Malignant Component Research Articles

A role for immunotherapy: preventing macrophage anergy in the tumour environment

The tumour microenvironment is shaped by the interaction of tumour cells with a variety of “non” malignant cellular and acellular components. It is the secretion of cytokines, chemokines, metabolites and other mediators in the tumour stroma that shapes the natural evolution of cancer. Whereas the tumour strives to promote an immunosuppressive environment to limit anti-tumour immune response, infiltrating immune cells aim to control tumour growth. The balance between these two conflicting interests shapes the immune contexture of cancer and ultimately patient prognosis. In an effort to characterize the role played by macrophages, we have developed an in vitro system using human pancreatic tumour cell lines and a human monocyte-macrophage leukemic cell line (ThP1). We have investigated the immunosuppressive properties of pancreatic cancer cell lines and how the immune properties of macrophages are influenced by the tumour supernatant in vitro. We have applied our findings to a clinically relevant murine model of pancreatic cancer. We found that, despite some heterogeneity, the profile of MIAPACA-2, BxPC3 and PANC-1, included IL-8, MCP-1, SCF and VEGF secretion. Not surprisingly, when ThP1 cell were cultured in the presence of increasing concentrations of tumour supernatant and stimulated with LPS, we observed a significant downregulation of their ability to produce cytokines associated with an M1 profile (e.g. IL-6, IL-12p70, IL-23, TNF-α). However, ThP1 also failed to display an M2 profile; IL-10 and IL-1ra were similarly downregulated. ThP1 stimulated with LPS in the presence of tumour supernatant also had impaired secretion of a number of other cytokines such as IL-18, MIP-1α and MIP-1β and MCP-1. In contrast, they appeared to maintain secretion of VEGF and IL-7. Next we investigated how the immune stimulant IMM-101, an immunotherapeutic agent comprising heat-killed whole cell Mycobacterium obuense, might be able to shift this anergic phenotype. IMM-101 is currently under clinical evaluation in two Phase II clinical trials in pancreatic (EudraCT number 2010-022757-42) and colorectal cancer (EudraCT number 2011-003958-85). We found that despite the presence of tumour supernatant, macrophages stimulated with IMM-101 retained the ability to secrete the full range of cytokines and we did not observe the impairment reported after LPS stimulation. We believe the immunological properties of IMM-101 make this a potential candidate for successful immunotherapy.

Diagnosis of a Tail Gut Cyst By Endosonographically Guided-Fine Needle Aspiration

Background: Retrorectal cyst hamartomas or tail gut cysts (TGC) are rare developmental cysts that arise in the retrorectal region. They are most commonly seen in middle-aged women. Traditionally, pathologic diagnosis of TGC was provided on surgical resection. However, recently, endoscopic ultrasound (EUS) with fine needle aspiration (FNA) has been used to establish diagnosis. So far only one case of tail gut cyst diagnosed by EUS-guided FNA has been reported. We report another rare case of tail gut cyst diagnosed by EUS-guided FNA.Figure: EUS image of TGC.Case Report: A 46-year-old female with lower abdominal pain was referred to our institution for evaluation of perirectal mass noted upon digital rectal examination. She had an unremarkable colonoscopy. CT abdomen revealed a multiloculated cystic mass anterior to the lower sacrum to the right of midline and posterolateral to the rectum. EUS showed a well delineated hypoechoic mass with a few cystic spaces measuring 3.7 x 3.4 cm in the retrorectal space anterior to the sacrum at 15 cm from the anal verge. The lesion involved the serosa and had both solid and cystic components. FNA of the lesion was performed and was consistent with anucleate squamous cells with mild atypia, keratin debris with scattered multinucleated histiocytes consistent with TGC. Post procedure, patient developed perirectal abscess due to inadequate antibiotic prophylaxis which was drained. Patient improved clinically and is scheduled to follow-up with surgery for further management. Conclusion: TGC affecting the anorectum can be asymptomatic or cause mass related symptoms such as pain or constipation. Malignant components have only been rarely reported in these anomalies. Differential includes epidermoid cyst, dermoid cyst and rectal duplication cyst. These are usually unilocular versus TGCs which are multilocular. EUS-guided FNA may provide an accurate and reliable diagnosis of TGC. This less invasive technique has the potential to be used as an alternative to surgery for establishing diagnosis. This may allow observation and avoid surgery in asymptomatic patients. Further studies are needed to help establish the safety and efficacy of this promising method.

Second Annual Workshop of the Mid-Atlantic Chapter of the American Society of Peritoneal Surface Malignancy

Second Annual Workshop of the Mid-Atlantic Chapter of the American Society of Peritoneal Surface Malignancy, Mercy Medical Center, Baltimore, MD, USA, 20–21 June 2013 The annual workshop is dedicated to the regional advancement and coordination of efforts to control the peritoneal surface component of gastrointestinal and gynecologic malignancy. It was attended by surgeons, medical oncologists, radiologists, gastroenterologists and nurses involved in clinical and laboratory research efforts to optimally manage peritoneal metastases and peritoneal mesothelioma. During the first day of the 2-day meeting, presentations were coordinated with live video transmission from the operating room at Mercy Medical Center (MD, USA). The live surgery, didactic speeches and patient presentations were displayed for open discussion in real-time. Twenty regional and global opinion leaders spoke and interacted regarding clinical and research information relevant to the rapidly developing multidisciplinary subspecialty of peritoneal surface oncology.

Carcinoma ex pleomorphic adenoma of the upper lip: a case of an unusual malignant component of squamous cell carcinoma

BackgroundSquamous cell carcinoma (SCC) as the malignant component of carcinoma ex pleomorphic adenoma (CXPA) occurring in upper lip is rare.Case reportA 55-year-old male patient presented with an asymptomatic mass of the upper lip that had noticed 8 years previously. The mass was clinically suspected to be a benign salivary gland tumor based on palpation and magnetic resonance imaging findings. A needle biopsy was then carried out, and the pathological diagnosis was pleomorphic adenoma. The tumor was removed under general anesthesia. Histopathological examination revealed well-demarcated tumor tissues showing typical histologic features of pleomorphic adenoma. However, SCC tissue with several mitotic figures was found in the central area of the tumor tissue. The tumor was finally diagnosed as CXPA. There was no evidence of recurrence or metastasis 6 years postoperatively.ConclusionThis is the first report of CXPA of the upper lip with an unusual malignant component of SCC.

Expression, Tissue Distribution and Function of miR-21 in Esophageal Squamous Cell Carcinoma

ObjectiveMiR-21 is an oncomir expressed by malignant cells and/or tumor microenvironment components. In this study we focused on understanding the effects of stromal miR-21 on esophageal malignant cells.DesignMiR-21 expression was evaluated in formalin-fixed paraffin-embedded samples from patients with esophageal squamous-cell carcinoma (SCC) by quantitative RT-PCR. MiR-21 tissue distribution was visualized with in situ hybridization. A co-culture system of normal fibroblasts and esophageal cancer cells was used to determine the effects of fibroblasts on miR-21 expression levels, and on SCC cell migration and invasion.ResultsMiR-21 was overexpressed in SCCs, when compared to the adjacent non-tumor tissues (P = 0.0007), and was mainly localized in the cytoplasm of stromal cells adjacent to malignant cells. Accordingly, miR-21 expression was increased in tumors with high versus low stromal content (P = 0.04). When co-cultured with normal fibroblasts, miR-21 expression was elevated in SCC cells (KYSE-30), while its expression was restricted to fibroblasts when co-cultured with adenocarcinoma cells (OE-33 and FLO-1). MiR-21 was detected in conditioned media of cancer cell lines, illustrating the release of this miRNA into the environment. Co-culturing with normal fibroblasts or addition of fibroblast conditioned media caused a significant increase in cell migration and invasion potency of KYSE-30 cells (P<0.0001). In addition, co-culturing cancer cells with fibroblasts and expression of miR-21 induced the expression of the cancer associated fibroblast (CAF) marker S100A4.ConclusionsMiR-21 expression is mostly confined to the SCC stroma and its release from fibroblasts influences the migration and invasion capacity of SCC cells. Moreover, miR-21 may be an important factor in “activating” fibroblasts to CAFs. These findings provide new insights into the role of CAFs and the extracellular matrix in tumor microenvironment formation and in tumor cell maintenance, and suggest miR-21 may contribute to cellular crosstalk in the tumor microenvironment.

Conventional spindle cell–type malignant peripheral nerve sheath tumor arising in a sporadic schwannoma

Malignant peripheral nerve sheath tumor is a malignant tumor showing nerve sheath differentiation. Approximately one-half of malignant peripheral nerve sheath tumors arise from a benign peripheral nerve sheath tumor, which is commonly a neurofibroma in patients with neurofibromatosis type 1. Malignant peripheral nerve sheath tumor arising in a sporadic schwannoma of soft tissue is extremely rare. In this condition, malignant cells usually show epithelioid morphology, meeting the diagnostic criteria for epithelioid malignant peripheral nerve sheath tumor. Here, we present an extraordinary case of spindle cell-type malignant peripheral nerve sheath tumor arising in a schwannoma on the back of a 58-year-old woman without neurofibromatosis. The malignant component showed hypercellular spindle cell proliferation with high mitotic activities; in contrast, the benign component showed hypocellular spindle cell proliferation in a palisading pattern and with Verocay bodies. Immunohistochemical S-100 protein staining showed a clear contrast between the malignant (negative) and benign (positive) components, which was useful for differentiating cellular schwannoma. Recognizing this rare condition is helpful in the pathologic diagnosis of schwannoma showing cellular proliferation in part.

Impact of the histological type on the prognosis of patients with prenatally diagnosed sacrococcygeal teratomas: the results of a nationwide Japanese survey

To identify the impact of the histological diagnosis on the prognosis of prenatally diagnosed sacrococcygeal teratoma (SCT), we analyzed the data obtained during prenatal surveillance and assessed the postnatal outcomes in a large cohort of fetuses with SCT in Japan. A nationwide retrospective cohort study was conducted among 97 fetuses prenatally diagnosed with SCT between 2000 and 2009. Of these, 84 had a histological diagnosis. In addition, we conducted a second surveillance program of the prognosis of 72 patients who were reported to be alive at the initial surveillance conducted 2 years previously. The tumors comprised 51 (61 %) mature teratomas, 33 (39 %) immature teratomas and 0 (0 %) malignant teratomas. Immature teratomas were also associated with a significantly higher mortality rate (immature teratomas: 8/31, mature teratomas: 2/48). Late recurrence was observed in six of 72 cases (8.3 %). Among these six cases, recurrence with a malignant component was observed in four patients. All six patients were successfully treated. Mature teratoma was the most common histological type observed in this study. The patients with immature teratomas exhibited an increased risk of mortality. Late recurrence was observed in 8.3 % of the cases.

Hybrid Peripheral Nerve Sheath Tumors, Including a Malignant Variant in Type 1 Neurofibromatosis

The authors report a small case series of hybrid nerve sheath tumors occurring in the setting of type 1 neurofibromatosis. Four lesions were benign and consisted of plexiform neurofibromas with considerable areas of perineuriomatous differentiation in patients with type 1 neurofibromatosis. In these lesions, biphasic (Schwannian and perineuriomatous) differentiation was apparent on immunohistochemistry, with the perineuriomatous areas staining for epithelial membrane antigen, glut-1, and claudin-1 and being negative for S-100 protein. Three patients were members of a single family, with a history of various malignant neoplasms. Included in the series is 1 hybrid lesion in which neurofibromatous and perineuriomatous areas were clearly visible on hematoxylin- and eosin-stained slides. The lesion was unique in that it manifested malignant change in the S-100 protein-positive component, which was classified as malignant peripheral nerve sheath tumor. The malignant component showed areas with an epithelioid cell morphology.

CD10 is frequently expressed in classical seminomas.

CD10 is a cell surface metalloproteinase widely expressed in various normal tissue and in epithelial, stromal or both components of various malignancies. The aim of our study was to investigate, for the first time, the expression of CD10 in a series of 135 cases of testicular germ cell tumours in order to asses its possible diagnostic and biologic significance. The expression of CD10 was studied, using immunohistochemistry, in 96 pure forms and 39 mixed forms of germinal cell tumours of the testis. Immunostaining for CD10 was positive in 68/74 (92%) seminomas and 16/24 (67%) seminomatous component of mixed germ cell tumours. The intratubular germ cell neoplasia of the unclassified type always expressed CD10. Anaplastic seminomas, embryonal carcinomas, teratoma and spermatocytic seminomas were negative for CD10. Our findings indicate that only seminomas and intratubular germ cell neoplasia, the precursors of germ cell tumours, express CD10, but when they differentiate along embryonal, somatic, trophoblastic, yolk sac lines they lose CD10 expression. CD10 could be considered a useful marker to differentiate seminoma from other forms of testicular germ cell tumours and for a better estimation of the seminomatous component in mixed germ cell tumours.

Cell mates: paracrine and stromal targets for prostate cancer therapy

After many years of limited treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), multiple systemic therapies are now available, providing patients with significant improvements in survival, symptom control and bone health. Most of the recent advances in this area have been based on better understanding of mCRPC biology, particularly with respect to the key role of androgen receptor signalling. However, most therapies are targeted towards the malignant epithelial cell component of the cancer and it should not be forgotten that cancer cells exist in close and symbiotic relationships with other components of the tumour. Paracrine and stromal signals are often critical to the growth of the cancer and represent new potential therapeutic targets that are separate from the malignant epithelial cells. The stroma produces numerous growth factors, including vascular endothelial growth factor family members, platelet-derived growth factors and fibroblast growth factors, which are all critical for tumour growth. Targeting prostate-cancer-associated fibroblasts in order to destroy the physical and functional scaffold of a cancer is also a logical approach. The interaction between prostate cancer and the immune system remains an active topic of basic and clinical research, with cytokines, chemokines and growth factors being potential targets for therapy. The biology of epithelial-mesenchymal transition and of circulating tumour cells might also provide insight into new therapeutic targets.

Relationship between primary and metastatic testicular germ cell tumors: a clinicopathologic analysis of 100 cases

Testicular germ cell tumors (GCTs) commonly metastasize to the retroperitoneal lymph nodes (RPLNs). We evaluated 100 cases of RPLN dissection specimens with viable GCTs after chemotherapy and compared them with their corresponding orchiectomy specimens. The mean age of patients was 28 years (range, 15-58 years). The testicular tumors consisted of mixed GCT (n = 72), teratoma (n = 18), seminoma (n = 4), embryonal carcinoma (n = 3), yolk sac tumor (n = 1), and no viable tumor (n = 2). Somatic malignant components were found in 5 cases. The metastatic tumors in the RPLNs consisted of only teratoma (n = 77) and non-teratomatous GCT (n = 23). Twenty-one patients had only teratoma in the RPLNs but not in the testis, and 10 patients had metastatic non-teratomatous GCT components that were not observed in the testis. Six patients had somatic malignant components in the RPLNs, but only one of them had such a component in the testis. Overall, 13 patients died of disease in a mean of 42 months, and the patients with only teratoma in the RPLNs had a lower mortality rate (9%) than those with non-teratomatous components (26%) (P = .044). One patient with somatic components in the primary GCT and 3 patients with somatic components in the metastases died of disease. Our study demonstrates that there is frequent discordance of histologic composition between primary and metastatic testicular GCTs. Teratoma is the most common component in treated GCTs and is usually associated with a more favorable clinical outcome than non-teratomatous GCTs. The presence of somatic components in the RPLNs metastasis indicates a poor prognosis.

Watchful waiting for some children with a mediastinal mass: the potential role for 18 F-fluorodeoxyglucose positron emission tomography: a case report and review of the literature

BackgroundBenign hyperplastic thymus is a rare but important differential diagnosis of anterior mediastinal lesions. Histological and radiological criteria are used to distinguish this benign condition from other malignant diseases but have their limitations, and biopsy of mediastinal masses can be risky. We report for the first time the diagnostic value of fluorodeoxyglucose 18 F positron emission tomography for patients with incidentally identified anterior mediastinal masses to avoid biopsy in some cases.Case presentationA 2 year old girl presented with new onset of emesis and constipation leading to the incidental discovery of an anterior mediastinal mass on radiograph. Chest computed tomography revealed cystic components within the mass concerning for a malignancy. Biopsy of the lesion and bone marrow aspiration and biopsy were negative but there was concern that the mediastinal biopsy may have missed the malignant component of the lesion. Hence, a positron emission tomography scan was obtained that showed mild homogeneous fluorodeoxyglucose 18 F avidity within the mass similar to that of normal thymus. The diagnosis of benign hyperplastic thymus was made.ConclusionThe differential diagnosis of an incidentally found anterior mediastinal mass includes malignancy, but benign lesions such as benign hyperplastic thymus must also be considered, particularly when the complete blood count and biochemical profile are normal. Fluorodeoxyglucose 18 F positron emission tomography can help guide a clinician’s decision for further interventions and treatment.

Salivary Duct Carcinoma: New Developments—Morphological Variants Including Pure In Situ High Grade Lesions; Proposed Molecular Classification

Salivary duct carcinoma (SDC) is an aggressive primary salivary malignancy which microscopically resembles high-grade ductal carcinoma of the breast, with both in situ and invasive patterns. It is typically found in older men, most often in the parotid. It can arise de novo or as the malignant component of carcinoma ex pleomorphic adenoma. SDC is generally a hematoxylin and eosin stain-based diagnosis, with special stains and immunohistochemistry acting mainly in a confirmatory role. Other than epithelial markers, SDC expresses androgen receptors in most cases, with true HER2 positivity seen in about 15 %. Based on these data and analogous to similar schemes in the breast, it is suggested that SDCs can be classified into three main groups: luminal androgen receptor positive, HER2+ and basal phenotype. This may form the basis for prognostic information and new therapeutic possibilities. In addition to the usual type of SDC, a few less common morphological variants have been reported: papillary, micropapillary, mucin-rich, sarcomatoid and oncocytic, as well as pure in situ cases.

A distinct histopathological variant of a malignant melanoma with perivascular pseudorosettes: A case report

Although a rare condition, rosette formation in malignant melanoma has been previously documented. The present study describes the second documented case of malignant melanoma with perivascular pseudorosettes. A 38-year-old male presented with a black nodule on his back. Histopathological study revealed diffuse proliferation of neoplastic cells in the dermis and subcutis. A section of the tumor (~30%) was composed of a conventional malignant melanoma component. The remaining area was comprised of medium-sized polygonal cells with slightly eosinophilic cytoplasm and small-to-medium, round nuclei. Melanin pigment was rarely observed. A noteworthy observation was the presence of perivascular pseudorosette formations, which were characterized by their radial arrangement around the blood vessels, with a perivascular, anuclear zone. Immunohistochemically, the neoplastic cells were diffusely positive for S-100 protein and Melan-A and focally positive for HMB-45. Clinicopathological analyses of cases of malignant melanoma with rosette formations revealed that the types of rosette included the Homer-Wright type (two cases), perivascular pseudorosettes (two cases) and an unclassifiable type (one case). Immunohistochemical analysis is a useful method for forming a diagnosis as Melan-A or HMB-45 are generally expressed in all cases. Rosette formation in malignant melanoma is a distinct histopathological variant and may be an under-recognized phenomenon. Therefore, its recognition is significant for obtaining an accurate diagnosis of malignant melanoma.

Impact of treatment strategies on local control and survival in uterine carcinosarcomas.

e16526 Background: Carcinosarcoma is a biphasic neoplasm composed of a mixture of malignant epithelial and mesenchymal components. Uterine carcinosarcomas comprise only 3% of all uterine malignancies, however they account for a disproportionally higher rate of mortality from uterine cancer because of their agressive nature. No standardized treatment has yet been established. The purpose of this study was to determine the clinical characteristics, patterns of recurrence and survival outcomes in patients with uterine carcinosarcoma treated in our institution. Methods: Records of the patients with uterine carcinosarcoma were retrospectively evaluated and 29 pts with carcinosarcoma diagnosed between 2007 and 2012 were identified. All patients were initially treated surgically by the same surgeon with comprehensive staging, i.e. total abdominal hysterectomy, bilateral salphingooopherectomy , bilateral pelvic and paraaortic lymph node dissection and omentectomy. Demographic features, tumor characteristics, treatment regimens and patient outcomes in terms of relapse-free survival (RFS) and overall survival (OS) were analyzed. Results: Median age was 63 (range 43-78). 13 patients (45%) had stage I disease, 5 patients (17%) had stage III and 11 patients (38%) had stage IV disease at diagnosis. Median tumor size was 6 cm (range 1.7-20 cm) and lymphovascular invasion was present in 17 patients 59%). Twenty patients (69%) received chemotherapy (90% with paclitaxel and carboplatin) for 6 cycles. One patient received radiotherapy. Median follow up was 13 mos. Seventeen patients (59%) relapsed and 20 patients (69%) died on follow up. Two patients had vaginal cuff recurrence, 4 had pelvic, 4 had abdominal and 7 had distant recurrences. All recurrences were fatal. 3 year RFS was 31%. 3 year OS was 15%. Conclusions: Our data show that uterine carcinosarcomas tend to be more at more advanced stage at diagnosis and despite the use of chemotherapy and radiotherapy, overall prognosis is poor. Surgery remains the mainstay of treatment. More effective adjuvant strategies are needed to reduce relapse and death rates because recurrences are generally fatal.

Adult with cerebellar anaplastic pilocytic astrocytoma associated with BRAF V600E mutation and p16 loss

Pilocytic astrocytoma (PA) is the most common pediatric tumor, with the vast majority being benign (WHO Grade I). Herein, we present a rare sporadic (not radiation- or NF1-associated) anaplastic PA arising from the cerebellum of an adult patient. The diagnosis was based on the coexistence of classic PA and more cellular foci, associated with both tumor necrosis and up to 27 mitoses per 10 high power fields. Based on these features, the tumor was felt to be equivalent in biological behavior to that of a WHO Grade III astrocytoma. Additional genetic studies revealed the presence of a BRAF V600E mutation. In comparison to the foci of classic PA, the malignant component showed increased p53 protein expression, decreased p16 protein expression, and hemizygous p16 gene deletion by FISH analysis. This case provides additional support for the concept of anaplastic transformation in PA and further elucidates the possible molecular pathways associated with malignant progression.

De novo Ovarian Squamous Cell Carcinoma. A Case Report and Review of Literature

Malignant ovarian tumours comprise of a spectrum of clinicopathologic entities. Many have comparable presenting clinical features, some are associated with unique and intriguing histomorphological features. Not only does a histopathology define a tumour’s ontogeny and biology, they may also predict prognosis and help plan an adjuvant therapy. What follows is a 17th case report of an exceedingly rare primary ovarian tumour (pure, de novo), squamous cell carcinoma (SCC). However, it is known that 2 % of mature teratomas harbour malignant component and up to 80 % will be squamous. Some pure SCCs will arise in association with a foci of endometriosis and very rarely entirely de novo [1–4]. SCC of ovary are aggressive tumours, which may be amenable to multimodality treatment. Due to conflicting evidence from literature, the best therapeutic option cannot be deciphered. Treatment needs to be tailored to patient profile.

Precursors and pathogenesis of ovarian carcinoma

The ultimate goal of defining cancer specific precursors is to facilitate early detection and intervention before the development of invasive malignancy. Unlike other malignancies involving the female genital tract such as cervical or endometrial carcinomas, precursor lesions of ovarian carcinomas have not been well characterised, resulting in a failure to develop effective screening programs. Recent clinicopathological and molecular studies have provided new insight into the origin and pathogenesis of ovarian carcinomas. It has been shown that ovarian cancer is comprised of different tumour types differing not only in morphology, but also in pathogenesis, molecular alterations and clinical progression. A dualistic model of ovarian carcinogenesis has been proposed. Type I tumours which include low grade serous, low grade endometrioid, clear cell, mucinous carcinomas and Brenner tumours, are generally indolent and tend to be genetically stable, although clear cell carcinoma would probably belong to an intermediate category. They demonstrate a step-wise progression from a benign precursor such as a benign to borderline tumour or endometriosis and are characterised by genetic aberrations targeting specific cell signalling pathways. Type II tumours comprise high grade serous, high grade endometrioid, and undifferentiated carcinomas as well as malignant mixed mesodermal tumours. They are clinically aggressive and exhibit high genetic instability with frequent p53 mutations. Mounting evidence suggests that many high grade serous carcinomas originate from the epithelium of the distal fallopian tube, and that serous tubal intraepithelial carcinoma (STIC) represents the putative precursor of these neoplasms. Low grade serous carcinomas arise via transformation of benign and borderline serous tumours, thought to be derived from inclusion cysts originating from the ovarian surface or tubal epithelium. Recently it has been suggested that papillary tubal hyperplasia may be a putative precursor lesion for serous borderline tumours. Both endometrioid and clear cell carcinomas develop from endometriosis, via alterations affecting different genetic pathways. The origin of mucinous and transitional cell neoplasms is not well characterised, although new data suggest a possible origin from transitional cell nests present at the tubal-mesothelial junction. Likewise, the pathogenesis of carcinosarcomas is also not well established because of their rarity but there is accumulating evidence that the carcinomatous component determines the course of the disease and gives rise to the malignant mesenchymal component. This review discusses recent developments in the pathogenesis of ovarian carcinoma, with particular emphasis on the putative precursor lesions that give rise to the major histological subtypes. Recognition of these lesions is not only important in improving the understanding of ovarian carcinogenesis, but it will also influence our approach to prevent, detect and treat these tumours.

Expression of receptor tyrosine kinases in esophageal carcinosarcoma

Esophageal carcinosarcoma (ECS) is a rare malignant neoplasm associated with a poor patient prognosis. It is characterized by the presence of both malignant epithelial and mesenchymal components. Molecular-targeted therapy of several receptor tyrosine kinases (RTKs) has been reported to be effective in the treatment of various malignant tumors, including carcinosarcoma of several organs. This study aimed to assess the therapeutic potential of targeting RTKs in ECS. Overexpression of RTKs was assessed in 21ECS cases by immunohistochemistry (IHC). Positively stained cases were further examined for RTK gene mutations and amplifications by direct sequencing analysis and fluorescence insitu hybridization. In epithelial components, KIT, platelet-derived growth factor receptor (PDGFR)A, PDGFRB, MET, epidermal growth factor receptor (EGFR) and HER-2 were overexpressed in 1 (4.8%), 1 (4.8%), 0 (0%), 11 (52.4%), 13 (61.9%) and 2 (9.5%) cases, respectively. In the mesenchymal components the corresponding numbers of cases were 2 (9.5%), 2 (9.5%), 0 (0%), 12 (57.1%), 11 (52.4%) and 0 (0%). No mutations in the c-kit, PDGFRA and c-met genes were found. Among 19EGFR-positive tumors, 2 had EGFR missense mutations (T790A, exon 20) only in the mesenchymal component. Gene amplification or high polysomy of c-kit, PDGFRA, c-met and EGFR was observed in 1 (33.3%), 0 (0%), 3 (18.8%) and 10 (52.6%) cases, respectively. In conclusion, various RTKs, particularly MET and EGFR were overexpressed in ECSs suggesting that molecular-targeted therapies directed to MET, EGFR or other RTKs may be effective in inhibiting the growth or progression of the epithelial and/or mesenchymal component of ECS.

Sinonasal teratocarcinosarcoma: a clinicopathologic and immunohistochemical study of 6 cases

Teratocarcinosarcoma (TCS) is a rare and unusual malignant neoplasm of the sinonasal tract with a heterogenous morphology and an aggressive behavior. Patients are predominantly adults with a male predominance. The aim of this study was to describe clinicopathologic and immunohistochemical features of 6 cases of TCS. The ages ranged from 18 to 67 years (mean, 33 years) with a male-to-female ratio of 5:1. Most tumors were located in the nasal cavity. Nasal obstruction and epistaxis were the common presenting symptoms. Histologically, all tumors exhibited a heterogeneous morphology with varying proportions of benign and malignant epithelial, mesenchymal, and neuroepithelial elements. Adenocarcinoma was the malignant epithelial component in all cases. The mesenchymal elements were composed of benign to malignant spindle cells. Osteosarcomatous areas were seen in 2 cases and rhabdomyosarcoma in 1 case. Rhabdoid differentiation was also seen in 1 case. Immunohistochemical stains CKAE1/AE3 and CK Cam 5.2 were positive in the epithelial elements, vimentin in mesenchymal, and CD56 and neuron-specific enolase in neuroepithelial elements. Follow-up was available in 4 patients and ranged from 21 to 40 months (mean, 31 months). Lung and dura metastasis, respectively, were seen in 1 patient each. However, all 4 patients are alive and free of disease to date. In conclusion, TCS is a rare but highly malignant tumor with aggressive behavior characterized by benign and malignant epithelial, mesenchymal, and neuroepithelial components. Two patients in our series were younger than 20 years. The occurrence of rhabdoid differentiation and osteosarcomatous component seen in our series were rarely described in literature. Recognition of all the components requires adequate sampling, which is crucial for a correct diagnosis.