Thyroid Hürthle cell tumors: research of potential markers of malignancy.

INTRODUCTION: Hurthle cell tumors (HCTs) are rare thyroid neoplasia. To date, capsular and/or vascular invasion are the only findings predicting malignancy. Recently, mutation of 19p13, encoding two proteins involved in cell proliferation and apoptosis (GRIM-19 and p19), has been described. The aim of our study is to evaluate the cellular proliferation index (Ki67), GRIM-19 and p19 expression as diagnostic markers of malignancy in HCT. MATERIALS AND METHODS: Eighty patients with HCT (32 carcinomas, 48 adenomas) whom underwent surgery in our center were included. Samples of both neoplastic lesions and adjacent normal thyroid tissue were analyzed by means of tissue micro-arrays. Correlations between expressions of Ki67, GRIM-19 and p19 and final histology were analyzed. RESULTS: Mean size of the lesion was higher in carcinomas than in adenomas (p = 0.01). GRIM-19 and p19 were significantly underexpressed in Hurthle cells tumors compared to normal tissue (p = 0.0004 and p = 0.0001, respectively). Ki67 and GRIM-19 were, respectively, higher and down-expressed in carcinomas compared to adenomas (p = 0.0004 and p = 0.005, respectively). On multivariate analysis, size correlates with carcinoma diagnosis. Neither GRIM-19 nor Ki67 index was related to size. The expression of p19 was reduced in both adenoma and carcinoma but differences were not statistically significant (p = 0.13). CONCLUSIONS: Our study suggest that Ki67 and GRIM-19 correlate with malignancy in HCT. The expression of p19 is down-regulated in HCT, but it is not diagnostic of carcinoma. Ki67 and GRIM-19 may potentially help as cytological markers of malignancy in HCT.

[Mucinous nevus of late onset]. / Nævus mucineux de révélation tardive.

INTRODUCTION: Mucinous nevus is a rare disease characterized by mucin deposits in the dermis, with only 23 cases reported to date. It belongs to the connective tissue nevus family and is characterized by dermal mucin deposits. Two histological subtypes have been described: pure mucinous dermal nevus (connective tissue nevus of the proteoglycan [CTNP]) and combined mucinous nevus (combined CTNP) associating epidermal nevus with dermal mucin deposits. Lesions generally appear in childhood or early adulthood. We report herein the case of a 59-year-old man with a symptomatic lesion. OBSERVATION: A 59-year-old man consulted for unilateral lesions occurring linearly along the Blaschko line on the right lower limb, composed of brown verrucous papules, which started at the age of 50. The patient complained of itching caused by friction from clothes. Histological examination of a papule highlighted an acanthotic epidermis, with elongation of rete ridges and mucin deposits in the dermis showing uptake of alcian blue stain. The clinicopathological analysis enabled diagnosis of combined CTNP. We treated this nevus by surgical dermabrasion and observed a slight and cosmetically acceptable scar. DISCUSSION: To our knowledge, our patient is the oldest reported to date and the only one to have complained of symptoms. Our review of the literature highlights the importance of skin biopsy to guide aesthetic or symptomatic treatment. CO2 laser and dermabrasion are recommended for combined CTNP as they treat the epidermal component with low risk of secondary scarring. However, these techniques should be avoided in pure dermal CTNP, where surgical excision alone is acceptable in order to achieve optimal cosmetic results.

[Adult kwashiorkor: a rare complication of bariatric surgery]. / Kwashiorkor chez l'adulte : une complication rare de la chirurgie bariatrique.

INTRODUCTION: Kwashiorkor is a clinical manifestation of global protein-calorie malnutrition that is described mainly in children in developing countries initially presenting eczema-like skin disease associated with hydrops. OBSERVATION: We report the case of a 44-year-old woman with dark skin who had undergone bariatric surgery for treatment of stage-III obesity without regular monitoring and who was hospitalized in our dermatology department four years later. She had diffuse oedema and asteatotic eczema-like cutaneous lesions on pigmented skin that had developed for two months despite daily application of topical corticosteroids. Clinical signs, the collapse of serum albumin and histopathological analysis of skin tissue were evocative of kwashiorkor. Her symptoms subsided after several weeks of a nutritional programme. DISCUSSION: Kwashiorkor is a clinical entity described chiefly in children in developing countries. Cutaneous involvement comprising asteatotic eczema-like skin associated with diffuse oedema is prominent. Treatment with protein supplementation alone is effective and avoids many complications such as infections and haemodynamic disorders. Obesity is a serious and common disease in Western countries affecting one third of the world's population, and for which treatment with bariatric surgery may be indicated. Without regular monitoring, this surgery can cause severe protein deficiency. Consequently, in the future there will seemingly be a greater likelihood of kwashiorkor in adults as an iatrogenic complication of obesity treatment. Its semiology needs to be underlined because of the simplicity and efficacy of treatment.

[Dermato-neuro syndrome during scleromyxedema: efficacy of plasmapheresis and intravenous immunoglobulin]. / Dermatoneuro syndrome au cours d'un scléromyxœdème: efficacité des plasmaphérèses et des immunoglobulines intraveineuses.

BACKGROUND: Dermato-neuro syndrome is a specific neurological complication of scleromyxedema presenting with fever, coma, seizures and flu-like syndrome. To our knowledge, it has only been reported about twenty times in the literature. Its outcome is uncertain. We describe the case of a patient in whom a favorable outcome was achieved using a combination of plasmapheresis and intravenous immunoglobulin (IVIG). PATIENTS AND METHODS: A 57-year-old woman was diagnosed 14 years ago with scleromyxedema resistant to multiple lines of treatment. In November 2011, she presented an initial episode of epileptic seizure followed by post-seizure coma, and later, confusional state with visual hallucinations. She recovered spontaneously within a few days. CT scan, MRI, EEG and screening for infection were perfectly normal, resulting in suspicion of neurological involvement associated with her scleromyxedema. In December 2012 and August 2013, she presented two further episodes of status epilepticus, followed once more by a confusional state, with etiological explorations again proving unfruitful. On this occasion, her confusional state persisted for two months until the initiation of plasmapheresis and IVIG. This combination therapy led to rapid regression of all neurological symptoms and an improvement in her general condition. DISCUSSION: The dermato-neuro syndrome is a rare neurological complication of scleromyxedema. Its pathophysiology is unknown. The monoclonal gammopathy induced by the scleromyxedema could account for the patient's hypercoagulable state and for the formation of neutrophilic aggregates leading to impaired microcirculation. Treatment is empirical and poorly codified. The course of the disease is unpredictable and may be lethal.

Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer.

BACKGROUND: Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated. PATIENTS AND METHODS: Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT). RESULTS: A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01). CONCLUSIONS: These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study.

[Importance of thorough removal of all affected tissues before grafting epidermolysis bullosa lesions: ten-year follow-up of one patient with multiple grafts]. / Nécessité d'une exérèse complète des tissus lésés dans les épidermolyses bulleuses : suivi sur dix ans d'une patiente multigreffée.

We present the case of a patient suffering from dominantly inherited dystrophic epidermolysis bullosa and followed over a period of ten years. Skin lesions of this patient have been treated with multiple thin skin grafts applied over Integra®. The experience proved that, in order to have a perfect graft take, it was necessary to remove all the affected tissues, which includes an abnormally thickened dermis, and also a portion of the subcutaneous tissue.

[Severe skin reaction with mucous membrane inflammation during MINE chemotherapy]. / Réaction cutanée sévère avec mucite au cours d'une chimiothérapie de type MINE.

BACKGROUND: MINE chemotherapy is used to treat refractory Hodgkin's disease. Cutaneous adverse effects of MINE regimen are uncommon and chiefly consist of erythema and oedema of the extremities. More recently, a number of cases of panniculitis and subcutaneous inflammatory oedema have been described. OBSERVATION: We report the case of a 17-year-old girl developing acute and painful oedema of the limbs with panniculitis of the trunk. This incident was associated with inflammatory lesions of mucous membrane, in particularly in the genital area and on the tongue. These signs occurred 7 days after initiation of MINE chemotherapy, with no other drugs being introduced. A drug-induced reaction was suspected due to the absence of any other aetiology, particularly infectious disease. The condition gradually improved with symptomatic pain therapy. The patient's chemotherapy was subsequently modified. DISCUSSION: The chronology of the symptoms, spontaneous improvement after the end of treatment, and the absence of other potential causative factors resulted in a hypothesis of a cutaneous adverse reaction to the MINE regimen. The signs could be due to capillary leak syndrome resulting from the toxicity of vinorelbine on endothelial cells. Dermatologists should be aware of these cutaneous adverse effects and of the inflammatory lesions of mucous membrane newly described herein.

[Recurring pyoderma gangrenosum in pregnancy]. / Pyoderma gangrenosum récidivant lors des grossesses.

BACKGROUND: We report the case of a 25-year-old patient developing pyoderma gangrenosum (PG) during the third trimester of her first and second pregnancies. CASE REPORT: A 25-year-old woman developed PG on her left calf during week 32 of her second pregnancy; previously, during week 36 of her first pregnancy, the patient had presented abdominal pain with inflammatory syndrome. She underwent caesarean delivery at week 37 of pregnancy. Surgery was complicated by aseptic abdominal and parietal abscesses as well as aseptic endometritis with neutrophil infiltrate. She underwent two further surgical interventions that were followed by skin manifestations typical of PG. The two newborns were otherwise healthy. After five years of follow-up, we found no disorders usually associated with neutrophilic dermatosis. DISCUSSION: Pyoderma gangrenosum is extremely rare in pregnancy, with only 16 cases being reported in the international literature: nine during pregnancy and seven post-partum. The question is thus raised of a possible relationship between this neutrophilic dermatosis and pregnancy. The association could be due to the pathergy phenomenon or to the increase in G-CSF levels occurring in pregnant women.

Liver fibrosis staging with contrast-enhanced ultrasonography: prospective multicenter study compared with METAVIR scoring.

We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis.

Semaphorin, neuropilin and VEGF expression in glial tumours: SEMA3G, a prognostic marker?

Gliomas are characterised by local infiltration, migration of tumour cells across long distances and sustained angiogenesis; therefore, proteins involved in these processes are most likely important. Such candidates are semaphorins involved in axon guidance and cell migration. In addition, semaphorins regulate tumour progression and angiogenesis. For cell signalling, class-4 semaphorins bind directly to plexins, whereas class-3 semaphorins require additional neuropilin (NRP) receptors that also bind VEGF(165). The anti-angiogenic activity of class-3 semaphorins can be explained by competition with VEGF(165) for NRP binding. In this study, we analysed the expressions of seven semaphorins of class-3, SEMA4D, VEGF and the NRP1 and NRP2 receptors in 38 adult glial tumours. In these tumours, SEMA3B, SEMA3G and NRP2 expressions were related to prolonged survival. In addition, SEMA3D expression was reduced in high-grade as compared with low-grade gliomas. In contrast, VEGF correlated with higher grade and poor survival. Thus, our data suggest a function for a subset of class-3 semaphorins as inhibitors of tumour progression, and the prognostic value of the VEGF/SEMA3 balance in adult gliomas. Moreover, in multivariate analysis, SEMA3G was found to be the only significant prognostic marker.

Prognostic molecular markers with no impact on decision-making: the paradox of gliomas based on a prospective study.

This study assessed the prognostic value of several markers involved in gliomagenesis, and compared it with that of other clinical and imaging markers already used. Four-hundred and sixteen adult patients with newly diagnosed glioma were included over a 3-year period and tumour suppressor genes, oncogenes, MGMT and hTERT expressions, losses of heterozygosity, as well as relevant clinical and imaging information were recorded. This prospective study was based on all adult gliomas. Analyses were performed on patient groups selected according to World Health Organization histoprognostic criteria and on the entire cohort. The endpoint was overall survival, estimated by the Kaplan-Meier method. Univariate analysis was followed by multivariate analysis according to a Cox model. p14(ARF), p16(INK4A) and PTEN expressions, and 10p 10q23, 10q26 and 13q LOH for the entire cohort, hTERT expression for high-grade tumours, EGFR for glioblastomas, 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only. This study confirms the prognostic value of several markers. However, the scattering of the values explained by tumour heterogeneity prevents their use in individual decision-making.

[Imaging in the diagnosis and the staging of gallbladder tumors]. / Place de l'imagerie dans le diagnostic et le bilan des tumeurs de la vésicule biliaire.

Most of gallbladder tumors are benign. Adenoma, cholesterol polyps, or adenomyomatosis are most frequently typical on ultrasonographic images. All symptomatic lesions must be considered as indications for surgery. It may be difficult to identify precancerous or malignant lesion. Polyps over 1cm are indication for preventive cholecystectomy. In case of suspicious polyp or suspicious wall thickening, endoscopic ultrasonography can be helpful to evaluate local tumoral spread and eliminate differential diagnosis. Unfortunately, diagnosis of gallbladder cancer is often late, when surgical resection can't be curative. Computed tomography and magnetic resonance imaging examinations are then useful for local and metastatic staging.

[Solitary intracerebral langerhans cell histiocytosis: report of one case and literature review]. / Histiocytose langerhansienne encéphalique isolée à forme pseudotumorale: une observation et revue de la littérature.

INTRODUCTION: Langerhans cell histiocytosis is a multivisceral pathology. Neurological manifestations are rare. EXEGESIS: We report the case of a 31 year old man hospitalized for left partial motor seizure revealing a right frontal tumor with criteria for histiocytosis X. The histological and biological examination found criteria for Langerhans cell histiocytosis (CD1a and S100 reactivity). The check-up for extracerebral localisations of the disease was negative. The outcome was favourable after a total surgical resection. The review of the literature and a discussion on neurological manifestations of this disease were carried out. CONCLUSION: A neurological manifestation can be the first and only symptom of a Langerhans cell histiocytosis.

[Mycosis fungoides presenting as annular erythema]. / Mycosis fongoïde à type d'érythème annulaire centrifuge.

INTRODUCTION: Mycosis fungoides is a lymphoma, the classical clinical form of which involves erythematosquamous lesions. However, it can present various atypical aspects: hyper pigmentation or hypo pigmentation, suggestive of pyoderma gangrenosum or ichtyosis. We report a case of mycosis fungoides, unusual in its presentation in the form of centrifugal annular erythema. OBSERVATION: A 78 year-old man had developed a parapsoriasis in plaques for more than 20 years. In May 2002 he consulted because of the recent infiltration of one of the plaques, without concomitant pruritus. The clinical examination revealed 3 lesions of the popliteal groove of the right groin and the left cheek suggestive of centrifugal annular erythema. Histology, revealing Pautrier microabscesses, was compatible with the diagnosis of mycosis fungoides. Evolution was marked by the spontaneous regression of the plaque on the face and remission of the other two plaques after local treatment with chloromethin and topical corticosteroids. Nevertheless, new plaques appeared despite continued treatment, combined with PUVA therapy sessions. DISCUSSION: When searching the literature, we only found one other case of mycosis fungoides, the clinical aspect of which was a centrifugal annular erythema, but in which the histological examination confirmed the diagnosis of mycosis fungoides. Our case report is also unusual in the clinical regression of the lesion on the face, without treatment; this has only been reported in two cases. Mycosis fungoides can appear in various clinical forms. The centrifugal annular erythema form is rare, but this diagnosis should be evoked.

Bilateral symptomatic adrenal myelolipoma.

Adrenal myelolipomas are rare, nonfunctioning benign tumors that consist of mature fat and bone-marrow elements. In the first half of this century, most adrenal myelolipomas were found incidentally at autopsy. These tumors are usually unilateral and asymptomatic. Today they are detected by ultrasonography, computerized tomography, or magnetic resonance imaging scan, done for other reasons. Adrenal myelolipomas can be diagnosed because of their characteristic images. Thus they are classified as "incidentalomas." We report the case of a 50-year-old man who had bilateral adrenal myelolipomas and whose right-side tumor was symptomatic. To our knowledge it is the third operated case reported in the literature. A right adrenalectomy was performed, keeping the asymptomatic left adrenal myelolipoma to preserve adrenal function.

Cathepsin D in normal and neoplastic thyroid tissues.

BACKGROUND: Cathepsin D is a widely distributed lysosomal acidic endopeptidase. It is an estrogen-regulated protein that is a prognostic factor in breast cancer. The aim of this study was to measure cathepsin D concentrations in thyroid tissues and to correlate these concentrations with clinical and pathologic parameters. METHODS: Cathepsin D and thyroglobulin concentrations were measured in the cytosol of normal thyroid tissues (n = 14), benign nodules (n = 6), and thyroid carcinomas (n = 32) with an immunoradiometric assay. Statistical analysis was based on the Kruskal-Wallis and Wilcoxon tests and on the Spearman rank correlation coefficient. RESULTS: The mean level of cathepsin D, expressed as picomoles per milligram protein minus thyroglobulin, was higher in the 32 carcinomas, 29.1 +/- 15.5, than in the 14 normal thyroid tissues, 8.4 +/- 2.5 (p < 0.001) or in the 6 benign nodules, 11.2 +/- 7.3 (p = 0.003). Cathepsin D concentrations correlated with tumor size; Spearman rank correlation coefficient was rs = 0.44 (p = 0.012). No significant difference was found regarding histologic type. Cathepsin D concentrations were inversely correlated with the thyroglobulin level in the tumor; Spearman rank correlation coefficient was rs = -0.60 (p < 0.001). CONCLUSIONS: Cathepsin D concentration is higher in thyroid carcinoma than in normal thyroid tissue. Increased cathepsin D concentrations correlate with thyroid tumor size but not with histologic type. Further studies should be done to confirm the potential prognostic value of cathepsin D in patients with thyroid carcinomas.

[Lipoprotein lipase activity in human milk; inhibition in vitro of the glucuro-conjugation of bilirubin (author's transl)]. / Activite de la lipoproteine lipase dans les laits de femme; inhibiteurs in vitro de la conjugaison de la bilirubine

The lipolytic activities of esterase, lipase and lipoprotein lipase were measured in 17 samples of human milk. Lipase and esterase activities were the same in all samples. However, lipoprotein lipase activity was increased only in samples provided from mothers whose infants had prolonged neonatal jaundice; after storage these samples inhibited the glucuro-conjugation of bilirubin in vitro and their concentration in non-esterified fatty acids was high. The mechanism of action of this enzyme is discussed in relation to the physico-chemical state of fat globules.

Simultaneous determination of hemoglobin and coproporphyrin by second derivative differential spectrophotometry: application to the diagnosis of meconium aspiration.

We describe a simple, fast method for simultaneous measurement of hemoglobin and coproporphyrin in urine and amniotic fluid, by second-derivative differential spectrophotometry. Both pigments were determined in biological samples without prior extraction. Despite the slightly overlapping spectra, the method permitted satisfactory resolution and avoided interspectral interference. Its sensitivity, sufficiently good, allowed to detect hemoglobin and coproporphyrin in slightly pathological urine and amniotic fluid as an aid to the diagnosis of meconium aspiration.

Advantage of zero-crossing-point first-derivative spectrophotometry for the quantification of calcium oxalate crystalline phases by infrared spectrophotometry.

The main component of urinary calculi in industrialized countries is calcium oxalate. Its detection in stones is easily performed by infrared spectrophotometry. However its two crystalline forms calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD), which are linked to different aetiologies, provide similar patterns, with overlapping vibrations leading to difficulties in differentiation and quantitation of both the phases in mixtures. Some minor but characteristic bands of each crystalline species are emphasized for analytical purposes. The method of zero-crossing-point first-derivative spectrophotometry was applied to calcium oxalate species quantitation and revealed to be easy, accurate, precise and very well adapted to routine laboratories.

Topoisomerase II alpha and telomerase expression in papillary thyroid carcinomas.

BACKGROUND: Altered topoisomerase II alpha (Topo II alpha) expression and telomerase activity (TA) reflect tumour cell growth and malignant transformation. METHODS: We examined TA by using a TRAP assay and expression of Topo II alpha by immunohistochemical analysis in a series of 27 cases of papillary thyroid carcinoma (PTC). RESULTS: Topo II alpha labelling index (LI) ranged from 0.1 to 4.2% and was significantly associated with patient age (r=-0.42, p=0.003), with higher levels of Topo II alpha in patients under 40 years. There was no relationship between Topo II alpha LI, AGES score or other clinical outcome. TA was detected in 14 PTC, with relative levels ranging from 1.2 to 102 units. A significant positive correlation between the multiplicity of tumoral foci and the TA levels (p<10(-2)) was noted. CONCLUSION: We concluded that Topo II alpha cannot be used as a marker of tumour aggressiveness. Furthermore, enhanced Topo II alpha expression in PTCs from patients less than 40 years old suggests that this age group might benefit from Topo II inhibitor chemotherapy.