[Microcystic serous cystadenoma: An uncommon neoplasm of pancreas. Report of two cases]. / Cystadénome séreux microkystique : une tumeur rare du pancréas. À propos de deux observations.

Microcystic variant of serous cystadenoma of the pancreas is a rare neoplasm; essentially located in the body or tail of the pancreas and associated with the von Hippel-Lindau. Often, patients are asymptomatic and the neoplasm is incidentally discovered. Usually radiographic manifestations are characteristic. Histopathological examination revealed uniform clear cuboidal cells; they can be confused with other clear cell neoplasms like renal cell carcinomas, well-differentiated neuroendocrine tumors and solid pseudopapillary tumors of the pancreas. Immunohistochemistry can be help to establish the diagnosis and to remove differential diagnosis. Serous cystadenoma is a benign neoplasm whose prognosis is excellent. We herein report two cases of microcystic serous cystadenomas of the pancreas diagnosed in two asymptomatic women and review analysis in the literature to remind the main features of this lesion and the main differential diagnosis.

[Hemophagocytic lymphohistiocytosis associated with a lymphohistiocytic pattern anaplastic large cell lymphoma: a case report]. / Syndrome d'activation macrophagique révélant un lymphome anaplasique à grandes cellules de variante lymphohistiocytaire : à propos d'un cas.

We report the case of a 16-year-old girl with an anaplastic large cell lymphoma of lymphohistiocytic pattern revealed by a hemophagocytic syndrome. Histologically, the lymphomatous population was concealed by clusters of histiocytes. Immunohistochemical study allowed the diagnosis. The combination of these two entities is rarely described and may be a source of delay in diagnosis of a life-threatening condition.

[Second expert review on lymphoma: assessment of a one year activity in a general hospital]. / Expertise systématique des lymphomes diagnostiqués au cours d'une année d'activité d'un centre hospitalier : évaluation.

A standardized second histological review for lymphomas was established by the French National Cancer Institute in 2010. The objective of our study was to assess the clinical impact of this process between a general hospital (reader 1) and an expert (reader 2). This prospective study was conducted between April 1st 2010 and April 1st 2011. Fifty-four cases of lymphoma were subjected to an expert review following the "LYMPHOPATH" recommendations and diagnoses of readers 1 and 2 were compared according to the WHO 2008 classification of lymphomas. We distinguished serious discrepancies (lymphoma versus other malignancy) from subtyping disagreement with or without impact on therapeutic strategy. We also determined the delays between the initial reception of the sample and reader 1's (period A) and reader 2's (period B) reports, respectively. Any additional analysis performed by second reader was also reported. Our study revealed one case of subtyping discordance (1.85%). The mean delays were 7 days for period A and 20 days for period B, respectively. Additional immunohistochemical techniques were requested by reader 2 in 11 cases (20.4%). These data provide evidence to suggest that in our department, a second review targeted on difficult diagnoses, rare lymphomas or when further analyses are required would be more relevant than a standardized second review.

[Atypical carcinoid of the arytenoid: report of six cases]. / Carcinoïde atypique de l'aryténoïde: à propos de six observations.

In order to illustrate the clinical and histological presentations of laryngeal atypical carcinoids and their potential course, we report six cases. We evaluated the factors predictive of local recurrence and metastatic diffusion. For each case, we noted the mitotic index, the quality of the resection, the limits of the tumor and the presence of necrosis. An immunohistochemical study was carried out with a series of antibodies (cytokeratins; D(2)40; CD31; MIB1; P53; P16; TTF1...). The clinical presentation we observed was quite similar to that reported in the literature. These tumors are CK7+, CK8+, CK19+, CK5-6-, CK14- and CK20-. P16 is constantly positive. Only the mitotic index and the lymphatic presence of embolus were correlated with the time course. The tumor is more aggressive when the mitotic index is high and an unfavorable course is observed when there are lymphatic emboli or when the Ki67 index is higher than 5%.

[Hodgkin's disease variant of Richter's syndrome. Two cases and literature review]. / Syndrome de Richter de type pseudohodgkinien. A propos de deux cas et revue de la littérature.

We report the clinical and immunohistological features of two cases of chronic lymphocytic leukaemia (CLL) with Hodgkin's transformation. These cases occurred in a 70-year-old man with a three-year history of CLL and in a 76-year-old man with a few months history of CLL. Microscopic examination showed the presence of large tumor cells with the morphological and immunophenotypic features of classical Hodgkin and Reed-Sternberg (R-S) cells, in a background of otherwise typical B-CLL. The transformation of CLL into large B cell lymphoma (Richter's syndrome) is a well-documented phenomenon. Only rarely does CLL transform into Hodgkin's lymphoma, but this diagnosis is often easy and offers few differential diagnoses. The major points of interest lie in the pathogenetic relationship between CLL and Hodgkin's disease, and in the potential clinical implications of this peculiar condition. Literature on the subject indicates that identical IgH gene rearrangements in micromanipulated R-S and CLL cells have been identified in 7/12 cases. In these patients, the R-S and CLL cells belong to the same clonal population, suggesting a progression from the underlying CLL cells. This group appears to have a poor prognosis, identical to classical Richter's syndrome. In other cases, the R-S cells were often Epstein-Barr virus (EBV) positive and did not share the clonal rearrangements identified in CLL cells, suggesting that Hodgkin's disease in these patients could represent a second malignancy, EBV-related and favored by immunosuppression, associated with a better prognosis.

Influence of MMP-2 and MMP-9 promoter polymorphisms on gene expression and clinical outcome of non-small cell lung cancer.

Matrix metalloproteinases (MMP) including MMP-2 and MMP-9 play a major role in tumour invasion by proteolysing the extracellular matrix. Their activation, particularly that of MMP-9, is partly dependent on plasmin that is inhibited by TFPI-2 (tissue factor pathway inhibitor-2), a serine protease inhibitor whose gene expression is decreased in about one-third of non-small cell lung cancers (NSCLC). In addition, MMP-2 and MMP-9 are essential in the development of NSCLC and can be regulated by functional promoter polymorphisms. In this study, the -1306C/T MMP-2, -735C/T MMP-2 and -1562C/T MMP-9 polymorphisms were analysed in 90 NSCLC patients and 90 controls. In addition, the promoter region of the TFPI-2 gene was screened for sequence variations in both groups by DHPLC. A -167G/A polymorphism was identified in 3% of controls whereas none of the 90 patients exhibited this genetic variation in the TFPI-2 promoter region. Moreover, no difference in -1306C/T MMP-2, -735C/T MMP-2 and -1562C/T MMP-9 genotypes was found between cases and controls. However, the homozygous -1562CC MMP-9 genotype was more frequent in patients with squamous cell carcinoma than in controls (p=0.018). When genotype distributions were compared to MMP-2 and MMP-9 gene expression in tumours, no relationship was found with the -1306 MMP-2 and -1562 MMP-9 polymorphisms. In contrast, tumour MMP-2 gene expression was lower in homozygous -735CC patients than in those with CT or TT genotypes. In addition, the survival time was longer in patients with the MMP-2 -735T allele than in those with the CC genotype (p=0.02). The relative risk of death was increased 2.6-fold in -735CC patients (p=0.045; 95% CI=1.0-6.7). The results of this study suggest that the -735C/T MMP-2 polymorphism might be an independent prognostic marker in NSCLC, but this should be confirmed in a larger cohort of patients.

Expression of sex steroid hormone receptors in C cell hyperplasia and medullary thyroid carcinoma.

Previous studies have shown that C cells are twice as numerous in male than in female thyroids and that C cell hyperplasia (CCH) is much more frequent in men. These findings suggest regulation involving sex steroid hormones through the expression of sex steroid hormone receptors on C cells. To investigate this hypothesis, we performed an immunohistochemical study of estrogen receptors alpha (ER alpha) and beta (ER beta), progesterone receptors (PR), and androgen receptors (AR) on specimens from a series of 40 patients operated on for a medullary thyroid carcinoma (MTC; n=28; female 18, male 10) and/or CCH (n=19; female 6, male 13). ER beta was the only receptor to be consistently expressed in CCH (100%) and MTC (96.5%), whereas ER alpha was never expressed. PR and AR were rarely expressed in MTC (7 and 14%, respectively). AR was expressed in half the CCH cases (53%), with a trend to male predominance (61% in men vs 33% in women). Our study is the first to describe ER beta expression in CCH. In addition, our findings suggest that CCH, and possibly MTC, might be influenced by sex steroid hormones, namely, estrogens and androgens, through the expression of ER beta and AR on C cells.

[PEComa of soft tissue: report of an articular case]. / PECome des tissus mous: à propos d'un cas de localisation articulaire.

We report a case of PEComa (or perivascular epithelioid cell tumor) in an unusual articular localization in a 13-year-old boy. The tumor, of 4 cm in diameter, showed an infiltrative pattern and was composed of both epithelioid and spindle cells with clear to granular eosinophilic cytoplasm and some multinucleated giant cells. Focal nuclear pleomorphism was present and we found up to 2 mitotic figures /50 high power field. There was no necrosis. Immunohistochemistry showed HMB-45 and smooth muscle actin positivity. Ultrastructurally, premelanosomes were present. Some rare cases of PEComa were reported in the soft tissues. The immunohistological profile (HMB-45 and smooth muscle actin positivity and PS-100 negativity) is helpful to the diagnosis. The histological prognostic criteria of these tumors are not well established. We discuss here the differential diagnosis, notably clear cell sarcoma of soft tissue.

[Mullerian "inclusions" within an intramammary lymph node]. / "Inclusions" müllériennes dans un ganglion lymphatique intra-mammaire.

We report a case of mullerian "inclusions" within an intra-mammary lymph node. Discovered on a routine mammography, the inclusions appeared in the right breast as a focus of microcalcifications. The 63-year-old patient was asymptomatic. Microcalcifications were associated with benign appearing epithelial formations which were positive for estrogen receptor antibodies and negative for thyroglobulin, calretinin and smooth muscle actin antibodies. Three years later, the patient developed a peritoneal low-grade serous carcinoma. Mullerian inclusions within lymph nodes are rather frequent below the diaphragm but exceptional above. Even in a supra-diaphragmatic localization, they can be associated with a pelvic serous tumor.

Balanced Translocations Disrupting SMARCB1 Are Hallmark Recurrent Genetic Alterations in Renal Medullary Carcinomas.

BACKGROUND: Renal medullary carcinoma (RMC) is a rare and highly aggressive neoplasm that most often occurs in the setting of sickle cell trait or sickle cell disease (SCD). Most patients present with metastatic disease resistant to conventional chemotherapy, and therefore there is an urgent need for molecular insight to propose new therapies. OBJECTIVE: To determine the molecular alterations and oncogenic pathways that drive RMC development. DESIGN, SETTING, AND PARTICIPANTS: A series of five frozen samples of patients with RMC was investigated by means of gene expression profiling, array comparative genomic hybridization, and RNA and whole exome sequencing (WES). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RNA and DNA sequencing read data were analyzed to detect gene fusions and somatic mutations. Gene fusions mutations were validated by real-time polymerase chain reaction and fluorescence in situ hybridization. Gene expression profiling was analyzed by unsupervised hierarchical clustering and Gene Set Enrichment Analysis (Broad Institute, Cambridge, MA, USA). RESULTS AND LIMITATIONS: We observed inactivation of the tumor suppressor gene SMARCB1 in all tumors. In all four cases developed in patients with SCD, we identified an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence and thus contribute to its inactivation. Gene expression profiling revealed that RMC shares common oncogenic pathways with pediatric malignant rhabdoid tumors, another tumor subtype characterized by SMARCB1 deficiency. CONCLUSIONS: RMCs are characterized by an original mechanism of interchromosomal balanced translocations that disrupt the SMARCB1 sequence. WES reveals that RMCs show no other recurrent genetic alteration and an overall stable genome, underscoring the oncogenic potency of SMARCB1 inactivation. PATIENT SUMMARY: Our comprehensive molecular study supports a pivotal role of the tumor suppressor gene SMARCB1 in the development of renal medullary carcinoma. The use of therapeutic strategies based on the biologic effects of its inactivation should now open new perspectives for this typically lethal malignancy.

Beneficial role of overexpression of TFPI-2 on tumour progression in human small cell lung cancer.

Tissue factor pathway inhibitor-2 (TFPI-2) is a potent inhibitor of plasmin, a protease which is involved in tumour progression by activating (MMPs). This therefore makes TFPI-2 a potential inhibitor of invasiveness and the development of metastases. In this study, low levels of TFPI-2 expression were found in 65% of patients with small cell lung cancer (SCLC), the most aggressive type of lung cancer. To study the impact of TFPI-2 in tumour progression, TFPI-2 was overexpressed in NCI-H209 SCLC cells which were orthotopically implanted in nude mice. Investigations showed that TFPI-2 inhibited lung tumour growth. Such inhibition could be explained in vitro by a decrease in tumour cell viability, blockade of G1/S phase cell cycle transition and an increase in apoptosis shown in NCI-H209 cells expressing TFPI-2. We also demonstrated that TFPI-2 upregulation in NCI-H209 cells decreased MMP expression, particularly by downregulating MMP-1 and MMP-3. Moreover, TFPI-2 inhibited phosphorylation of the MAPK signalling pathway proteins involved in the induction of MMP transcripts, among which MMP-1 was predominant in SCLC tissues and was inversely expressed with TFPI-2 in 35% of cases. These results suggest that downregulation of TFPI-2 expression could favour the development of SCLC.

Monitoring of tumour progression using bioluminescence imaging and computed tomography scanning in a nude mouse orthotopic model of human small cell lung cancer.

Human small cell lung carcinoma (SCLC) is the most aggressive type of lung cancer but no clinically relevant animal model has been developed to date. Such a model would be valuable to study the molecular aspects of tumour progression and to test the effectiveness of new treatment agents. We generated a reproducible and reliable nude mouse orthotopic model of human SCLC with NCI-H209 tumour cells genetically modified to express firefly luciferase. Cells were analysed for long-term stability of bioluminescence and a clone was passaged twice subcutaneously to enhance tumorigenicity. Cells resuspended in Matrigel and/or EDTA RPMI medium containing a (99m)Tc-labelled tin colloid used as tracer were implanted intrabronchially with a catheter inserted into the trachea and positioned in the main bronchus using X-ray-guided imaging. Deposition of cells into the lung was then assessed by scintigraphy. The growth of the primary tumour was sensitively and non-invasively followed by bioluminescence imaging that allowed real-time monitoring of tumour progression in the same animals over a 2-12-week period. Additional 3D bioluminescence imaging and computed tomography scanning were used to document tumour location and measurements that were confirmed by histological analyses. In conclusion, this original nude mouse orthotopic model resembles various stages of human small cell lung cancer, and therefore could be used to evaluate new treatment strategies.

The intracellular localization of ID2 expression has a predictive value in non small cell lung cancer.

BACKGROUND: ID2 is a member of a subclass of transcription regulators belonging to the general bHLH (basic-helix-loop-helix) family of transcription factors. In normal cells, ID2 is responsible for regulating the balance between proliferation and differentiation. More recent studies have demonstrated that ID2 is involved in tumor progression in several cancer types such as prostate or breast. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we investigated, for the first time, the relationship between the expression of ID2 in non-small cell lung cancer (NSCLC) patients and the clinicopathological features and prognosis of these patients. Immunohistochemistry was performed on tissue microarrays, which included 62 NSCLC tumors. In malignant tissues, ID2 expression has been detected in both the nuclear and cytoplasmic compartments, but we have demonstrated that only nuclear expression of ID2 is inversely correlated with the differentiation grade of the tumor (p = 0.007). Interestingly, among patients with poorly differentiated tumors, high nuclear expression of ID2 was an independent and unfavorable prognostic factor for survival (p = 0.036). CONCLUSIONS: These results suggest that ID2 could be involved in tumor dedifferentiation processes of NSCLC, and could be used as prognostic marker for patients with poorly differentiated tumors.

Transient RNA silencing of tissue factor pathway inhibitor-2 modulates lung cancer cell invasion.

Tissue Factor Pathway Inhibitor-2 (TFPI-2) is a potent inhibitor of plasmin which activates metalloproteinases (MMPs) involved in extracellular matrix (ECM) degradation. Its secretion in ECM makes TFPI-2 a potential inhibitor to regulate tumour invasion and metastasis. Moreover, TFPI-2 is frequently downregulated, particularly in aggressive cancers. In this study, we silenced TFPI-2 in the NCI-H460 non-small cell lung cancer cell line and evaluated the role of TFPI-2 in cell invasion and its impact on MMPs expression. As the effects of siRNA are transient, the consequences of both gene silencing and restoration to normal expression could be studied kinetically in the same cells. We showed that TFPI-2 expression by NCI-H460 cells was effectively downregulated using specific small interfering RNA and this silencing was associated with an increase in the invasive potential of tumour cells while migration was not affected. We also showed that mRNA levels and protein expression of MMP-2, -3, -9, -14 were not influenced by TFPI-2 silencing. Moreover, the gelatinase activity of MMP-2 and MMP-9 was unmodified. In contrast, MMP-1 mRNA levels and protein were significantly and similarly increased in cells transfected with TFPI-2 siRNA. In conclusion, this study confirms that TFPI-2 downregulation can contribute to tumour invasion of lung cancer cells.