Margin status of basal cell carcinoma: What can be done better?

PURPOSE: Guidelines on clinical margins for basal cell carcinoma (BCC) excisions were recently published, yet the ambiguity regarding the margin continues for surgeons and pathologists. The purpose of this study was to determine the incomplete excision rate of BCC, determine the factors associated with incomplete excision, and evaluate the completeness of reporting between surgeon and pathologist. METHODS: A single-center retrospective analysis was conducted on pathology reports from single excisions of BCC specimens between January 1, 2019 to December 31, 2020. The primary outcome was the incomplete excision rate (positive margins) as reported by pathologist. Logistic regression was used to determine the relationship between incomplete excision rate and anatomical location, pathologist, and surgeon. The completeness of surgeon pathology requisition forms was evaluated qualitatively. RESULTS: Seven hundred and fifty-six pathology reports were included. The incomplete excision rate was 12% (n = 94). The most common site of incomplete excision was head and neck (n = 87, 15%), followed by trunk (n = 5, 7%), and extremities (n = 2, 2%). Five hundred and seventy-nine specimens from 6 surgeons and 9 pathologists were included in the logistic regression analysis. The Wald test showed that the location was significantly associated with incomplete excision (p < 0.05), whereas surgeon and pathologist reports were not (p > 0.05). Regarding missing information, only 47 (6%) pathology reports included "excision" in the requisition form. Four hundred and three (53%) specimens had no clinical history. CONCLUSIONS: The incomplete excision rate found in this study falls within the report range in the literature. Neither surgeon nor pathologist had significant association with incomplete excision. Incomplete excision rate of BCC may be inflated owing to the lack of standardization in requisition form and pathology reporting.

What is your count? An observational study of lymph node counting in 2,028 colorectal cancer resections.

BACKGROUND: Lymph node status and lymph node count (LNC) are predictors of colorectal cancer outcome. Under-sampling of lymph nodes may lead to clinically relevant stage migration. METHODS: Colorectal cancer (CRC) cases with a synoptic report, accessioned 2012-2020 at a regional laboratory, were extracted and retrospectively studied. LNC, positive lymph node count (PLNC), tumour deposits present (TDpos), and 'y' (staging) prefix (YS) were retrieved and tabulated by pathologist using custom software. Statistical analyses were done with R. DATA AND RESULTS: The cohort had 2,543 CRC resections. Seventeen pathologists interpreted >50 cases (range: 56-356) each and collectively saw 2,074. After cases with unavailable data were purged, 2,028 cases remained with 43,996 lymph nodes, of which 2,637/43,996 were positive. 368 cases had a 'y' prefix, and 379 had TDpos. The 17 pathologists' median LNC/case was 19.0 (range: 14.0-24.0), and the mean PLNC per case was 1.4 (range: 1.0-2.0). Kruskal-Wallis rank sum tests showed there were differences in LNC (p<0.001) among pathologists; however, PLNC did not show this association (p = 0.2917). T-tests showed that mean LNC (p<0.001) and PLNC (p<0.035) differed between YS. 138 of 2,028 cases had less than the 12 LNC target. Logistic regression revealed a strong association between meeting the LNC target and pathologist (p<0.001) but TDpos was non-predictive (p = 0.4736). CONCLUSIONS: Positive lymph node call rate has a good consistency in the laboratory; however, lymph node count varies significantly between pathologists. Standardized counting criteria are needed to improve uniformity and could be aided by synoptic reporting data.

Predictors of disease recurrence in high-risk non-metastatic renal cell carcinoma patients post-surgical resection A single-center, retrospective study.

INTRODUCTION: Approximately 20-40% of kidney cancer patients treated for localized disease experience post-surgical recurrence. Several prognostic models exist to help clinicians determine the risk of distant recurrence, but these models vary in criteria and endpoints. We aimed to examine the recurrence rate and clinicopathologic factors as predictors of recurrence in high-risk renal cell carcinoma (RCC) patients. METHODS: We conducted a single-center, retrospective chart review of pT3 RCC patients who underwent a nephrectomy between January 2000 and December 2015. Patients registered in clinical trials for adjuvant therapy and those with fewer than three years of followup were excluded. Kaplan-Meier survival analysis and univariate and multivariate Cox regression were performed to identify the rate and predictors of disease recurrence. RESULTS: Eighty-eight pT3 RCC patients were included, and 39 patients had recurrence with a median of 23.5 months (range 1.6-127.5). Nine patients had disease recurrence beyond 58 months. Kaplan-Meier log-rank tests identified patients with negative surgical margins and low Fuhrman nuclear grades had greater recurrence-free survival. Univariate Cox regression revealed positive surgical margins, high Fuhrman nuclear grade, and large tumor sizes were significant predictors. In the multivariate Cox regression model, high Fuhrman nuclear grade and positive surgical margins were significant predictors of recurrence. CONCLUSIONS: Disease recurrence occurred in 44% of pT3-staged patients. High Fuhrman nuclear grade and positive surgical margins were associated with time to recurrence. Physicians should use prognostic models to facilitate conversations about disease recurrence and continue to monitor high-risk patients beyond the recommended five-year followup period. We recommend monitoring pT3 resected patients for up to 10 years post-surgery.

Neuroanatomical location of brain metastases from solid tumours based on pathology: An analysis of 511 patients with a comparison to the provided clinical history.

Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011-2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization.

Role of EBUS-TBNA/EUS-FNA and mass spectrometry for diagnosis and typing of lymph node amyloidosis: 10-year experience in two tertiary care academic centers.

BACKGROUND: The objectives of this study were to investigate the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)/endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of amyloidosis coupled with the feasibility of mass spectrometry (MS) for amyloid subtyping. METHODS: All patients who had amyloid diagnosed by EBUS-TBNA/EUS-FNA at two tertiary care centers from 2011 to 2020 were retrieved along with the MS subtype, clinical findings, and outcomes. RESULTS: Eight patients were included: seven underwent EBUS-TBNA of mediastinal lymph nodes, and one underwent EUS-FNA of a periportal lymph node. Ages ranged from 37 to 79 years (median, 69 years), with equal numbers of men and women. Presenting clinical history included one case each of follicular lymphoma, lymphoplasmacytic lymphoma, rheumatoid arthritis, possible sarcoid, cirrhosis, and chronic renal insufficiency, and one case each of suspected pulmonary and cardiac amyloidosis. All cases showed waxy, amorphous material on direct smears (n = 5) or ThinPrep slides (n = 3), which were confirmed as amyloid on Congo Red staining. Immunohistochemistry showed dominant lambda staining in two of three cases. MS was performed in all cases and identified five of the light-chain (AL) type, one of the heavy-chain/AL type, and two suggestive of AL amyloidosis. Bone marrow biopsy performed in seven patients demonstrated that three had monoclonal plasma cells and one had lymphoplasmacytic lymphoma. Two of four patients with systemic amyloidosis received chemotherapy and remained alive, whereas three with localized disease remained stable under observation. CONCLUSIONS: EBUS-TBNA/EUS-FNA is effective for amyloidosis diagnosis and provides adequate material for ancillary tests, including MS, which can identify the precursor amyloidogenic protein, leading to appropriate patient management.

Prevalence of Thyroid Transcription Factor-1 (TTF-1)-Negative Small Cell Carcinoma and Napsin A Positivity in Small Cell Carcinoma in a Cross-Sectional Study of Lung Core Biopsies.

Background The prevalence of thyroid transcription factor-1 (TTF-1) and napsin A expression are poorly characterized in lung core biopsies of small cell carcinoma. Locally, the TTF-1 clone is 8G7G3/1 (Agilent/Dako), and the napsin A clone is IP64 (Leica Biosystems). Methods All in-house lung core biopsy reports for cases accessioned at a regional laboratory from January 2011 to December 2020 were retrieved and analyzed using a validated hierarchical free-text string matching algorithm (HFTSMA) to establish the diagnosis. TTF-1 and napsin A were manually coded with the assistance of a logical text parsing tool. All TTF-1-negative small cell lung carcinoma (SCLC) cases had a full report review by pathologists. Results The cohort had 5,867 lung core biopsies, and 232 cases were confirmed as small cell carcinoma on pathologist review. TTF-1 immunostain results were available in 173 SCLC cases, and 16 cases of TTF-1-negative SCLC were confirmed on full report review. These 16 cases had at least one positive neuroendocrine (NE) marker and positive keratin staining; cases with mixed histology or positive CK5/6 staining were excluded. Ki-67 was done in 10/16 cases; the average Ki-67 was 75%. Napsin A was negative in 50/51 small cell carcinomas, and 0/3 TTF-1-negative SCLC had napsin A positivity. Conclusions Standardized immunostain reporting would simplify such analyses. Based on the cohort, approximately 9% (16/173) of SCLC is TTF-1 negative. Napsin A positivity in suspected small cell carcinoma should prompt consideration of an alternate diagnosis or explanation.

PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity.

BACKGROUND: PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9's oncogenic roles in melanoma and other cancers remain unclear. METHODS: PCSK9's association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9-/- mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations. RESULTS: PCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the low-density lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9-/- mice. CONCLUSIONS: Tumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9's oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.

The physician factor and anatomical site in 8846 consecutive mediastinal lymph node aspirations in a cross-sectional study.

Mediastinal lymph node fine needle aspiration (MLN-FNA) is a common procedure; however, the physician factor in pathological category, and anatomical site are not routinely assessed. Cytology reports for endobronchial ultrasound (EBUS)/endoscopic ultrasound (EUS) MLN-FNA specimens (8846) were retrieved for July 2012-Dec 2019, classified by hierarchical free text string match algorithm into 51 diagnostic categories, four mutually exclusive diagnostic groups (benign |suspicious |malignant |insufficient), and 24 anatomical sites. Pathologist and submitting physician/surgeon bias were assessed using logistic regression and funnel plots|control charts centered on the group median (diagnostic/capture) rate. Eleven pathologists and seven submitting physician/surgeon were involved in more than 250 specimens each. Overall, the MLN-FNAs were benign|suspicious|malignant|insufficient in 46%|4%|25%|24% of specimens. Percent malignant (number of samples) varied by station; 7| 4R| 4L| 2R| 10R| 11R| 11L were respectively 21%(3,101), 27%(2,453), 19%(1,289), 41%(435), 27%(497), 24%(357), 26%(229). The number of outlier (P < 0.05/P < 0.001) pathologists of 11 from the group median rate for benign|suspicious|malignant|insufficient was 0/0| 3/1| 0/0| 3/0 respectively. The outlier (P < 0.05/P < 0.001) submitting physicians/surgeons of 7 for benign|suspicious|malignant|insufficient was 3/2| 2/2| 3/2| 3/2 respectively. The physician and anatomical site are significant predictors of MLN-FNA pathology.

Routine Pathological Examination of Clinically Presumed Dupuytren Disease: Does It Add Value?

BACKGROUND: In surgery for Dupuytren disease (DD), palmar fascia specimens are routinely submitted for pathological evaluation. The purpose of this study was to determine the rate of discordant diagnosis and the value of, and costs associated with, routine pathological analysis of palmar fascia tissue extracted in surgery for clinically diagnosed DD. METHODS: All pathology reports for in-house palmar fascia specimens obtained in surgery for clinically diagnosed DD (time period: January 2001 to December 2020) were retrieved from one academic institution. All specimens were classified by a hierarchical free-text string matching algorithm (HFTSMA) and searched for evidence of malignancy. The primary outcome was percentage of concordant, discrepant, and discordant diagnoses. Secondary outcomes included anatomical location and costs. The HFTSMA was used to capture the anatomical location. Costs included professional, laboratory processing, and ancillary fees based on the Ontario Schedule of Benefits. RESULTS: The search retrieved 1323 pathology reports, with 1480 palmar fascia specimens, from 1078 individual patients. By diagnosis, 96.1% of specimens (1422/1480) were concordant (fibromatosis), 3.9% (58/1480) were discrepant (scarring/fibrosis, benign fascia/connective tissue, or other benign findings), and 0% (0/1480) were discordant. The most common location was ring finger (n = 381, 48.7%). Ancillary testing was minimal. The cost per palmar fascia specimen was estimated to be CAD $34.57. The institutional costs were approximately CAD $2558.18/year. CONCLUSIONS: Routine pathological examination of specimens in cases of clinically diagnosed DD does not yield additional clinically important findings and may not warrant their costs.

Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients.

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.

A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.

Stability of diagnostic rate in a cohort of 38,813 colorectal polyp specimens and implications for histomorphology and statistical process control.

This work sought to quantify pathologists' diagnostic bias over time in their evaluation of colorectal polyps to assess how this may impact the utility of statistical process control (SPC). All colorectal polyp specimens(CRPS) for 2011-2017 in a region were categorized using a validated free text string matching algorithm. Pathologist diagnostic rates (PDRs) for high grade dysplasia (HGD), tubular adenoma (TA_ad), villous morphology (TVA + VA), sessile serrated adenoma (SSA) and hyperplastic polyp (HP), were assessed (1) for each pathologist in yearly intervals with control charts (CCs), and (2) with a generalized linear model (GLM). The study included 64,115 CRPS. Fifteen pathologists each interpreted > 150 CRPS/year in all years and together diagnosed 38,813. The number of pathologists (of 15) with zero or one (p < 0.05) outlier in seven years, compared to their overall PDR, was 13, 9, 9, 5 and 9 for HGD, TVA + VA, TA_ad, HP and SSA respectively. The GLM confirmed, for the subset where pathologists/endoscopists saw > 600 CRPS each(total 52,760 CRPS), that pathologist, endoscopist, anatomical location and year were all strongly correlated (all p < 0.0001) with the diagnosis. The moderate PDR stability over time supports the hypothesis that diagnostic rates are amendable to calibration via SPC and outcome data.

Evolution of anatomic pathology workload from 2011 to 2019 assessed in a regional hospital laboratory via 574,093 pathology reports.

OBJECTIVE: Quantify changes in workload in relation to the anatomic pathologist workforce. METHODS: In house pathology reports for cytology and surgical specimens from a regional hospital laboratory over a nine- year period (2011-2019) were analyzed, using custom computer code. Report length for the diagnosis+microscopic+synoptic report, number of blocks, billing classification (L86x codes), billings, national workload model (L4E 2018), regional workload model (W2Q), case count, and pathologist workforce in full-time equivalents (FTEs) were quantified. Randomly selected cases (n = 1,100) were audited to assess accuracy. RESULTS: The study period had 574,093 pathology reports that could be analyzed. The coding accuracy was estimated at 95%. From 2011 to 2019: cases/year decreased 6% (66,056 to 61,962), blocks/year increased 20% (236,197 to 283,751), L4E workload units increased 23% (165,276 to 203,894), W2Q workload units increased 21% (149,841 to 181,321), report lines increased 19% (606,862 to 723,175), workforce increased 1% (30.42 to 30.77 FTEs), billings increased 13% ($6,766,927 to $7,677,109). W2Q in relation to L4E underweights work in practices with large specimens by up to a factor of 2x. CONCLUSIONS: Work by L4E for large specimens is underrated by W2Q. Reporting requirements and pathology work-up have increased workload per pathology case. Work overall has increased significantly without a commensurate workforce increase. The significant practice changes in the pathology work environment should prompt local investment in the anatomic pathology workforce.

Application of Next Generation Quality/Statistical Process Control and Expert-Led Case Review to Increase the Consistency of Diagnostic Rates in Precancerous Colorectal Polyps.

BACKGROUND: Prior work suggests high interrater variability in the pathologist diagnostic rate (PDR) of the precancerous polyp sessile serrated adenoma (SSA). OBJECTIVES: To improve the diagnostic consistency in the pathological evaluation of colorectal polyp specimens with diagnostic rate awareness, using funnel plots (FPs)/control charts (CCs), and a focused group case review. METHODS: All colorectal polyp specimen (CRPS) reports September 2015 to August 2017 were analyzed at one institution. PDRs were extracted using a hierarchical free-text string matching algorithm and visualized using FPs, showing pathologist specimen volume versus PDR, and CCs, showing pathologist versus normed PDR. The FPs/CCs were centered on the group median diagnostic rate (GMDR). Pathologists were shown their baseline SSA diagnostic rate in relation to the practice, and in January 2017, there was a focused group case review/open discussion of approximately 40 sequential cases signed as SSA with a gastrointestinal pathology expert. RESULTS: Nine pathologists interpreted more than 250 CRPSs per year. FPs/CCs for the first and second years showed 6/4 and 3/1 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for SSA and 0/0 and 0/0 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for tubular adenoma (TA). An in silico kappa (ISK) for SSA improved from 0.52 to 0.62. CONCLUSION: Diagnostic rate awareness facilitated by FPs/CCs coupled with focused expert-led reviews may help calibrate PDR. Variation in SSA PDRs still remains high in relation to TA. ISK represents an intuitive, useful metric and Next Generation Quality/Statistical Process Control a promising approach for objectively increasing diagnostic consistency.

Variation in breast cancer grading in 1,636 resections assessed using control charts and in silico kappa.

OBJECTIVE: Assess interpretative variation in Nottingham grading using control charts (CCs) and in silico kappa (ISK). METHODS: In house invasive breast cancer cases (2011-2019) at two institutions with a synoptic report were extracted. Pathologist interpretative rates (PIRs) were calculated and normed for Nottingham grade (G) and its components (tubular score (TS), nuclear score (NS), mitotic score (MS)) for pathologists interpreting >35 cases. ISKs were calculated using the ordered mutually exclusive category assumption (OMECA) and maximal categorical overlap assumption (MCOA). RESULTS: The study period included 1,994 resections. Ten pathologists each assessed 38-441 cases and together saw 1,636; these were further analyzed. The PIR medians (normed ranges) were: G1:24%(18-27%), G2:53%(43-56%) and G3:26%(19-33%). The MCOA ISK and the number of statistical outliers (p< 0.05/p< 0.001) to the group median interpretive rate (GMIR) for the ten pathologists was G1: 0.82(2/0 of 10), G2: 0.76(1/1), G3: 0.71(3/1), TS1: 0.79(1/0), TS2: 0.63(5/1), TS3: 0.66(5/1), NS1: 0.37(5/4), NS2: 0.60(4/3), NS3: 0.59(4/4), MS1: 0.78(3/1), MS2: 0.78(3/1), MS3: 0.77(2/0). The OMECA ISK was 0.62, 0.49, 0.69 and 0.71 for TS, NS, MS and G. CONCLUSIONS: The nuclear score has the most outliers. NS1 appears to be inconsistently used. ISK mirrors trends in conventional kappa studies. CCs and ISK allow insight into interpretive variation and may be essential for the next generation in quality.

Langerhans Cell Histiocytosis Associated With Renal Cell Carcinoma Is a Neoplastic Process: Clinicopathologic and Molecular Study of 7 Cases.

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder composed of Langerhans cells admixed with reactive mononuclear and granulocytic cells, associated with prominent eosinophils. LCH is considered a neoplasm, driven in most cases by oncogenic RAS/RAF/MEK/ERK pathway mutations. The disease predominantly affects children. Urinary system involvement has rarely been reported in a multisystem disease setting. We describe 7 patients who presented with LCH occurring within (6 cases) or after (1 case) a resected clear cell (n=6) or clear cell papillary (n=1) renal cell carcinoma (RCC), identified prospectively in our routine and consultation files (2012 to 2019). The patients included 5 women and 2 men, with a median age of 54 years (range, 39 to 73 y), none with a history of LCH or LCH manifestations before the time of RCC diagnosis. The median size of the RCC was 3.5 cm (range, 1.8 to 8.3 cm). Treatment included partial (5 cases), or radical (2 cases) nephrectomy. All RCCs on gross examination showed at least focal cystic changes and were low grade (World Health Organization [WHO]/International Society of Urologic Pathologists [ISUP] grade 1 to 2). The LCH foci were detected as incidental histological finding within the resected RCC in all six cases and they were limited to few high-power fields (<2 mm) in 5 of 6 cases, but in the sixth case, they occupied almost the entire clear cell papillary RCC (2 cm nodule). No LCH manifestations were detected in the normal kidney or in perinephric fat. The seventh patient developed LCH within inguinal deep soft tissue followed by systemic manifestations 6 years after clear cell RCC. Langerhans cell immunophenotype was supported by the reactivity for S-100, CD1a, and langerin and by the negative pankeratin. Successful pyrosequencing of microdissected LCH DNA revealed the V600E BRAF mutation in all 6 cases of LCH within RCC. To our knowledge, only 3 similar cases were published since 1980; the only case tested for BRAF mutation showed wild-type BRAF. This is the first study analyzing the morphologic and genetic features of a cohort of LCH associated with RCC. In our experience, these cases may be underrecognized in practice, or may erroneously be diagnosed as RCC dedifferentiation or high-grade sarcomatoid transformation. Finally, the detection of BRAF mutation further confirms that LCH in this setting is indeed a neoplasm, rather than a reactive lesion.

Radiographic and metabolic evolution of prostate cancer lung metastasis detected by prostate-specific membrane antigen and fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography.

We describe the case of a 75-year-old patient who progressed over a 12-year period from localized to symptomatic metastatic prostate cancer (PrCa) with lung as the sole organ of involvement. In this case, the specific sequence of positron emission tomography (PET)-based next-generation imaging with 18F-sodium fluoride-, 18F-fluoro-2-deoxy-D-glucose-, and 18F-DCFPyL PET/computed tomography and biopsies allowed illustration of the pathway of disease progression from nonglycolytic hormone-sensitive PrCa to glycolytic castrate-resistant PrCa without neuroendocrine features. The observations provide a unique insight into the timelines of anatomical and metabolic progression of metastatic PrCa. They highlight the value of close radiographic surveillance of metastatic PrCa with modern imaging to guide early treatment interventions.

Immunohistochemistry Use by Diagnostic Category and Pathologist in 4477 Prostate Core Biopsy Sets Assessed at Two Hospitals.

BACKGROUND: Immunohistochemistry (IHC) use in prostate cores is not routinely determined and its value assessed. METHODS: Pathology reports for cases accessioned 2011 to 2017 at two hospitals were retrieved. IHC orders by pathologist and hospital were extracted with a custom program and tabulated. The diagnostic category (and highest grade cancer if applicable) was obtained by a hierarchical (free text) string matching algorithm. RESULTS: The study period contained 4477 biopsy sets. Categorized by worst pathology (% stained), the cohort was: benign: 1184 cases (42%); prostatic intraepithelial neoplasia: 168 (68%); suspicious: 323 (93%); grade group 1 cancer (WHO1): 900 (78%); grade group two (WHO2): 840 (60%); WHO3 cancer: 451 (54%); WHO4 cancer: 363 (46%); WHO5 cancer: 215 (56%); cancer grade not specified: 33 (52%). The hospital was a predictor; site A(2716 biopsies) and site B(1761) accounted for 10,183 and 14,852 IHC, respectively. The cases with IHC decreased in the last 4 years (site A: 57->45%, site B: 79->73%). Thirty-five pathologists read >20 cases each and together interpreted 4418 (range, 21 to 415; median, 88). In total 24,766 IHCs were done on the 4,418 cases (5.6/case). The mean/median/SD/max/min IHCs/case for the 35 pathologists was 5.6/4.1/3.9/15.2/0.9. High IHC users (1st and 2nd quintile pathologists) called more suspicious for malignancy but not significantly more WHO1 than low IHC users. CONCLUSIONS: IHC use is most frequent at the benign/malignant interface, and dependent on the pathologist and hospital; however, it is independent of WHO1 cancer rate. Diagnostic rate information can inform and define appropriate and rational IHC use. We plan to follow IHC utilization retrospectively in relation to the diagnostic category going forward.