Neoplastic Elements Research Articles

Primary Malignant Bone Tumours at the University Teaching Hospital in Lusaka Zambia

Introduction: Primary malignant bone tumours include malignancies arising primarily from bone tissue. This is opposed to secondary bone tumours in which case the neoplastic elements arise primarily from other sites within the body and secondarily spread to bone. Primary malignant bone tumours are generally considered rare. Wherever primary malignant bone tumours occur they tend to pose serious challenges in terms of diagnosis, management and morbidity and mortality. However there is a lack of organised local information demonstrating the burden of disease resulting from these tumours.Objectives: The main objective of this study was to establish the pattern of primary malignant bone tumour distribution at the UTH. The specific objectives of the study included to: Outline of the socio-demographic characteristics of patients, determining the frequency of primary malignant bone tumours at UTH and the hospital prevalence of primary malignant bone tumours including their histological distribution and the clinical presentation.Materials and Methods: A retrospective cross-sectional survey of patients who presented to The University Teaching Hospital (UTH), Lusaka, Zambia with histologically confirmed primary malignant bone tumours was conducted for the period from the 1st of January 2008 to the 31st of December 2012.Results: There were a total of hundred and fifty three (153) patients seen in total. Sixty six (43%) were females while 87 (57%) were males. The age range was 3yrs to 78yrs. The mean age was 31.6 yrs. Sixty nine percent (69%) of the patients were aged 40 years and below. The age distribution of primary malignant bone tumours showed a bimodal pattern of distribution with peaks in the second and sixth decades of life. The majority (35%) of the patients reported Lusaka Province as their domicile, while the least (2.0%) hailed from North Western Province. The highest number of patients, 39 (25.5%) was recorded in 2012 and the lowest number 20 (13%) was recorded in 2011. Based on National Cancer Registry data, from 2008 to 2011, the overall proportion of patients with primary malignant bone tumours compared to all the other cancers recorded at UTH ranged between 1.7 to 2.8%. The majority, 84 (55.3%), of the patients had osteosarcoma, followed, in descending order, by multiple myeloma 42 (27.6%), chondrosarcoma 11 (7.2%), Ewing’s sarcoma 8 (5.3%), fibrosarcoma 3 (2.0%) and lymphoma 2 (1.3%). The majority of patients (35.5%) reported pain and swelling alone as a presenting complaint while 19.8% of the patients presented with pathological fractures. The single and most commonly reported anatomical site was from multiple myeloma which has a general skeletal involvement (27%); the second most commonly involved site was the femur 23.7%, followed by the tibia 17.1%, and the humerus 7.5%.Conclusion: Notwithstanding the inconclusive nature of the information on geographic distribution of tumours, the findings in the study paralleled those reported in literature.

Bevacizumab and other novel therapies for recurrent oligodendroglial tumors.

Oligodendroglioma (WHO Grade 2) and anaplastic oligodendroglioma (WHO Grade 3) are glial tumors composed of neoplastic cellular elements that resemble oligodendrocytes. The treatment of recurrent, alkylator refractory oligodendroglial tumors is challenging given the paucity of effective treatment and lack of randomized controlled trials on which to base therapy. Notwithstanding the lack of prospective, randomized data, treatment of oligodendroglial tumors with bevacizumab can be recommended tentatively recognizing that preliminary studies suggest efficacy. Somatic mutations of the isocitrate dehydrogenase enzymes (IDH1 and IDH2) appear to play a critical role in the pathogenesis of most oligodendroglial tumors and agents that target these mutations are a potential therapeutic option. Additionally, reversal of CpG island hypermethylated phenotype status through inhibition of DNA methyltransferase with an inhibitor such as decitabine may provide a target for future studies.

Endoscopic ultrasound-guided fine-needle aspiration cytology in pancreaticobiliary carcinomas: diagnostic efficacy of cell-block immunocytochemistry

Endoscopic ultrasound-guided fine-needle aspiration cytology was demonstrated to be a useful tool for the diagnosis and staging of pancreaticobiliary neoplastic lesions. Nonetheless, the diagnostic value of this procedure may be limited by low cellularity of the specimen, contamination of intestinal cells and unfeasibility of ancillary immunocytochemical procedures. The present study was to evaluate its usefulness in the diagnosis of neoplastic lesions. A series of 46 pancreaticobiliary carcinomas with available cell block preparations was submitted to immunocytochemistry against cytokeratins, carcinoembryonic antigen, E-cadherin, CD10 and p53. The sensitivity, specificity, positive and negative predictive values of the cytological smear in the discrimination of malignant lesions were calculated and compared with those of cell block preparation with the immunocytochemical stains against p53 and CD10. According to our findings, the use of cell block preparations together with immunostains against p53 and CD10 allowed to discriminate malignant versus benign specimens with higher sensitivity than the only cytological examination. In detail, CD10 immunostaining was of significant help for the discrimination between cytological contaminants, such as benign gastrointestinal cells, and the neoplastic elements of pancreaticobiliary well differentiated adenocarcinomas. Also, intense nuclear immunoreactivity for p53 was encountered in about 2/3 of the cases and identified pancreatic malignancy with high sensitivity. We suggest that immunocytochemistry against both CD10 and p53 could be applied case by case, mainly to differentiate gastrointestinal and pancreatic benign cellular contaminants showing hyperplasia or reactive changes from differentiated pancreaticobiliary adenocarcinomas.

MED12 somatic mutations in fibroadenomas and phyllodes tumours of the breast.

Somatic mutations in exon 2 of the mediator complex subunit 12 (MED12) gene have been identified in 60% of breast fibroadenomas (FAs). The aim of this study was to define whether phyllodes tumours (PTs) would harbour MED12 somatic mutations in a way akin to FAs. A collection of 73 fibroepithelial tumours (including 26 FAs, 25 benign PTs, nine borderline PTs and 13 malignant PTs) from 64 patients was retrieved from the authors' institution. Sections from formalin-fixed paraffin-embedded (FFPE) blocks were microdissected to ensure an enrichment in neoplastic stromal elements of >70%. DNA samples extracted from tumour and matched normal tissues were subjected to Sanger sequencing of exon 2 of the MED12 gene. MED12 exon 2 somatic mutations, including 28 somatic single nucleotide variants and 19 insertions and deletions, were found in 65%, 88%, 78% and 8% of FAs, benign PTs, borderline PTs and malignant PTs, respectively. Malignant PTs harboured MED12 exon 2 somatic mutations significantly less frequently than FAs, benign and borderline PTs. Although MED12 exon 2 somatic mutations probably constitute the driver genetic event of most FAs, benign and borderline PTs, our results suggest that the majority of malignant PTs may be driven by other genetic/epigenetic alterations.

Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas

ObjectiveTo evaluate the role of the neurochemical navigation with 5-aminolevulinic acid (5-ALA) during intraoperative MRI (iMRI)-guided resection of the intracranial malignant gliomas. MethodsThe analysis included 99 consecutive surgical cases. Resection of the bulk of the neoplasm was mainly guided by the updated neuronavigation based on the low-field-strength (0.3T) iMRI, whereas at the periphery of the lesion neurochemical navigation with 5-ALA was additionally used. ResultsIn total, 286 tissue specimens were obtained during surgeries for histopathological examination. According to iMRI 98 samples with strong (91 cases), weak (6 cases), or absent (1 case) fluorescence corresponded to the bulk of the lesion and all of those ones contained tumor. Out of 188 tissue specimens obtained from the “peritumoral brain,” the neoplastic elements were identified in 89%, 81% and 29% of samples with, respectively, strong (107 cases), weak (47 cases) and absent (34 cases) fluorescence. Positive predictive values of the tissue fluorescence for presence of neoplasm within and outside of its boundaries on iMRI were 100% and 86%, respectively. ConclusionNeurochemical navigation with 5-ALA is useful adjunct during iMRI-guided resection of intracranial malignant gliomas, which allows identification of the tumor extension beyond its radiological borders.

Cervical paravertebral osteolipoma: case report and literature review.

Lipomas are the most frequent soft tissue tumors. Osteolipomas are a rare variant that can be difficult to diagnose. We report the case of a 66-year-old man consulting with a tumor of 2 years development in the right paravertebral cervical region. Neurologically, the patient had no sign of myelopathy or neurological focality. Magnetic resonance imaging showed a mass with a lipid component and calcifications inside within the right paravertebral musculature with a possible origin in the right C3 posterior root. A computed tomography scan and guided biopsy were performed, revealing hematic material and small bone spicules with no apparent neoplastic element. The tumor was totally removed, including the right C3 posterior branch, and was confirmed to be an osteolipoma on biopsy. The patient remains asymptomatic at 6-month follow-up. The osteolipoma is a benign tumor of soft tissue, characterized by lipoma areas with mature bone tissue differentiation, and even with hematopoietic marrow.

Composite pleomorphic xanthoastrocytoma-epithelioid glioneuronal tumor with BRAF V600E mutation - report of three cases.

We report three examples of a composite pleomorphic xanthoastrocytoma-epithelioid glioneuronal tumor (PXA-EGT) occurring in an adolescent male and two young women. All were superficial and two were located in proximity to the optic nerves. Previously reported composite PXA-gangliogliomas (PXA-GG), have been considered “collision tumors” since little intermingling of the two elements has been present. In contrast, we hypothesized that the two elements of the PXA-EGT might instead derive from a common origin. To test this, we sampled the separate regions of these biphasic tumors and assessed each component for the BRAF V600E mutation, a genetic feature seen in two-thirds of pure PXAs. The BRAF mutation was found in both tumor areas in all cases, suggesting a common origin for the components, rather than a collision tumor. These biphasic PXA-EGT cases represent a new histomorphological combination of neuroepithelial neoplastic elements. These cases further expand the range of glial neoplasia in which epithelioid morphology is encountered, and add to the growing list of biphasic tumors harboring the BRAF V600E mutation.

The Value of Peritoneal Washing Cytology During Intra-Abdominal Surgery for Female Genital Tract Neoplasms

BackgroundPeritoneal washing cytology is a technique performed during surgery for genital neoplasms to detect subclinical intraperitoneal metastases from these tumors. The aim of this study was to evaluate PWC utility in presumed benign and malignant female genital tract neoplasms by comparing the results of peritoneal cytology and corresponding histopathological specimens. Patients and MethodsThe 305 cases of female genital lesions with available staging (International Federation of Gynecology and Obstetrics) were considered. In cases with positive cytology, without neoplastic involvement of the ovarian and uterine surfaces, the salpinx was accurately examined to reveal primary malignant fallopian tubal neoplasms. For malignant ovarian neoplasms, the correlation rate between cytological and histopathological findings was statistically evaluated using the Fisher exact test. Statistical significance was defined as P < .05. ResultsHistopathological diagnosis revealed that of 32 cases with positive cytology, 21 examples corresponded to primary ovarian serous carcinomas (65.625%). Moreover, the serous carcinoma was the subtype that most frequently revealed neoplastic elements on PWC (21 examples in 22 cases, 95.4%). Only 1 of these malignancies with positive cytology and pT1a stage presented simultaneous invasive and in situ serous carcinoma of contralateral tubal fimbria. Only 1 of serous endometrial carcinomas that involved an endometrial polyp was associated with positive cytology and with simultaneous carcinoma of tubal fimbria. ConclusionIn conclusion, PWC remains a useful procedure for staging malignant genital tract neoplasms and can be necessary to detect occult fallopian tube malignancies.

Cutaneous Infiltrates of Acute Myelogenous Leukemia Simulating Inflammatory Dermatoses

Some cases of specific cutaneous manifestations of acute myelogenous leukemia (AML) may mimic inflammatory dermatoses both clinically and histopathologically, presenting with an inconspicuous maculopapular eruption and with only sparse dermal infiltrates. The authors studied the histopathological and immunohistochemical features of 17 biopsies from 16 patients (11 men and 5 women, age range 15-85 years) presenting with minimal skin infiltrates as the first manifestation of AML or as first sign of recurrence after complete remission of the disease. In all cases, the diagnosis of leukemia has been confirmed by bone marrow examination. Two of these cases had been sent to one of us for second expert consultation. Patients presented with generalized, exanthematic maculopapular eruptions, sometimes with a hemorrhagic note, that were mostly interpreted clinically as drug reactions. Histopathologically, the lesions showed sparse, superficial, and mid-dermal infiltrates with minimal perivascular and periadnexal accentuation. Infiltrating cells consisted mostly of neoplastic monocytoid elements with only few reactive lymphocytes and histiocytes. Immunohistochemical stainings revealed in the majority of cases positivity for CD68 (14 of 16 patients), naphthol chloroacetate esterase (NaSDCl) (7 of 10 patients), and myeloperoxidase (6 of 9 patients). Other markers tested were positive only in a minority of cases. These cases represent a pitfall both in the clinical and in the histopathological diagnosis of cutaneous AML. Accurate morphologic and phenotypic correlation together with a high index of suspicion allows a precise diagnosis in these unconventional cases.

Atypical epithelioid cell myofibroblastoma of the breast with multinodular growth pattern: A potential pitfall of malignancy

Myofibroblastoma (MFB) of the breast is the prototypical benign spindle cell tumor arising from the mammary stroma. Over the last two decades, several morphological variants of this tumor have been recognized. Epithelioid cell MFB is composed predominantly of neoplastic elements with epithelioid morphology. It represents a potential diagnostic pitfall of malignancy, especially when evaluating small biopsies. We report a unique case of a mammary epithelioid cell MFB composed of large mono- to multi-nucleated cells showing mild to moderate nuclear pleomorphism, predominantly arranged in a multinodular growth pattern. This tumor needs to be distinguished from invasive apocrine, oncocytic, pleomorphic lobular carcinoma, as well as metastases. Immunohistochemistry revealed the fibroblastic/myofibroblatic (positivity for vimentin, desmin, CD34 and focally for α-smooth muscle actin) nature of proliferating cells, and therefore was crucial for a correct diagnosis.

Parathyroid hormone-related protein (PTHrP) modulates adhesion, migration and invasion in bone tumor cells

Parathyroid-hormone-related protein (PTHrP) has been shown to be an important factor in osteolysis in the setting of metastatic carcinoma to the bone. However, PTHrP may also be central in the setting of primary bone tumors. Giant cell tumor of bone (GCT) is an aggressive osteolytic bone tumor characterized by osteoclast-like giant cells that are recruited by osteoblast-like stromal cells. The stromal cells of GCT are well established as the only neoplastic element of the tumor, and we have previously shown that PTHrP is highly expressed by these cells both in vitro and in vivo. We have also found that the stromal cells exposed to a monoclonal antibody to PTHrP exhibited rapid plate detachment and quickly died in vitro. Therefore, PTHrP may serve in an autocrine manner to increase cell proliferation and promote invasive properties in GCT. The purpose of this study was to use transcriptomic microarrays and functional assays to examine the effects of PTHrP neutralization on cell adhesion, migration and invasion. Microarray and proteomics data identified genes that were differentially expressed in GCT stromal cells under various PTHrP treatment conditions. Treatment of GCT stromal cells with anti-PTHrP antibodies showed a change in the expression of 13 genes from the integrin family relative to the IgG control. Neutralization of PTHrP reduced cell migration and invasion as evidenced by functional assays. Adhesion and anoikis assays demonstrated that although PTHrP neutralization inhibits cell adhesion properties, cell detachment related to PTHrP neutralization did not result in associated cell death, as expected in mesenchymal stromal cells. Based on the data presented herein, we conclude that PTHrP excreted by GCT stromal cells increases bone tumor cell local invasiveness and migration.

Lactoferrin in Malignant Human Tumours: New Insights from an Immunohistochemical Meta-Analysis

Lactoferrin (LF), an iron-binding glycoprotein, is well known to have different physiological activities in humans; in normal conditions, it has been found in milk, blood, urine as well as in many external and mucosal secretions. Herein we have performed a meta-analysis regarding LF immunohistochemical expression as well as its localization pattern in human malignant tumours obtained from personal observations and literature suggestions. The observed heterogeneity in LF immunoexpression between different malignancies as well as inside the same tumour was also discussed in order to acquire a possible explanation for its presence and function. We suggest that neoplastic elements should be able to produce LF in order to make a greater amount of iron available for their turnover; alternatively, the localization of LF in malignant cells may not reflect an intracellular synthesis, reflecting instead the degree of trans-membranous iron transfer as the consequence of defective or functionally impaired LF-receptors, already documented elsewhere on the surface of target cells as well as in human neoplastic cell lines.

Ubiquitin carboxy-terminal hydrolase L1 may be involved in the development of mammary phyllodes tumors

Phyllodes tumors (PTs) are characterized by co-proliferation of the stroma and epithelium, with the stroma being the neoplastic element. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that was originally considered to be a neuronal-specific marker, but later reports have shown both tumorigenic and antitumorigenic roles for UCHL1. Although a role for UCHL1 has been explored in many cancers, a study on PTs has never been reported. We assessed UCHL1 expression in 49 cases of PTs and 16 fibroadenomas using immunohistochemistry and examined associations with clinicopathological features. In normal breast, strong staining for UCHL1 was consistently observed in the nerve bundles, if present, in breast stroma. Scattered stromal cells showed negative to weak staining. The ductal and lobular units, in contrast, showed no staining. In contrast to the 16 fibroadenomas, of which only 3 showed mild staining, UCHL1 expression was consistently observed in all 49 PTs. There was a significantly increasing trend of UCHL1 expression with increasing PT grade (P < 0.001); strong staining was observed in 24 % of benign PTs, but was present in 56 and 90 % of borderline and malignant PTs, respectively. Consistently, UCHL1 was focally positive in regions of benign to borderline malignancy, but strongly and diffusely immunoreactive in regions of malignancy in cases of malignant PTs. In addition to PT grade, UCHL1 expression correlated with increasing stromal atypia (P = 0.01), but not with other clinicopathological parameters. In conclusion, the consistent expression of UCHL1 in PTs and an increasing trend of UCHL1 expression with an increasing PT grade suggest a role for UCHL1 in the pathogenesis and malignant progression of PTs.

Mesenchymal chondrosarcoma of the maxilla: Case report and clinicopathologic review

Mesenchymal chondrosarcoma is extremely rare, accounting for around 1% of all chondrosarcomas. It occurs in the axial skeleton, the head and neck region and a high proportion of extraskeletal sites. Fewer than 40 cases of mesenchymal chondrosarcoma in the maxilla have been reported in English literature. The neoplasm is aggressive, with a high tendency for late recurrence and delayed distant metastasis. Here we present a 50-year-old man with palatal mucosal swelling for 6 months. The initial clinical impression was a benign minor salivary gland neoplasm. The biopsy revealed hyaline cartilage, alternating with undifferentiated small round cells, pathognomonic for mesenchymal chondrosarcoma. Diagnosis of biopsy specimens remains a challenge because of variable tumor components, and specimens may contain only one of the two neoplastic elements. The patient received radical surgery and has been disease free for 40 months. Clinicians and pathologists should be aware of this entity in the differential diagnosis of maxillofacial neoplasms, to prevent misdiagnosis and delayed intervention.

Very rare case of rectal carcinosarcoma

Dear Sir, Carcinosarcoma is a rare type of malignant neoplasm, which was first described by Virchow in 1864. It is composed of two types of neoplastic cells, epithelial, and mesenchymal ones. This neoplasm has a poor prognosis and may develop in many organs, including the uterus and ovaries of older women, the head and neck region, and the lungs and kidneys. Within the gastrointestinal tract, carcinosarcoma is most commonly found in the esophagus [1] and only rarely in the large intestine. Among case reports before 2011, 16 fulfilled the criteria for carcinosarcoma of the large intestine, and of these, only 5 involved the rectum. We report a case of carcinosarcoma of the rectum with necrosis of the intestinal wall. An 83-year-old male was admitted to the surgical ward with signs of massive lower gastrointestinal tract bleeding. The patient had congestive heart failure, diabetes, and chronic respiratory failure secondary to venous thromboembolism. On digital rectal examination, a stenotic, bleeding tumor of the rectum, infiltrating the perianal tissues on the right side could be felt. The distal margin of the tumor was palpable at the level of anorectum, while its superior margin was unreachable. Anal endosonography revealed a tumor (30 mm × 53 mm × 40 mm in size) occupying the right half of the anal canal, infiltrating the sphincter muscles (internal and external), with areas of necrosis (Fig. 1). Fig. 1 a The endosonographic study shows a hyperechoic tumor, measuring 30 × 53 mm in a transversal plane, taking up the right half of the anal canal lumen, infiltrating the anal sphincters, b With anechoic areas of necrosis Due to the deterioration of the patient’s overall condition and continued signs of active bleeding from the tumor, the patient qualified for emergency surgery (ASA IV). Intraoperatively, on rectal examination, a stenotic tumor with an ulceration at the right side of the rectal wall was confirmed. The necrotic tissue was partially removed, the rectum was rinsed with normal saline, then, the site of bleeding was coagulated, and internal packing of the rectum was carried out. An exploratory laparotomy was performed through an infraumbilical midline incision. A loop sigmoidostomy was created due to necrosis of the rectal wall and perirectal tissue. The remaining abdominal organs did not reveal any abnormalities on palpation (e.g., distant metastases). There were no complications in the early postoperative period. However, due to the patient’s poor overall condition, he was not a candidate for oncological treatment. The patient was discharged home on postoperative day 14 and advised to return for the histopathology results. He died 5 weeks after the surgery, due to cardiorespiratory failure. The histopathology examination of the specimen revealed carcinosarcoma of the rectum which was confirmed by immunohistochemical staining which was positive for cytokeratin, vimentin, and smooth muscle antigen (Fig. 2). This mixed neoplasm was formed from epithelial elements of a well-differentiated adenocarcinoma as well as from mesenchymal neoplastic elements, showing differentiation toward muscle tissue. Fig. 2 a Staining using anti-cytokeratin antibodies used to identify cells of epithelial origin; b Staining using anti-vimentin antibodies to identify cells of mesenchymal-origin; c Staining using anti-SMA (smooth muscle antigen) antibodies Carcinosarcoma of the colon is a rare neoplasm composed of both carcinomatous and sarcomatous elements. It has also been called as sarcomatoid carcinoma, carcinoma with mesenchymal stroma, carcinoma with sarcomatous change, spindle cell carcinoma, and pleomorphic anaplastic carcinoma [2]. The prognosis of this carcinoma is poor because it invades deep into the bowel wall, has widespread metastases, and is resistant to multi-agent chemotherapy. Up to now, all the described cases of rectal carcinosarcoma included lymph node metastases at the time of diagnosis [3–5]. Our patient did not have any distant metastases noted at explorative laparotomy. However, the local spread of the neoplasm led to necrosis of a fragment of the rectal wall and secondary bleeding, a complication which had not been described previously. The only published case with necrosis of the intestinal wall involved the carcinosarcoma of the ascending colon [6]. Survival in the reported cases of rectal carcinosarcoma was never more than 6 months. Our patient died within a mere 5 weeks, which should be attributed to the advanced local state of the cancer at the time of diagnosis and the patient’s poor general condition which prevented further treatment. The case presented in this article is, to the best of our knowledge, the first involving bleeding into the gastrointestinal tract secondary to perforation of the rectal wall as a complication associated with this neoplasm. Therefore, the rare diagnosis of carcinosarcoma should be considered in patients with gastrointestinal bleeding.

Albumin storage in neoplastic astroglial elements of gangliogliomas

PurposeLow-grade neuroepithelial tumors are frequent neuropathological findings in patients with pharmacoresistant epilepsies. Little is known regarding epileptogenic mechanisms in this group of neoplasms with gangliogliomas (GG) as the most common entity. Presence of hemosiderin deposits in GG points to impairment of the blood-brain barrier (BBB). Therefore, we hypothesized a potential role of BBB dysfunction and astrocytic albumin uptake as potential epileptogenic factor in GG. MethodsPrussian blue staining and fluorescent double-immunohistochemistry with antibodies against albumin, GFAP, CD34 and GLUT-1 were used to analyze hemosiderin deposits and astroglial albumin accumulation in tumor and adjacent pre-existing brain tissue of GG (n=10) and several control groups, i.e. dysembryoplastic neuroepithelial tumors (DNT; n=5), focal cortical dysplasia with balloon cells (FCD IIb; n=10), astrocytomas WHO grade II (n=5) and clear renal cell carcinoma brain metastases (RCCM, n=6). ResultsOur results revealed strong hemosiderin deposits in GG. Intriguingly, we noted substantial albumin uptake exclusively in neoplastic glial cell components of GG and DNT, whereas no significant albumin was present in perilesional reactive astrocytes. Strikingly, we did not observe substantial albumin uptake in further controls. ConclusionGlial albumin uptake was restricted to long-term epilepsy associated, vasculature-containing tumors. Intratumoural BBB dysfunction in concert with subsequent accumulation of albumin by neoplastic glial cell elements represent a new putatively epileptogenic mechanism for long-term epilepsy-associated tumors.

Astrocyte-Specific Expression Patterns Associated with the PDGF-Induced Glioma Microenvironment

BackgroundThe tumor microenvironment contains normal, non-neoplastic cells that may contribute to tumor growth and maintenance. Within PDGF-driven murine gliomas, tumor-associated astrocytes (TAAs) are a large component of the tumor microenvironment. The function of non-neoplastic astrocytes in the glioma microenvironment has not been fully elucidated; moreover, the differences between these astrocytes and normal astrocytes are unknown. We therefore sought to identify genes and pathways that are increased in TAAs relative to normal astrocytes and also to determine whether expression of these genes correlates with glioma behavior.Methodology/Principal FindingsWe compared the gene expression profiles of TAAs to normal astrocytes and found the Antigen Presentation Pathway to be significantly increased in TAAs. We then identified a gene signature for glioblastoma (GBM) TAAs and validated the expression of some of those genes within the tumor. We also show that TAAs are derived from the non-tumor, stromal environment, in contrast to the Olig2+ tumor cells that constitute the neoplastic elements in our model. Finally, we validate this GBM TAA signature in patients and show that a TAA-derived gene signature predicts survival specifically in the human proneural subtype of glioma.Conclusions/SignificanceOur data identifies unique gene expression patterns between populations of TAAs and suggests potential roles for stromal astrocytes within the glioma microenvironment. We show that certain stromal astrocytes in the tumor microenvironment express a GBM-specific gene signature and that the majority of these stromal astrocyte genes can predict survival in the human disease.

Fascin expression in endocervical neoplasia: correlation with tumour morphology and growth pattern

BackgroundFascin is an actin-binding protein that potentiates migratory and invasive behaviour in neoplastic cells and has been shown to be upregulated in various malignancies. In this study fascin expression was...

Gene Expression Analysis Uncovers Similarity and Differences Among Burkitt Lymphoma Subtypes

AbstractAbstract 2494 Background.Burkitt lymphoma (BL) is currently listed in the WHO classification of lymphoid tumors as a single genetic and morphological entity with variation in clinical presentation. In particular, three clinical subsets of BL are recognized: endemic (eBL), sporadic (sBL) and immunodeficiency associated (ID-BL). Each affects different populations and can present with different features. So far, possible differences in their gene expression profiles (GEP) have not been investigated. In this study we aimed to 1) assess whether BL subtypes present with differences in their GEP; 2) investigate the relationship of the different BL subtypes with the non-neoplastic cellular counterparts; 3) Identify genes and programs specifically deregulated in BLs and possibly contributing to the malignant phenotype. Methods.We studied by GEP 128 cases of B-cell derived malignancies and 20 samples of normal B-cell subpopulations GEP analysis. In particular, we included 40 BLs (13 eBLs, 21 sBLs 6 HIV-BLs), 40 follicular lymphomas, 10 chronic lymphocytic leukemias, 10 GCB-type diffuse large B-cell lymphomas, 10 ABC-type DLBCL, 5 primary mediastinal B-cell lymphomas, 13 HIV-related DLBCL, as well as 10 germinal center (GC), 5 naïve and 5 memory cells samples. GEP results were confirmed by dividing BL cases into training and test subgroups. In addition, as further validation, we performed immunohistochemistry (IHC) on tissue microarrays containing 85 BL cases as well as functional assays in vitro and in vivo, by focusing on the role of RBL2, a tumor suppressor gene involved in cell cycle control and mutated in eBL. Specifically, we used cell transfection and shRNAs (for mimicking MYC over-expression and RBL2 silencing), soft agar and invasion capability assays, and xenografted mouse models. Results.First, we found that BLs constitute a unique molecular entity, with a relatively homogeneous GEP, distinct from other B-cell malignancies. Indeed, by unsupervised analysis all BLs clearly clustered apart of other lymphomas. However, by supervised analysis, we found that BL subtypes presented slight differences in their GEPs. Particularly, eBLs and ID-BLs appeared to be almost identical, diverging from sBLs. Specifically, they varied for genes involved in cell cycle control, BCR-signaling, and TNF/NFKB-pathways. Of note, eBLs and ID-BLs on one hand, and sBLs on the other (roughly corresponding to EBV+ vs. EBV− cases) also differed for genes target of mi-R127a, which is altered in EBV+ cases as a direct consequence of viral integration.To further investigate cell cycle regulation in BLs, we inferred a network of RBL2-depending genes by reverse engineering, by uncovering possible RBL2 transcriptional targets. Interestingly, we found that eBL and sBL diverged for genes belonging to such network. Notably, we provided evidences that RBL2 can cooperate with MYC in inducing a neoplastic phenotype in vitro and in vivo. In particular, lymphoblastoid cells engineered to carry both MYC over-expression and RBL2 silencing presented with increased colony formation and matrix invasion capabilities, and higher efficiency in inducing tumor formation in nude mice if compared to single transfectants (MYC+ or RBL2−).Moreover, as the present WHO classification does not definitely identify the counterpart of eBL, we compared BLs GEP to those of normal B-cells. We found that all BL subtypes were intimately related to GC cells (by showing an early stage GC differentiation arrest), differing from them for molecules specially involved in cell proliferation, immune response, and signal transduction.Finally, as further validation of GEP, we studied by IHC the expression of SPARC and CYR61, two molecules involved in human tumorigenesis. Indeed, they turned out to be consistently expressed by neoplastic elements in all instances, as indicated by GEP analysis. Conclusions.Our study provided substantial insights on the pathobiology of BLs, by offering novel evidences which may be relevant for its classification and possibly future treatment. Disclosures:No relevant conflicts of interest to declare.

Mammary-type Tubulolobular Carcinoma of Anogenital Mammary-like Glands With Prominent Stromal Elastosis

To the Editor: Following the original description of mammary type tubulolobular carcinoma of the anogenital area, presumably originating in anogenital mammary-like glands (AGMLG) in 2006,7 we have recently observed a similar case. The neoplasm in this newly encountered case fulfilled the criteria for a tubulolobular carcinoma as defined in mammary pathology,5 and was almost identical to the original cutaneous example.7 Additionally, there was prominent stromal elastosis, a feature identical to that seen in association with invasive breast carcinomas, and not earlier recognized in carcinomas of the anogenital area. The patient was a 45-year-old female who presented with a 2-cm, asymptomatic solitary nodule in the vulva with unknown duration. Clinical investigation revealed no extracutaneous involvement; specifically, there was no mammary tumor. An enlarged lymph node in the right inguinal area was noted, but it proved negative on sentinel node biopsy, as did 2 other lymph nodes from the same region, and 3 left inguinal lymph nodes removed during a lymphadenectomy. After a wide surgical excision (specimen 4×2×1.2 cm), the patient is alive without signs of metastasis or recurrence at 4-year follow-up. Histopathologically, the tumor was composed of uniform round-to-ovoid cells arranged in a single-file pattern intermixed with areas manifesting round tubules often showing decapitation secretion at the luminal border. The neoplastic elements were arranged in a targetoid fashion or grew diffusely. The tubules were mainly composed of a single-cell layer without any evidence of a peripheral myoepithelial cell layer. Rare small solid aggregations were also noted. There were areas with perineural and intraneural invasion, especially in the foci, in which the tumor areas resembled an infiltrative lobular carcinoma (Figs. 1A–D). Immunohistochemically, the tumor cells in both ductal-like and lobular-like components reacted positively for E-cadherin. A remarkable feature was the prominent stromal elastosis emerging as clumps and masses of elastic material around individual neoplastic tubules (periductal elastosis) within the stroma (diffuse elastosis) and in association of vessel walls (vascular elastosis) highlighted by elastic stains (Fig. 1E, F). The residua of intact AGMLG were not recognized.FIGURE 1.: An infiltrative neoplasm in the dermis (A) containing areas with tubular formation and areas resembling infiltrative lobular carcinoma of the breast; areas of periductal, diffuse, and vascular elastosis can be discerned (B–D). Stromal elastosis is highlighted by elastic stains (E, F).In the breast, tubulolobular carcinoma was originally described as a tubular variant of lobular carcinoma,5 but many investigators nowadays regard neoplasm as a variant of invasive ductal carcinoma with a lobular growth pattern.2,12 There was only 1 earlier report of this tumor type in the skin.7 The neoplasm was suggested to originate from AGMLG, a normal constituent of the anogenital area, earlier considered to represent ectopic breast tissue.14 Lesions of AGMLG show a striking microscopic resemblance to their mammary counterparts.15 A majority of these lesions are epithelial or biphasic stromal epithelial neoplasms, including fibroadenoma and phyllodes tumors.8,9,10 Stromal changes in lesions of AGMLG seem to be also identical to those seen in their mammary counterparts. The most prominent stromal lesion is probably pseudoangiomatous stromal hyperplasia recognized in the anogenital area in 2005.6 In this case study, stromal elastosis seemed identical to that seen in mammary carcinomas. This feature is unusual for dermatopathologic cases. The prototype of the changes in the elastic tissue compartment, sometimes associated with cutaneous neoplasms, is a solar elastosis attributed to the degradation of collagen or elastic fibers owing to excessive sun exposure. Stromal elastosis in mammary carcinoma is an entirely different pathologic process characterized by the presence of excess elastic fibers in a diffuse manner within the stroma in the periductal location or around blood vessels. It is usually seen in invasive mammary carcinomas, especially ductal carcinomas but has been rarely found in benign lesions3 or even intact breast, wherein it is less prominent.4 Infiltrating neoplastic cells, when invading the basal lamina of the mammary ducts, are thought to stimulate periductal fibroblasts or myofibroblasts to produce elastic fibers.1,11,13 In normal circumstances, these cells are not engaged in elastic fibers production. Grossly, such stromal elastosis can be recognized as “chalky streaks.”1 This case of tubulolobular carcinoma of the vulva further highlights similarities between lesions of AGMLG and their mammary counterparts, including “secondary” stromal phenomena. Stromal elastosis is not a feature in invasive carcinomas of the skin, regardless of the histopathologic type. The likely explanation is that the stroma of AGMLG is physiologically different from the dermis and reacts to various stimuli in a manner similar to the mammary stroma. Maria Teresa Fernandez-Figueras, MD* Michal Michal, MD† Dmitry V. Kazakov, MD, PhD† *Department of Pathology Hospital Universitari Germans Trias i Pujol, Autonomous University of Barcelona Barcelona, Spain †Sikl's Department of Pathology Charles University Medical Faculty Hospital Pilsen, Czech Republic