Objective
In patients with large B‐cell lymphoma (LBCL) according to WHO, the prognostic significance of MYC translocation is still not sufficiently clarified. We therefore aimed to investigate ...whether prognostication could be improved in patients with MYC translocation positive LBCL by additional stratification according to MYC and BCL2 protein expression levels or MYC translocation partner gene as well as concurrent BCL2 and/or BCL6 translocation (DH).
Methods
From an unselected consecutive cohort of >600 patients with LBCL investigated with fluorescent in situ hybridization (FISH), 64 patients were diagnosed with MYC translocation positive LBCL and included in the study. They were further investigated for supplemental translocations with FISH and MYC and BCL2 protein expression with immunohistochemistry (IHC).
Results
MYC expression >75% was associated with both reduced progression‐free survival (PFS) and overall survival (OS) (PFS: HR 6.8 (95% CI 1.5‐31), P = 0.004. OS: HR 4.3 (95% CI 0.9‐21), P = 0.05). Immunoglobulin (IG) MYC translocation partner gene was related to high MYC protein expression (P = 0.047) but was not prognostic for PFS (P = 0.8) or OS (P = 0.6). DH did not confer a worse outcome compared to MYC single hit (SH). These findings were confirmed in a comparable, independent validation cohort of 28 patients with MYC translocation positive LBCL. All patients included in the survival analyses were treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R‐CHOEP (R‐CHOP + etoposide).
Conclusion
These findings suggest that in patients with LBCL stratification by MYC protein expression level significantly improves the prognostic impact associated with MYC translocation.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Lymphomas of the nasal cavity and paranasal sinuses (NPS) are rare. Knowledge on sinonasal B‐cell lymphoma (SNBCL) primarily comes from case series or single‐center studies on small cohorts. We ...sought to determine the subtype distribution, clinical characteristics, disease behavior, and prognosis on a nationwide scale, with an emphasis on prognostic factors for the most common sinonasal lymphoma, primary sinonasal diffuse large B‐cell lymphoma (PSDLBCL). We collated all data from medical records and national databases on patients registered with SNBCL from 1980 through 2018 in the national pathology registry and collected all tissue samples for validation of diagnosis. We included 205 patients and found 10 different subtypes of lymphoma. Diffuse large B‐cell lymphoma (DLBCL) was the predominant subtype (80%). The incidence of SNBCL was 0.14/100,000 person‐years. The five‐year progression‐free survival (PFS) and overall survival rates for PSDLBCL were 50% and 56%, respectively. For PSDLBCL, Rituximab showed a statistically significant effect (Hazard Ratio 0.22, p < 0.001), whereas consolidative radiotherapy combined with immunochemotherapy was of limited value (PFS, p = 0.93). When treatment failure occurred, DLBCL showed a distinct pattern of recurrence/dissemination to the NPS, skin, breast, central nervous system (CNS), and/or testis. Collectively, DLBCL comprised a clear majority of SNBCLs, although nine other subtypes were represented. Data showed that immunochemotherapy increased survival for PSDLBCL and that the addition of radiotherapy did not benefit patients. Furthermore, treatment failure for sinonasal DLBCL showed a possible common pathogenesis with primary extranodal lymphomas of specific locations (e.g., CNS, skin, breast, and testis).
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cryptorchidism, or undescended testis (UDT) occurs in 1%–4% of newborn males and leads to a risk of infertility and testicular malignancy. Recent research suggests that infertility and malignancy in ...UDT may be caused by abnormal development of the neonatal germ cells, or gonocytes, which normally transform into spermatogonial stem cells (SSC) or undergo apoptosis during minipuberty at 2–6 months in humans (2–6 days in mice). We aimed to identify the current knowledge on how UDT is linked to infertility and malignancy.
Here we review the literature from 1995 to the present to assess the possible causes of infertility and malignancy in UDT, from both human studies and animal models.
Both the morphological steps and many of the genes involved in germ cell development are now characterized, but the factors involved in gonocyte transformation and apoptosis in both normal and cryptorchid testes are not fully identified. During minipuberty there is evidence for the hypothalamic–pituitary axis stimulating gonocyte transformation, but without known direct control by LH and androgen, although FSH may have a role. An arrested gonocyte maybe the origin of later malignancy at least in syndromic cryptorchid testes in humans, which is consistent with the recent finding that gonocytes are normally absent in a rodent model of congenital cryptorchidism, where malignancy has not been reported.
The results of this review strengthen the view that malignancy and infertility in men with previous UDT may be caused by abnormalities in germ cell development during minipuberty.
Systematic review (secondary, filtered)
Level I.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We investigated the intratumoral source of PD‐L1 expression and the infiltration of tumor‐associated macrophages (TAMs) in large B‐cell lymphomas (LBCLs) with or without MYC‐translocation, as well as ...possible correlations to BCL2‐and BCL6‐translocations and cell of origin (COO). One‐hundred and twenty‐six patient samples were studied in a cohort enriched for MYC‐translocated tumors with 34 samples carrying this translocation. Demonstration of intratumoral distribution and cellular source of PD‐L1 was enabled by immunohistochemical (IHC) dual staining specifically highlighting PD‐L1 expression in lymphoma B‐cells with antibodies against PD‐L1 and PAX5. Additional IHC with antibodies against CD68 and CD163 identified TAMs. We found that CD68‐positive TAMs were the main source of PD‐L1 protein expression in contrast to lymphoma B cells which rarely expressed PD‐L1. Semiquantitative IHC demonstrated a significant correlation between CD68 and PD‐L1 protein expression. Unsupervised hierarchical analysis of PD‐L1, CD68, and CD163 IHC data subsequently demonstrated three potential clusters defined by expression of the three biomarkers. Cluster A consisted of patient samples with significantly lower expression of PD‐L1, CD68, and CD163, but also significantly higher prevalence of BCL2‐translocation and MYC‐BCL2‐double‐hit (DH) compared to the other two clusters. In cluster C we found a significant accumulation of BCL6 translocated tumors. This cluster in contrast had the highest protein expression of PD‐L1, CD68, and CD163. Cluster B tumors had an intermediate expression of the three biomarkers, but no accumulation of the specific genetic translocations. Our data, which were based on morphological analysis, immunophenotyping and genotyping by fluorescence in situ hybridization were in line with new concepts of LBCL taxonomy integrating genetic, phenotypical, and immunological characteristics with identification of new subgroups where MYC translocation and MYC‐BCL2 DH may identify a noninflamed subtype. These findings may furthermore hold significant predictive value especially regarding immune checkpoint blockade therapy, but further molecular characterization should be done to substantiate this hypothesis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In large B‐cell lymphoma (LBCL), MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) are associated with poor prognosis, and there is an unmet need for novel treatment targets in this patient ...group. Treatments targeting the PD‐L1/PD‐1 pathway are still poorly elucidated in LBCL. PD‐L1 expression might predict response to treatment targeting the PD‐L1/PD‐1 pathway. We therefore investigated the relationship between PD‐L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. We detected MYC, BCL2, and BCL6 translocation by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 had DH and 81 without MYC translocation. PD‐L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD‐L1 mRNA expression by next‐generation RNA sequencing (NGS) in another 77 patients. Twenty‐four patients overlapped, ie, were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. PD‐L1 protein expression level was significantly lower in patients with MYC (n = 42, median = 3.3%, interquartile range IQR 0.0‐10.8) or DH translocations (n = 31, median = 3.3%, IQR 0.0‐10.0) compared with patients with no MYC (n = 35, median = 16.7%, IQR 3.3‐30.0) or no DH translocations (n = 46, 13.3%, IQR 2.5‐30.0), P = .004 and P ≤ .001, respectively. PD‐L1 mRNA expression was also significantly lower in patients with MYC or DH translocations, P = .001 and P = .006, respectively. Higher PD‐L1 protein and mRNA expression levels were associated with non–germinal centre (GC) type compared with germinal centre B‐cell (GCB)‐type diffuse LBCL (DLBCL), P = .004 and P = .002, respectively. In conclusion, we report an association between low PD‐L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD‐L1/PD‐1‐inhibitors compared with patients without these translocations. This should be evaluated in larger, prospective, consecutive trials.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Organotypic culture of human fetal testis has achieved fertilization-competent spermatids followed by blastocysts development. This study focuses on whether the organotypic culture of testicular ...tissue from infant boys with cryptorchidism could support the development of spermatogonia and somatic cells. Frozen-thawed tissues were cultured in two different media, with or without retinoic acid (RA), for 60 days and evaluated by tissue morphology and immunostaining using germ and somatic cell markers. During the 60-day culture, spermatocytes stained by boule-like RNA-binding protein (BOLL) were induced in biopsies cultured with RA. Increased AR expression (p < 0.001) and decreased AMH expression (p < 0.001) in Sertoli cells indicated advancement of Sertoli cell maturity. An increased number of SOX9-positive Sertoli cells (p < 0.05) was observed, while the percentage of tubules with spermatogonia was reduced (p < 0.001). More tubules with alpha-smooth muscle actin (ACTA, peritubular myoid cells (PTMCs) marker) were observed in an RA-absent medium (p = 0.02). CYP17A1/STAR-positive Leydig cells demonstrated sustained steroidogenic function. Our culture conditions support the initiation of spermatocytes and enhanced maturation of Sertoli cells and PTMCs within infant testicular tissues. This study may be a basis for future studies focusing on maintaining and increasing the number of spermatogonia and identifying different factors and hormones, further advancing in vitro spermatogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Key Clinical Message
B‐cell lymphoblastic lymphoma is an aggressive malignant disease. Necropsy and microscopical examination revealed widespread disease with a high proliferation index. This is the ...first reported case of B‐cell lymphoblastic lymphoma presenting in the ocular region and only the second reported lymphoma of the nictitating membrane.
B‐cell lymphoblastic lymphoma is an aggressive malignant disease. Necropsy and microscopical examination revealed widespread disease with a high proliferation index. This is the first reported case of B‐cell lymphoblastic lymphoma presenting in the ocular region and only the second reported lymphoma of the nictitating membrane.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling ...compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling. Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high‐dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first‐line treatment with high‐dose melphalan followed by autologous stem cell transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed that a good response to anti‐myeloma treatment increased the extent of formative bone surfaces with canopy, and reduced the extent of eroded surfaces without canopy, reverting the uncoupled bone remodelling, while improving canopy coverage. The association between improved coupling and the canopy coverage supports the notion that canopies are critical for the coupling of bone formation to resorption. Furthermore, this study supports the observation that systemic bone disease in MM can be reversed in MM patients responding to anti‐myeloma treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Extranodal NK/T-cell lymphoma (ENKTCL), nasal type is a very rare and aggressive non-Hodgkin lymphoma. Most commonly it occurs in the upper aerodigestive tract. But, it can also manifest at locations ...such as the skin, soft tissue, gastrointestinal tract (GI), lungs, testis, etc. These locations are designated as extranasal ENKTCL. The patients with the latter have often more adverse clinical features and poorer survival rate compared with nasal sites. We present a case of an 83-year-old patient with a primary ENKTCL, nasal type, with extranasal presentation in the right upper eyelid.
Materials for the literature review was obtained by a comprehensive search on PubMed, which yielded 82 eligible cases with extranasal ENKTCL.
Sixty-eight cases (83 %) were localized as primary ENKTCL in the lungs (17), central nervous system (CNS) (14), testis (11), GI-tract (7), skin (6), orbit and intraocular tissue (4), pancreas (2), adrenal gland (2), breast (1), etc. 14 cases (17 %) presented as extended or disseminated diseases involving exclusively organs outside the upper aerodigestive tract. There was no systematic pattern of organ involvement in the extended/disseminated ENKTCL. 63 % of the patient with localized extranasal ENKTCL and about 50% of patients with extended/disseminated disease were reported to have died of the disease. Treatment strategies varied with no preferred option. Among the used treatment options were chemotherapy, radiotherapy, surgery, stem cell transplantation alone or in different combinations.
ENKTCL is a highly aggressive disease which may present in extranasal areas. Although the tumors respond to both chemotherapy and radiotherapy, durable complete remissions are very rare.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The aim of the present study was to describe a rare case of orbital precursor B-lymphoblastic lymphoma (B-LBL) in an adult. A 56-year-old male in complete remission of a gastric precursor B-LBL was ...referred to our orbital clinic due to rapid development of left-sided painless periorbital swelling, diplopia, and proptosis. Complete ophthalmoplegia was observed. Notably, magnetic resonance imaging showed swelling of the medial and inferior rectus muscles in the left orbit and biopsies were performed. Following histological diagnosis of precursor B-LBL, the patient was treated with radiotherapy (2Gy × 20) and chemotherapy according to the NOPHO ALL 2008 protocol. The disease progressed and the patient succumbed after 5 months. Histomorphologically, a lymphoblastic infiltrate was observed within the skeletal muscle tissue. The tumor cells were small and immature, and stained strongly for cluster of differentiating (CD)10, CD79a, paired box 5 and B cell lymphoma-2. The Ki-67 proliferative index was 90%. Multiplex ligation-dependent probe amplification and array comparative genomic hybridization detected whole chromosomal gain of X and 12, and both hemizygous and homozygous deletion on 9p comprising cyclin dependent kinase inhibitor 2A/B. Furthermore, array comparative genomic hybridization detected copy number imbalances consisting of focal or smaller deletions on chromosomes 1, 9, 10, 11 and 20. The final diagnosis was precursor B-LBL relapse in the extraocular muscles. Orbital precursor B-LBL is extremely rare in adults, and the diagnosis may be challenging to make. It is recommended to obtain material for cytogenetic and molecular analyses.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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