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A thorough updating of the best-selling, vital reference and textbook on melanocytic proliferations PRAISE FOR THE FIRST EDITION: \"Well-written and entertaining\" —Modern Pathology \"An extremely helpful guide for the practicing dermatopathologist or general pathologist\" —Archives of Pathology and Laboratory Medicine \"An incredibly relevant clinical-histopathologic text\" —Doody's Melanocytic proliferations comprise a large number of pigmented lesions of the skin and muscosa. Of these, melanoma is of particular interest to clinicians and their patients. The rising number of incidences of melanoma has led to increased interest in the disease from diagnostic, management, and basic science perspectives. The Melanocytic Proliferations: A Comprehensive Textbook of Pigmented Lesions is the most complete single-source treatment of the subject available—thoroughly updated to reflect the very latest studies and clinical experience in diagnosing and treating melanocytic proliferation. This new edition of the bestseller presents an experience- and evidence-based review of pigmented lesions that encompasses the biology, diagnosis, and treatment of melanocytic proliferations and disorders, including melanoma. It comes with over 300 new color images—bringing the total to over 600—and contains two completely new chapters: Dermatoscopic Diagnosis of Melanoma; and Reflectance Confocal Microscopy. Chapter coverage includes: • An approach to the clinical diagnosis of melanoma, its precursors, and its clinical mimics • Freckles and lentigines • Benign acquired nevi • Dermal dendritic melanocytic proliferations/dermal melanocytoses • Spitz nevus • Combined nevus, deep penetrating nevus, plexiform spindle cell nevus, and borderline tumors of the deep penetrating nevus variant • Recurrent melanocytic nevus • Congenital nevi • Dysplastic melanocytic nevi, de novo intradermal epithelioid and lentiginous melanocytic dysplasias, and nevi at specific anatomic sites • Melanoma • Conjunctival melanocytic proliferations • Use of adjunctive immunoperoxidase, molecular, and ultrastructural studies in the diagnosis of melanocytic proliferations • Biology of melanoma • Borderline melanocytic proliferation • Dermatoscopic diagnosis of melanoma • Reflectance confocal microscopy • Therapy of melanoma The Melanocytic Proliferations: A Comprehensive Textbook of Pigmented Lesions is an incredibly important text for all clinical pathologists, dermatopathologists, surgical pathologists, dermatologists, cosmetic physicians, and surgeons.

Germ cell cancer (GCC) is curable in metastatic stages. The International Germ Cell Cancer Collaborative Group (IGCCCG) reports a poor prognosis subgroup with a 5-year survival of 48%. High-dose chemotherapy with PBSC transplantation (HD-PBSCT) in these patients showed promising results in phase II, but failed to show significant advantage in randomized trials. We report our monocenter series of all poor and selected intermediate prognosis germ cell tumor patients treated with multiple-course HD-PBSCT and secondary surgery of remaining tissue. We performed a retrospective analysis of our complete series of 44 patients (40 poor prognosis and 4 intermediate prognosis) treated by HD-PBSCT as part of first-line therapy from 1999 to 2010. The CR rate after up to four cycles of HD-PBSCT and radical resection of residual manifestations was 73%. The 3-year survival rate was 79.5% (median follow-up of 51.5 months; range: 7–143 months). Disease-related death rate was 16%. HD-PBSCT-related death did not occur. One patient died postsurgery. Multiple courses of HD-PBSCT with radical secondary surgery is safe and effective in poor prognosis metastatic GCC. Despite disappointing phase III studies it is of high interest to further study this field.

Current (high throughput omics-based) data support the model that human (malignant) germ cell tumors are not initiated by somatic mutations, but, instead through a defined locked epigenetic status, representative of their cell of origin. This elegantly explains the role of both genetic susceptibility as well as environmental factors in the pathogenesis, referred to as ‘genvironment’. Moreover, it could also explain various epidemiological findings, including the rising incidence of this type of cancer in Western societies. In addition, it allows for identification of clinically relevant and informative biomarkers both for diagnosis and follow-up of individual patients. The current status of these findings will be discussed, including the use of high throughput DNA methylation profiling for determination of differentially methylated regions (DMRs) as well as chromosomal copy number variation (CNV). Finally, the potential value of methylation-specific tumor DNA fragments (i.e., XIST promotor) as well as embryonic microRNAs as molecular biomarkers for cancer detection in liquid biopsies will be presented.

Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20–40 years) and are classified as seminoma or non‐seminoma. TGCTs are commonly treated by orchiectomy and chemo‐ or radiotherapy. However, a subset of metastatic non‐seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small‐molecule inhibitor JQ1 in tumour therapy, which interferes with the function of ‘bromodomain and extraterminal (BET)’ proteins. JQ1‐treated TGCT cell lines display up‐regulation of genes indicative for DNA damage and cellular stress response and induce cell cycle arrest. Embryonal carcinoma (EC) cell lines, which presented as JQ1 sensitive, display down‐regulation of pluripotency factors and induction of mesodermal differentiation. In contrast, seminoma‐like TCam‐2 cells tolerated higher JQ1 concentrations and were resistant to differentiation. ECs xenografted in vivo showed a reduction in tumour size, proliferation rate and angiogenesis in response to JQ1. Finally, the combination of JQ1 and the histone deacetylase inhibitor romidepsin allowed for lower doses and less frequent application, compared with monotherapy. Thus, we propose that JQ1 in combination with romidepsin may serve as a novel therapeutic option for (mixed) TGCTs.

Germ cell cancers (GCC) are the most frequent malignancy in young Caucasian males. GCC can consist of seminomas (SE) and non-seminomas (malignant NS: embryonal carcinoma (EC), yolk sac tumor (YS), choriocarcinoma (CH) and teratoma (TE)). Current serum-markers used for diagnosis and follow-up (AFP, hCG) are predominantly related to YS and CH and marker positivity can vary during disease. Therefore, stable markers consistently identifying more GCC components, specifically the stem cell components SE and EC, are of interest. Expression of the embryonic stem cell miR-371-3 and miR-302/367 clusters in SE/EC/YS suggest possible application of these micro-RNAs as GCC tumor-markers. The TSmiR protocol constitutes a complete, quality-controlled pipeline for the detection of miRs in serum, based on magnetic bead-based purification and qPCR quantification. As a proof of principle, TSmiR was applied to five independent serum sample series including 80 GCCs, 47 controls, 11 matched pre/post orchidectomy samples and 12 no-GCC testicular masses. GCC serum samples showed a consistent, significant (p < 0.0064) increase of miR-371/372/373/367 levels. Analogous, serum levels returned to baseline after orchidectomy (stage-I disease). Moreover, there was a trend toward higher miR levels in patients with metastasis. These results imply suitability for diagnosis and follow-up. TSmiR showed an overall sensitivity of 98%, clearly outperforming the traditional serum markers AFP/hCG (36%/57%, sensitivityAFP = 3%/45%; sensitivityhCG = 62%/66%, SE/NS). TSmiR misclassified one tumor as a control. Serum AFP/hCG and TSmiR combined identified all T samples correctly. In conclusion, TSmiR constitutes a highly sensitive and reproducible serum test for GCC patients, suitable to be prospectively tested for diagnostic and follow-up purposes. [Display omitted] •TSmiR is a complete quality controlled pipeline for the detection of miRs in serum.•Based on magnetic bead-based purification/qPCR quantification, no pre-amplification.•High sensitivity/specificity for GCC detection in five independent sample series.•miR levels return to baseline after surgery/are increased in metastasized disease.•Therefore, TSmiR is a potential valuable tool for diagnosis & follow-up of GCC.

The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY region, as well as anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present being at risk when blocked in an embryonic stage of development. GGCC originates from either germ cell neoplasia in situ (testicular environment) or gonadoblastoma (ovarian-like environment). These precursors are characterized by presence of the markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. One of the aims is to stratify individuals with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies, and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with DNA, mRNA, and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of available knowledge in the context of predicting the risk of GGCC in individual patients.

Introduction and objectives Postchemotherapy residual tumor resection (PC-RTR) is an important part of the multimodal treatment for patients with metastatic germ cell tumors. Simultaneous retroperitoneal and thoracic metastases often require consecutive surgical procedures. This study analyzes the histologic findings after abdominal and thoracic surgery in order to tailor the sequence and intensity of surgery. Patients and methods From a total of 671 PC-RTRs from 2008 to 2021 we analyzed 50 patients with stage III non-seminomatous germ cell tumor (NSGCT) who had undergone both retroperitoneal and thoracic postchemotherapy residual tumor resection after first-line and salvage chemotherapy. Results All patients included had stage III NSGCT. 39 and 11 patients received first-line and salvage chemotherapy, respectively. 45 (90%) patients received retroperitoneal resection first, followed by thoracic surgery. Three patients (6%) underwent thoracic surgery before retroperitoneal surgery and two patients (4%) underwent simultaneous surgery. Overall, the histology of retroperitoneal and thoracic specimens was discordant in 23% of cases. After first-line chemotherapy, of fourteen patients with necrosis in retroperitoneal histology, four patients had vital carcinoma in lung histology. In patients with teratoma in the retroperitoneum, the thoracic findings were concordant in most cases (78%). When teratomatous elements were also present in the orchiectomy specimen, concordance was 100%. After salvage chemotherapy, the discordance rate was 55%. Conclusion The data presented in this study underline that retroperitoneal residual masses with necrosis cannot reliably predict histologic findings of thoracic specimens. Patients with teratoma in the retroperitoneum have a high likelihood of teratoma in the thoracic specimen. Patient summary In this report we the compared the findings of metastasic testicular cancer patients who received thoracic and retroperitoneal surgery. We concluded that the findings of one location cannot entirely predict the results of another location.

Radiation therapy is a common treatment modality for lung cancer, and resistance to radiation can significantly affect treatment outcomes. We recently described that lung cancer cells that express more germ cell cancer genes (GC genes, genes that are usually restricted to the germ line) can repair DNA double-strand breaks more rapidly, show higher rates of proliferation and are more resistant to ionizing radiation than cells that express fewer GC genes. The gene encoding TRIP13 appeared to play a large role in this malignant phenotype. However, the molecular regulatory mechanism of TRIP13 in radiation resistance remained largely unknown. Here, we show that TRIP13 is a key contributor to non-small cell lung cancer (NSCLC) treatment resistance, particularly in patients following radiation treatment, for whom levels of TRIP13 expression are correlated with a poor prognosis. Repeated irradiation of led to an increase of basal TRIP13 levels and radioresistance. This effect of radioresistance could be enhanced or abrogated by overexpressing or knocking out TRIP13. Elevated TRIP13 is also correlated with enhanced repair of radiation-induced DNA damage. We further showed the proteins NBS1 and RAD51 (homologous recombination. HR) and XRCC5 (non-homologous end-joining, NHEJ) to act downstream of TRIP13, although inhibition of TRIP13 mostly reduced the HR associated proteins in response to induced resistance to irradiation. This study elucidates a novel mechanism of treatment resistance in NSCLC cells, in which TRIP13 promotes HR mediated DNA repair and resistance to ionizing radiation.

Nanos RNA-binding proteins are critical factors of germline development throughout the animal kingdom and their dysfunction causes infertility. During evolution, mammalian Nanos paralogues adopted divergent roles in germ cell biology. However, the molecular basis behind this divergence, such as their target mRNAs, remains poorly understood. Our RNA-sequencing analysis in a human primordial germ cell model-TCam-2 cell line revealed distinct pools of genes involved in the cell cycle process downregulated upon NANOS1 and NANOS3 overexpression. We show that NANOS1 and NANOS3 proteins influence different stages of the cell cycle. Namely, NANOS1 is involved in the G1/S and NANOS3 in the G2/M phase transition. Many of their cell cycle targets are known infertility and cancer-germ cell genes. Moreover, NANOS3 in complex with RNA-binding protein PUM1 causes 3′UTR-mediated repression of FOXM1 mRNA encoding a transcription factor crucial for G2/M phase transition. Interestingly, while NANOS3 and PUM1 act as post-transcriptional repressors of FOXM1, FOXM1 potentially acts as a transcriptional activator of NANOS3, PUM1, and itself. Finally, by utilizing publicly available RNA-sequencing datasets, we show that the balance between FOXM1-NANOS3 and FOXM1-PUM1 expression levels is disrupted in testis cancer, suggesting a potential role in this disease.

Purpose Treatment of metastatic germ cell cancer (GCC) is based on the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification published in 1997. 5-year survival rates were reported to be 91%, 79%, and 48% for patients with good, intermediate and poor prognosis, respectively. However, treatment results may have improved over time due to cumulative experience, improved supportive care and modern-type chemotherapy. Methods Patients with metastatic GCC who received cisplatin-based chemotherapy at two institutions in Munich between 2000 and 2013 were retrospectively studied. Clinical characteristics, treatment and outcomes were analyzed with respect to the IGCCG prognostic classification. Results Of 225 patients (median age 35 years), 72 (32%) had seminoma (S) and 153 (68%) nonseminoma. 175 (78%), 30 (13%) and 20 patients (9%) had good, intermediate and poor prognosis according to the IGCCCG classification. The 2-year-progression free survival of patients with good, intermediate and poor prognosis was 91%, 83% and 37%, and the 5-year-overall survival (OS) was 98%, 96%, and 66%, respectively. There was no significant difference in the OS between patients in the good and intermediate prognosis group. Conclusion Compared to data from the original IGCCCG classification system, the outcome of patients with metastatic GCC has considerably improved over time. While the prognosis of intermediate-risk patients is excellent, treatment in the poor-prognosis group remains to be improved.