Nicole K. Andeen

The phenotypes of podocytes and parietal epithelial cells may overlap in diabetic nephropathy.

Reversal of diabetic nephropathy (DN) has been achieved in humans and mice, but only rarely and under special circumstances. Since progression of DN is related to podocyte loss, reversal of DN requires restoration of podocytes. Here we identified and quantified potential glomerular progenitor cells that could be a source for restored podocytes. DN was identified in 31 human renal biopsy cases and separated into morphologically early or advanced lesions. Markers of podocytes (WT-1, p57), parietal epithelial cells (claudin-1) and cell proliferation (Ki-67) were identified by immunohistochemistry. Podocyte density was progressively reduced with DN. Cells marking as podocytes (p57) were present infrequently on Bowmans capsule in controls, but significantly increased in histologically early DN. Ki-67 expressing cells were identified on the glomerular tuft and Bowmans capsule in DN, but rarely in controls. Cells marking as PECs were present on the glomerular tuft, particularly in morphologically advanced DN. These findings show evidence of phenotypic plasticity in podocyte and PEC populations and are consistent with studies in the BTBR ob/ob murine model in which reversibility of DN occurs with podocytes potentially regenerating from PEC precursors. Thus, our findings support, but do not prove, that podocytes may regenerate from PEC progenitors in human DN. If so, progression of DN may represent a modifiable net balance between podocyte loss and regeneration.

DnaJ Homolog Subfamily B Member 9 Is a Putative Autoantigen in Fibrillary GN

Fibrillary GN is a rare form of GN of uncertain pathogenesis that is characterized by the glomerular accumulation of randomly arranged, nonbranching fibrils (12-24 nm) composed of Ig and complement proteins. In this study, we used mass spectrometry to comprehensively define the glomerular proteome in fibrillary GN compared with that in controls and nonfibrillary GN renal diseases. We isolated glomeruli from formalin-fixed and paraffin-embedded biopsy specimens using laser capture microdissection and analyzed them with liquid chromatography and data-dependent tandem mass spectrometry. These studies identified DnaJ homolog subfamily B member 9 (DNAJB9) as a highly sampled protein detected only in fibrillary GN cases. The glomerular proteome of fibrillary GN cases also contained IgG1 as the dominant Ig and proteins of the classic complement pathway. In fibrillary GN specimens only, immunofluorescence and immunohistochemistry with an anti-DNAJB9 antibody showed strong and specific staining of the glomerular tufts in a distribution that mimicked that of the immune deposits. Our results identify DNAJB9 as a putative autoantigen in fibrillary GN and suggest IgG1 and classic complement effector pathways as likely mediators of the destructive glomerular injury in this disease.

Can MRI biomarkers at 3 T identify low-risk ductal carcinoma in situ? ☆,☆☆

OBJECTIVE The objective was to explore whether 3-T magnetic resonance imaging (MRI) can identify low-risk ductal carcinoma in situ (DCIS). METHODS Dynamic contrast-enhanced and diffusion-weighted (DWI) MRI features of 36 DCIS lesions [8 low risk, Van Nuys Pathologic Classification (VNPC) 1; 28 high risk, VNPC 2/3] were reviewed. An MRI model that best identified low-risk DCIS was determined using multivariate logistic regression. RESULTS Low-risk DCIS exhibited different DWI properties [i.e., higher contrast-to-noise ratio (P=.02) and lower normalized apparent diffusion coefficients (P=.04)] than high-risk DCIS. A model combining these DWI features provided best performance (area under receiver operating characteristic curve =0.86). CONCLUSIONS DWI may help identify DCIS lesions requiring less therapy.

Metastatic Treated Malignant Germ Cell Tumors: Is SALL4 a Better Marker Than Placental Alkaline Phosphatase?

Studies have shown that in the metastatic setting and after treatment, expression of immunohistochemical markers may be diminished or lost. Transcription factor SALL4 (sal-like protein 4) has been recognized as a sensitive marker for both primary and metastatic malignant germ cell tumors (MGCTs), but has not been tested in the posttreatment setting. We sought to determine the level of SALL4 expression in treatment-resistant metastatic MGCT in comparison with pan-GCT marker placental alkaline phosphatase (PLAP). Thirty-six previously treated MGCTs, 16 untreated primary testicular MGCTs, and 4 cytology specimens were immunostained for SALL4 and PLAP, and staining characteristics were evaluated. In the treated MGCT group, there was diffuse SALL4 nuclear immunoreactivity in the majority of cases (27/36, 75%), labeling seminoma, yolk-sac tumor, embryonal carcinoma, and primitive neuroectodermal components. No treated metastatic MGCT lacked SALL4 immunoreactivity. In contrast, PLAP was diffusely expressed in only 14/36 (39%) cases of treated MGCTs, showed scattered focal weak to moderate positivity in 13/36 (36%), and was virtually absent in 9/36 (25%) cases. Both markers had scattered expression limited to the epithelial components of teratomatous regions. SALL4 also outperformed PLAP on a small sample of cytology blocks. Although SALL4 is not entirely specific, it is a highly sensitive marker with strong diffuse nuclear reactivity in the majority of MGCTs in the posttreatment setting, at significantly higher levels than PLAP (P<0.001). Persistent expression of SALL4 in metastatic MGCTs resistant to chemoradiation also raises the possibility for targeted systemic therapy as the anti-SALL4 peptide continues to be developed.

A large juvenile xanthogranuloma within the tongue.

J uvenile xanthogranuloma (JXG) is a benign, selflimiting disorder that typically involves the cutaneous regions of the head and neck. Infrequently, the oral cavity is involved, which presents unique diagnostic and treatment considerations. We present the first descriptive case report of a large, entirely submucosal JXG of the tongue. Withdrawal from review was granted by the Institutional Review Board of the University of Washington.

Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas

Superficial malignant peripheral nerve sheath tumour (MPNST) is a rare, soft tissue neoplasm that shares morphological features and some molecular events with spindle/desmoplastic melanoma (SDM). Herein, we sought to identify molecular targets for therapy by using targeted RNA/DNA sequencing and gene expression of key immunological players. DNA and RNA from formalin‐fixed paraffin‐embedded tissue were extracted and processed. Massive high‐throughput deep parallel sequencing was performed with the Oncomine comprehensive panel, enabling detection of relevant single‐nucleotide variants, copy number variations, gene fusions and indels for 143 unique genes on the Ion torrent sequencer for clinical trial research programmes. Gene expression analysis was carried out with a customized 770‐gene expression panel combining markers for 24 different immune cell types and 30 common cancer antigens, including key checkpoint blockade genes analysed with the Ncounter system. Fifty‐one patients (SDM, 16/11; MPNST, 24; male, n = 37; female, n = 16) had sufficient DNA and RNA for testing. NF1 deleterious mutations and/or deep/homozygous deletions were identified in 73% of MPNSTs and 67% of SDMs, with 50% of the mutations involving the RAS‐binding domain. Inactivating/deleterious mutations of TSC1/TSC2 were identified in 40% and 41% of MPNSTs and SDMs, respectively. Activating mutations affecting the EGFR‐like and the negative regulatory domains of NOTCH1 and KDR (VEGFR2) were identified in 45% and 40% of SDMs and in 30% and 8% of MPNSTs, respectively. Differential gene expression and gene clustering analysis showed significantly perturbed immune pathway components, including nuclear factor‐κB (NF‐κB), JAK–STAT, and CXCL12–CXCR4, and differentially expressed CD274 and CTLA4, in both SDM and MPNST. Angiogenesis (KDR and NOTCH1) and mammalian target of rapamycin complex (mTORC) pathways offer a rationale for anti‐angiogenic and selective mTORC inhibition as treatment strategies for MPNST and SDM. Cytokines and the JAK–STAT, TNF and NF‐κB axes were perturbed in both SDM and MPNST. These pathways have been targeted in haematological malignancies and present promising targets for these tumours. Copyright

CT of Atypical and Uncommon Presentations of Hepatocellular Carcinoma

OBJECTIVE The purpose of this article is to familiarize radiologists with uncommon presentations of hepatocellular carcinoma (HCC) with an emphasis on the CT spectrum of atypical appearances. CONCLUSION HCC is the fifth most common neoplasm worldwide and the second most common cause of cancer-related death. In many cases, HCC can be confidently diagnosed with noninvasive imaging. However, there are numerous unusual appearances of HCC with which the radiologist must be familiar.

Cavernous hemangioma with extensive sclerosis masquerading as intrahepatic cholangiocarcinoma - A pathologist's perspective.

A patient presented with an acute episode of bright red blood in her stool. The incidental liver mass seen in segment 4 was suspected to represent a cholangiocarcinoma due to associated mild intrahepatic biliary ductal dilatation and suspicion for capsular retraction. Pathology confirmed that this lesion represented a sclerosing hemangioma. This case report corroborates prior observations that degenerative changes in hemangiomas—sclerosis, narrowing of vascular channels, thrombosis, infarct, hemorrhage—may produce atypical radiographic findings. Since these atypical radiographic features may suggest a primary or metastatic malignancy, the protean appearance of hemangiomas remains an important consideration in the evaluation of hepatic masses.

Renal ApoA-1 Amyloidosis with Glu34Lys Mutation and Intra-amyloid Lipid Accumulation

Apolipoprotein A-1 (ApoA-1) amyloidosis occurs as a nonhereditary condition in atherosclerotic plaques, but it can also manifest as a hereditary disorder caused by mutations of the APOA1 gene. Hereditary ApoA-1 amyloidosis presents with diverse organ involvement based on the position of the mutation. We describe a case of ApoA-1 amyloidosis with a Glu34Lys mutation; testicular, conjunctival, and renal involvement; and the notable finding of lipid deposition within the amyloid deposits.

Collapsing glomerulopathy in older adults

Collapsing glomerulopathy has been described in settings of viral infections, drug, genetic, ischemic, renal transplant, and idiopathic conditions. It has a worse prognosis than other morphologic variants of focal segmental glomerulosclerosis, and may be treated with aggressive immunosuppression. In this study, we sought to characterize the clinical and morphologic findings in older adults with collapsing glomerulopathy. Renal biopsies and associated clinical data from patients aged 65 or older with a diagnosis of collapsing glomerulopathy were retrospectively reviewed at 3 academic institutions. Patients (n = 41, 61% male, median age 71) usually had hypertension (88%), nephrotic range proteinuria (91%), and renal insufficiency (median serum creatinine 2.5 mg/dL). A likely precipitating drug (5%) or vascular procedure (5%) was identified in a minority of cases; viral infections were infrequent. Renal biopsies contained a median of 40% globally and 16% segmentally sclerotic glomeruli. Approximately 60% of cases had moderate or severe arteriosclerosis, arteriolar hyalinosis, and/or tubular atrophy and interstitial fibrosis; 7% had atheroembolic disease and 5% had thrombotic microangiopathy. In 28 patients with available follow-up information, eight (19%) were treated with immunosuppressives, which were not tolerated by 2. At a median interval of 14 months, 5 (18%) patients had died, 12 (43%) had end stage renal disease, and 12 were alive with renal insufficiency and proteinuria. Treatment with immunosuppressive therapy did not have a significant benefit with regard to the primary outcome of overall or renal survival. One steroid-treated patient with diabetes died 6 weeks after biopsy, with invasive rhinoorbital Rhizopus infection. In conclusion, collapsing glomerulopathy in older patients is usually not associated with viral infections, and is accompanied by significant chronic injury in glomeruli, vasculature, and tubulointerstitium. Aggressive immunosuppression likely contributed to one death in a patient with diabetes, and did not yield an overall or renal survival advantage in this cohort.