identified with one enriched for nodal presentation and loss of 14q11.2 (TCRA loci). T/NK-cell lymphomas with a nodal presentation (nodal-group) were significantly associated with older age, lack of nasal involvement, and T-cell lineage compared to those with an extranodal presentation (extranodal-group). On multivariate analysis, nodal presentation was an independent factor associated with short survival. Comparing the molecular signatures of the nodal and extranodal groups it was seen that the former was characterized by upregulation of PD-L1 and T-cell-related genes, including CD2 and CD8, and downregulation of CD56, consistent with the CD8+/CD56-immunophenotype. PD-L1 and CD2 protein expression levels were validated using multiplexed immunofluorescence. Interestingly, nodal group lymphomas were associated with 14q11.2 loss which correlated with loss of TCR loci and T-cell origin. Overall, our results suggest that T/NK-cell lymphoma with nodal presentation is distinct and deserves to be classified separately from T/NK-cell lymphoma with extranodal presentation. Upregulation of PD-L1 indicates that it may be possible to use anti-PD1 immunotherapy in this distinctive entity. In addition, loss of 14q11.2 may be a potentially useful diagnostic marker of T-cell lineage.

Case of primary central nervous system histiocytic sarcoma with prominent proliferation of histiocytic cells between the trabeculae of reactive glial cells.

Histiocytic sarcoma (HS) is an extremely rare malignant neoplasm that exhibits morphologic and immune-phenotype evidence of histiocytic differentiation. The disease most commonly involves the lymph nodes, gastrointestinal tract, skin, and soft tissue, as well as in the central nervous system (CNS) being relatively rare. Here we report a case of primary CNS HS with unusual histopathological characteristics. A 65-year-old woman presented with CNS HS in the left frontal lobe region, showing two distinct histological patterns. Approximately half of the lesion displayed histological characteristics typical of HS, including diffuse invasion of large round-to-ovoid pleomorphic cells, with mitotic figures (Ki-67 index: 30%) and coagulative necrotic foci. The other half exhibited prominent proliferation of histiocytic cells between the trabeculae of reactive glial cells, with rare mitotic figures (Ki-67 index: < 1%) and no necrotic foci. There were transitions between two morphologies. The HS tumor cells and the histiocytic cells between the trabeculae of reactive glial cells possessed nearly identical histomorphologic and immunophenotypic features, although the HS tumor cells showed a more pronounced degree of cytologic atypia and mitotic activity. To our knowledge, this is the first reported case of HS with prominent proliferation of the histiocytic cells between the trabeculae of reactive glial cells. Here we present the detailed histological, immunohistochemical, and molecular findings. Investigating cases of HS may provide insight into the pathogenesis of this disease.

Immunoglobulin G4-positive staining of orbital lesions in thyroid eye disease: Report of two cases.

We report two cases with immunoglobulin G4 (IgG4)-positive staining of orbital lesions and thyroid eye disease (TED). Case 1 was a 63-year-old male with right upper eyelid swelling due to right lacrimal gland enlargement. Case 2 was a 49-year-old male with bilateral proptosis due to multiple orbital masses. Both the biopsied right lacrimal gland in Case 1 and the orbital masses on both sides in Case 2 showed infiltration of immunoglobulin-G4-positive plasma cells.

Immunoglobulin G4-positive lymphoplasmacytic infiltration in a sarcoidal eyelid mass.

A 62-year-old woman presented with a one month history of a hard, nonmobile subcutaneous mass along the right nasojugal fold. Hematological studies showed elevated serum immunoglobulin G4 levels. Histopathological examination of the biopsy sample disclosed immunoglobulin G4-positive lymphoplasmacytic infiltration with a storiform fibrosis, vein occlusion, and epithelioid granulomas with necrosis. Systemic review corresponded to a sarcoidosis. Without treatment, the eyelid mass did not recur six months after the excisional biopsy.

Clinicopathological analysis of 12 patients with Epstein-Barr virus-positive primary intestinal T/natural killer-cell lymphoma (EBV+ ITNKL).

AIMS: Epstein-Barr virus-positive (EBV+ ) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL. METHODS AND RESULTS: We enrolled 12 patients with EBV+ ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL (PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection (CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression (P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR-γ rearrangement was found in six patients (50%). Interestingly, EBV+ intra-epithelial lymphocytosis was observed in one case with a background of CAEBV. CONCLUSIONS: This study is the first to shed light on the significant heterogeneity of EBV+ ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice.

Orbital myxoma comorbid with acute myelomonocytic leukemia.

We report the first case of orbital myxoma in a 10-year-old girl with a history of acute myelomonocytic leukemia diagnosed at the age of 10 months. She presented with a mass in the right orbit, which was excised completely. There was no recurrence during the 6 months of follow-up.

Steatocystoma simplex of the lacrimal caruncle: a case report.

BACKGROUND: This is the third reported case of a steatocystoma simplex in the lacrimal caruncle. CASE PRESENTATION: A 60-year-old male presented with a history of a slowly progressing mass in the right lacrimal caruncle since several years before his initial visit. At the first examination, a yellowish, relatively smooth surface mass was observed in the right lacrimal caruncle. The caruncular mass was completely removed under local anesthesia. The pathological findings of this mass were consistent with a steatocystoma. At the 6-month follow-up, there was no sign of recurrence or development of the steatocystoma or any other masses. CONCLUSION: Although steatocystoma simplex rarely occurs in the lacrimal caruncle, it needs to be considered as a possible diagnosis for patients with a mass lesion in the caruncle.

Medulloblastoma with epithelioid features in the cerebellar vermis.

A 6-year-old girl was admitted with a mass lesion in the cerebellar vermis. She underwent subtotal tumor resection, and on immunohistopathology the tumor consisted of two different parts: typical medulloblastoma (MB) characteristics and atypical teratoid/rhabdoid tumor (AT/RT) features, despite positive integrase interactor 1 expression. The patient was diagnosed with MB with epithelioid features. Chemoradiation therapy was started because of tumor recurrence at the primary site and dissemination to the spinal cord, as determined on magnetic resonance imaging 2 weeks after surgery. The patient died due to tumor progression 13 months after initial diagnosis, although transient partial remission was achieved.

Case of cholangiocellular carcinoma in a patient with glycogen storage disease type Ia.

Glycogen storage disease (GSD) type Ia is caused by a deficiency in glucose-6-phosphatase. Long-term complications, including renal disease, gout, osteoporosis and pulmonary hypertension, develop in patients with GSD type Ia. In the second or third decade, 22-75% of GSD type Ia patients develop hepatocellular adenoma (HCA). In some of these patients, the HCA evolves into hepatocellular carcinoma. However, little is known about GSD type Ia patients with HCA who develop cholangiocellular carcinoma (CCC). Here, we report for the first time, a patient with GSD type Ia with HCA, in whom intrahepatic CCC was developed.