ABSTRACT
During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.
Subject(s)
Antibodies, Viral , BNT162 Vaccine , COVID-19 , Germinal Center , Antigens, Viral , COVID-19/prevention & control , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , VaccinationABSTRACT
New therapies are being developed for breast cancer, and in this process, some "old" biomarkers are reutilized and given a new purpose. It is not always recognized that by changing a biomarker's intended use, a new biomarker assay is created. The Ki-67 biomarker is typically assessed by immunohistochemistry (IHC) to provide a proliferative index in breast cancer. Canadian laboratories assessed the analytical performance and diagnostic accuracy of their Ki-67 IHC laboratory-developed tests (LDTs) of relevance for the LDTs' clinical utility. Canadian clinical IHC laboratories enrolled in the Canadian Biomarker Quality Assurance Pilot Run for Ki-67 in breast cancer by invitation. The Dako Ki-67 IHC pharmDx assay was employed as a study reference assay. The Dako central laboratory was the reference laboratory. Participants received unstained slides of breast cancer tissue microarrays with 32 cases and performed their in-house Ki-67 assays. The results were assessed using QuPath, an open-source software application for bioimage analysis. Positive percent agreement (PPA, sensitivity) and negative percent agreement (NPA, specificity) were calculated against the Dako Ki-67 IHC pharmDx assay for 5%, 10%, 20%, and 30% cutoffs. Overall, PPA and NPA varied depending on the selected cutoff; participants were more successful with 5% and 10%, than with 20% and 30% cutoffs. Only 4 of 16 laboratories had robust IHC protocols with acceptable PPA for all cutoffs. The lowest PPA for the 5% cutoff was 85%, for 10% was 63%, for 20% was 14%, and for 30% was 13%. The lowest NPA for the 5% cutoff was 50%, for 10% was 33%, for 20% was 50%, and for 30% was 57%. Despite many years of international efforts to standardize IHC testing for Ki-67 in breast cancer, our results indicate that Canadian clinical LDTs have a wide analytical sensitivity range and poor agreement for 20% and 30% cutoffs. The poor agreement was not due to the readout but rather due to IHC protocol conditions. International Ki-67 in Breast Cancer Working Group (IKWG) recommendations related to Ki-67 IHC standardization cannot take full effect without reliable fit-for-purpose reference materials that are required for the initial assay calibration, assay performance monitoring, and proficiency testing.
Subject(s)
Breast Neoplasms , Immunohistochemistry , Ki-67 Antigen , Humans , Ki-67 Antigen/metabolism , Ki-67 Antigen/analysis , Breast Neoplasms/metabolism , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Female , Immunohistochemistry/methods , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/analysis , Canada , Sensitivity and Specificity , Tissue Array Analysis/methodsABSTRACT
Mucoepidermoid carcinoma (MEC) is exceedingly rare in the breast, with <45 cases reported in the literature. Although estrogen receptor/progesterone receptor/human epidermal growth factor 2 triple-negative, MEC is characterized as a special subtype of breast carcinoma with significantly better prognosis than conventional basal-type tumors. Cutaneous hidradenoma (HA) is considered a benign adnexal neoplasm showing histomorphologic overlap with MEC. Rare cases of HA have also been reported in the breast, but these are relatively uncharacterized. In this study, we examined the clinicopathologic, immunohistochemical (IHC), and genetic features of 8 breast HAs, in comparison to 3 mammary MECs. All cases were positive for MAML2 break-apart fluorescence in situ hybridization. Eight cases demonstrated a CRTC1::MAML2 fusion, and one MEC harbored a CRTC3::MAML2 fusion; the latter is a novel finding in the breast. Mutational burden was very low, with only one HA exhibiting a MAP3K1 pathogenic alteration. By IHC, both MEC and HA demonstrated cell type-dependent expression of high- and low-molecular-weight keratins and p63, as well as negative to low-positive estrogen receptor and androgen receptor. Smooth muscle myosin and calponin highlighted an in situ component in the 3 cases of MEC; expression of these myoepithelial markers was negative in HAs. Additional distinguishing characteristics included the growth pattern and tumor architecture, the presence of glandular/luminal cells in HA, and overall higher IHC expression of SOX10, S100 protein, MUC4, and mammaglobin in MEC. Morphologic findings were also compared to a series of 27 cutaneous nonmammary HAs. Mucinous and glandular/luminal cells were identified in significantly more mammary HAs than nonmammary lesions. The findings provide insight into the pathogenesis of MAML2-rearranged neoplasms of the breast, underscore the overlapping genetic features of MEC and HA, and highlight similarities to their extramammary counterparts.
ABSTRACT
BACKGROUND: Membranous nephropathy is an uncommon cause of nephrotic syndrome in pediatrics. METHODS: We reviewed our kidney biopsy records for patients ≤ 20 years of age with membranous nephropathy without evidence of systemic lupus erythematosus within 6 months of biopsy (January 1995-September 2020). Staining for PLA2R, NELL1, THSD7A, SEMA3B, EXT2 (3 biopsies), and IgG-subclass were performed. RESULTS: Sixteen children (≤ 12 years) and 25 adolescents (13-20 years) were identified. Four children and 15 adolescents showed autoantigen positivity: PLA2R+/SEMA3B- (13), SEMA3B+/PLA2R+ (2), SEMA3B+/PLA2R- (1), NELL1 (1), EXT2+ (2), and THSD7A (0). Co-morbidities associated with PLA2R positivity included IPEX syndrome, active hepatitis B, Von Hippel Lindau syndrome, solitary kidney, type 1 diabetes, hyperuricemia, pregnancy (1), obesity (3), type II diabetes, H. pylori, viral prodrome, and nephrolithiasis. The SEMA3B+/PLA2R- adolescent was pregnant, the NELL1+ adolescent was obese, and the two EXT2+ adolescents eventually met the clinical criteria for lupus (4, 9 years post-biopsy). Co-morbidities among the remaining 24 patients included remote hepatitis B (2), Down's syndrome, lysinuric protein intolerance, recurrent UTIs, hypothyroidism, pregnancy (3), and obesity (2). Follow-up data was available for 12 children and 16 adolescents. Of the 12 children, 6 achieved complete remission, 4 achieved partial remission, and 2 had no response to treatment (1 transplant). Of the 16 adolescents, 4 achieved complete remission, 4 achieved partial remission, and 8 had no response to treatment (3 transplants). A child with "full-house" immunofluorescence staining achieved spontaneous disease remission. CONCLUSION: Our non-lupus membranous nephropathy cohort represents one of the largest pediatric studies to date. A higher resolution version of the Graphical abstract is available as Supplementary information.
Subject(s)
Diabetes Mellitus, Type 2 , Glomerulonephritis, Membranous , Hepatitis B , Adolescent , Child , Humans , Autoantibodies , Autoantigens , Glomerulonephritis, Membranous/pathology , Immunoglobulin G , Obesity , Receptors, Phospholipase A2/metabolism , Young AdultABSTRACT
BACKGROUND: Acute kidney injury (AKI) is seen in one-fifth of pediatric patients with COVID-19 requiring hospital admission, and is associated with increased morbidity, mortality, and residual kidney impairment. The majority of kidney pathology data in patients with COVID-19 is derived from adult case series and there is an overall lack of histologic data for most pediatric patients with COVID-19. METHODS: We assembled a multi-institutional cohort of five unvaccinated pediatric patients with COVID-19 and associated kidney dysfunction with available histology. RESULTS: Three complex patients with current or prior SARS-CoV-2 infection had multifactorial thrombotic microangiopathy with clinical features of hemolytic uremic syndrome (in two) or disseminated intravascular coagulation (in one); one died and another developed chronic kidney disease stage 5. Two with recently preceding SARS-CoV-2 infection presented with nephrotic syndrome; one had IgA vasculitis and one had minimal change disease. Within a short follow-up time, none has returned to baseline kidney function. CONCLUSION: Although uncommon, COVID-19-associated kidney injury can have significant morbidity in the unvaccinated pediatric and adolescent population. A higher resolution version of the Graphical abstract is available as Supplementary information.
Subject(s)
Acute Kidney Injury , COVID-19 , IgA Vasculitis , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Adolescent , Adult , COVID-19/complications , Child , Humans , Kidney/pathology , SARS-CoV-2ABSTRACT
Nodular fasciitis is a benign, self-limited, pseudosarcomatous neoplasm that can mimic malignancy due to its rapid growth, cellularity, and mitotic activity. Involvement of the breast is rare and diagnosis on biopsy can be challenging. In this largest series to date, we examined the clinicopathologic and molecular characteristics of 12 cases of nodular fasciitis involving the breast/axilla. All patients were female, with a median age of 32 years (range 15-61). The lesions were 0.4 to 5.8 cm in size (median 0.8). All cases presented as palpable masses, and two patients had overlying skin retraction. Microscopically, lesions were relatively well-circumscribed nodular masses of bland myofibroblastic spindle cells within a variably myxoid stroma. Infiltrative growth into adipose tissue or breast epithelium was frequent. Mitotic figures were present in all cases, ranging from 1 to 12 per 10 high-power fields (median 3). Immunohistochemically, all cases expressed smooth muscle actin and were negative for pan-cytokeratin, p63, desmin, CD34, and nuclear beta-catenin. Targeted RNA sequencing performed on 11 cases identified USP6 gene fusions in eight; one additional case was positive by break-apart fluorescence in situ hybridization. The common MYH9-USP6 rearrangement was detected in four cases; another case had a rare alternative fusion with CTNNB1. Three cases harbored novel USP6 gene fusions involving NACA, SLFN11, or LDHA. All fusions juxtaposed the promoter region of the 5' partner gene with the full-length coding sequence of USP6. Outcome data were available for eight patients; none developed recurrence or metastasis. Five patients elected for observation without immediate excision, and self-resolution of the lesions was reported in three cases. Albeit uncommon, nodular fasciitis should be considered in the differential diagnosis of breast spindle cell lesions. A broad immunohistochemical panel to exclude histologic mimics, including metaplastic carcinoma, is important. Confirmatory detection of USP6 rearrangements can aid in classification, with potential therapeutic implications.
Subject(s)
Breast Neoplasms/pathology , Fasciitis/pathology , Oncogene Fusion/genetics , Ubiquitin Thiolesterase/genetics , Adolescent , Adult , Breast Neoplasms/genetics , Fasciitis/genetics , Female , Humans , Middle Aged , Young AdultABSTRACT
RATIONALE & OBJECTIVE: Kidney biopsy data inform us about pathologic processes associated with infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We conducted a multicenter evaluation of kidney biopsy findings in living patients to identify various kidney disease pathology findings in patients with coronavirus disease 2019 (COVID-19) and their association with SARS-CoV-2 infection. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We identified 14 native and 3 transplant kidney biopsies performed for cause in patients with documented recent or concurrent SARS-CoV-2 infection treated at 7 large hospital systems in the United States. OBSERVATIONS: Men and women were equally represented in this case series, with a higher proportion of Black (n=8) and Hispanic (n=5) patients. All 17 patients had SARS-CoV-2 infection confirmed by reverse transcriptase-polymerase chain reaction, but only 3 presented with severe COVID-19 symptoms. Acute kidney injury (n=15) and proteinuria (n=11) were the most common indications for biopsy and these symptoms developed concurrently or within 1 week of COVID-19 symptoms in all patients. Acute tubular injury (n=14), collapsing glomerulopathy (n=7), and endothelial injury/thrombotic microangiopathy (n=6) were the most common histologic findings. 2 of the 3 transplant recipients developed active antibody-mediated rejection weeks after COVID-19. 8 patients required dialysis, but others improved with conservative management. LIMITATIONS: Small study size and short clinical follow-up. CONCLUSIONS: Cases of even symptomatically mild COVID-19 were accompanied by acute kidney injury and/or heavy proteinuria that prompted a diagnostic kidney biopsy. Although acute tubular injury was seen among most of them, uncommon pathology such as collapsing glomerulopathy and acute endothelial injury were detected, and most of these patients progressed to irreversible kidney injury and dialysis.
Subject(s)
Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , COVID-19/complications , COVID-19/pathology , Proteinuria/etiology , Proteinuria/pathology , Adult , Aged , Diagnosis, Differential , Female , Follow-Up Studies , Humans , Kidney/pathology , Male , Middle AgedABSTRACT
BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a glomerular disease defined by non-organized glomerular deposits of heavy and light chain-restricted immunoglobulin and is rarely reported in children. METHODS: We characterized a series of nine pediatric patients from two academic centers with biopsy-proven PGNMID and additionally describe two patients with monotypic IgG in the setting of IgM deposition. RESULTS: Each patient presented with hematuria and/or proteinuria; however, only five had elevated serum creatinine. Prodromal or concurrent infection was identified in six patients, low C3 in five, and alternate complement pathway gene variants in two. No monoclonal serum proteins were identified in five tested patients. Seven patients had monotypic deposits composed of IgG3-λ, two showed IgG3-κ, and one each IgG1 and IgG3 with lambda dominance in the setting of IgM deposition. The glomerular pattern was predominantly mesangial proliferative or membranoproliferative glomerulonephritis (MPGN). Treatment and outcomes were variable; four patients have recent PGNMID diagnoses and therefore minimal follow up, one had relatively stable kidney function for over a decade, and six experienced kidney failure, with four receiving transplants. Recurrent deposits of the same isotype were identified in five of six transplanted kidneys, corresponding to three of four transplanted patients. One of these patients developed PGNMID recurrences in three separate kidney allografts over a 20-year disease course. CONCLUSIONS: Our study emphasizes the need for upfront IgG subclass investigation in pediatric mesangial or MPGN with IgG deposition and monotypic or biased light-chain staining. Furthermore, this pediatric experience suggests expanded pathogenic considerations in PGNMID. Graphical abstract.
Subject(s)
Antibodies, Monoclonal/analysis , Glomerulonephritis, Membranoproliferative , Immunoglobulin G/analysis , Child , Glomerulonephritis, Membranoproliferative/diagnosis , Humans , Immunoglobulin M/analysisABSTRACT
Angiosarcoma (AS) is the most frequent primary sarcoma of the breast but nevertheless remains uncommon, accounting for <0.05% of breast malignancies. Secondary mammary AS arise following radiation therapy for breast cancer, in contrast to primary AS which occur sporadically. Essentially all show aggressive clinical behavior independent of histologic grade and most are treated by mastectomy. MYC amplification is frequently identified in radiation-induced AS but only rarely in primary mammary AS (PMAS). As a heterogeneous group, AS from various anatomic sites have been shown to harbor recurrent alterations in TP53, MAP kinase pathway genes, and genes involved in angiogenic signaling including KDR (VEGFR2) and PTPRB. In part due to its rarity, the pathogenesis of PMAS has not been fully characterized. In this study, we examined the clinical, pathologic, and genomic features of ten cases of PMAS, including one patient with bilateral disease. Recurrent genomic alterations were identified in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), each at higher frequencies than reported in AS across all sites. Six tumors harbored a KDR p.T771R hotspot mutation, and all seven KDR-mutant cases showed evidence suggestive of biallelism (four with loss of heterozygosity and three with two aberrations). Of the seven tumors with PI3K alterations, six harbored pathogenic mutations other than in the canonical PIK3CA residues which are most frequent in breast cancer. Three AS were hypermutated (≥10 mutations/megabase (Mb)); hypermutation was seen concurrent with KDR or PIK3CA mutations. The patient with bilateral disease demonstrated shared alterations, indicative of contralateral metastasis. No MYC or TP53 aberrations were detected in this series. Immunohistochemistry for VEGFR2 was unable to discriminate between KDR-mutant tumors and benign vascular lesions of the breast. These findings highlight the underrecognized frequency of KDR and PIK3CA mutation in PMAS, and a significant subset with hypermutation, suggesting a pathogenesis distinct from other AS.
Subject(s)
Breast Neoplasms/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Hemangiosarcoma/genetics , Vascular Endothelial Growth Factor Receptor-2/genetics , Adult , Female , Humans , Middle Aged , MutationABSTRACT
AIMS: Metanephric adenomas (MAs) are conventionally regarded as rare renal tumours with indolent behaviour; limited case reports have described MAs with aggressive features. Conventional MAs harbour hotspot BRAF V600E mutations. A BRAF V600E senescence pathway, mediated by cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16, has been proposed to confer MA benignity. Aside from BRAF, the molecular landscape in both conventional MAs and those with aggressive features has not been fully characterised. The aim of this study was to molecularly profile a series of MAs to investigate the correlation between genomic findings and clinical outcome. METHODS AND RESULTS: We retrospectively examined the histomorphology and patient outcomes of 11 conventional MAs and one MA with aggressive features. Each was subjected to capture-based next-generation DNA sequencing of 479 cancer-related genes and immunohistochemical profiling. All tumours were positive for WT1 immunostaining and BRAF V600E mutation. One conventional MA contained an additional somatic BRCA2 pathogenic mutation. The MA with aggressive features had a biphasic appearance: one component was epithelial, with areas morphologically consistent with conventional MA; the second component was sarcomatous, with areas of solid and angiosarcomatous growth. Differential profiling of the two populations revealed identical BRAF, EIF1AX and TERT promoter hotspot mutations in the epithelial and sarcomatous components. Deep deletion of CDKN2A and MYC amplification were identified only in the sarcomatous component. CONCLUSIONS: Although the vast majority of MAs show indolent behaviour, rare pathogenic alterations can occur in conventional MAs in addition to BRAF. Molecular profiling of a case with aggressive clinical and pathological features shows genetic evidence for malignant evolution in MAs.
Subject(s)
Adenoma/genetics , Adenoma/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Adult , Aged , DNA Mutational Analysis , Female , Humans , Male , Middle Aged , Mutation , Proto-Oncogene Proteins B-raf , Retrospective StudiesABSTRACT
BACKGROUND: Myelin figures, or zebra bodies, seen on electron microscopy were historically considered pathognomonic of Fabry disease, a rare lysosomal storage disorder caused by alpha-galactosidase A deficiency and associated with X-linked recessive mode of inheritance. More recently, iatrogenic phospholipidosis has emerged as an important alternate cause of myelin figures in the kidney. METHODS: We report two families with autosomal dominant nephropathy presenting with proteinuria and microscopic hematuria, and the kidney biopsies were notable for the presence of myelin figures and zebra bodies. RESULTS: Laboratory and genetic work-up for Fabry disease was negative. Genetic testing in both families revealed the same heterozygous missense mutation in LMX1B (C.737G>A, p.Arg246Gln). LMX1B mutations are known to cause nail-patella syndrome, featuring dysplastic nails and patella with or without nephropathy, as well as isolated LMX1B-associated nephropathy in the absence of extrarenal manifestations. CONCLUSIONS: LMX1B mutation-associated nephropathy should be considered in hereditary cases of proteinuria and/or hematuria, even in the absence of unique glomerular basement membrane changes indicative of nail-patella syndrome. In addition, LMX1B mutation should be included in the differential diagnosis of myelin figures and zebra bodies on kidney biopsy, so as to avoid a misdiagnosis.
Subject(s)
Kidney Diseases/genetics , LIM-Homeodomain Proteins , Transcription Factors , Adult , Child , Diagnosis, Differential , Fabry Disease/diagnosis , Humans , Kidney Diseases/diagnosis , Kidney Diseases/pathology , Mutation, Missense , Myelin Sheath/pathology , Retrospective StudiesABSTRACT
BACKGROUND: Membranous nephropathy (MN) has been recognized to occur in patients with human immunodeficiency virus (HIV) infection since the beginning of the HIV epidemic. The prevalence of phospholipase A2 receptor (PLA2R)-associated MN in this group has not been well studied. METHODS: We conducted a retrospective review of electronic pathology databases at three institutions to identify patients with MN and known HIV at the time of renal biopsy. Patients with comorbidities and coinfections known to be independently associated with MN were excluded. RESULTS: We identified 11 HIV-positive patients with biopsy-confirmed MN meeting inclusion and exclusion criteria. Patient ages ranged from 39 to 66 years old, and 10 of 11 patients (91%) were male. The majority of patients presented with nephrotic-range proteinuria, were on anti-retroviral therapy at the time of biopsy and had low or undetectable HIV viral loads. Biopsies from 5 of 10 (50%) patients demonstrated capillary wall staining for PLA2R. Measurement of serum anti-PLA2R antibodies was performed in three patients, one of whom had positive anti-PLA2R antibody titers. Follow-up data was available on 10 of 11 patients (median length of follow-up: 44 months; range: 4-145 months). All patients were maintained on anti-retroviral therapy (ARV) and 5 patients (52%) received concomitant immunosuppressive regimens. Three patients developed end-stage renal disease (ESRD) during the follow-up period. CONCLUSIONS: MN in the setting of HIV is often identified in the setting of an undetectable viral loads, and similar to other chronic viral infection-associated MNs, ~ 50% of cases demonstrate tissue reactivity with PLA2R antigen, which may be seen without corresponding anti-PLA2R serum antibodies.
Subject(s)
Glomerulonephritis, Membranous/pathology , HIV Infections/immunology , Renal Insufficiency, Chronic/pathology , Acute Kidney Injury/etiology , Acute Kidney Injury/immunology , Acute Kidney Injury/pathology , Adult , Aged , Anti-HIV Agents/therapeutic use , Autoantibodies/immunology , Disease Progression , Female , Glomerulonephritis, Membranous/etiology , Glomerulonephritis, Membranous/immunology , Glomerulonephritis, Membranous/metabolism , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/metabolism , Humans , Kidney Failure, Chronic/etiology , Male , Microscopy, Fluorescence , Middle Aged , Receptors, Phospholipase A2/immunology , Receptors, Phospholipase A2/metabolism , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/immunology , Viral LoadABSTRACT
PURPOSE: The detection rate of breast ductal carcinoma in situ (DCIS) has increased significantly, raising the concern that DCIS is overdiagnosed and overtreated. Therefore, there is an unmet clinical need to better predict the risk of progression among DCIS patients. Our hypothesis is that by combining molecular signatures with clinicopathologic features, we can elucidate the biology of breast cancer progression, and risk-stratify patients with DCIS. METHODS: Targeted exon sequencing with a custom panel of 223 genes/regions was performed for 125 DCIS cases. Among them, 60 were from cases having concurrent or subsequent invasive breast cancer (IBC) (DCIS + IBC group), and 65 from cases with no IBC development over a median follow-up of 13 years (DCIS-only group). Copy number alterations in chromosome 1q32, 8q24, and 11q13 were analyzed using fluorescence in situ hybridization (FISH). Multivariable logistic regression models were fit to the outcome of DCIS progression to IBC as functions of demographic and clinical features. RESULTS: We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4%) and TP53 (18.4%). There was an inverse association between PIK3CA kinase domain mutations and progression (Odds Ratio [OR] 10.2, p < 0.05). Copy number variations in 1q32 and 8q24 were associated with progression (OR 9.3 and 46, respectively; both p < 0.05). CONCLUSIONS: PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC. These results may guide efforts to distinguish low-risk from high-risk DCIS.
Subject(s)
Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/genetics , Carcinoma, Intraductal, Noninfiltrating/pathology , Genome-Wide Association Study , Genomics , Aged , Aged, 80 and over , Carcinoma, Ductal, Breast/therapy , DNA Copy Number Variations , Female , Genetic Predisposition to Disease , Genome-Wide Association Study/methods , Genomics/methods , Humans , In Situ Hybridization, Fluorescence , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Tumor BurdenABSTRACT
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.
Subject(s)
Kidney Diseases/pathology , Kidney Glomerulus/pathology , Aged , Aged, 80 and over , Female , Humans , Kidney Diseases/etiology , Male , Retrospective StudiesABSTRACT
The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with 'monosomy', 'co-amplification/polysomy', low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or 'non-classical' HER2 FISH results. Breast cancers (2001-2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) 'monosomy' (ratio ≥2.0, mean HER2/cell<4.0); (2) 'co-amplified' (ratio<2.0, mean HER2/cell ≥6.0); (3) 'low amplified' (ratio ≥2.0, mean HER2/cell 4.0-5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a 'non-classical' HER2 amplified result; 1.4% 'monosomy', 0.8% 'co-amplified', 2.1% 'low amplified', and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the 'co-amplified' group. The 'monosomy' group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the 'low-amplified' category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. 'Co-amplified' cases have the highest frequencies of aggressive characteristics and 'monosomy' cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.
Subject(s)
Breast Neoplasms/diagnosis , In Situ Hybridization, Fluorescence , Receptor, ErbB-2/analysis , Biomarkers, Tumor/analysis , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Gene Amplification , Humans , Immunohistochemistry , Neoplasm GradingABSTRACT
Merkel cell carcinoma and melanoma can each occur primarily in breast skin, or metastasize to the breast. The breast is a rare site of metastasis of essentially any and every type of tumor, including carcinomas, sarcomas, and hematolymphoid neoplasms, and 10-30% of breast metastases may represent the initial presentation of disease. Although metastases generally recapitulate histologic features of the primary tumor, they are diagnostically challenging given their rarity and morphologic overlap with breast carcinoma, including special types of breast cancer. Histologic clues may include lack of carcinoma in situ, lack of central elastosis, pattern of infiltration around normal breast structures, yet none of these are specific. Careful correlation with clinical history and judicious use of immunostain panels is essential in approaching these cases.
Subject(s)
Breast Neoplasms/pathology , Carcinoma, Merkel Cell/secondary , Melanoma/secondary , Skin Neoplasms/pathology , Biopsy , Breast Neoplasms/chemistry , Breast Neoplasms/secondary , Carcinoma, Merkel Cell/chemistry , Diagnosis, Differential , Female , Humans , Immunohistochemistry , Melanoma/chemistry , Predictive Value of Tests , Skin Neoplasms/chemistryABSTRACT
Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.
Subject(s)
Acute Kidney Injury/pathology , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Immunologic Factors/antagonists & inhibitors , Immunotherapy/adverse effects , Neoplasms/drug therapy , Nephritis, Interstitial/pathology , Thrombotic Microangiopathies/pathology , Acute Kidney Injury/blood , Acute Kidney Injury/chemically induced , Acute Kidney Injury/therapy , Adult , Aged , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Biopsy , Creatinine/blood , Female , Glucocorticoids/therapeutic use , Humans , Immunotherapy/methods , Kidney/blood supply , Kidney/pathology , Kidney Function Tests , Male , Middle Aged , Neoplasms/immunology , Nephritis, Interstitial/blood , Nephritis, Interstitial/chemically induced , Nephritis, Interstitial/therapy , Renal Dialysis , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/chemically induced , Thrombotic Microangiopathies/therapyABSTRACT
Cancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early neoplasias, which are often found concurrently with carcinomas and are histologically distinguishable from normal breast tissue, are less advanced in phenotype than carcinomas and are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative whole-genome sequencing of early neoplasias, matched normal tissue, and carcinomas from six patients, for a total of 31 samples. By using somatic mutations as lineage markers we built trees that relate the tissue samples within each patient. On the basis of these lineage trees we inferred the order, timing, and rates of genomic events. In four out of six cases, an early neoplasia and the carcinoma share a mutated common ancestor with recurring aneuploidies, and in all six cases evolution accelerated in the carcinoma lineage. Transition spectra of somatic mutations are stable and consistent across cases, suggesting that accumulation of somatic mutations is a result of increased ancestral cell division rather than specific mutational mechanisms. In contrast to highly advanced tumors that are the focus of much of the current cancer genome sequencing, neither the early neoplasia genomes nor the carcinomas are enriched with potentially functional somatic point mutations. Aneuploidies that occur in common ancestors of neoplastic and tumor cells are the earliest events that affect a large number of genes and may predispose breast tissue to eventual development of invasive carcinoma.
Subject(s)
Breast Neoplasms/genetics , Cell Transformation, Neoplastic/genetics , Genome, Human , Mutation , Alleles , Aneuploidy , Breast Neoplasms/pathology , Carcinoma/genetics , Carcinoma/pathology , Disease Progression , Female , Gene Frequency , High-Throughput Nucleotide Sequencing , Humans , Polymorphism, Single NucleotideABSTRACT
PURPOSE: Activating genetic changes in the phosphatidylinositol-3-kinase (PI3K) signaling pathway are found in over half of invasive breast cancers (IBCs). Previously, we discovered numerous hotspot PIK3CA mutations in proliferative breast lesions. Here, we investigate the spatial nature of PI3K pathway signaling and its relationship with PI3K genotype in breast lesions. METHODS: We identified PI3K phosphosignaling network signatures in columnar cell change (CCL), usual ductal hyperplasia (UDH), ductal carcinoma in situ (DCIS), and IBC in 26 lesions of known PIK3CA genotype from 10 human breast specimens using a hyperspectral-based multiplexed tissue imaging platform (MTIP) to simultaneously quantitate PI3K/MAPK pathway targets (pAKT473, pAKT308, pPRAS40, pS6, and pERK) in FFPE tissue, with single-cell resolution. RESULTS: We found that breast lesional epithelia contained spatially heterogeneous patterns of PI3K pathway phosphoprotein signatures, even within microscopic areas of CCL, UDH, DCIS, and IBC. Most lesions contained 3-12 unique phosphoprotein signatures within the same microscopic field. The dominant phosphoprotein signature for each lesion was not well correlated with lesion genotype or lesion histology, yet samples from the same patient tended to group together. Further, 5 UDH/CCL lesions across different patients had a common phosphosignature at the epithelial-stromal interface (possible myoepithelial cells) that was distinct from both the adjacent lesional epithelium and distinct from adjacent stroma. CONCLUSION: We present the first spatial mapping of PI3K phosphoprotein networks in proliferative breast lesions and demonstrate complex PI3K signaling heterogeneity that defies simple correlation between PIK3CA genotype and phosphosignal pattern.
Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Intraductal, Noninfiltrating/metabolism , Class I Phosphatidylinositol 3-Kinases/genetics , Phosphoproteins/metabolism , Single Molecule Imaging/methods , Adult , Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/genetics , Carcinoma, Intraductal, Noninfiltrating/genetics , Female , Genetic Heterogeneity , Humans , Hyperplasia , MAP Kinase Signaling System , Middle Aged , MutationABSTRACT
Renal injury in hematopoietic cell transplant recipients may be related to a combination of factors including chemotherapy, radiation, infection, immunosuppressive agents, ischemia, and graft-versus-host disease, and can involve glomerular, tubulointerstitial, and vascular structures. We reviewed renal pathology from 67 patients at a single institution (2009-2014), including 14 patients with biopsy for clinical dysfunction, 6 patients with surgical kidney resection for other causes, and 47 autopsy patients. Kidney specimens frequently contained multiple histopathologic abnormalities. Thrombotic microangiopathy, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis were the most common glomerular findings. Pathologies not previously reported in the hematopoietic cell transplant setting included collapsing glomerulopathy, antiglomerular basement membrane disease, fibrillary glomerulonephritis, and in the case of two surgical resections distinctive cellular segmental glomerular lesions that defied classification. Kidney specimens frequently demonstrated acute tubular injury, interstitial fibrosis, arteriolar hyaline, and arteriosclerosis. Other kidney findings at autopsy included leukemia and amyloid (both recurrent), diabetic nephropathy, bacterial infection, fungal invasion, and silver deposition along glomerular and tubular basement membranes. Also in the autopsy cohort, C4d immunohistochemistry demonstrated unexpected membranous nephropathy in two patients, yet C4d also colocalized with arteriolar hyaline. This retrospective hematopoietic cell transplant cohort illustrates multifaceted renal injury in patients with renal dysfunction, as well as in patients without clinically recognized kidney injury.