Primary cutaneous large B-cell lymphomas: relevance of the 2017 World Health Organization classification: clinicopathological and molecular analyses of 64 cases.

AIMS: We applied the 2017 World Health Organization (WHO) classification criteria to categorise a series of 64 primary cutaneous large B-cell lymphomas (PCLBCLs), containing a majority (≥80%) of large cells and a proliferative rate of ≥40%, raising the problem of the differential diagnosis between PCLBCL, leg type (PCLBCL-LT) and primary cutaneous follicle centre lymphoma, large cell (PCFCL-LC). The aims were to determine the reproducibility and prognostic relevance of the 2017 WHO criteria. METHODS AND RESULTS: Morphology and phenotype identified 32 PCLBCLs-LT and 25 PCFCLs-LC; seven cases (11%) remained unclassified. Morphology was less reproducible than immunophenotype. Pertinent markers for the differential diagnosis were MUM1, FOXP1, CD10, and IgM. bcl-2 and bcl-6 were expressed by both PCFCLs-LC and PCLBCLs-LT at substantial levels. Neither Ki67 expression nor p63 expression was of diagnostic value. MYD88 was found to be mutated only in PCLBCLs-LT (n = 22, 69%). According to Hans/Hans modified algorithms, 23 of 25 PCFCLs-LC had germinal centre (GC) status, and the 32 PCLBCLs-LT had non-GC status. Overall survival was poorer for PCLBCLs-LT than PCFCLs-LC (P = 0.0002). Non-GC cases had poorer overall survival than GC cases (P = 0.0007). In PCLBCLs-LT, MYC expression was associated with cutaneous relapses (P = 0.014). When GC/non-GC status was applied to unclassified cases, only a single case remained discordant. CONCLUSIONS: Our results support the 2017 WHO classification criteria for PCLBCL diagnosis. The Hans modified algorithm using CD10 and MUM1 distinguished PCFCLs-LC from PCLBCLs-LT with optimal diagnostic value without requiring bcl-6 immunolabelling (poorly reproducible). Rare unclassified cases may constitute a provisionally heterogeneous subgroup for which GC/non-GC status (relevant for prognosis) may guide therapeutic decisions.

Vasculitis secondary to anti-C1q antibodies induced by Toxocariasis.

INTRODUCTION: Vasculitides occurring during parasitic infection are rare and may imply different mechanisms. METHODS: A case report of cutaneous vasculitis and visceral damage during a larva migrans syndrome. RESULTS: We report the case of a 64-year-old man who developed a purpura along with fever, respiratory failure, abdominal pain and myalgia. Immunological screening showed a high titer of both antinuclear antibodies and anti-double-stranded DNA antibodies along with anti-C1q antibodies. Toxocara canis serology returned highly positive with a positive western-blot. The use of antiparasitic drugs in combination with corticosteroids resulted in a dramatic improvement in the patient's condition. CONCLUSIONS: Clinicians should be aware of the systemic complications that may occur during Toxocara canis infection, including vasculitis and immunological disorder.

Complex Management of Nephrotic Syndrome and Kidney Failure during Pregnancy in a Type 1 Diabetes Patient: A Challenging Case.

Pregnancy with chronic kidney disease is challenging, and patients with diabetic nephropathy are at particular risk of a rapid kidney function decline during pregnancy. While indications for the management of pregnant patients with initial diabetic nephropathy are widely available in the literature, data on patients with severe nephrotic syndrome and kidney function impairment are lacking, and the decision on whether and when dialysis should be initiated is not univocal. We report a type 1 diabetes patient who started pregnancy with a severe nephrotic syndrome and shifted from CKD stage 3b to stage 5 during pregnancy. The management was complicated by a fetal heart malformation and by poorly controlled diabetes. The evidence for and against starting dialysis was carefully evaluated, and the choice of strict nephrological and obstetrical monitoring, nutritional management, and diuretic treatment made it possible to avoid dialysis in pregnancy, after ruling out pre-eclampsia. This experience enables examination of some open issues and contributes to the discussion of when to start dialysis in pregnancy.

[Interstitial mycosis fungoid: a rare variant of mycosis fungoids. Two cases]. / Le MF interstitiel : une variante rare de mycosis fongoïde.

Mycosis fungoids can present with various clinical and histological features, with only a few of them being recognized as distinct entities in the current WHO and EORTC classifications. Histologically, mycosis fungoids (MF) usually show a superficial perivascular or band-like lymphocytic infiltrate with epidermotropism. We here report two cases of a rare histological variant of MF, called interstitial in the literature. Our first patient, a 71-year-old male, had a previously diagnosed MF, which clinically evolved towards nodules, showing histologically an interstitial lymphocytic infiltrate without epidermotropism and without large cell transformation. The second patient was a 64-year-old female with widespread plaques and nodules. Histologically, a dense dermal interstitial infiltrate was observed, with foci of epidermotropism, without large cell transformation. At relapse after treatment, she presented with plaques, papules and nodules, histologically showing a slight interstitial lymphocytic infiltrate that resembled granuloma annulare or inflammatory morphea. In both patients, clinical aspect suggested MF and a dominant T-cell clone was found in lesional skin. Nodules in MF are not always the hallmark of large cell transformation, but may correspond to unusual interstitial lesions. Diagnosis of such rare variant may be difficult and requires a good clinical pathological correlation together with the search for foci of epidermotropism on skin biopsy and for a dominant cutaneous T-cell clone.

[Nephropathy associated with hypocomplementemic urticarial vasculitis: A case report and literature review]. / Néphropathie associée à une vascularite urticarienne hypocomplémentémique : présentation d'un cas clinique et revue de la littérature.

Hypocomplementemic urticarial vasculitis is a rare systemic vasculitis, affecting small vessels, characterised by chronicle urticaria, hypocomplementemia, and systemic manifestations. Renal involvement, whose prevalence varies between 9% and 60%, is mainly glomerular. We here report the case of a 59 years old woman presenting kidney failure, associated with chronicle urticaria and arthralgias. Laboratory investigation showed haematuria, proteinuria, hypocomplementemia and anti-SSa antibody positivity. A percutaneous kidney biopsy revealed focal and segmental glomerulonephritis associated with an acute interstitial nephritis. Hypocomplementemic urticarial vasculitis diagnosis was established after identifying anti-C1q antibodies. The lack of a dry syndrome, the negativity of a Schirmer test and the lack of sialadenitis on a salivary gland biopsy excluded an associated Gougerot-Sjögren Syndrome. The patient was treated with hydroxychloroquine and low-dose steroids, enabling a clinical and biological recovery. Of the 82 cases in the literature describing hypocomplementemic urticarial vasculitis associated nephropathies, 72 (88%) were a glomerular impairment, most frequently secondary to membranoproliferative glomerulonephritis. Only 6 (7%) tubulo-interstitial nephritis have been reported, 4 of them being associated with a glomerulonephritis. Patients were more likely to be women, aged in their third decade. The most frequent renal manifestations were haematuria (60%), and proteinuria (52%). Kidney failure was rarely observed (22%), with a fairly good renal prognosis. Hypocomplementemic urticarial vasculitis was associated with a systemic disease in 11 (13%) patients. In the absence of recommendations, the treatment strategy remains to be defined.

Late cardiac adverse events in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitor (ICI)-associated early cardiac adverse events (CAEs), mostly acute and fulminant myocarditis, have been well characterized and mainly occur during the first 90 days after ICI therapy initiation. ICI-associated late CAEs (occurring after the first 90 days of treatment) have not yet been described. METHODS: First, we compared characteristics of a cohort involving early (defined as a CAE time to onset (TTO) of <90 days after ICI therapy initiation) and late (defined as a CAE TTO of ≥90 days after ICI therapy initiation) ICI-associated CAE consecutive cases who were referred to three French cardio-oncology units. Second, ICI-associated CAE cases were searched in VigiBase, the WHO global individual case safety report database, and early and late ICI-associated CAEs were compared. RESULTS: In the cohort study, compared with early CAE cases (n=19, median TTO of 14 days), late ICI-associated CAE cases (n=19, median TTO of 304 days) exhibited significantly more left ventricular systolic dysfunction (LVSD) and heart failure (HF) and less frequent supraventricular arrhythmias. In VigiBase, compared with early cases (n=437, 73.3%, median TTO 21 days), the late ICI-associated CAE reports (n=159, 26.7%, median TTO 178 days) had significantly more frequent HF (21.1% vs 31.4%, respectively, p=0.01). Early and late ICI-associated CAE cases had similarly high mortality rates (40.0% vs 44.4% in the cohort and 30.0% vs 27.0% in VigiBase, respectively). CONCLUSIONS: Late CAEs could occur with ICI therapy and were mainly revealed to be HF with LVSD. TRIAL REGISTRATION NUMBERS: NCT03678337, NCT03882580, and NCT03492528.

Non-traumatic diaphragmatic rupture with liver herniation due to endometriosis: A rare evolution of the disease requiring multidisciplinary management.

A 35 year old woman with chronic pelvic endometriosis suffered from right scapular pain. MRI imaging showed a right diaphragmatic rupture with liver herniation. Surgical procedure was performed by thoracotomy. The liver was put back into the abdomen, endometriosis was resected from the diaphragm, interrupted non absorbable suture of the diaphragm was performed and an absorbable mesh was placed. Endometriosis was confirmed on histological analysis of the resected diaphragm. To study this pathology, we performed a systematic review of the literature and found 12 similar cases of diaphragmatic rupture due to endometriosis. Right diaphragm is often involved and rupture is always located on the tendinous portion. Symptoms are mainly cyclic right scapular pain and cathamenial pneumothorax. MRI should be performed in case of suggestive symptoms and a systematic exploration of the diaphragm should be performed at laparoscopy for an early treatment of the lesions to prevent progression to rupture.

Usefulness of Flow Cytometry for the Detection of Cutaneous Localization in Malignant Hematologic Disorders.

BACKGROUND: Histological evaluation of malignant hematologic involvement of the skin can be challenging and needs an extended immunohistochemistry panel. We assessed the ability of flow cytometry (FCM) to detect neoplastic cell subsets in skin biopsies as a useful tool that supplements the histological examination in a complementary way. METHODS: Two hundred and forty-three consecutive skin biopsies were retrospectively analyzed between April 2012 and July 2017. RESULTS: Among them, 147 samples, corresponding to 128 patients, were analyzed at diagnosis. Eighty-seven patients had erythrodermic inflammatory dermatoses, and 41 patients had cutaneous hematologic neoplasms. Cutaneous T-cell lymphomas were the most frequent disorders, accounting for 70% of cases (29/41). Cutaneous B-cell lymphoma was found in only 17% of cases (7/41) and immature hematologic malignancies in 5% (2/41). Three patients had secondary skin involvement. The sensitivity of FCM skin biopsy analysis was 78.1% (32/41). Among the 243 samples, 27 patients had mycosis fungoides (MF) or Sezary syndrome (SS) with available FCM data. A loss of CD26 expression was identified in 92% of cases of transformed MF or SS versus 40% of cases of non-transformed MF (P = 0.0057 χ²). Among the 12 MF patients with negative CD26 expression, six progressed to SS versus none in the positive group (50% vs. 0% P = 0.0168 χ²). CONCLUSIONS: FCM analysis of the skin biopsies is a sensitive method and a useful tool for improving the sensitivity of diagnosis of hematologic skin neoplasms. Among the MF patients, a loss of CD26 expression could be a marker of higher risk of progression. © 2019 International Clinical Cytometry Society.

Eculizumab reversed severe distal ischemic syndrome and glomerulonephritis with isolated C3 deposits associated with anti-factor H autoantibodies: a case report.

B-cell clones can produce a monoclonal immunoglobulin, which may be responsible for visceral involvements. Kidney involvement is frequent, affecting 20 to 50% of patients with multiple myeloma. One mechanism underlying this involvement is a dysregulation of the complement alternative pathway, leading to C3 glomerulopathies. We report a patient who had a multiple myeloma, C3 glomerulopathy related to factor H autoantibody, and digital ischemia, who was treated successfully with eculizumab, an anti-complement therapy, without any relapse in 2 years of follow-up.

[Bile salt nephropathy/cholemic nephrosis]. / Néphropathie à cristaux biliaires/néphropathie cholémique.

Bile cast nephropathy is a tubulo-interstitial nephropathy. Its diagnosis may be under-estimated. It develops in patients who have cholestatic jaundice, with high bilirubinemia. Bile salts are freely filtered through glomerulus. Under certain circumstances, it forms casts into the tubule and cause an acute tubular necrosis. The diagnosis evidence is histologic, but fulfilment of renal biopsy is often made difficult, because of the hemostatic abnormalities that patients with hepatocellular injury develop. The treatment is supportive and etiological. We report here the case of a patient who presented a drug-induced hepatic jaundice, complicated with acute kidney failure secondary to bile cast nephropathy. We present the histological diagnosis evidence.

Early loss of two renal grafts obtained from the same donor: role of ecstasy?

Early loss of renal grafts is generally caused by vascular or immunologic complications. We describe two patients who received a kidney transplant from the same donor and lost their grafts during the first posttransplant week. Both cases presented necrotizing graft vasculopathy without inflammatory element. The donor was a 21-year-old woman who regularly used "ecstasy" over a 2-year period. After an extensive work-up to investigate the potential causes of graft loss, we considered the possibility of ecstasy being the cause of these two renal-graft losses.

Recurrence of ANCA-positive glomerulonephritis immediately after renal transplantation.

Recurrence of crescentic necrotizing glomerulonephritis after renal transplantation is rare. Successful renal transplantation in patients with antineutrophil cytoplasmic autoantibody (ANCA) glomerulonephritis has been reported. The presence of ANCA at transplantation does not appear to increase the rate of relapse after kidney allografting. Therapy with cyclophosphamide and corticoids usually is effective. We report a case of recurrent perinuclear ANCA crescentic necrotizing glomerulonephritis immediately after renal transplantation that was treated successfully by cyclophosphamide, plasma exchange, and intravenous polyvalent immunoglobulin.

Skin manifestations in CD4+, CD56+ malignancies.

CD4+ CD56+ hematologic neoplasms were recently individualized. We report three cases of CD4+ CD56+ malignancies with cutaneous lesions in three cases and also bone marrow involvement in two cases. Two patients relapsed 2 and 3 months after polychemotherapy. Two patients died within 3-10 months. A constant immunophenotype was observed with the co-expression of CD4 and CD56, the absence of B and T-cell markers. The salient fact of this report is the presence of T-cell clonal rearrangement. The clinical and pathological features closely resemble the specific cutaneous manifestations in acute leukemia with monocytic differentiation, especially the granulocytic sarcoma. Because of the positivity of the CD56, natural killer cell proliferations were discussed. Since 1994, 50 cases of CD4+, CD56+ cutaneous neoplasms have been reported with specific clinical, cytologic and immunohistochemical features. The diagnosis is more difficult when the cutaneous location is exclusive; on the contrary, the cytological features of the blood and medullar cells with cytoplasmic vacuoles and pseudopodia are characteristic of this hematologic neoplasm. The presence of CD123 antigen in most of the cases is an argument for a plasmacytoid dendritic cell proliferation and it is also a good marker for primary cutaneous lesions.

[Clinical aspects of human polyomaviruses in renal transplantation]. / Manifestations cliniques des polyomavirus humains en transplantation rénale.

A THREAT FOR RENAL ALLOGRAFT: Human polyomavirus infections (BK virus, JC virus), known for the past 30 years, were considered as common in renal transplantation until the recently reported studies describing the responsibility of BKv (and less JCv) in the occurrence of tubulo-interstitial nephritis in around 5% of renal transplant recipients, with worsening of the renal function leading to graft failure in 10 to 45% of infected patients. Their description coincided with the use of new immunosuppressors (tacrolimus and mycophenolate mofetil) without, however, their responsibility clearly incriminated. EARLY DIAGNOSIS FOR EFFICIENT TREATMENT: The presence of cells infected by the polyomavirus ("decoy cells") in the urine and the detection of BKv or JCv DNA by PCR in the plasma and urine are viral replication markers which strongly suggest the possibility of a polyomavirus nephropathy. TWO CLINICAL VARYING FORMS: Polyomavirus infection is frequent and often asymptomatic. The diagnosis requires the detection of large nucleus "decoy cells" in fresh urine. Polyomavirus renal allograft disease is characterised by the association of decoy cells and renal failure related to a tubulo-interstitial nephropathy and the presence of DNA of the virus in the plasma. The diagnosis requires identification of intra-nuclear viral inclusions in epithelial cells using immunohistochemistry, in situ hybridisation, or electron microscopy techniques. A DIFFICULT DIAGNOSIS: Confusion between interstitial nephritis and acute cellular rejection is the major risk leading to therapeutic error. Risk factors include over-immunosuppression and/or treatment of rejection episodes which could increase viral replication as well as the emergence of mutant BKv strains at the origin of tubulo-interstitial nephritis, leading to acute and chronic dysfunction of the renal transplantation.

Increased HIF-1α expression correlates with cell proliferation and vascular markers CD31 and VEGF-A in uveal melanoma.

PURPOSE: Overexpression of hypoxia inducible factor-1 α (HIF-1α) has been found in several cancers and is thought to correlate with aggressive disease. The purpose of our study was to investigate the influence of HIF-1α on clinical outcome in uveal melanoma (UM) along with proliferative (MIB-1) and vascular (CD31, VEGF-A) markers. METHODS: A retrospective analysis was carried out on UM tumors from 88 patients. HIF-1α, MIB-1, CD31, and VEGF-A expression, as well as necrosis, were assessed by immunohistochemistry and hematoxylin/eosin on paraffin-embedded UM tumor sections by using a tissue microarray. The bivariate analysis involving HIF-1α expression and clinicopathologic covariates was performed by using the χ(2) test. The association of clinicopathologic covariates and HIF-1α expression with patient survival was evaluated by using the Kaplan-Meier approach and Cox proportional-hazards regression analysis. RESULTS: Among our study population, 56 patients (63.6%) had high levels of HIF-1α expression. High expression of HIF-1α was associated with high expression of MIB-1 (P = 0.04), CD31 (P = 0.03), and VEGF-A (P < 0.0001), as well as necrosis (P = 0.04). However, high HIF-1α expression was not correlated with cell type, largest macroscopic tumor dimension or thickness, anterior margin, pigmentation, or mitotic figures. Patients with high HIF-1α expression did not show a reduced survival when compared to patients with low HIF-1α expression (P = 0.92). Finally, HIF-1α expression was not increased after irradiation. CONCLUSIONS: An increase in HIF-1α expression was significantly associated with proliferative (MIB-1) and vascular (CD31 and VEGF-A) markers, as well as necrosis, in UM. However, there was no correlation between high HIF-1α expression and patient survival.