Proceedings From the ASCO/College of American Pathologists Immune Checkpoint Inhibitor Predictive Biomarker Summit.

PURPOSE: Immune checkpoint inhibition (ICI) therapy represents one of the great advances in the field of oncology, highlighted by the Nobel Prize in 2018. Multiple predictive biomarkers for ICI benefit have been proposed. These include assessment of programmed death ligand-1 expression by immunohistochemistry, and determination of mutational genotype (microsatellite instability or mismatch repair deficiency or tumor mutational burden) as a reflection of neoantigen expression. However, deployment of these assays has been challenging for oncologists and pathologists alike. METHODS: To address these issues, ASCO and the College of American Pathologists convened a virtual Predictive Factor Summit from September 14 to 15, 2021. Representatives from the academic community, US Food and Drug Administration, Centers for Medicare and Medicaid Services, National Institutes of Health, health insurance organizations, pharmaceutical companies, in vitro diagnostics manufacturers, and patient advocate organizations presented state-of-the-art predictive factors for ICI, associated problems, and possible solutions. RESULTS: The Summit provided an overview of the challenges and opportunities for improvement in assay execution, interpretation, and clinical applications of programmed death ligand-1, microsatellite instability-high or mismatch repair deficient, and tumor mutational burden-high for ICI therapies, as well as issues related to regulation, reimbursement, and next-generation ICI biomarker development. CONCLUSION: The Summit concluded with a plan to generate a joint ASCO/College of American Pathologists strategy for consideration of future research in each of these areas to improve tumor biomarker tests for ICI therapy.

Donor-Derived Renal Cell Carcinoma in a Kidney Allograft: A Case Report.

Renal cell carcinoma (RCC) in the kidney allograft is a relatively rare complication most commonly seen approximately a decade or more after transplant. We report a case of diffuse multifocal RCC within 6 months of transplant. The initial signal leading to an abnormality in the graft was an elevated routine cell-free DNA. Initial imaging findings appeared consistent with post-transplant lymphoproliferative disorder; however, biopsy would ultimately yield RCC. The patient's diffuse disease necessitated radical nephrectomy. Tumor DNA fingerprinting was employed in this case to show the tumor originated from donor tissue rather than host, indicating primary rather than metastatic disease. Early RCC is a rare complication. Most cases are detected at an early stage, likely as a result of increased surveillance with ultrasound imaging. A donor's social history including significant tobacco use should be considered when evaluating the risk of malignancy transmission in the allograft. Clinicians should be aware of multifocal RCC as a potential differential diagnosis for diffuse nodular infiltrates in the allograft.

Papillary Renal Cell Carcinoma With Microcystic Architecture Is Strongly Associated With Extrarenal Invasion and Metastatic Disease.

Papillary renal cell carcinoma (PRCC) is well-recognized as a morphologically and molecularly heterogenous group of kidney tumors with variable clinical behavior. Our goal was to analyze a unique histologic pattern of PRCC we have observed in routine practice to evaluate for potential clinical significance or distinct molecular signature. We identified 42 cases of PRCC showing a morphologically distinct architecture characterized by numerous epithelial-lined cysts containing the papillary tumor (herein called "microcysts"), which are typically separated by fibrous stroma. Of the initial 42 case test set with microcystic features, 23 (55%) were stage pT3a or higher. Most tumors had strong and diffuse cytoplasmic immunoreactivity for CK7 (93%, 37/40) and AMACR (100%, 40/40). Fumarate hydratase staining was retained in all cases tested (39/39). We performed next-generation sequencing on 15 of these cases with available tissue and identified chromosomal alterations commonly reported in historically "type 1" PRCC, notably multiple chromosomal gains, particularly of chromosomes 7 and 17, and MET alterations. However, alterations in pathways associated with more aggressive behavior (including SETD2, CDKN2A, and members of the NRF pathway) were also identified in 6 of 15 cases tested (40%). Given this molecular and immunophenotypic data, we subsequently reviewed an additional group of 60 consecutive pT2b-pT3 PRCCs to allow for comparisons between cases with and without microcysts, to assess for potential associations with other recently described histologic patterns (ie, "unfavorable architecture": micropapillary, solid, and hobnail), and to assess interobserver reproducibility for diagnosing architectural patterns and grade. Of the total combined 102 PRCCs, 67 (66%) had microcystic architecture within the intrarenal component but were commonly admixed with other patterns (39% had micropapillary, 31% solid, and 31% hobnail). Twenty-seven cases (26%) had metastatic disease, and 24 of these 27 (89%) had microcystic architecture in the intrarenal tumor. Within the pT3 subset, 21 of 22 cases with metastases (95%) had extrarenal invasion as either individual microcysts in renal sinus fat or aggregates of microcysts bulging beyond the confines of the capsule. Backward elimination and stepwise regression methods to detect features significantly associated with adverse outcome identified solid architecture (hazard ratio [HR]: 6.3; confidence interval [CI]: 2.1-18.8; P=0.001), hobnail architecture (HR: 5.3; CI: 1.7-16.7; P=0.004), and microcystic architecture at the tumor-stromal interface (HR: 4.2; CI: 1.1-16.7; P=0.036) as strongest. Of architectural patterns and grade, the microcystic pattern had a substantial interobserver agreement (κ score=0.795) that was highest among the 6 observers. In summary, PRCCs with microcystic architecture represents a subset of historically "type 1" PRCC with a predilection for morphologically distinctive extrarenal involvement and metastatic disease. Microcysts co-vary with other "unfavorable" architectural patterns also associated with higher risk for aggressive disease (ie, micropapillary, hobnail, and solid), but microcysts were more common and have superior interobserver reproducibility. These findings suggest that microcystic PRCC should be recognized as a potentially aggressive histologic pattern of growth in PRCC.

Current CPT Coding and Payment Policy Implications for Immunohistology Services.

Immunohistology is essential to the practice of modern surgical and cytopathology. There are 3 major types of immunohistologic services provided in clinical practice: traditional immunohistochemistry, morphometric analysis of tumor immunohistochemistry, and immunofluorescence. Proper Current Procedural Terminology coding for these services has been updated to reflect current medical practice. Subsequent to changes in the Current Procedural Terminology coding structure for these services, the valuation of these services have been reviewed by the American Medical Association/Specialty Society Relative Value Update Committee and new valuations instituted by the Centers for Medicare and Medicaid Services. Although valuations for services may be established, the circumstances of payment may be affected by Medicare Contractor's Local Coverage Determinations or service limits imposed by the National Correct Coding Initiative.

Acute renal failure: a rare side effect of sunitinib therapy.

Sunitinib is an oral multiple tyrosine kinase receptor inhibitor. It is usually well tolerated but can cause fatigue, malaise, and rash. Sunitinib-induced cardiotoxicity has been well described, but nephrotoxicity is very rare. Here, we report a rare case of acute renal failure caused by sunitinib therapy in a 73-year-old Caucasian female who was enrolled in a phase II trial of sunitinib therapy for clear cell ovarian cancer. At presentation, her blood urea nitrogen (BUN) was 91 mg/dl and creatinine was 9.2 mg/dl. Sunitinib therapy was discontinued, and she was treated conservatively with intravenous fluid. Creatinine gradually returned to normal, and fatigue resolved. She was diagnosed with sunitinib-induced acute renal failure. The nephrologists and oncologists should be aware of sunitinib-induced rare nephrotoxicity, and patients should be closely monitored.

The physicians quality reporting initiative: measure development, implementation and current procedural terminology coding.

The Physicians Quality Reporting Initiative (PQRI) was instituted in the latter half of 2007. PQRI is a voluntary reporting system in which the aim is to improve patient care, whereas at the same time, an eligible practitioner may receive an incentive payment for successful participation. Two pathology-specific measures were instituted in 2008; 1 for breast cancer reporting and the other for colon cancer reporting. In 2009, Current Procedural Terminology Category II code 3250F was instituted, which allows proper coding of cases from metastatic sites when ICD 9 code and Current Procedural Terminology Category I inclusion criteria are met. After the review of the 2007 data obtained from other specialties, submission of invalid codes was predominantly attributed to failure to adhere to measurement specifications. With increased awareness and experience, the amount of invalid code submission will decrease. More performance measures would be needed to make the program available to more pathologists. PQRI is thought by many to be the first step in transforming to a Pay for Performance Program.

Persistent hematuria after induction of remission in Wegener granulomatosis: a therapeutic dilemma.

Wegener granulomatosis (WG) is a systemic disease that is often associated with an immune-mediated form of glomerulonephritis (GN). Renal disease most often manifests as microscopic hematuria with or without red blood cell or mixed cellular casts, proteinuria, and an elevated serum creatinine concentration.We conducted the current study to determine whether persistent hematuria, in the setting of apparent clinical remission, may reflect glomerular injury and not active renal disease. We performed a retrospective analysis of data from 82 patients with new-onset WG, of whom 25 had GN at presentation.Twenty of 25 patients with GN achieved sustained remissions (>6 consecutive months' duration). During initial periods of active disease the median peak serum creatinine was 1.9 mg/dL (range, 0.6-13.6 mg/dL). The median time to remission was 4 months (range, 2-13 mo). After effective therapy, median creatinine was 1.1 mg/dL (range, 0.4-1.8 mg/dL). Ten of 20 patients had prolonged hematuria over a period of >6 months. Within this subset, 5 subsequently normalized urine over a median period of 11 months and 5 did not achieve normal urine sediment over a median follow-up of 38 months. Thus, 10 of 25 patients with WG and GN had sustained hematuria in spite of apparent prolonged clinical remission.Patients with WG and GN may achieve enduring remissions that allow withdrawal of medications in spite of continued microscopic hematuria with or without red blood cell casts that may persist for months or even years. Continued use of aggressive immunosuppressive therapies in such patients would be ill-advised and could lead to irreversible and even life-threatening side effects from cyclophosphamide or high-dose corticosteroids.

Demonstration of immune complex deposits using fluorescence microscopy of hematoxylin and eosin-stained sections of Hollande's fixed renal biopsies.

A new method that may be useful in the evaluation of renal biopsies is described using fluorescence microscopy on standard hematoxylin and eosin-stained sections of kidney tissue fixed in Hollande's fixative. We describe brightly fluorescing immune complex deposits within glomerular basement membranes and mesangial matrices that correlate well with the results of standard direct immunofluorescence on frozen tissue and electron microscopy. In a blind analysis of 261 consecutive renal biopsies, we determine that this method has diagnostic utility for identification of immune complex glomerulonephritis and significantly extends the usefulness of standard histologic preparations before the use of special stains or procedures.

HER2/neu amplification in breast cancer: stratification by tumor type and grade.

The presence of HER2/neu gene amplification is prognostically and therapeutically significant for patients with breast cancer. We sought to determine whether a relationship exists between HER2/neu gene amplification and the histologic type and grade of tumor. The histologic features and corresponding HER2/neu amplification results of 401 cases of invasive breast carcinoma were reviewed. Lobular carcinomas were less likely than ductal carcinomas to have HER2/neu amplification. Amplification was less frequent in Scarff-Bloom-Richardson grade I ductal carcinomas than in grades 2 and 3. Metastatic carcinomas frequently displayed HER2/neu amplification (6/20 [30%]). Our results support a correlation between HER2/neu amplification and the histologic type and grade of breast cancer. We suggest reexamination of tumors diagnosed as Scarff-Bloom-Richardson grade I invasive ductal carcinomas or lobular carcinomas if the lesion displays HER2/neu amplification to assure the exclusion of a higher grade of lesion or of missed ductal components.