Rare Aggressive Malignancy Research Articles

The epidemiological and clinical characteristics of Langerhans cell sarcoma in the United States: A population study based on SEER data from 2000 to 2019.

Langerhans cell sarcoma (LCS) is a rare aggressive malignancy with a poor prognosis. Our knowledge about this condition is limited and mainly based on case reports, making it challenging to understand its epidemiology, clinical features, and patient outcomes. We conducted a retrospective study of LCS patients diagnosed between 2000 and 2019 using the Surveillance, Epidemiology, and End Results (SEER) database. The data were stratified based on age, race, stage, clinical pattern, and treatment method. Our study found that 57 LCS cases were reported in SEER registries between 2000 and 2019. Among these cases, most patients (50.9%) were over 60 years old and White (71.9%) with almost equal males to females ratio. About 45.6% of cases were localized while 47.4% were at distant stages. Of the patients, 50.9% underwent surgery, 45.6% received chemotherapy, and only 21.1% received radiotherapy. The overall survival rate for patients diagnosed with LCS in the United States is generally low with a 1-year overall rate of 63.8%. Certain factors can negatively impact prognosis, such as advanced stages of the disease, secondary tumors, or more than 1 tumor per patient. LCS is a rare disease with poor survival rates. Future research should incorporate global data for further statistically significant results. Moreover, investigating the molecular, genetic, and pathophysiological backgrounds of these tumors is crucial for developing targeted management strategies and improving prognosis.

Endoscopic resection of primary sinonasal mucosal melanoma with orbital invasion: How I do it

Primary sinonasal mucosal melanoma is a rare aggressive malignancy. In this video, a case of a 68-year-old female who presented with diplopia for 2 weeks is described. The present video reports the endoscopic endonasal surgical excision of a primary sinonasal mucosal melanoma. The video contains patient's medical history, preoperative radiological evaluations and step-by-step description of surgical steps of the procedure with the utilization of computer-assisted navigation system.

Efficacy and safety of anlotinib combined with sintilizumab in locally advanced or metastatic anaplastic thyroid carcinoma.

6103 Background: Anaplastic thyroid carcinoma (ATC) is rare aggressive and fatal malignancy with poor prognosis. Antiangiogenic and multikinase inhibitors and programmed cell death protein-1 (PD-1) antibodies have conferred benefits for ATC. We aimed to assess the efficacy and safety of anlotinib plus sintilizumab in patients with locally advanced or advanced ATC. Methods: In this prospective study, patients with histologically confirmed locally advanced or metastatic ATC, received a combination therapy of anlotinib and sintilizumab. Anlotinib was started at 12 mg once daily for 14 days and combined with sintilizumab at a fixed dose of 200 mg every three weeks. The primary end point was objective response rate (ORR), assessed in patients who received at least one dose of treatment. Tumor samples were characterized by next-generation sequencing in 12 patients and PD-L1 expression levels in 14 patients. Results: Between June 1st, 2022 and August 21st, 2023, 18 patients with locally advanced or metastatic ATC were enrolled and received combination treatment. Best overall response (BOR) within all patients was 5.6% (1/18) complete remission, 38.9% partial remission (7/18), 33.3% stable disease (6/18), and 22.2% progressive disease (4/18). ORR was 44.4% for all patients and 80.0% for 5 patients with BRAF V600E mutation. The only one patient with PD-L1 negative also reached PR. Median follow up time was 14.6 months for all patients and 16.1 months for patients with BRAF V600E mutation. The median progression-free survival was 7.5 months (0.5 to 56.3 months) for all patients and 5.7 months (1.0 to 13.1 months) for patients with BRAF V600E mutation. Duration of treatment was 5.9 months (0.5 to 38.2 months), and 8 of 18 ATC patients are still on therapy. Grade III/IV toxicities were observed in 4 of 18 patients, necessitating dose reduction/discontinuation of anlotinib. The 1-year overall survival (OS) rate was 61.1% and median OS was 12.9 months (0.6 to 56.3 months), with 8 ATC patients being still alive without progression. Conclusions: The combination of anlotinib and sintilizumab demonstrated promising activity and manageable toxicity in patients with locally advanced or metastatic ATC, suggesting its potential as a viable therapeutic option for this patient population. Clinical trial information: ChiCTR2200067045. [Table: see text]

An Update on Cutaneous Angiosarcoma Diagnosis and Treatment.

Cutaneous angiosarcoma (CAS) is a rare aggressive malignancy that most commonly manifests in White men older than 60 years and often appears as an enlarging ecchymosis on the head, neck, or scalp. Surgery with negative margins is the first-line treatment. The role of Mohs micrographic surgery (MMS) is uncertain but can be used in smaller, well-circumscribed lesions on the head and neck. The greatest impact that dermatologists can have in the management of CAS is through a thorough total-body skin examination and heightened awareness resulting in a shortened time to diagnosis. Until quality evidence allows for the creation of consensus guidelines, multidisciplinary care at a cancer center that specializes in rare difficult-to-treat tumors is essential in optimizing patient outcomes.

Where does it come from? A large pelvi-abdominal mass with points to ponder

Ureteral leiomyosarcoma is a very rare aggressive retroperitoneal malignancy with limited possibility of an accurate pre-operative diagnosis. Incidence of ureter leiomyosarcoma is extremely rare. Hence, there is paucity of reported cases in the literature. We present a case of a 60-year-old postmenopausal woman presenting with abdominal distension and discomfort. This was initially reported as a malignancy arising from left ovary, as the lesion had apparent convergence toward left adnexal region and the left ovary was not seen separately. In addition, there was moderate hydronephrosis of the left kidney and left ureter was not separately made out from the lesion. Leiomyosarcoma should be considered as a differential diagnosis in cases of ureter stricture and retroperitoneal tumors causing ureteric obstruction.

Clinical efficacy of lurbinectedin in metastatic neuroendocrine carcinomas of the genitourinary tract: Multi-institutional real-world experience.

601 Background: Neuroendocrine carcinomas (NEC) of the genitourinary (GU) tract, including small cell (SC) NEC and large cell (LC) NEC, are rare aggressive malignancies. Although highly sensitive to cisplatin-based chemotherapy, GU metastatic NEC (mNEC) have limited data to support next therapies. Lurbinectedin, a marine-derived alkylating drug and a selective inhibitor of oncogenic transcription and DNA repair pathways, is FDA-approved for small cell lung cancer (SCLC) after progression on frontline platinum-based therapy, with a disease control rate (DCR) of 68.6%. It is unknown whether DCR is similar in SCLC and GU mNEC. Methods: We report the first multi-institutional series (n=14) of lurbinectedin in GU mNEC. Imaging-based best overall responses (BOR) were noted as complete (CR), partial (PR), stable (SD), progressive (PD) or non-evaluable (NE). DCR includes CR, PR, and SD. We use the Kaplan-Meier method for overall survival (OS) and progression-free survival (PFS) from lurbinectedin start date. We define duration of response (DoR) from response date to progression or last contact date for patients (pts) with CR or PR. Results: Most pts had a median age at metastasis of 70.5 years (ICR: 64-74.5) [Table]. Primary locations were bladder (7/14, 50%), prostate (5/14, 35.7%) and ureter (2/14, 12.3%). Histology at diagnosis mostly consisted of mixed or pure SCNEC, with one exception of LCNEC. Most pts had visceral disease, prior immunotherapy and at least 2 prior lines of therapy for mNEC before lurbinectedin (8/14, 57.1%). DCR was 6/14 (42.8%), including 5 bladder pts and 1 prostate pt. Among bladder pts, BOR included one CR (1/7, 14.3%) for the LCNEC case, 2 PR (2/7, 28.6%), 2 SD (2/7, 28.6%) and 2 PD (2/7, 28.6%). Most prostate and ureteral pts either progressed on lurbinectedin or were NE (Prostate: 1 PR, 2 PD, and 2 NE; Ureteral: 1 PD and 1 NE). For all 14 pts, median OS was 11.47 months (95% CI: 2.17-13.63) and median PFS was 2.8 mo (1.4-10.9). Median DoR was 7.38 mo (2.3-9.53) for 4 responding pts (CR or PR). Treatment was stopped due to progression (9/14, 64.3%), three adverse events [thrombocytopenia, electrolyte abnormalities, cerebrovascular accident] (3/14, 21.4%), and pt preference (1/14, 7.1%). Conclusions: Lurbinectedin offers encouraging responses (DCR: 5/7, 71.4%) close to those in SCLC, in previously treated bladder mNEC. One CR was noted for a bladder pt with LCNEC. Responses were less appreciated in prostate and ureteral mNEC due to NE responses and limited number. Larger cohorts are needed to confirm survival benefit and genetic analyses are warranted to identify characteristics of responders. [Table: see text]

A Meta-Analysis Comparing the Relative Efficacy of Pediatric-Inspired Regimens Versus Hyper-CVAD for the Treatment of Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma in Adolescents, Young Adults, and Adults

Background: Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL)are rare aggressive hematologic malignancies. Children with ALL/LBL have an overall favorable prognosis; however, adult patients (pts) have a poorer outcome. As a result, pediatric or pediatric-inspired regimens with asparaginase (ASP) have been used in adolescents and young adult (AYA) pts with ALL/LBL with promising results. Unfortunately, there are no prospective randomized studies comparing this approach with hyper-CVAD, a commonly used adult regimen not containing ASP. A meta-analysis was conducted to assess the efficacy of pediatric-inspired ASP-containing regimens compared with hyper-CVAD in treating ALL/LBL in AYA and adult pts. Methods: We performed a systematic literature review (using databases including PubMed, Embase, and Cochrane Library) to identify relevant studies comparing ASP-containing regimens and hyper-CVAD in pts with ALL/LBL published up to April 21, 2022. The search strategy consisted of title/abstract key words and subject headings describing key concepts of “acute lymphoblastic leukemia,” “lymphoblastic lymphoma,” “asparaginase,” “hyper-CVAD,” “refractory,” and “minimal residual disease.” Abstracts were screened for inclusion to identify full texts that were assessed for eligibility. To determine the effects of intervention on complete response (CR) and overall survival (OS) (2 commonly reported outcomes across identified studies), odds ratios (OR) and hazard ratios (HR) were calculated. A meta-analysis was conducted using both random- and fixed-effects models to estimate the pooled OR and HR, 95% confidence intervals (CIs), and 95% prediction intervals (PIs). Scenario analyses identified potential sources of heterogeneity and bias. Results: The initial search identified 46 primary publications of potential relevance: 12 studies directly compared ASP-containing regimens and hyper-CVAD, but none were randomized. Based on direct comparison studies, ASP-containing regimens had statistically significant improvement in median OS (4 studies), 2-year OS (1 study), 3-year OS (3 studies), and 5-year OS (1 study) compared with hyper-CVAD. Four studies with comparable demographics were suitable for meta-analysis (n=702 total pts; n=366 ASP-containing regimens; n=336 hyper-CVAD): 2 studies in AYA (aged 13-43 yrs) and 2 in adults of any age (aged >16 yrs). ASP-containing regimens in the included studies were all based on Berlin-Frankfurt-Münster (BFM) or Cancer and Leukemia Group B (CALGB)-10403 protocols. Pts treated with ASP-containing regimens had a significantly higher chance of achieving CR (random- and fixed-effects model: OR, 2.04 [95% CI: 1.31, 3.18]) and improved OS (random-effects model: HR, 1.76 [95% CI: 1.36, 2.29]; fixed-effects model: HR, 1.75 [95% CI: 1.36, 2.24]) than those treated with hyper-CVAD. There was a low level of heterogeneity among studies for both CR (I 2=0%, tau^2=0.00, P=0.86) and OS (I 2=0%, tau^2=0.02, P=0.79) data. One study evaluated 2 different ASP-containing regimens vs hyper-CVAD. Two separate meta-analyses were executed: 1 pooling results from both treatment arms (base case) and 1 considering them separately (scenario 1). A further analysis was limited to just 2 studies, where the proportionality assumption for the HR was robust and the results consequently most statistically reliable (scenario 2). Compared with the base case, both scenarios yielded similar estimates of treatment effect but with greater heterogeneity and wider PIs. This analysis has limitations: the type of ASP-containing regimen varied (1 study assessed L-ASP regimens, 2 assessed pegaspargase, and 1 did not specify), the studies each took place in different countries potentially contributing to heterogeneity in cultural, genetic, and healthcare practices, and not all details of pts' clinical characteristics were reported to inform on comparability of the pt populations. Further, without head-to-head studies, there was no way to address whether treatment cost or institutional bias affected the results. Conclusion(s): Meta-analysis suggests that ASP-containing regimens are associated with improved rates of CR and OS in AYA (median age range 13-43 yrs) and adult (median age range 16-60 yrs) pts.

Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma.

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are rare aggressive hematologic malignancies. Current treatment consists of intensive chemotherapy leading to 80% overall survival but is associated with severe toxic side effects. Furthermore, 10-20% of patients still die from relapsed or refractory disease providing a strong rationale for more specific, targeted therapeutic strategies with less toxicities. Here, we report a novel MYH9::PDGFRB fusion in a T-LBL patient, and demonstrate that this fusion product is constitutively active and sufficient to drive oncogenic transformation in vitro and in vivo. Expanding our analysis more broadly across T-ALL, we found a T-ALL cell line and multiple patient-derived xenograft models with PDGFRB hyperactivation in the absence of a fusion, with high PDGFRB expression in TLX3 and HOXA T-ALL molecular subtypes. To target this PDGFRB hyperactivation, we evaluated the therapeutic effects of a selective PDGFRB inhibitor, CP-673451, both in vitro and in vivo and demonstrated sensitivity if the receptor is hyperactivated. Altogether, our work reveals that hyperactivation of PDGFRB is an oncogenic driver in T-ALL/T-LBL, and that screening T-ALL/T-LBL patients for phosphorylated PDGFRB levels can serve as a biomarker for PDGFRB inhibition as a novel targeted therapeutic strategy in their treatment regimen.

A Systematised Literature Review of Real-World Treatment Patterns and Outcomes in Unresectable Advanced or Metastatic Biliary Tract Cancer.

Biliary tract cancers are rare aggressive malignancies typically diagnosed when the disease is metastatic or unresectable, precluding curative treatment. We aimed to identify treatment guidelines, real-world treatment patterns, and outcomes for unresectable advanced or metastatic biliary tract cancers in adult patients. Databases (MEDLINE, Embase, Cochrane Database of Systematic Reviews) were systematically searched between 1 January, 2000 and 25 November, 2021, and supplemented by hand searches. Eligible records were (1) treatment guidelines and (2) observational studies reporting real-world treatment outcomes, for unresectable advanced or metastatic biliary tract cancers. Only studies performed in the UK, Germany, France, Australia, Canada and South Korea were extracted, to moderate the number of records for synthesis while maintaining representation of a wide range of biliary tract cancer incidences. A total of 66 relevant unique full-text records were extracted, including 16 treatment guidelines and 50 observational studies. Among guidelines, chemotherapies were most strongly recommended at first line (1L); the combination of gemcitabine and cisplatin (GEMCIS) was recommended as the standard of care in 1L. Recommendations for systemic chemotherapy in the second line (2L) conflicted because of uncertainties around survival benefit. Guidelines on further lines of treatment included a range of locoregional modalities and stenting or best supportive care without providing clear recommendations because of data paucity. Fifty observational studies reporting real-world treatment outcomes were extracted, of which 25 (50%) and 9 (18%) reported outcomes in 1L and 2L, respectively; 22 (44%) reported outcomes for treatments described as 'palliative'. In 1L, outcomes for systemic chemotherapy were most frequently described (23/25 studies), and GEMCIS was the most common systemic chemotherapy used (10/23 studies) in line with guidelines. Median overall survival with 1L systemic chemotherapy was <12 months in most studies (16/23; range 4.7-22.3 months). Most 2L studies (10/11) described outcomes for systemic chemotherapy, most commonly for fluoropyrimidine-based regimen (5/10 studies). Median overall survival with 2L systemic chemotherapy was <12 months in 5/10 studies (range 4.9-21.5 months). Median progression-free survival was reported more rarely than median overall survival. Some studies with small sample sizes or specifically selected patient populations (e.g. higher performance status, or patients who had already responded to treatment) achieved higher median overall survival. At the time of this review, treatment options for unresectable advanced or metastatic biliary tract cancers confer poor real-world survival. For over a decade, GEMCIS remained the 1L standard of care, highlighting the lack of therapeutic innovation in this indication and the urgent unmet need for novel treatments with improved outcomes in this aggressive condition. Additional observational studies are needed to further understand the effectiveness of currently available treatments, as well as newly available therapies including the addition of immunotherapy in the evolving treatment landscape.

Performance of DNA-based biomarkers for classification of adrenocortical carcinoma: a prognostic study.

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with heterogeneous clinical outcomes. Recent studies proposed a combination of clinical/histopathological parameters (S-GRAS score) or molecular biomarkers (BMs) to improve prognostication. We performed a comparative analysis of DNA-based BMs by evaluating their added prognostic value to the S-GRAS score. A total of 194 formalin-fixed, paraffin-embedded (FFPE) ACC samples were analysed, including a retrospective training cohort (n = 107) and a prospective validation cohort (n = 87). Targeted DNA sequencing and pyrosequencing were used to detect somatic single-nucleotide variations in ACC-specific genes and methylation in the promoter region of paired box 5 (PAX5). The European Network for the Study of Adrenocortical Tumors (ENSAT) tumour stage, age, symptoms at presentation, resection status, and Ki-67 were combined to calculate S-GRAS. Endpoints were overall (OS), progression-free (PFS), and disease-free survival (DFS). Prognostic role was evaluated by multivariable survival analysis and their performance compared by Harrell's concordance index (C index). In training cohort, an independent prognostic role was confirmed at multivariate analysis for two DNA-based BMs: alterations in Wnt/β-catenin and Rb/p53 pathways and hypermethylated PAX5 (both P< .05 for PFS and DFS, hazard ratio [HR] 1.47-2.33). These were combined to S-GRAS to obtain a combined (COMBI) score. At comparative analysis, the best discriminative prognostic model was COMBI score in both cohorts for all endpoints, followed by S-GRAS score (C index for OS 0.724 and 0.765, PFS 0.717 and 0.670, and DFS 0.699 and 0.644, respectively). Targeted DNA-based BM evaluated on routinely available FFPE samples improves prognostication of ACC beyond routinely available clinical and histopathological parameters. This approach may help to better individualise patient's management.

Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT): Patient Characteristics, Treatment, and Outcome-A Systematic Review.

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare aggressive ovarian malignancy mainly affecting children, adolescents, and young adults. Since the discovery of mutations in the SMARCA4 gene in 2014, SCCOHT has become the subject of extensive investigation. However, international uniform treatment guidelines for SCCOHT are lacking and the outcome remains poor. The aim of this systematic review is to generate an overview of all reported patients with SCCOHT from 1990 onwards, describing the clinical presentation, genetic characteristics, treatment, and outcome. A systematic search was performed in the databases Embase, Medline, Web of Science, and Cochrane for studies that focus on SCCOHT. Patient characteristics and treatment data were extracted from the included studies. Survival was estimated using Kaplan-Meier's methodology. To assess the difference between survival, the log-rank test was used. To quantify the effect of the FIGO stage, the Cox proportional hazard regression model was estimated. The chi-squared test was used to study the association between the FIGO stage and the surgical procedures. Sixty-seven studies describing a total of 306 patients were included. The median patient age was 25 years (range 1-60 years). The patients mostly presented with non-specific symptoms such as abdominal pain and sometimes showed hypercalcemia and elevated CA-125. A great diversity in the diagnostic work-up and therapeutic approaches was reported. The chemotherapy regimens were very diverse, all containing a platinum-based (cisplatin or carboplatin) backbone. Survival was strongly associated with the FIGO stage at diagnosis. SCCOHT is a rare and aggressive ovarian cancer, with a poor prognosis, and information on adequate treatment for this cancer is lacking. The testing of mutations in SMARCA4 is crucial for an accurate diagnosis and may lead to new treatment options. Harmonization and international collaboration to obtain high-quality data on diagnostic investigations, treatment, and outcome are warranted to be able to develop international treatment guidelines to improve the survival chances of young women with SCCOHT.

Incidence of other multiple primary malignancies in patients with adrenocortical carcinoma.

e16621 Background: Adrenocortical carcinoma (ACC) is an exceedingly rare aggressive endocrine malignancy with about 1 new case per million people diagnosed annually in the US. Higher incidence of ACC has been reported in patients (pts) with inherited syndromes such as Lynch syndrome and Li-Fraumeni syndrome. However, the incidence rate of developing multiple primary cancers in this population is unknown. The aim of this study is to investigate the frequency of additional malignancies in ACC patients. Methods: Using the Mayo Clinic Cancer Registry, we identified 63 pts who were treated for ACC from 2010- 2018 with updated follow up data until 01/31/2023. Electronic medical records were reviewed. Results: Among the patient cohort, 22 pts were male. 18/63 (29%) pts were found to have at least one additional malignancy, including basal cell carcinoma (3/18, 17%), melanoma (3/18, 17%), thyroid cancer (3/18, 17%), prostate cancer (3/18, 17%), squamous cell carcinoma of skin (2/18, 11%), renal cell carcinoma (2/18, 11%), breast cancer (2/18, 11%), leukemia (2/18, 11%), lung cancer (1/18, 6%), transitional cell malignant neoplasm of kidney (1/18, 6%), squamous cell carcinoma of tonsil (1/18, 6%), ovarian cancer (1/18, 6%), seminoma (1/18, 6%) and bladder cancer (1/18, 6%). 8/18 (45%) pts had more than one (2-3) non-ACC malignancies. The median age at diagnosis of ACC was 56 years (02-83). The median age at diagnosis of non-ACC malignancies was 54 years (25-72). Most of the patients (13/18) were diagnosed with non-ACC malignancy within 5 years of diagnosis of ACC. Most pts (13/18, 72%) were diagnosed with non-ACC malignancy first. Germline mutation information was not available except for 2 pts with known family history (FH) of Lynch syndrome and 2 pt with a known FH of Li-Fraumeni syndrome. FH was available in 38 pts, out of which 29 pts had FH of cancer identified in first-degree relatives. Among the 18 pts with additional malignancies, 12 pts had FH of cancer in first-degree relatives. All except 2 pts underwent curative treatment for their non-ACC malignancies, and 14 pts had no evidence of disease at death or the time of last follow-up. Conclusions: The rate of other multiple primary malignancies in pts with ACC is high, indicating possible genetic predisposition associated with this disease; Early genetic consultation and evaluation for known and novel germline mutations may need to be considered for these pts to improve long-term outcomes.

FDG PET/CT Findings of Malignant Rhabdoid Tumor Arising From a Renal Allograft.

Malignant rhabdoid tumor of the kidney is a rare aggressive malignancy with poor prognosis. We describe FDG PET/CT findings in a case of malignant rhabdoid tumor of the renal allograft with regional lymph node and pulmonary metastases. The primary renal tumor and lymph node metastases showed intense FDG uptake. The pulmonary metastases showed minimal FDG uptake due to small size. Posttreatment FDG PET/CT showed no evidence of residual disease. This case suggests that FDG PET/CT may be useful in the management of malignant rhabdoid tumor from the transplanted kidney.

Transcriptomic and immunophenotypic characterization of two cases of adamantinoma-like Ewing sarcoma of the thyroid gland.

Adamantinoma-like Ewing sarcoma (ALES) is a rare aggressive malignancy occasionally diagnosed in the thyroid gland. ALES shows basaloid cytomorphology, expresses keratins, p63, p40, frequently CD99, and harbours the t(11;22) EWSR1::FLI1 translocation. There is debate on whether ALES resembles more sarcoma or carcinoma. We performed RNA sequencing from two ALES cases and compared findings with skeletal Ewing's sarcomas and nonneoplastic thyroid tissue. ALES was investigated by in situ hybridization (ISH) for high-risk human papillomavirus (HPV) DNA and immunohistochemistry for the following antigens: keratin 7, keratin 20, keratin 5, keratins (AE1/AE3 and CAM5.2), CD45, CD20, CD5, CD99, chromogranin, synaptophysin, calcitonin, thyroglobulin, PAX8, TTF1, S100, p40, p63, p16, NUT, desmin, ER, FLI1, INI1, and myogenin. An uncommon EWSR1::FLI transcript withretained EWSR1 exon 8 was detected in both ALES cases. Regulators of EWSR1::FLI1 splicing (HNRNPH1, SUPT6H, SF3B1) necessary for production of a functional fusion oncoprotein, as well as 53 genes (including TNNT1, NKX2.2) activated downstream to the EWSR1::FLI1 cascade, were overexpressed. Eighty-six genes were uniquely overexpressed in ALES, most of which were related to squamous differentiation. Immunohistochemically, ALES strongly expressed keratins 5, AE1/AE3 and CAM5.2, p63, p40, p16, and focally CD99. INI1 was retained. The remaining immunostains and HPV DNA ISH were negative. Comparative transcriptomic profiling reveals overlapping features of ALES with skeletal Ewing's sarcoma and an epithelial carcinoma, as evidenced by immunohistochemical expression of keratin 5, p63, p40, CD99, the transcriptome profile, and detection of EWSR1::FLI1 fusion transcript by RNA sequencing.

Primary Sinonasal Neuroendocrine Carcinoma Invading the Orbit: Case Report and Review of Literature

Primary sinonasal neuroendocrine carcinoma (SNEC) is a rare aggressive sinonasal malignancy which typically occurs in the ethmoidal bone or sinuses, with a slight male preponderance. No risk factors have been identified. With a very few reported cases. Most patients present in advanced stages due to the lack of significant symptoms. Nomenclature has been ambiguous, but SNECs can be classified as well-, moderately- or poorly differentiated. Its treatment is not well established. We report the case of a large cell neuroendocrine carcinoma (LCNEC) in a 34 years old patient presented the occurrence of a right epistaxis. The beginning of the symptomatology goes back to 1 year before, with right nasal obstruction of progressive onset, associated with right epistaxis and bloody rhinorrhea with right chronic eye watering. Nasosinusal MRI shows a right nasal mass enhanced strongly after injection of gadolinium, extension to contralateral ethmoidal cells with orbital bone lysis and cribriform plate of the Ethmoid bone. The Histopathologic analysis of the mass biopsy showed a poorly differentiated carcinomatous tumor proliferation with positive neuroendocrine markers. The multidisciplinary decision taken was the treatment by chemotherapy before surgery.

Nectin-4: a Tumor Cell Target and Status of Inhibitor Development.

This study aims to gather the current state of the literature about anti-Nectin-4 innovative associations in solid tumors and to investigate underlying resistance mechanisms. Antibody-drug conjugate (ADC) targeting Nectin-4 efficacy gained attention and offers a promising association with other antineoplastic drugs especially in urothelial carcinoma. The heterogeneity of Nectin-4 expression across the molecular subtypes was highlighted especially in urothelial cancers. A unique study using preclinical models demonstrated an upregulation of P-gp expression, which may explain the anti-Nectin-4 resistance mechanisms. Further studies are urgently needed to understand anti-Nectin-4 sensitivity and resistance phenomenon. The growing therapeutic associations of enfortumab vedotin offer optimistic opportunities in management and treatment of wide range of solid tumors including rare aggressive malignancies.

Role of non-coding RNAs and exosomal non-coding RNAs in retinoblastoma progression.

Retinoblastoma (RB) is a rare aggressive intraocular malignancy of childhood that has the potential to affect vision, and can even be fatal in some children. While the tumor can be controlled efficiently at early stages, metastatic tumors lead to high mortality. Non-coding RNAs (ncRNAs) are implicated in a number of physiological cellular process, including differentiation, proliferation, migration, and invasion, The deregulation of ncRNAs is correlated with several diseases, particularly cancer. ncRNAs are categorized into two main groups based on their length, i.e. short and long ncRNAs. Moreover, ncRNA deregulation has been demonstrated to play a role in the pathogenesis and development of RB. Several ncRNAs, such as miR-491-3p, miR-613,and SUSD2 have been found to act as tumor suppressor genes in RB, but other ncRNAs, such as circ-E2F3, NEAT1, and TUG1 act as tumor promoter genes. Understanding the regulatory mechanisms of ncRNAs can provide new opportunities for RB therapy. In the present review, we discuss the functional roles of the most important ncRNAs in RB, their interaction with the genes responsible for RB initiation and progression, and possible future clinical applications as diagnostic and prognostic tools or as therapeutic targets.

Primary Vitreoretinal Lymphoma: Current Diagnostic Laboratory Tests and New Emerging Molecular Tools.

Primary vitreoretinal lymphoma (PVRL), a rare aggressive malignancy primarily involving the retina and/or the vitreous, is a major diagnostic challenge for clinicians (who commonly misdiagnose it as chronic uveitis) as well as for pathologists (for biological and technical reasons). Delays in diagnosis and treatment are responsible for visual impairments and life-threatening consequences, usually related to central nervous system involvement. The identification of lymphoma cells in vitreous fluid, obtained by vitrectomy, is required for diagnosis. Of note, the scarcity of neoplastic cells in small volumes of vitreous sample, and the fragility of lymphoma cells with degenerative changes caused by previous steroid use for presumed uveitis makes diagnosis based on cytology plus immunophenotyping difficult. Interleukin levels, immunoglobulin heavy chain or T-cell receptor gene rearrangements, and MYD88 mutation are applied in combination with cytology to support diagnosis. We aim to describe the current laboratory technologies for PVRL diagnosis, focusing on the main issues that these methods have. In addition, new emerging diagnostic strategies, such as next-generation sequencing analysis, are discussed. The genetic profile of PVRL remains largely unexplored. Better knowledge of genetic alterations is critical for precision medicine interventions with target-based treatments of this lymphoma for which no standardised treatment protocol currently exists.

P11.71.B Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) in a patient with blastic plasmacytoid dendritic cell neoplasm: a rare neurologic manifestation in a rare disease

Abstract Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid hematological malignancy. Skin lesions, bone marrow, lymph nodes or visceral organs can be involved. 30% of patients will have infiltration to the nervous system,occult asymptomatic infiltration is frequent. Immunophenotype express CD4, CD56, and CD123, and flow cytometry is essential. Material and Methods 70-yo Hispanic male with a 1-month history of multiple violaceous cutaneous nodules and adenopathies.Neurological complaints included diplopia, hypoesthesia in the left face, dysphagia, gait difficulties, and generalized weakness with distal hypoesthesia. Examination revealed multiple cranial neuropathy (bilateral VI and VII nerve palsies, left V3 and VIII palsies and IX, X involvement), global areflexia, length-dependent weakness, ataxic gait and cerebellar syndrome. An inguinal ganglionar biopsy retrieved cells positive for CD4, TCL1, CD68 and CD123, whereas CD3, CD20, CD7, CD8, CD30 and myeloperoxidase were negative. PET/CT showed multiple supra and infradiaphragmatic adenopathies, bilateral pleural, pericardial and abdominal implants. Bone marrow biopsy was negative. Brain MRI showed contrast enhancement in the cerebellar folia and in the roots of the cranial nerves clinically involved. Multiple CSFs demonstrated high protein count (281- 310mg/dl), normal glucose and cell count; CSF flow cytometry and cytology reported no blastic infiltration (negative CD4, CD56 and CD123), CSF onconeuronal antibodies were negative. Nerve conduction studies fulfilled definite electrodiagnostic EFNS criteria for CIDP. Sural nerve biopsy reported inflammatory demyelination without infiltration. Systemic chemotherapy (Cyclophosphamide/Vincristine) with intrathecal cytarbine/methotrexate was administered. Results Favorable initial, but brief response was noticed for the cranial nerves and gait. He had neurological relapse with gait impossibility. Neuraxis MRI showed no contrast enhancement in the brain but new contrast enhancement of lumbosacral roots. Nerve conduction studies reported severe worsening criteria of CIDP. The PET/CT demonstrated complete response. Five days of methylprednisolone (1gr IV) followed by oral prednisone were prescribed (50 mg qd). However, two weeks later he suffered clinical neurological worsening with respiratory failure. IVIg was started (.4g/kg/day for 5 days) with no improvement; palliative care decision was consented. Conclusion We report the case of an adult male with multiple cranial nerve palsy, cerebellar syndrome and refractory rapidly progressive asymmetric polyneuropathy with BPDCN. CIDP in the absence of multiple attempts to demonstrate nervous system infiltration led us to consider this as a paraneoplastic phenomenon refractory to treatment. To our knowledge no CIDP has been reported in this rare disease

A Primary Extracutaneous Presentation of Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare aggressive cutaneous neuroendocrine malignancy with a mortality rate of around 33%. The presence of advanced disease at the time of diagnosis is associated with poor prognosis. Twofold etiologies have been described in the pathogenesis of Merkel cell carcinoma: chronic exposure to ultraviolet (UV) light and Merkel cell polyomavirus (MCPvY). MCC usually affects sun-exposed skin areas, and the presence of cutaneous nodules is the hallmark of the disease. However, there have been case reports in the literature where the diagnosis of MCC was made in the absence of any cutaneous findings. We present a case report of Merkel cell carcinoma that is unique in its presentation because of the presence of pulmonary and hepatic nodules and the absence of cutaneous lesions.