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Background: Adolescent and young adult (AYA) patients with cancer are poorly recruited to molecularly targeted trials and have not witnessed the advances in cancer treatment and survival seen in other age groups. We report here a pan-European proof-of-concept study to identify actionable alterations in some of the worst prognosis AYA cancers: bone and soft tissue sarcomas. Design: Patients aged 12–29 years with newly diagnosed or recurrent, intermediate or high-grade bone and soft tissue sarcomas were recruited from six European countries. Pathological diagnoses were centrally reviewed. Formalin-fixed tissues were analysed by whole exome sequencing, methylation profiling and RNA sequencing and were discussed in a multidisciplinary, international molecular tumour board. Results: Of 71 patients recruited, 48 (median 20 years, range 12–28) met eligibility criteria. Central pathological review confirmed, modified and re-classified the diagnosis in 41, 3, and 4 cases, respectively. Median turnaround time to discussion at molecular tumour board was 8.4 weeks. whole exome sequencing (n = 48), methylation profiling (n = 44, 85%) and RNA sequencing (n = 24, 50%) led to therapeutic recommendations for 81% patients, including 4 with germ line alterations. The most common were for agents targeted towards tyrosine kinases (n = 20 recommendations), DNA repair (n = 18) and the PI3K/mTOR/AKT pathway (n = 15). Recommendations were generally based on weak evidence such as activity in a different tumour type (n = 68, 61%), reflecting the dearth of relevant molecular clinical trial data in the same tumour type. Conclusions: We demonstrate here that comprehensive molecular profiling of AYA patients' samples is feasible and deliverable in a European programme.

Background Soft tissue sarcomas (STS) are rare, heterogeneous tumours and biomarkers are needed to inform management. We previously derived a prognostic tumour microenvironment classifier (24-gene hypoxia signature). Here, we developed/validated an assay for clinical application. Methods Technical performance of targeted assays (Taqman low-density array, nanoString) was compared in 28 prospectively collected formalin-fixed, paraffin-embedded (FFPE) biopsies. The nanoString assay was biologically validated by comparing to HIF-1α/CAIX immunohistochemistry (IHC) in clinical samples. The Manchester (n = 165) and VORTEX Phase III trial (n = 203) cohorts were used for clinical validation. The primary outcome was overall survival (OS). Results Both assays demonstrated excellent reproducibility. The nanoString assay detected upregulation of the 24-gene signature under hypoxia in vitro, and 16/24 hypoxia genes were upregulated in tumours with high CAIX expression in vivo. Patients with hypoxia-high tumours had worse OS in the Manchester (HR 3.05, 95% CI 1.54–5.19, P = 0.0005) and VORTEX (HR 2.13, 95% CI 1.19–3.77, P = 0.009) cohorts. In the combined cohort, it was independently prognostic for OS (HR 2.24, 95% CI 1.42–3.53, P = 0.00096) and associated with worse local recurrence-free survival (HR 2.17, 95% CI 1.01–4.68, P = 0.04). Conclusions This study comprehensively validates a microenvironment classifier befitting FFPE STS biopsies. Future uses include: (1) selecting high-risk patients for perioperative chemotherapy; and (2) biomarker-driven trials of hypoxia-targeted therapies.

Purpose:Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation.Experimental Design:We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing.Results:We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation–damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women.Conclusions:This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.

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Primary non-neuroendocrine tumours of the pituitary gland and sella are rare lesions often challenging to diagnose. We describe two cases of clinically aggressive primary glomus tumour of the pituitary gland. The lesions occurred in a 63-year-old male and a 30-year-old female who presented with headache, blurred vision and hypopituitarism. Neuroimaging demonstrated large sellar and suprasellar tumours invading the surrounding structures. Histologically, the lesions were characterised by angiocentric sheets and nests of atypical cells that expressed vimentin, smooth muscle actin and CD34. Perivascular deposition of collagen IV was also a feature. Case 2 expressed synaptophysin. INI-1 (SMARCB1) expression was preserved. Both lesions were mitotically active and demonstrated a Ki-67 labelling index of 30%. Next-generation sequencing performed in case 1 showed no mutations in the reading frame of 37 commonly mutated oncogenes, including BRAF and KRAS. Four pituitary glomus tumours have previously been reported, none of which showed features of malignant glomus tumour. Similar to our two patients, three previous examples displayed aggressive behaviour.

A 51-year old presented with a 6-month history of increasing pelvic/lower back pain with nocturnal waking and episodes of anorexia and vomiting. Examination revealed right torticollis and Horner’s syndrome, and a large abdominal mass arising from the pelvis. Magnetic resonance and positron emission tomography imaging revealed A) a 14cm heterogeneous enhancing mass, abutting the left kidney with standardised uptake value max=2.9, B) a large heterogeneous enhancing pelvic mass C) mesenteric adenopathy standardised uptake value max=10.3 and D) 6cm right lung apex mass standardised uptake value max=4.3.Computerised tomography-guided biopsy of lesion A was reported as neurofibroma with occasional atypia, lesion B a benign uterine leiomyoma and lesion C follicular Lymphoma world health organisation Grade 2.Although she had been given the diagnosis of Neurofibromatosis Type-1 (NF1) 25-years previously following removal of an intradural extramedullary schwannoma she had no cutaneous stigmata of NF1. Genetic analysis of blood lymphocyte DNA identified a pathogenic variant in SMARCB1 confirming a diagnosis of schwannomatosis..Following 6-months chemotherapy for lymphoma, surgery was performed to remove lesion A. Histology revealed a malignant peripheral nerve sheath tumour with areas of low and high-grade change. An incidental, well-differentiated small bowel neuroendocrine carcinoma was also excised. Close surveillance continues with no recurrence after six years. This case study describes a novel finding of three separate synchronous primary malignancies in a patient with schwannomatosis and a proven SMARCB1 pathogenic variant.

Purpose Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women are more protected from aggressive cutaneous squamous cell carcinoma (cSCC) due to strong immune activation. Methods We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients (N= 738, N=160) with carcinoma cSCC, in FVB/N mice exposed to equal doses of DMBA, and in human keratinocytes by whole exome sequencing, bulk and single cell RNA sequencing. Results We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test if sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T cell infiltration independently of mutations. In contrast, males increase the rate of mitoses and proliferation in response to carcinogen. Human female skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at ultraviolet radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. Conclusions This work shows the immune response is sex biased in cSCC, and highlights female immunity offers greater protection than male immunity. Translational relevance Sex bias affects cancer incidence, mortality and therapy response; and the molecular landscape of cancer differs by sex. However, it is not known if the sex discrepancy is due to a difference in behaviour and exposure to carcinogens, or due to sex-linked susceptibility. This work reveals men are inherently more susceptible to cutaneous aggressive squamous cell carcinoma, in contrast to women who activate stronger immune responses when challenged with the same carcinogens. The loss of immunity particularly affects women. Personalised medicine approaches stratify cancer patients by genotype; however, to date, the potential for cancer stratification, prevention strategies and therapy by sex and immune competency has not been explored. These data indicate men require targeted prevention programs and increased monitoring. Furthermore, we provide a rationale to prioritise men and immunosuppressed women for adjuvant therapy and immunotherapy.

Objective: Soft tissue sarcoma (STS) is a rare malignancy with a 5 year overall survival rate of 55%. Neoadjuvant radiotherapy is commonly used in preparation for surgery, but methods to assess early response are lacking despite pathological response at surgery being predictive of overall survival, local recurrence and distant metastasis. Multiparametric MR imaging (mpMRI) is used to assess response in a variety of tumours but lacks a robust, standardised method. The overall aim of this study was to develop a feasible imaging protocol to identify imaging biomarkers for further investigation. Methods: 15 patients with biopsy-confirmed STS suitable for pre-operative radiotherapy and radical surgery were imaged throughout treatment. The mpMRI protocol included anatomical, diffusion-weighted and dynamic contrast-enhanced imaging, giving estimates of apparent diffusion coefficient (ADC) and the area under the enhancement curve at 60 s (iAUC60). Histological analysis of resected tumours included detection of CD31, Ki67, hypoxia inducible factor and calculation of a hypoxia score. Results: There was a significant reduction in T1 at visit 2 and in ADC at visit 3. Significant associations were found between hypoxia and pre-treatment iAUC60, pre-treatment ADC and mid-treatment iAUC60. There was also statistically significant association between mid-treatment ADC and Ki67. Conclusion: This work showed that mpMRI throughout treatment is feasible in patients with STS having neoadjuvant radiotherapy. The relationships between imaging parameters, tissue biomarkers and clinical outcomes warrant further investigation. Advances in knowledge: mpMRI-based biomarkers have good correlation with STS tumour biology and are potentially of use for evaluation of radiotherapy response.

Introduction: Yearly, around 45,000 new diagnoses of cancer in the adolescent and young adult (AYA) population are made in Europe, with sarcoma and brain tumors being some of the most prevalent tumor types.Despite great progress being made in understanding the molecular landscape of cancer in children and adults, AYA cancer biology is still poorly understood. Material and Methods: To identify clinically relevant molecular alterations in this patient population, we aimed to recruit 50 evaluable patients aged between 12 and 29 with high-risk, sarcoma at initial diagnosis or relapse, using the EORTC-SPECTA platform (deRojas et al. IJC, 2020) and perform in depth molecular analysis (WES, RNAseq, array-based DNA methylation profiling) and central pathology review. Between April 2019 and July 2020, 71 patients were recruited from nine sites within six European countries. In total, 48 patients were evaluable. The remainder (32%) failed quality control, mainly due to poor quality of the formalin-fixed and paraffin-embedded tumor tissue. Median age at diagnosis was 19 years (range 6 to 28 years), including 25 cases of newly diagnosed sarcoma and 23 cases of recurrent sarcoma. Results: Central pathology review was performed for all evaluable patients. The local diagnosis was confirmed in 41 cases (85.4%) and changed in 7 cases (14.6%), including new diagnoses of BCOR sarcomas (n=3) and teratoma (n=1). DNA methylation analysis was performed for all cases with adequate DNA (n=46), and profiles were categorized according to the Heidelberg classifier (Koelsche et al., Nature Communication, 2021). The classifier confirmed the diagnosis of central pathology in 32 cases (69.6%). The remaining cases showed discrepancies mainly due to poor DNA quality. Whole-exome and RNA sequencing were performed on all samples where DNA and/or RNA quality permitted (98% and 48% respectively).Pathology and molecular profiling results were discussed at a monthly combined clinico-pathological tumor board, with the goal of adapting treatment strategies based on molecular profile either for this treatment episode or for future progression. Actionable molecular alterations were identified in 39 cases. Treatment was adapted in 3 cases and confirmed in 1. Treatment was not adapted in the remainder because they were undergoing primary treatment (n=14), undergoing an alternative treatment for progression (n=10), due to death prior to molecular tumor board (n=10) or loss to follow-up (n=1). Conclusion: Despite expected logistic challenges associated with sample quality and analysis, actionable alterations were identified in 81.2% of evaluable patients, confirming that there is an unmet clinical need in this population. Moreover, we have identified remediable organizational factors to reduce sample failures and increase the turnaround speed of recommendations in this overlooked AYA cancer population. Citation Format: Marie Morfouace, Peter Horak, Simon Kreutzfeldt, Patrick Shenjere, Eva Wardelmann, Evgeniya Denisova, Aleksandra Stevovic, Francisco J. Bautista, Julio Oliveira, Winette van der Graaf, Stefan Fröhling, Martin G. McCabe. First results of the EORTC-SPECTA project on comprehensive molecular profiling of adolescent and young adult sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2005.

E-cadherin is expressed in hematopoietic erythroid precursors, but to our knowledge, its expression in blastic plasmacytoid dendritic cell neoplasm (BPDCN) has not been described. We report a case of BPDCN showing strong expression of E-cadherin, arising in a patient with history of primary myelofibrosis. Four more cases of BPDCN tested all showed strong expression of E-cadherin. Lack of awareness of this pattern of expression may lead to erroneous diagnosis of acute erythroid leukemia. It is increasingly becoming important to correctly identify this group of neoplasms, as approved new anti-CD123–targeted therapies are becoming available.

Introduction & Objectives: Abdominopelvic sarcomas are rare soft tissue tumours associated with high rates of local recurrence. Complete macroscopic resection of the tumour remains the primary treatment. This study assesses the surgical outcomes of patients with abdominopelvic sarcomas treated at a single tertiary urology referral centre over a 5-year period. Materials & Methods: Electronic patient records of all abdominopelvic sarcoma resections performed between May 2013 and November 2018 were retrospectively reviewed. The following parameters were assessed: Histology, pre-operative haemoglobin (Hb) level, ECOG performance status, grade, tumour size, stage and margin status. The 8th edition Union for International Cancer Control (UICC) stage classification system was utilised for retroperitoneal sarcoma (RPS) patients. Log-rank and Kaplan-Meir methods were utilised to complete univariate analysis for overall survival (OS) and disease-free survival (DFS). Results: In total, 53 patients with abdominopelvic sarcomas underwent surgical resection. Median age at surgery was 65 years (27-83 years). Median follow-up was 23 months (1-72 months). The 3 year OS and DFS were 74% and 41% respectively. Histologic subtypes are summarised in table 1. The 3 year OS of well-differentiated liposarcoma (WDLPS) and other histologic subtypes (OHS) was 91.7% and 67% respectively (p=0.041). The 3 year DFS of WDLPS and OHS was 92.3% and 19.8% respectively (p

Renal myopericytoma is an extremely rare entity with just 11 cases reported in the literature. We report the case of a 57 year old Caucasian man who was found to have a renal myopericytoma following nephrectomy for suspected renal cell carcinoma. Renal myopericytoma has a distinct morphological overlap with other pericytic tumours and significant histological variation has been noted between cases reported to date. Further characterising this novel tumour is vital to identify subtypes within this spectrum, understand its behaviour and to identify imaging trends which may lead to pre-operative diagnosis in order to potentially avoid radical treatment.

Background For most adolescent and young adult (AYA) cancers, age-specific molecular features are poorly understood. SPECTA, an academic translational research infrastructure for biomaterial collection and molecular analysis, will explicitly recruit AYA patients and will therefore collect empirical data to bridge the molecular gap between pediatric and adult oncology. Trial Design The initial pilot study, activated in February 2019 across Europe, will recruit 100 patients aged 12-29 years with newly diagnosed or relapsed high-grade gliomas and high-grade bone and soft tissue sarcomas. The primary objective of the pilot is to determine feasibility and recruitment rates. Formalin-fixed tumor tissue, whole blood and clinical data from study participants will be prospectively collected; the biomaterial will be stored centrally at the Integrated BioBank of Luxembourg (IBBL). Whole exome sequencing (WES) of matched tumor and blood, and tumor RNA sequencing and DNA methylation profiling will be performed at the German Cancer Research Center (DKFZ), Heidelberg. Virtual central pathology review of scanned diagnostic slides will be undertaken by an international expert panel, and diagnostic material returned to the participating centers. A multidisciplinary molecular tumor board will release a clinically validated report to referring clinicians within 4-6 weeks after biopsy. SPECTA-AYA constitutes a major opportunity to gain knowledge about the tumor biology of this unique age group. It incorporates notable innovative aspects: AYA specificity, pan-European academic collaboration, centralized biobanking, comprehensive molecular profiling, and virtual central pathology review, among others. SPECTA-AYA will help untangle the tumor particularities of AYAs with cancer and aims to improve their access to novel drugs and personalized medicine. Legal entity responsible for the study EORTC (European Organisation for Research and Treatment of Cancer). Funding Walgreens Boots Alliance. Disclosure W. Van der Graaf: Research grant / Funding (self): Novartis; Honoraria (institution), Advisory / Consultancy: Bayer. F. Bielle: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Spouse / Financial dependant: Celgene; Research grant / Funding (self), Shareholder / Stockholder / Stock options, Spouse / Financial dependant: Crossject; Research grant / Funding (self), Shareholder / Stockholder / Stock options, Spouse / Financial dependant: Sanofi; Research grant / Funding (self), Shareholder / Stockholder / Stock options, Spouse / Financial dependant: AbbVie. M. Preusser: Honoraria (self): Bayer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Gerson Lehrman Group (GLG); Honoraria (self): CMC Contrast; Honoraria (self): GlaxoSmithKline; Honoraria (self): Mundipharma; Honoraria (self): Roche; Honoraria (self): Astra Zeneca; Honoraria (self): AbbVie; Honoraria (self): Lilly; Honoraria (self): Medahead; Honoraria (self): Daiichi Sankyo; Honoraria (self): Merck Sharp & Dohme. S. Frohling: Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Pfizer. M.G. McCabe: Advisory / Consultancy: Ipsen Pharma. All other authors have declared no conflicts of interest.

We evaluated the outcomes for patients with peripheral T-cell lymphoma (PTCL) undergoing front-line chemotherapy at our institutions between 2002 and 2012. One hundred and fifty-six patients were eligible, comprising PTCL not otherwise specified (NOS) (n = 50, 32.0%), angioimmunoblastic T-cell lymphoma (AITL) (n = 44, 28.2%), anaplastic large-cell lymphoma (ALCL) ALK negative (n = 23, 14.7%), ALCL ALK positive (n = 16, 10.3%), and other (n = 23, 14.7%). Most patients received CHOP (66.0%) and 13.0% received an autologous hematopoietic progenitor cell transplant (HPCT). With a median follow-up of 63.4 months, 5-year overall survival (OS) and progression-free survival (PFS) was 38.8% and 19.8% respectively. Independent risk factors for inferior OS were age60 years, International Prognostic Index (IPI) ≥ 2 and lack of complete response to induction. When responding patients were compared by receipt of an autologous HPCT versus not, HPCT was associated with improved PFS (p = .001) and OS (p = .046) and remained significant for PFS in multivariate analysis suggesting a possible therapeutic benefit.

Background: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial. Methods: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan–Meier and Cox regression. Results: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44–3.59, P

Our aims are to determine levels of circulating cellular and protein biomarkers in hepatocellular carcinoma (HCC) patients and to analyse any relationships with clinical parameters. Fifty-four consenting patients were recruited. Circulating tumour cells (CTCs) were enumerated (by CellSearch) and characterised via filtration [by isolation by size of epithelial tumour cells (ISET)] with downstream immunohistochemistry (IHC). Glypican-3 (GPC3) expression in tumour biopsies and CTCs (by IHC) was compared, and levels of circulating caspase-cleaved and full-length cytokeratin 18 (CK18, measured using M30 and M65 ELISAs) were examined as a putative prognostic factor and marker of tumour burden. CTCs were identified in 14 out of 50 (28 %) patients by CellSearch and in 19 out of 19 (100 %) patients by ISET. The presence of GPC3-positive CTCs by ISET was 100 % concordant with the presence of GPC3-positive cells in the original tumour (n = 5). No statistically significant correlations were observed between CTC number and clinical characteristics, although trends were noted between CTC subtypes, Child–Pugh score and tumour node metastasis stage. Serum M30 and M65 levels (as continuous variables) significantly correlated with overall survival (OS) in a univariate analysis (p = 0.003 and p

Epithelioid haemangioma of the penis is a rare condition which usually presents a solid single nodule. We report a case in a 43-year-old man who presented with painful erections and sleep disturbance with two palpable penile nodules. Magnetic resonance imaging with an artificially induced erection revealed these as individual lesions, and local excision was successfully undertaken. Pathological diagnosis of epithelioid haemangioma was confirmed with positive staining for CD31. Although rare, penile epithelioid haemangioma should be considered as a differential in an atypical penile mass. Induction in of an artificial erection prior to MRI can aid diagnosis and treatment is typically with surgical excision.

We previously demonstrated that circulating tumour cells (CTCs) are detectable by the MelCAM and high molecular weight melanoma-associated antigen (HMW-MAA)-dependent CellSearch platform. However, CTCs which do not express these capture and detection markers are not detectable by CellSearch. Consequently, we explored the use of isolation by size of epithelial tumour cells (ISET), a marker independent, filtration-based device to determine the prevalence and heterogeneity of CTCs in metastatic cutaneous melanoma patients. Ninety patients were prospectively recruited and blood samples taken before treatment. Patients' blood was filtered using the ISET platform. CTCs were enumerated using dual immunohistochemistry with positive selection by S100 expression and exclusion of leucocytes and endothelial cells expressing CD45 or CD144, respectively. A panel of markers (Melan-A, MITF, MelCAM, high molecular melanoma-associated antigen, CD271 and MAGEC) was also examined. Fifty-one patients (57%) had CTCs (range 1-44 CTCs/4 ml blood) and 12 patients also had circulating tumour microemboli. Seven patients had S100- CTCs, 11 patients' CTCs were S100+ and 33 patients had S100+ and S100- CTCs. Substantial intrapatient and interpatient heterogeneity was observed for all other melanoma-associated markers. CTCs in metastatic cutaneous melanoma are detectable using the flexible marker-independent ISET platform. CTCs display significant marker expression heterogeneity implying that marker-dependent platforms would not detect all CTCs and multimarker assays are now required to reveal the biological significance of this CTC heterogeneity.

Patients with adenoid cystic carcinoma of the salivary glands show over-expression of KIT in a high proportion of cases. Options for systemic treatment are limited in locally advanced and metastatic disease. We explored the efficacy of imatinib and cisplatin combined in this group of patients. A Gehan's two-stage, phase II trial was conducted on 28 patients. Those with progressive, locally advanced, and metastatic disease with an over-expression of KIT were treated with single agent imatinib 800 mg daily for two months, followed by a combination of imatinib 400mg daily and cisplatin 80 mg/m(2) at four-weekly intervals for six cycles. This was followed by maintenance single agent imatinib 400mg daily until the disease progressed. Response was monitored using fluorodeoxyglucose positron emission tomography (FDG-PET) and morphological imaging using computed tomography, magnetic resonance, and chest radiographs (CT/MRI/CXR). Morphological imaging showed partial response in three of 28 patients, and five patients showed a response on FDG-PET. In addition, 19 patients had useful stabilisation of disease. The median time to progression and overall survival was 15 months (range 1-43) and 35 months (range 1-75), respectively. The combination of imatinib and cisplatin was reasonably well tolerated. This combination may provide stabilisation in locally advanced and metastatic adenoid cystic carcinoma of the salivary glands.

Primary pulmonary osteosarcoma is very rare. Most cases are secondary deposits from primaries arising in the appendicular skeleton. Four cases of primary osteogenic sarcoma of the lung are described and the literature reviewed for previously reported cases. These pulmonary tumors occur in patients who are in their fourth to seventh decades, that is, an older age group than their primary bone equivalent. There is a slight male predominance. There appears to be a propensity for the left lung, especially the left upper lobe. The clinical presentation is similar to primary (epithelial) lung cancer. Differentiation from pleomorphic carcinomas and other sarcomas is discussed. We know of no predisposing factor(s) in our cases for the development of this tumor.

Four cases of CD30-positive T-cell lymphoproliferative disorder (CD30+ LPD) of the oral mucosa are described. This article aims to draw attention to this entity and to emphasize its usual benign clinical behavior despite its resemblance to T-cell lymphoma. All the patients were adults. Three of the lesions were on the dorsal surface of the tongue and 1 affected the buccal mucosa. All biopsies showed a dense lymphoid infiltrate composed of CD30+ atypical T cells with a polymorphous infiltrate in the background, which included eosinophils. In 1 case, monoclonal T-cell expansion was detected by molecular techniques. Three cases tested for Epstein—Barr virus were all negative. It is concluded that primary CD30+ T-cell LPD of the oral mucosa can be regarded as the oral counterpart of cutaneous CD30+ LPD such as lymphomatoid papulosis or anaplastic large cell lymphoma. Recognition of the condition is important to avoid overtreatment.

first year that cutaneous warts on the hands were assessed, were included in this analysis (Melski et al., 1977; Stern et al., 1979). The Mann-Whitney (Wilcoxon) twosample test for medians and Student t test for means were used to test for statistical significant differences between groups. Poisson regression was used to calculate the association of developing subsequent SCCs or BCCs with the presence of cutaneous hand warts in 1985e1986 and other risk factors. Age, sex, geographic location, and population incidence rates were used to calculate expected number of tumors (Scotto et al., 1974; Stern et al., 1979). We performed a univariate analysis of the association of cutaneous warts with previous history of SCC or BCC, level of exposure to PUVA up to the year 1985, high UVB exposure (300 treatments or more), high doses of methotrexate (if given for 36 or more months), and high doses of cyclosporine (if given for 2 or more years). Factors significant on univariate analysis were included in the multivariable model.

We describe 2 new cases of malignant melanoma with divergent rhabdomyoblastic differentiation occurring in adult patients. The patients were women aged 67 and 51 years with primary cutaneous and uterine cervical melanoma, respectively. Rhabdomyoblastic differentiation in melanoma is very rare in adult patients, and to our knowledge, only 7 such cases have been described in the world literature, of which only 4 have conclusive documentation of the presence of rhabdomyoblastic differentiation. We present the fifth and sixth cases of adult melanomas with conclusive divergent rhabdomyoblastic differentiation, including the first noncutaneous (cervical) case; we also review the literature and highlight the potential for underrecognition of this phenomenon.

Extranodal non-Hodgkin's lymphoma (NHL) within the female genital tract is unusual, accounting for 1.5% of extranodal NHL, mostly in the ovaries. Primary NHLs of the uterus and cervix are rare, comprising only 0.54%–0.64% of all extranodal NHLs, most occurring in the cervix.1 Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) of the uterus is extremely rare, with only seven cases reported in the literature.2–8 We report a rare case of an extranodal marginal zone B cell lymphoma arising from the MALT tissue of the endometrium. A 77-year-old woman presented with utero-vaginal prolapse, urinary frequency and nocturia; she had no B symptoms. Examination revealed a cystocoele and a cervical prolapse. There was no palpable lymphadenopathy or hepatosplenomegally and she underwent vaginal hysterectomy and pelvic floor repair. The uterus and cervix measured 8.3×2.6×2.2 cm. The endometrium was 0.2 cm thick and the myometrium 1.6 cm thick; both appeared normal. Microscopically, the endometrium and superficial myometrium contained a nodular infiltrate of monotonous, small to medium-sized, lymphoid cells (figure 1A). The cells …

Some view ultrastructure as key to myofibrosarcoma diagnosis, whereas others argue that electron microscopy is too little used in contemporary practice to be considered an important diagnostic tool. These views are discussed in the context of 10 ultrastructurally confirmed cases of myofibrosarcoma, some occurring at rare sites such as skin and penis. Patient age ranged from 21 to 83 years, with a 6:4 male to female ratio. Size ranged from 2 to 7.5 cm and all had infiltrative margins. Histologically, all consisted of variably cellular fascicles of spindle cells with mild to moderately pleomorphic nuclei, small punctate nucleoli, and eosinophilic cytoplasm. All cases showed α-smooth muscle actin positivity and 2 showed very focal weak positivity for desmin. Ultrastructurally, the tumor cells contained rough endoplasmic reticulum, mainly peripheral smooth-muscle myofilaments, and fibronectin fibrils or fibronexus junctions at the cell surface. The most confident diagnosis of myofibrosarcoma is provided by ultrastructural examination. However, given the right histological appearance, use of a panel of antibodies that includes α-smooth muscle actin, desmin, and h-caldesmon, serves as an acceptable practical way of diagnosing myofibrosarcoma.

Clear-cell sarcoma (CCS) is a soft-tissue neoplasm that morphologically resembles cutaneous malignant melanoma but has a distinct molecular profile. Gastrointestinal and intra-abdominal CCSs are very rare. Here, the authors present 3 cases of intra-abdominal CCS and review the literature. Of these cases, 2 involved the small bowel, and 1 involved the peritoneum. Cases 1 and 3 had the characteristic CCS morphology, but case 2 was morphologically unusual and therefore difficult to diagnose. It had relatively small cells with less prominence of clear cells; many pseudoglandular structures were also present. It also showed aberrant expression of epithelial membrane antigen (EMA). The other 2 cases also involved some diagnostic uncertainty and were therefore referred to specialized centers. The authors wish to emphasize the importance of molecular studies in making a conclusive diagnosis of intra-abdominal CCS.

A 48-year-old woman presented with chest symptoms. Multiple lesions seen on chest imaging were found to be pulmonary chondromas following surgical resection. Whole body magnetic resonance scan performed to investigate the possibility of Carney triad demonstrated a gastric lesion. This was resected and found to be a gastrointestinal stromal tumor. No evidence of paragangliomata was found on imaging. A diagnosis of incomplete Carney triad was made. Carney triad is a rare multiple neoplastic association of pulmonary chondroma, gastrointestinal stromal tumor, and paraganglioma. At least 2 tumors are required for diagnosis. Most patients are young women. No genetic cause has been identified. Management involves surgical resection of tumors and follow-up for recurrence and investigation for other elements of the triad.

Alveolar rhabdomyosarcoma (ARMS) is one of the major categories of rhabdomyosarcomas; it encompasses malignant tumors of striated muscle and occurs more frequently in the extremities. It is uncommonly reported in young adults and extremely rarely found in middle-aged and elderly patients.A 54-year-old man presented to a rapid head and neck clinic with a history of rapid enlargement of neck lumps on the right side of his neck over a period of 5 weeks. The diagnosis of an undifferentiated malignant small round cell tumor was made from cytologic examination of the aspirated sample, and biopsy of the lesion was advised. On histologic analysis, diagnosis of solid variant of ARMS was made.A solid variant of ARMS in an older population has not been published in the literature within the settings of a rapid head and neck clinic. Therefore, the remote possibility of this diagnosis should be considered in the differential diagnosis of a malignant, round cell tumor in fine needle aspiration cytology in an older patient's neck lump.

Tumours and tumour-like lesions of myofibroblasts may present diagnostic difficulty because of their rarity and because of uncertainties in identifying the myofibroblast. The objectives of this review are to provide a definition of the myofibroblast and an account of its biology for facilitating an understanding of the cell and of myofibroblastic lesions; and to describe, in the context of common diagnostic problems, the features of benign and malignant myofibroblastic lesions. The main characteristics of the myofibroblast include a spindled or stellate morphology; immunostaining for alpha-smooth muscle actin and the extra domain A variant of cellular fibronectin; and an ultrastructure of rough endoplasmic reticulum, peripheral contractile filaments and the cell-to-matrix junction known as the fibronexus. On this basis, lesions traditionally regarded as myofibroblastic are shown to vary in their level of differentiation, and some appear to be smooth muscle rather than myofibroblastic. Immunohistochemistry and electron microscopy, used together, are emphasised as being important for maximum diagnostic confidence in some myofibroblastic lesions.

A case of multiple myeloma is reported in which the bone marrow contained sheets of histiocytes with light microscopic features mimicking Gaucher cells. The patient had no clinical evidence of inherited Gaucher's disease. These pseudo-Gaucher cells obscured neoplastic plasma cells causing diagnostic difficulty.

Background Melanoma subtypes are increasingly defined by genetic alterations (BRAF mutations in 50% and NRAS in 20% of cutaneous, c-Kit aberrations in acral and mucosal and GNA11 mutations in uveal melanomas. Targeted therapies such as vemurafenib in cutaneous and imatinib in mucosal melanomas have emerged. CMCs are a potential biomarker to assess response to treatment, monitor disease relapse and provide new targets for drug development. Molecular characterisation of CMCs may provide utility as a predictive biomarker to drug treatment. Methods The CellSearch marker dependent platform (Veridex, USA) enriches for CMCs utilising Melcam antibody for CMC capture and High Molecular Weight Melanoma associated Antigen (HMW-MAA) antibody for CMC detection. MART-1 was used as an additional CMC kit detection marker. The ISET marker independent platform (Isolation by Cell Size, Rarecells, France) enriches for CMCs based on cell size. Immunohistochemistry with CD45 and CD144 (leukocyte and endothelial cell markers) and S100 (melanoma marker) was performed to identify CMC characteristic staining and morphology. Results Twenty-three patients with metastatic disease were recruited prospectively (mucosal n = 13, uveal n = 10). CellSearch detected CMCs in 6/11mucosal (range 0-125, mean 21 median 1) and 7/10 uveal (range 0-510, mean 57 median 3) melanomas. MART-1 positive CMCs were detected in both subtypes but circulating tumour microemboli (CTM) were found only in mucosal melanomas. ISET detected CMCs in 10/12 mucosal (range 0-26, mean 4 median 2) and 7/10 uveal (range 0-19, mean 7 median 3) melanomas. CMCs were both S100+ and S100-. No CTM were detected by ISET. Comparison of the platforms in 20 patients (n = 10 of each mucosal and uveal melanomas) revealed variability in CMC detection between platforms (Spearman's correlation p = 0.17). Conclusions This is the first report of CMC detection by CellSearch in mucosal and uveal melanomas. Comparison with ISET revealed no relationship between numbers of CMCs detected in the same patients by each platform thus indicating significant CMC heterogeneity in CMC marker expression and size. Circulating tumour microemboli may indicate collective cell migration thus probing the biology of metastases formation. Disclosure G. Clack: Ownes stocks in Astra-Zeneca pharmaceuticals. A. Hughes: ownes shares in Astra-Zeneca pharmaceuticals. All other authors have declared no conflicts of interest.