Search

Aim Congenital monorchism is considered a condition in which an initially normal testis has existed but subsequently atrophied and disappeared due to a third trimester catastrophe (presumably torsion). Since inhibin B concentrations appear related to Sertoli and germ cells number, we evaluated pre- and postoperative inhibin B of boys with congenital monorchism to determine whether the well-known hypertrophy of the contralateral testis was reflected in inhibin B concentrations. Materials and Methods Twenty-seven boys consecutively diagnosed with congenital monorchism (median age 12 months) underwent follow-up with reproductive hormones 1 year postoperatively (median age 25 months). The results were compared with inhibin B of 225 boys with congenital nonsyndromic unilateral cryptorchidism, by converting values to multiple of the median (MoM) for age in normal boys. Results Ten boys (37%) had blind-ending vessels and ductus deferens (vanished testis) and the remaining (63%) had testicular remnants. At the time of diagnostic procedure, monorchid boys did not have significantly lower inhibin B (median 114, range 20–208) than unilateral cryptorchid boys (136, 47–393) (p = 0.27). During follow-up, MoM values of inhibin B increased in monorchid boys (median 0.59 to 0.98) and in unilateral cryptorchid boys (0.69 to 0.89) (both p Conclusion Generally, inhibin B MoM values were normalized during follow-up in boys with congenital monorchism, reflecting compensatory hypertrophy within the first 2.5 years of life. The compensatory capacity to increase was better in monorchism than in unilateral cryptorchidism.

Objectives: Extraosseous plasmacytoma (EOP) is a rare plasma cell neoplasm that tends to convert to plasma cell myeloma (PCM) in about 11% to 35% of cases. It has a predilection for the upper respiratory tract, prototypically affecting the nasal cavity and paranasal sinuses. Contemporary first-line treatment is radiotherapy, with more recent studies showing an added benefit of combining radiation with surgery. In this cohort study, we aimed to examine clinical presentation, treatment, and prognosis for all patients nationwide from 1980 through 2017. Furthermore, we determined the size and extension of tumors, investigating the rate at which minimally invasive surgery would have been possible. Methods: Patients were found in the national pathology registry, and all biopsies were collected for pathology review by a hematopathologist. We performed survival statistics for overall survival (OS), progression-free survival (PFS), and the cumulative incidence of conversion to PCM. Results: Twenty-three patients were included. The median age was 65, and patients were primarily men (78%). Tumors were located in either the nasal cavity (57%), maxillary sinus (39%), or sphenoid sinus (4%). In most cases, the tumor was Conclusion: SN-EOP responds well to radiotherapy, but relapse and conversion to PCM were not uncommon and entailed a poor prognosis. Most tumors were endoscopically resectable and non-invasive, making the majority of tumors suitable for surgery as an addition to radiation.

Compared to Asian and Latin American populations, sinonasal NK- or T-cell lymphoma is rare in Europe. All patients with sinonasal NK- or T-cell lymphoma in Denmark from 1980 to 2017 were validated histologically, and the disease behavior and demographics were extracted from medical records and national registries. Prognostic factors associated with mortality were determined using survival statistics. We included 56 patients: 40 extranodal NK/T-cell lymphoma (nasal type) (ENKTCL) and 16 peripheral T-cell lymphoma (not otherwise specified) (PTCL). The median age was 66, and most patients were male (72%). The ENKTCL and PTCL 5-year overall survival was 48% and 50%, respectively; progression-free survival was 38% for both. With ENKTCL, stage and performance status increased mortality significantly (HR = 8.6; p

Autologous stem-cell transplantation (ASCT) consists of infusion of previously harvested CD34+ hematopoietic stem cells after high-dose chemotherapy. This treatment can be curative for patients wit...

Inhibin-B is produced by Sertoli cells and decreased values might be associated with impaired fertility potential. The aim of the study was to evaluate the impact of bilateral orchidopexy on serum inhibin-B and follicle-stimulating hormone (FSH). A cohort study including 208 bilateral cryptorchid boys (median age: 1.7 year) was evaluated with serum inhibin-B and FSH in relation to histological parameters. Based on the fertility potential, the boys were divided into three subgroups. At follow-up (median age: 2.7 years) the boys were evaluated with FSH and in case of inhibin-B using multiple of the median (MoM). Inhibin-B MoM improved significantly at follow-up. In 32 boys with high FSH at orchidopexy 63% normalized FSH and 59% increased MoM inhibin-B, but 31% had impaired inhibin-B at follow-up. In 105 boys with transient hypogonadotropic hypogonadism, 52% increased inhibin-B MoM but 31% had impaired inhibin-B at follow-up. In 71 boys with normal FSH, inhibin-B, and G/T, 54% increased inhibin-B MoM and 15% had impaired inhibin-B at follow-up. The effect of the surgery was best in patients younger than 1 year. Orchidopexy, especially before 1 year of age, improves the fertility potential in bilateral cryptorchidism. At follow-up, 26% (54/208) had a risk of infertility based on inhibin-B.

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).

Positive staining of testicular germ cells for PLAP and c-Kit beyond infancy may be associated with the presence of GCNIS (Germ Cell Neoplasia In Situ). We recently reported our findings of positive staining of normal, infantile germ cells for PLAP, and c-Kit up to 2 years of age, contrary to previous studies. The present study aims to elucidate whether otherwise normal testes of boys undergoing puberty express PLAP, c-Kit, Oct3/4, or D2-40. Biopsies were taken from 31 boys (11.5–16.5 years of age, mean and median of 13.5 years), who underwent surgery either for torsion of the testis (15) or a history suspicious of intermittent torsion of the testis (16). 21 were biopsied on both sides, making a total of 52 biopsies. Four testes were necrotic. The biopsies were fixed in Stieve’s medium, cut into 2 μm sections, and mounted on coated slides. One slide was processed for H–E, and the others incubated with primary antibody for PLAP, c-Kit, D2-40, and Oct3/4. 87% of the boys stained positive for both PLAP and c-Kit. None were positive for either D2-40 or Oct3/4. None had any histological features characteristic of GCNIS. Only two boys showed no signs of having initiated spermatogenesis. Those positive for PLAP were likewise for c-Kit, and vice versa, except 2; one boy, 13 years, was positive for PLAP, but negative for c-KIT, another, 16 years, was negative for PLAP and positive for c-Kit. Three boys stained positive for PLAP and c-Kit on the right side, and negative on the left. One boy was negative for c-Kit on the right side, positive on the left, and positive for PLAP bilaterally. Positive staining of testicular germ cells for PLAP and c-Kit seems to be a normal finding in boys not having completed puberty. Rather than indicating pre-malignant transformation, the positivity is indicative of an ongoing maturational process of the germ cells.

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.

Background/Aim 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. Methods 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. Results 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. Conclusion 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. Type of study Systematic review (secondary, filtered) Level of evidence Level I.

Purpose:One of the concerns surrounding cryptorchidism is the risk of impaired fertility. Current guidelines recommend orchiopexy at age 6 to 12 months to optimize fertility outcome. We evaluated t...

Introduction The activation of the hypothalamic–pituitary–gonadal axis that occurs in male minipuberty during the first 5 months of life is important for early germ cell development. Orchidopexy during minipuberty may improve fertility potential as the germinative epithelium may benefit from the naturally occurring gonadotropin stimulation. We hypothesize that most boys with congenital nonsyndromic cryptorchidism display normal reproductive hormonal profiles and histological findings during minipuberty. Methods We included boys with congenital nonsyndromic cryptorchidism who underwent orchidopexy at less than 160 days of age, having no potential for spontaneous resolution clinically. At surgery, testicular biopsies and reproductive hormones were collected and compared with normal reference values. We measured the germ cells (G/T) and type A dark spermatogonia number per tubule. Results Thirty-five boys aged 37 to 159 (median age: 124) days at orchidopexy were included, five were bilateral. G/T was below the normal lower range in 26% (9/35) of the cases. In six of these cases, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were above 97.5 percentile, whereas one case had FSH below 2.5 percentile. Totally, 97% (33/34, one FSH was missing) exhibited a normal LH/FSH ratio. LH was more often above 97.5 percentile than FSH: 34% (12/35) versus 3% (1/34, p Conclusion Generally, reproductive hormonal profiles of the cryptorchid boys exhibited normal minipubertal pattern. Thus, 26% of the boys had reduced germ cell number, and transient hypogonadotropic hypogonadism could be suspected in few cases.

Despite early surgery, many boys with bilateral cryptorchidism at surgery have a reduced number of germ cells per tubular cross-section (G/T) in testicular biopsies and/or low inhibin-B with no elevated follicle-stimulating hormone (FSH) as expected based on a normal gonadotropin feed-back mechanism. Such boys have a high risk of later infertility because of insufficient gonadotropin stimulation and may benefit from adjuvant hormonal treatment. Testicular biopsies are not always wanted or accepted. The study aim was to investigate the value of a low inhibin-B and normal FSH to identify patients that might benefit from adjuvant hormonal treatment avoiding the need for testicular biopsy.A series of boys with cryptorchidism were evaluated with serum levels of inhibin-B and FSH in relation to G/T in testicular biopsies, which were compared to previously published age-matched normal control values.A total of 365 boys who underwent bilateral orchidopexy between 0.4 and 7.8 (median: 2) years of age were included. Twenty-seven (7%) patients had increased FSH and low G/T, whereas 11 of these also had low inhibin-B indicating hypergonadotropic hypogonadism. Moreover, 85 (23%) patients between 0.75 and 7.5 (median: 2) years of age had both low G/T (median: 0.3) and low inhibin-B (median: 56 pg/ml) but normal FSH (median: 0.6 U/l) indicating a gonadotropin insufficiency. Three patients with normal FSH and low inhibin B had normal G/T.Our study shows that if surgeons prefer to avoid testicular biopsies and only wish to rely on hormonal parameters (low inhibin-B and normal FSH) in order to diagnose a gonadotropin insufficiency as the cause of hypogonadism, they will identify only about 30% of such cases and overlook about 70% of patients sharing the same endocrinopathy. In addition, if surgeons treat patients for gonadotropin insufficiency only based on low inhibin-B and normal FSH they will solely treat patients with gonadotropin insufficiency and would not overtreat patients.Adjuvant hormonal treatment was indicated by a gonadotropin insufficiency discerned in 23% of boys with bilateral cryptorchidism. Without histology, the clinicians are left with more difficult clinical judgments to identify patients for adjuvant hormonal treatment. The positive predictive value of low inhibin-B and normal FSH corroborated by low G/T was 0.97 (85/85 + 3), but the sensitivity was low (0.30).

Background: Burkitt lymphoma rarely presents in head and neck (H&N) in Western countries. Aims/objectives: We aimed to characterise clinicopathological features of H&N Burkitt lymphoma in Denmark representing a non-endemic region. Material and methods: Clinical records were reviewed for a nationwide cohort of patients diagnosed with H&N Burkitt lymphoma in Denmark between 1980 and 2018. The diagnosis was histologically validated. Results: Thirty-four patients with H&N Burkitt lymphoma (highest incidence in age group 0–9 years, male-to-female ratio 4.7:1) were included. Thirty-three lymphomas (97%) were extranodal. The tumour was visible at the clinical examination in 81% (n = 22) of the cases. The palatine tonsils were the most frequent location (n = 13, 38%) and 52% (n = 17) of the patients were diagnosed in advanced stage. Lymphoma was the tentative clinical diagnosis in 23% of the cases. The 5-year overall- and disease-specific survival was 78% and 81%, respectively. Conclusions: Due to the rarity of Burkitt lymphoma of the H&N, there is a high risk of clinical misdiagnosis. Our findings suggest which symptoms and clinical presentations to be aware of in the diagnostics work up that could lead to the diagnosis of Burkitt lymphoma.

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.

Despite orchidopexy within the first year of life, 20-25% of boys with nonsyndromic cryptorchidism may risk infertility according to histological and hormonal data obtained during surgery. The aim of this study was to evaluate the acceptance rate of testicular tissue cryopreservation among parents of prepubertal boys with cryptorchidism. Fourteen boys with cryptorchidism and high infertility risk were offered cryopreservation as an additional procedure after orchidopexy based on abnormal histopathological findings at primary surgery, whereas 27 boys with bilateral cryptorchidism were offered cryopreservation at the initial orchidopexy. A total of 90% of parents (37/41, 13/14, and 24/27) gave consent to perform cryopreservation, despite being well-informed that the procedural efficacy is largely unproven and may only be needed in about 20% of cases. The number of germ cells per tubule cross-section was 0.03-1.70 (median 0.37) and 22 boys (54%, 22/41) had a value below the lower range. Twelve boys (29%, 12/41) had no type A dark spermatogonia in their biopsy. Cryopreservation of testicular tissue is the first step to introduce spermatogonial stem cell-based therapy into clinical male infertility treatment. At the time of orchidopexy, a testicular biopsy can be collected to ascertain the infertility risk, and it may be an option for boys with bilateral cryptorchidism to have spermatogonial stem cells frozen as a fertility reserve.

Clonal hematopoiesis of indeterminate potential (CHIP) is suspected of being a risk factor for patients with cancer. This study aimed to assess the clinical consequences of CHIP in patients with lymphoma intended for high-dose chemotherapy and autologous stem-cell transplantation (ASCT) in a population-based setting. We identified 892 lymphoma patients who had undergone stem cell harvest at all transplant centers in Denmark. A total of 565 patients had an available harvest sample, which was analysed for CHIP by next-generation sequencing, and the median follow-up was 9.1 years. Of the patients who were intended for immediate ASCT, 25.5% (112/440) carried at least one CHIP mutation. In contrast to previous single-center studies CHIP was not associated with inferior overall survival (OS) in multivariate analyses. However, patients with mutations in genes of the DNA repair pathway (PPM1D, TP53, RAD21, BRCC3) had a significant inferior OS (HR after 1 year of follow-up 2.79, 95% confidence interval 1.71–4.56; p < 0.0001), which also was evident in multivariate analysis (p = 0.00067). These patients had also increased rates of therapy-related leukemia and admission to intensive care. Furthermore, in patients who did not undergo immediate ASCT, a significant inferior OS of individuals with DNA repair mutations was also identified (p = 0.003).

Inhibin-B is produced by Sertoli cells and decreased values might be associated with impaired fertility potential. The aim of the study was to evaluate the impact of bilateral orchidopexy on serum inhibin-B and follicle-stimulating hormone (FSH).A cohort study including 208 bilateral cryptorchid boys (median age: 1.7 year) was evaluated with serum inhibin-B and FSH in relation to histological parameters. Based on the fertility potential, the boys were divided into three subgroups. At follow-up (median age: 2.7 years) the boys were evaluated with FSH and in case of inhibin-B using multiple of the median (MoM).Inhibin-B MoM improved significantly at follow-up. In 32 boys with high FSH at orchidopexy 63% normalized FSH and 59% increased MoM inhibin-B, but 31% had impaired inhibin-B at follow-up. In 105 boys with transient hypogonadotropic hypogonadism, 52% increased inhibin-B MoM but 31% had impaired inhibin-B at follow-up. In 71 boys with normal FSH, inhibin-B, and G/T, 54% increased inhibin-B MoM and 15% had impaired inhibin-B at follow-up. The effect of the surgery was best in patients younger than 1 year.Orchidopexy, especially before 1 year of age, improves the fertility potential in bilateral cryptorchidism. At follow-up, 26% (54/208) had a risk of infertility based on inhibin-B.

Extensive molecular analysis of large B-cell lymphomas (LBCL) have provided basis for new concepts of lymphoma taxonomy. These include stages of differentiation, phenotype (cell of origin) as well as genotype (including, but not confined to gene rearrangements) and immune microenvironment. The importance of the tumor microenvironment has recently regained focus due to development of immune checkpoint-inhibitors such as PD1/PD-L1 inhibitors, and LBCL may according to the new subtypes be stratified as microenvironment "inflamed" or "non-inflamed", which may hold prognostic as well as predictive value. We investigated the composition of the tumor microenvironment in LBCL with or without MYC-translocation regarding PD-L1 expression and the infiltration of tumor-associated macrophages (TAMs). 126 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 Pax-5. Additional IHC with antibodies against CD68 and CD163 identified tumor associated macrophages (TAMs). All IHC stainings were quantitated independently and blinded by two consultant hematopathologists in 10% intervals of all tumor cells both neoplastic B-cells, immune cells, and stromal cells. 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 (Fig.1). Quantitative IHC demonstrated a significant correlation between CD68 and PD-L1 protein expression. CD68 positive TAMS and thereby also PD-L1 expression was significantly lower in MYC translocated lymphomas compared to non-translocated. The correlation was significant for both MYC single-hit (SH) and MYC double-hit (DH) with concurrent BCL2 and/or BCL6 translocation, the latter now termed High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH). For a more detailed analysis we next performed unsupervised cluster analysis of PD-L1, CD68 and CD163 quantitative IHC data, which demonstrated three significant clusters (Clusters 1-3) defined by expression of the three biomarkers (Fig. 2). Cluster 3 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-DH compared to the other two clusters. In cluster 1 we found a significant accumulation of BCL6 translocated tumors. This cluster in contrast had the highest protein expression of PD-L1, CD68 and CD163. Our data which were based on morphological analysis, immunophenotyping and genotyping by FISH, 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. Disclosures No relevant conflicts of interest to declare.

Ascending testes have been documented to be descended in the scrotum within the first year of life and then reascended. The aim of this study was to investigate to what extent the fertility potential was impaired in boys with such testes compared to the fertility potential of boys with late referral congenital cryptorchidism.A total of 153 consecutive boys underwent bilateral orchiopexy at age 2 to 7 years (median 3.9) between 2011 and 2018. Of the patients 67 were diagnosed with bilateral ascended testes and 86 with late referral bilateral congenital cryptorchidism. We assessed serum levels of inhibin B and gonadotropins and histological parameters, number of germ cells per tubule cross-section and number of type A dark (Ad) spermatogonia per tubule cross-section. All values were compared to our normal material.Number of germ cells per tubule cross-section of boys with ascended testes (median 0.50, range 0 to 2.29) was not significantly higher compared to boys with congenital cryptorchidism (median 0.37, range 0 to 2.57; p=0.11). Mean number of germ cells per tubule cross-section was below normal range in 40 boys with ascending testes (60%) vs 57 boys with late referral congenital cryptorchidism (66%, p=0.40). Biopsies absent of Ad spermatogonia were noted in 31% of boys with ascending testes (21 of 67) vs 34% of boys with congenital cryptorchidism (29 of 86, p=0.76). Serum levels of inhibin B and gonadotropins did not differ between the 2 groups.The fertility potential of boys with bilateral ascended testes was impaired to almost the same level as that of boys with bilateral congenital cryptorchidism and should therefore be surgically corrected as soon as the diagnosis of ascended testes is settled.

Richter’s transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Approximately, 2–10% of patients with CLL develop RT, most often as diffuse large B-cell lymphoma. To assess the incidence of RT, we examined risk factors for RT and death among patients with RT in a nationwide CLL cohort (from 2008 to 2016). Among 3772 patients, 113 had biopsy-proven RT. With a median follow-up of 4.3 years, the 5-year cumulative incidence of RT was 2.8%. Advanced Binet stage (B/C) (p

Mantle cell lymphoma (MCL) shows a clinical aggressiveness that varies from patient to patient. Despite major advances in outcomes with current immunochemotherapy, the future development of therapies requires risk stratification to tailor therapy intensity. Within the group of reference pathologists for the ongoing trials of the European MCL Network, we performed a round robin test on a tissue microarray, to evaluate the reproducibility in assessing the biomarkers of outcome in MCL. Cytological subtype, Ki67-index and expression of p53 and SOX11 were evaluated on 20 diagnostic tumour samples by eight participating labs independently. We demonstrate that the assessment of the proliferation index by counting the Ki67 positive cells as well as assessment of SOX11 and p53 expression status are reproducible between labs. For the most established prognostic biomarker, Ki67, the intra-class correlation coefficient was very good when assessed as a continuous parameter (0.87). The agreement was lower when the values were analysed in a dichotomized way applying the commonly used cut-off of 30% [kappa=0.65, complete concordance of all labs in 13/20 (65%)]. Cases with discrepant results between labs in the dichotomized analysis showed mean values close to the cut-off of 30%. Centralized scoring and digital image analysis revealed results in line with the scores from individual labs. All cases in our cohort were additionally assessed for gene expression signatures and of TP53 gene alterations. Given the good reproducibility when guidelines of assessment are applied, the biomarker studied in this inter-laboratory test present potential candidates, to be enhanced for risk-stratification in the future clinical trials.

Cryptorchidism is associated with infertility in adulthood. Early orchiopexy is suggested to reduce the risk. Information is lacking on the potential link between infant germ cell maturation and the risk of future infertility. The objective of the study was to evaluate age-related germ cell development in cryptorchidism. Immunostaining for markers of germ cell development (octamer-binding transcription factor 3/4 [OCT3/4], placental alkaline phosphatase [PLAP], KIT proto-oncogene [C-KIT], podoplanin [D2-40], Lin-28 homolog A [LIN28], and G antigen 7 [GAGE-7]) was performed in testicular biopsies from 40 cryptorchid boys aged 4-35 months. Germ cell numbers and distributions were evaluated in cross sections of seminiferous tubules, with and without immunostaining. OCT3/4, D2-40, and LIN28 were generally expressed in the early stages of germ cell development, as shown by positive expression in germ cells in the central region of seminiferous tubules. In contrast, PLAP and GAGE-7 were expressed in both central and peripheral parts of the tubules in the early stages of development and expressed mainly in a peripheral position with advancing age. Germ cell maturation was delayed in this study population as compared with that observed in our previous study on germ cell markers in a healthy population. The number of GAGE-7-positive germ cells per tubular cross section obtained by immunostaining was significantly higher than that obtained by standard hematoxylin and eosin staining. Double immunostaining revealed heterogeneity in germ cell development in cryptorchid testes. These results shed light on the pathophysiology of germ cell development in boys with cryptorchidism.

Tumor lysis syndrome (TLS) is rare in diffuse large cell lymphoma (DLBCL). We present a DLBCL case with TLS developing upon first treatment with R‐CHOP despite prophylactic measures. Overnight, the patient developed severe hyperkalemia, which resulted in a fatal arrhythmia. Tumor lysis syndrome (TLS) is an oncologic emergency resulting from massive cancer cell lysis that occurs spontaneously or upon the start of chemotherapy. The release of intracellular tumor cell content (potassium, phosphorus, and uric acid) into the bloodstream leads to critical hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia 1. TLS ranges from mild and transient asymptomatic electrolyte derangement to severe cases of renal failure, cardiac arrhythmias, and death, but fulminant TLS is a rare event in diffuse large cell lymphoma (DLBCL). We report a case of fatal TLS in a patient with DLBCL upon the start of R‐CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

Introduction Cryptorchidism is a risk factor for testicular cancer in adult life. It remains unclear how prepubertal surgery for cryptorchidism impacts later development of adult testicular cancer. The aim of study was to investigate tools to identify the cryptorchid boys who later develop testicular cancer. Methods The study cohort consisted of 1403 men operated prepubertally/pubertally for undescended testis between 1971 and 2003. At surgery testicular biopsies were taken from the cryptorchid testes. The boys were followed for occurrence of testicular cancer. The testicular cancer risk was compared to the risk in the Danish Population. Testicular biopsies from the boys who developed testicular cancer during follow-up underwent histological examination with specific diagnostic immunohistochemical markers for germ cell neoplasia. Results The cohort was followed for 33,627 person years at risk. We identified 16 cases with testicular cancer in adulthood. The standardized incidence ratio was 2.66 (95% CI: 1.52–4.32). At time of primary surgery in prepubertal/pubertal age Intratubular Germ Cell Neoplasia (ITGCN) was diagnosed in 5 cases and the boys were unilaterally orchiectomized. At follow-up new immunohistochemical staining indicated ITGCN in two of the 16 cancer cases at reevaluation of the original biopsies from time of prepubertal/pubertal surgery. One had syndromic cryptorchid and developed seminoma, and another showed nonsyndromic cryptorchidism and developed embryonic teratocarcinoma. Totally, ITGCN was diagnosed in 0.5% (7/1403) of prepubertal cryptorchid boys, whereof 57% (4/7) in syndromic-cryptorchidism. Discussion ITGCN is predominantly observed prepubertally in boys with syndromic-cryptorchidism. In nonsyndromic cryptorchidism testicular cancer develops postpubertally, generally not based on dormant germ cells of ITGCN caused by an early fetal maldevelopment. Levels of Evidence LEVEL I.

*Gül, Murat ( Aksaray, Yazar ), Background: Gonadotoxic treatment of malignant diseases as well as some nonmalignant conditions such as cryptorchidism in young boys may result in infertility and failure to father children later in life. As a fertility preserving strategy, several centers collect testicular biopsies to cryopreserve spermatogonial stem cells (SSCs) worldwide. One of the most promising therapeutic strategies is to transplant SSCs back into the seminiferous tubules to initiate endogenous spermatogenesis. However, to obtain sufficient numbers of SSC to warrant transplantation, in vitro propagation of cells is needed together with proper validation of their stem cell identity. Materials and Methods: A minute amount of testicular biopsies (between 5 mg and 10 mg) were processed by mechanical and enzymatic digestion. SSCs were enriched by differential plating method in StemPro-34 medium supplemented with several growth factors. SSC-like cell clusters (SSCLCs) were passaged five times. SSCLCs were identified by immunohistochemical and immunofluorescence staining, using protein expression patterns in testis biopsies as reference. Quantitative polymerase chain reaction analysis of SSC markers LIN-28 homolog A (LIN28A), G antigen 1 (GAGE1), promyelocytic leukemia zinc finger protein (PLZF), integrin alpha 6 (ITGA6), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and integrin beta 1 (ITGB1) were also used to validate the SSC-like cell identity. Results: Proliferation of SSCLCs was achieved. The presence of SSCs in SSCLCs was confirmed by positive immunostaining of LIN28, UCHL1 and quantitative polymerase chain reaction for LIN28A, UCHL1, PLZF, ITGA6, and ITGB1, respectively. Conclusion: This study has demonstrated that SSCs from infant boys possess the capacity for in vitro proliferation and advance a fertility preservation strategy for prepubertal boys who may otherwise lose their fertility.

Introduction: In large B-cell lymphoma (LBCL) MYC translocation and MYC/BCL2 or BCL6 double hit (DH) is associated with poor prognosis and there is an unmet need for novel treatment targets in this patient group. Treatment targeting the PD-L1/PD-1 pathway has been successfully introduced in Hodgkin lymphoma and solid cancers but 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. Material and Methods: MYC, BCL2 and BCL6 translocations were detected 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 patients 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. 24 patients overlapped, i.e. were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. Results: PD-L1 protein expression level was lower in patients with MYC translocation (n=42, median=3,3%, IQR 0,0-10,8) or DH (n=31, median=3,3%, IQR 0,0-10,0) compared to patients with no MYC translocation (n=35, median=16,7%, IQR 3,3-30,0) or DH (n=46, 13,3%, IQR 2,5-30,0), P=0.004 and P Conclusions: We report a highly significant 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 to patients without these translocations. This should be evaluated in larger, prospective, consecutive trials. Disclosures No relevant conflicts of interest to declare.

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.

IntroductionRichter’s transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma. Studies have shown that 2–10% of patients with CLL develop RT including diffuse large B-cell lymphoma (DLBCL) and less common Hodgkin lymphoma (HL). This study aims to assess the risk factors for RT of CLL in a nationwide cohort. Additionally, we want to examine prognostic factors in patients with RT. These findings may guide management of treated as well as untreated patients with CLL in the risk of RT.MethodsClinical data for patients diagnosed with CLL between 2008 and 2016 will be retrieved from the Danish National CLL registry (DCLLR). Using the Danish unique person identification number, clinical data will be merged with histologically verified DLBCL and/or HL diagnoses retrieved from the Danish National Pathology Data Bank. This will ensure complete follow-up for all patients.The DCLLR includes data from more than 4000 patients with CLL ensuring a median follow-up of 3 years. With the reported incidences (2-10%) of RT, we expect to identify 80–200 CLL patients with RT enabling analysis of overall survival following RT. From time of CLL diagnosis, estimates of cumulative incidence of RT will be calculated using the Aalen-Johansen estimator. From time of RT diagnosis, survival analysis will be performed by Kaplan-Meier method. Cox proportional hazards models will be used for multivariable survival analysis.Ethics and disseminationApprovals for data collection and analysis was obtained from the Danish Data Protection Agency and the Danish Health Authorities. All data will be managed confidentially according to guidelines and legislation. The dissemination will include a publication of scientific papers and/or presentations of the study findings at international conferences.

Postnatal maturation of Sertoli cells is crucial for male fertility. The aim of this study was to assess the association between the Sertoli cell number per tubule cross-section (SC/T), the serum level of the Sertoli cell-produced inhibin B, and the A-dark spermatogonia number per tubule (Ad/T) in cryptorchid boys. Forty infant cryptorchid boys aged 4-35 months (median: 13 months) were included in the study. During orchiopexy, blood samples for serum inhibin B, luteinizing hormone (LH), and follicle stimulating hormone (FSH) and testicular biopsies were obtained. Histological sections were evaluated by quantitative immunohistochemical and immunofluorescence analysis including VASA and SOX9 (Sertoli cell marker) in order to measure the tubular germ cell number (G/T), Ad/T, and SC/T. The SC/T correlated negatively with age (p < 0.0002) and positively with G/T, Ad/T, inhibin B, FSH, and LH (all p < 0.01). Inhibin B correlated with LH (p < 0.0001), but not with FSH (p = 0.2077). The SC/T:G/T ratio positively correlated with age (p < 0.0001). Boys with Ad spermatogonia at surgery had a higher number of Sertoli cells compared to boys without Ad spermatogonia. In conclusion, a correlation between Sertoli cell number and inhibin B was proven, indicating that inhibin B possibly reflects the function of Sertoli cells in infant cryptorchid boys.

Ultrasound-guided fine-needle aspiration cytology (US-FNAC) is used to evaluate the involvement of lymph nodes in various malignant diseases. Its value in detecting sentinel lymph node (SN) metastasis preoperatively in melanoma patients is controversial and is the subject of this study. In this prospective validation study, 91 consecutive patients with melanoma clinical stage I (n=64) and II (n=27) were examined with US-FNAC before SN biopsy from 2012 to 2014 at a tertiary center. All patients underwent lymphoscintigraphy before the US-FNAC. Lymph nodes that showed any of the Berlin morphologic criteria on ultrasonography were examined using FNAC. The median Breslow thickness of the melanomas was 1.22 mm (range: 0.47-11.5 mm). Twenty-two percent of the patients had metastases in their SNs, 90% of which were smaller than 2 mm in largest diameter. The percentages of metastases with a size more than 1 mm were 50 and 29%, respectively, in the true-positive and false-negative US groups. The sensitivity, specificity, positive predictive value, and negative predictive value for overall US examination were 30, 81, 24, and 83%, respectively. None of the FNACs contained conclusive malignant cells. The specificity of the FNAC was 76%. Our results show that US-FNAC was not a useful diagnostic tool in our setting as it did not add significantly to the staging and management of patients with mainly thin cutaneous melanomas, perhaps because of the often small size of the SN metastases. It may be useful in the early diagnosis of lymph node metastases in a subgroup of melanoma patients with larger metastases.

Purpose A meta-analysis including 11,900 cases showed that maternal gestational smoking was associated with increased risk of cryptorchidism. The aim of study was to investigate whether a hormone profile of cryptorchid boys and a supplementing histopathological evaluation of testicular biopsies could add detailed knowledge to the impact of maternal gestational smoking on pathogenesis of cryptorchidism. Methods 601 cryptorchid boys aged 4 months to 14 years old were included. Because normal hormones have a pronounced age dependency, we compared results from boys whose mothers had smoked heavily (>10 cigarettes/day) during pregnancy with age matched cryptorchid controls of nonsmoking mothers (1:6). We studied: birthweight, germ-cell number/tubular cross section, frequency of germ cells positive for placental-like alkaline phosphatase (PLAP), gonadotropins and inhibin-B. Results 501 boys were sons of nonsmokers, 72 boys of intermittent smokers and 28 boys of heavy smokers. 39%, 44% and 61% respectively had bilateral cryptorchidism. Compared to age-matched cryptorchid controls of nonsmoking mothers, sons of heavy smokers had lower birthweight (p = 0.006), germ-cell number/tubular cross section (p = 0.009), frequency of germ cells positive for PLAP (p = 0.037) and inhibin-B (p = 0.042). Conclusions All findings could be associated with placental dysfunction with altered human chorionic gonadotropin production well described in women smoking during pregnancy. Type of study Prognosis study (prospective cohort study with >80% follow-up). Level of evidence Level 1.

Background: Somatic driver mutations in hematopoietic cells may lead to clonal hematopoiesis of indeterminate potential (CHIP). In patients with lymphoma CHIP has been associated with increased risk of therapy-related myeloid neoplasms (tMN) and inferior survival after autologous stem cell transplantation as demonstrated in a large single center study and in a case-control study (Gibson CJ et al., JCO 2017 and Berger G et al., Blood 2018). Here, we investigated the clinical impact of clonal hematopoiesis in a nation-wide population-based cohort of Danish lymphoma patients undergoing autologous transplant with prospective data from four national patient registries. Methods: Patients with lymphoma who had undergone leukapheresis at all danish transplant centers from 2000 to 2012 were identified. DNA and RNA was extracted from mobilized peripheral blood products. Targeted sequencing of all samples was performed using an Illumina TruSeq Custom Amplicon panel (Illumina, San Diego, CA, USA) designed to cover >95% of mutations associated with CHIP (ASXL1, ASXL2, BCOR, BRCC3, CBL, CREBBP, DNMT3A, ETV6, GNB1, IDH1, IDH2, JAK2, KRAS, NRAS, PPM1D, RAD21, SF3B1, SRSF2, TET2, TP53). To allow detection of low-level mutations and secure variant calling, unique molecular identifiers (UMI's) were used. Filtering of variants was done by stringent criteria consistent with earlier studies. Assessment of mutations was performed blinded to the patients' clinical data. Prospective clinical patient data was obtained for all patients from four national registries, including the Danish Lymphoma Registry (diagnosis, involvement, lymphoma treatment, relapse and death), the Danish National Patient Registry (hospital admission diagnoses and treatments), the Danish Cancer Registry (primary and secondary cancer diagnoses) and the Danish Pathology Database (histopathological examinations and diagnoses), respectively. Results: Samples from 574 patients were included. The median age was 55.5 years (IQR: 45.3 - 62.2) and the median follow-up time for survivors was 9.2 years (IQR: 7.1 - 11.2). The lymphoma subtypes were typical of patients selected for autologous transplantation; diffuse large B-cell lymphoma (191 pts), follicular lymphoma (102 pts), mantle cell lymphoma (88 pts), Hodgkin's lymphoma (80 pts), peripheral T-cell lymphoma (77 pts) and other histologies (36 pts). Of the 574 patients analyzed, 191 (33.3%) of the patients had somatic mutations meeting CHIP criteria (total mutations called=210). The most commonly mutated genes were DNMT3A (n=59, 28%), TET2 (n=48, 23%), PPM1D (n=34, 16%), ASXL1 (n=21, 10%) and TP53 (n=18, 8%). As expected CHIP mutations were more frequent in patients above 60 years (p=0.002). Prevalence of CHIP was associated with an inferior overall survival (p=0.004) and event-free survival (p=0.03). It was also associated with increased risk of biopsy-confirmed tMN (p=0.03) and higher probability of receiving blood transfusions after autologous transplant (p=0.027). Especially patients with mutations in DNA damage response genes PPM1D and TP53 (found in 48 pts, 8.3%) had a significantly increased risk of adverse outcomes. Both overall survival and event-free survival were significantly poorer with the presence of DNA damage pathway mutations (p The impact of low-level mutations and statistical modelling of interactions between parallel outcomes will be presented at the meeting. Conclusion: To our knowledge this is the first population-based study of clonal hematopoiesis in patients with lymphoma. We find that CHIP and particularly mutations in DNA damage response genes (PPM1D/TP53) are associated with increased mortality, which confirms findings from single center studies. These data support the evaluation of CHIP for risk assessment in lymphoma patients before high-dose chemotherapy. Our study also identifies increased rates of several clinically relevant adverse outcomes (severe infections, blood transfusions and secondary cancers) in lymphoma patients with clonal hematopoiesis. Figure 1. Figure 1. Disclosures Grønbæk: Janssen Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees.