CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Editors: Michael Cibull, MD, professor emeritus, University of Kentucky College of Medicine, Lexington; Rouzan Karabakhtsian, MD, attending pathologist, Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.; and Rachel Stewart, DO, resident physician, Department of Pathology and Laboratory Medicine, University of Kentucky.
Subtype classification of lung adenocarcinoma in patients undergoing complete resection
Correlating gene methylation in surgical margin imprints with recurrence in HNSCC
Pathological, clinical, and radiographical features of organizing pneumonia patterns
Impact of age and primary disease site on outcome
in LGSOC and LGSPC
Significance of tumor stage and nodal stage in squamous cell carcinoma of oropharynx
A study of overdiagnosis of high-grade dysplasia in Barrett’s esophagus
Use of Magee equations and histologic criteria to predict Oncotype DX recurrence score
Blood and lymphatic vessel invasion in pT1 colorectal cancer
Subtype classification of lung adenocarcinoma in patients undergoing complete resection
The classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and World Health Organization is based on the predominant histologic pattern—lepidic, papillary, acinar, micropapillary, or solid—present in the tumor. This classification has not been tested in multi-institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT). Of 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups—lepidic (LEP), acinar/papillary (ACN/PAP), and micropapillary/solid (MIP/SOL). The primary end point was overall survival; secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95 percent confidence intervals (CIs) were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. The significance level was set at 0.01 for pooled analysis. A total of 575 patients were included in the analysis. Overall survival was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for the MIP/SOL subgroup compared with the LEP or ACN/PAP subgroups (P<.01). This remained marginally significant after adjustment. MIP/SOL patients derived DFS and SDFS but not overall survival benefit from ACT (overall survival: HR, 0.71; 95 percent CI, 0.51–0.99; interaction P=.18; DFS: HR, 0.60; 95 percent CI, 0.44–0.82; interaction P≤.01; SDFS: HR, 0.59; 95 percent CI, 0.42–0.81; interaction P=.01). The authors concluded that the new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for overall survival, but it seems predictive for disease-specific outcomes.
Tsao MS, Marguet S, Le Teuff G, et al. Subtype classification of lung adenocarcinoma predicts benefit from adjuvant chemotherapy in patients undergoing complete resection [published online ahead of print April 27, 2015]. J Clin Oncol. doi:10.1200/JCO.2014.58.8335.
Correspondence: Dr. Ming-Sound Tsao at ming.tsao@uhn.ca
Correlating gene methylation in surgical margin imprints with recurrence in HNSCC
Securing negative surgical margins is a critical goal for head and neck surgery. Local recurrence develops even in some patients who have histologically negative surgical margins. Minimal residual tumor cells may lead to locoregional recurrence despite clear histologic margins reported at the time of resection of head and neck squamous cell carcinoma. To identify subclinical residual disease, the authors conducted a study in which they analyzed deep margin imprint samples collected on one-layer nitrocellulose sheets. Bisulfite-treated DNA samples from 73 eligible patients were amplified by quantitative methylation-specific polymerase chain reaction (QMSP) targeting six genes—
deleted in colorectal cancer (DCC), endothelin receptor type B (EDNRB), homeobox protein A9 (HOXA9), kinesin family member 1A (KIF1A), nidogen-2 (NID2), and N-methyl D-aspartate receptor subtype 2B (NR2B). QMSP values were dichotomized as positive or negative. The authors evaluated associations between the QMSP status of deep margin samples and clinical outcomes. They found that two-gene methylation combinations among the genes DCC, EDNRB, and HOXA9 were associated with decreased locoregional recurrence-free survival, recurrence-free survival, and overall survival. The methylated gene combination of EDNRB and HOXA9 in margin imprints was the most powerful predictor of poor locoregional recurrence-free survival (hazard ratio [HR], 3.31; 95 percent confidence interval [CI], 1.30–8.46; P=.012) independent of standard histologic factors. In addition, methylation of both EDNRB and HOXA9 indicated a trend toward reduced recurrence-free survival (HR, 2.74; 95 percent CI, 0.90–8.33; P=.075) and reduced overall survival (HR, 5.78; 95 percent CI, 0.75–44.7; P=.093) in multivariable analysis. The authors concluded that a panel of gene methylation targets in deep surgical margin imprints provides a potential predictive marker of postoperative locoregional recurrence. Intraoperative use of molecular margin imprint analysis may assist surgeons in obtaining rigorously negative surgical margins and improve the outcome of head and neck surgery.
Hayashi M, Wu G, Roh JL, et al. Correlation of gene methylation in surgical margin imprints with locoregional recurrence in head and neck squamous cell carcinoma. Cancer. 2015;121:1957–1965.
Correspondence: Dr. Wayne M. Koch at wkoch@jhmi.edu
Pathological, clinical, and radiographical features of organizing pneumonia patterns
Cryptogenic organizing pneumonia (COP) and acute fibrinous and organizing pneumonia (AFOP) are recognized patterns of organizing pneumonia, a condition that resembles pneumonia but is not caused by infection. The authors consider granulomatous organizing pneumonia (GOP) to be a similar histopathological entity in which non-necrotizing granulomata are intimately associated with the organizing connective tissue. To what degree COP, AFOP, and GOP represent distinct clinical and pathological disorders is unknown. The authors conducted a cross-sectional study to compare the pathological, clinical, and radiographical features of these organizing pneumonia patterns. Surgical lung biopsy specimens were reviewed for consecutive patients with organizing pneumonia who were referred to a metropolitan cancer center. Clinical information and computed tomography (CT) images were acquired from the hospital electronic medical record to determine the clinical and CT characteristics of each organizing pneumonia pattern. Sixty-one patients (35 men and 26 women), who were a mean age of 61.5 years (range, 8–85 years), were available for analysis. Of these, 43 (70 percent) patients had at least one prior cancer, 27 (44 percent) had received chemotherapy, and 18 (30 percent) had undergone radiation. Approximately half (32 patients) had respiratory symptoms, most commonly cough, dyspnoea, or wheezing. While symptoms and mortality rates did not differ among the organizing pneumonia groups, the AFOP patients more commonly had fever (P=.04). The GOP patients less commonly received chemotherapy (P=.03) and were most likely to present with masses or nodules (P=.04). The authors concluded that AFOP and GOP, the latter a newly described form of organizing pneumonia, possess clinical and pathological findings that set them apart from COP, suggesting an emerging spectrum of organizing pneumonia.
Feinstein MB, DeSouza SA, Moreira AL, et al. A comparison of the pathological, clinical and radiographical features of cryptogenic organising pneumonia, acute fibrinous and organising pneumonia and granulomatous organising pneumonia. J Clin Pathol. 2015;68:441–447.
Correspondence: Dr. Marc B. Feinstein at fein stem@mskcc.org
Impact of age and primary disease site on outcome
in LGSOC and LGSPC
Low-grade serous carcinoma of the ovary (LGSOC) and low-grade serous carcinoma of the peritoneum (LGSPC) are rare cancer subtypes characterized by young age at diagnosis and relative resistance to chemotherapy. The authors conducted a study to report their updated experience with women diagnosed with LGSOC or LGSPC to assess the validity of their original observations. Eligibility criteria for patients from their database were stage I to IV LGSOC or LGSPC, original diagnosis before January 2012, and adequate clinical information. All patients were included in progression-free survival, overall survival, and multivariable Cox regression analyses. A subset analysis was performed among patients with stage II to IV low-grade serous carcinoma treated with primary surgery followed by platinum-based chemotherapy. The authors identified 350 eligible patients. Median progression-free survival was 28.1 months and median overall survival was 101.7 months. In the multivariable analysis, when women diagnosed at age greater than 35 years were compared with women age 35 years or younger, the older group had a 43 percent reduction in likelihood of dying (hazard ratio [HR], 0.53; 95 percent confidence interval [CI], 0.37–0.74; P<.001). Having disease present at completion of primary therapy was associated with a 1.78 increased hazard of dying compared with being clinically disease free (P<.001). Similar trends were noted in the smaller patient cohort. In that cohort, women with LGSPC had a 41 percent decreased chance of dying (HR, 0.59; 95 percent CI, 0.36–0.98; P=.04) compared with those with LGSOC. The authors concluded that women younger than 35 years old with low-grade serous carcinoma and those with persistent disease at completion of primary therapy have the worst outcomes. Patients with LGSPC seem to have a better prognosis than those with LGSOC.
Gershenson DM, Bodurka DC, Lu KH, et al. Impact of age and primary disease site on outcome in women with low-grade serous carcinoma of the ovary or peritoneum: results of a large single-institution registry of a rare tumor. J Clin Oncol. 2015;33:2675–2682.
Correspondence: Dr. David M. Gershenson at dgershen@mdanderson.org
Significance of tumor stage and nodal stage in squamous cell carcinoma of oropharynx
Although human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC) tends to present at an advanced nodal stage (N stage), the prognosis is generally better than that for human papillomavirus (HPV)-negative OPSCC. Prior work has demonstrated the increasing incidence of HPV-related OPSCC in the United States. The authors conducted a study to determine whether the changing epidemiology of OPSCC is reflected in changes in the prognostic significance of tumor stage (T stage) and N stage in a population-based cohort. The Surveillance, Epidemiology, and End Results program was used to identify 13,328 patients 18 years old or older who were diagnosed with OPSCC from 1997 to 2008. The Kaplan-Meier method was used to estimate head and neck cancer-specific survival. Cox proportional hazards models were used to evaluate the associations between head and neck cancer-specific mortality (HNCSM) and T and N stages and the interaction of variables with the year of diagnosis. Using a median follow-up of 67 months, the authors noted 4,099 head and neck cancer deaths. Significant interaction was found between T stage and time (P for interaction=.01), with the effect of T stage on HNCSM increasing from 1997 to 2008. T stage retained a linear relationship with HNCSM. The effect of N stage on HNCSM declined over time (P for interaction=.0004). The American Joint Committee on Cancer (AJCC) staging system did not subdivide distinct prognostic subgroups for HNCSM by overall stage. The authors concluded that in this population-based study of OPSCC, the effect of N stage on cancer-specific mortality decreased over time as the impact of T stage increased. The AJCC staging system did not distinguish prognostic subgroups. These changes may reflect the increasing prevalence of HPV-related OPSCC. Additional study in HPV-defined cohorts is needed to tailor the AJCC staging system to better reflect HNCSM risk.
Keane FK, Chen YH, Neville BA, et al. Changing prognostic significance of tumor stage and nodal stage in patients with squamous cell carcinoma of the oropharynx in the human papillomavirus era. Cancer. 2015;121(15):2594–2602.
Correspondence: Dr. Danielle N. Margalit at dmargalit@lroc.harvard.edu
A study of overdiagnosis of high-grade dysplasia in Barrett’s esophagus
Numerous histological mimics of high-grade dysplasia in Barrett’s esophagus predispose to overdiagnosis and potential serious mismanagement, including unnecessary esophagectomy. The authors investigated the prevalence and sources of this problem. Biopsies from 485 patients diagnosed with Barrett’s high-grade dysplasia were screened for a multi-institutional international Barrett’s endoscopic ablation trial. Screening included review of the original diagnostic slides and an additional protocol endoscopy with extensive biopsy sampling. Observer variability by the study pathologists was assessed through two blinded diagnostic rounds on 437 biopsies from 26 random study endoscopies. Diagnostic reassessments revealed significantly lower rates of high-grade dysplasia. Only 248 (51 percent) patients were confirmed to have high-grade dysplasia. The remaining patients had inflamed gastric cardia without Barrett’s (n=18; 7 percent), Barrett’s without dysplasia (n=35; 15 percent), indefinite change (n=61; 26 percent), low-grade dysplasia (n=79; 33 percent), adenocarcinoma (n=43; 18 percent), and other diagnoses (n=1; less than one percent), yielding an alarming total of 194 (40 percent) patients who were overdiagnosed with Barrett’s high-grade dysplasia. The study pathologists achieved a high level of agreement (90 percent three-way interobserver agreement per biopsy; κ value, 0.77) for high-grade dysplasia. Confounding factors promoting overdiagnosis included Barrett’s inflammatory atypia (n=182), atypia limited to the basal metaplastic glands (n=147), imprecise criteria for low-grade neoplasia (n=102), tangential sectioning artifact (n=59), and reactive gastric cardiac mucosa (n=38). The authors concluded that the multiple diagnostic pitfalls uncovered should help raise pathologists’ awareness of this problem and improve diagnostic accuracy.
Sangle NA, Taylor SL, Emond MJ, et al; for International Photodynamic Group for High-Grade Dysplasia in Barrett’s Esophagus. Overdiagnosis of high-grade dysplasia in Barrett’s esophagus: a multicenter, international study. Mod Pathol. 2015;28:758–765.
Correspondence: Dr. M. P. Bronner at mary.bronner@hsc.utah.edu
Use of Magee equations and histologic criteria to predict Oncotype DX recurrence score
Oncotype DX is a multigene quantitative reverse transcription-polymerase chain reaction-based assay that estimates the risk of distant recurrence and predicts chemotherapy benefit for patients with estrogen receptor-positive breast cancers. Studies have suggested that standard histologic variables can provide similar information. Studies have shown that Oncotype DX (Genomic Health) recurrence scores can be estimated by incorporating standard histologic variables into Magee equations. Using a simple modification of the Magee equation, the authors of this study predicted the Oncotype DX recurrence score in an independent set of 283 cases. The Pearson correlation coefficient for the Oncotype DX and average modified Magee recurrence scores was 0.6644 (n=283; P<.0001). All of the cases with an average modified Magee recurrence score greater than 30 (n=8) or an average modified Magee recurrence score of less than nine (with an available Ki-67, n=5) would have been correctly predicted to have a high or low Oncotype DX recurrence score, respectively. Eighty-six percent (38 of 44) of cases with an average modified Magee recurrence score of 12 or less and 89 percent (34 of 38) of low-grade tumors (NS<6) with an estrogen receptor and progesterone receptor of 150 or more and a Ki-67 of less than 10 percent would have been correctly predicted to have a low Oncotype DX recurrence score. Using an algorithmic approach to eliminate high- and low-risk cases, between five percent and 23 percent of cases potentially would not have been sent for Oncotype DX testing by the authors’ institution, creating a potential cost-savings of $56,550 to $282,750. The authors concluded that the modified Magee recurrence score along with histologic criteria may be a cost-effective alternative to the Oncotype DX in risk stratifying certain breast cancer patients. The information needed is already generated by many pathology laboratories during the initial assessment of primary breast cancer, and the equations are free.
Turner BM, Skinner KA, Tang P, et al. Use of modified Magee equations and histologic criteria to predict the Oncotype DX recurrence score. Mod Pathol. 2015;28:921–931.
Correspondence: Dr. B. M. Turner at bradley_turner@urmc.rochester.edu
Blood and lymphatic vessel invasion in pT1 colorectal cancer
The authors evaluated the concordance in pathological assessments of blood and lymphatic vessel invasion in pT1 colorectal cancers and how diagnostic criteria influenced consistency in BLI assessment. Forty consecutive patients undergoing surgical resection of pT1 colorectal cancers were entered in the study. Hematoxylin-and-eosin–stained, D2-40-stained, and elastica-stained slides from the tumors were examined by 18 pathologists from seven countries. The 40 cases were divided into two cohorts with 20 cases each. In the first cohort, pathologists diagnosed blood and lymphatic vessel invasion (BLI) using criteria familiar to them; all Japanese pathologists used a criterion for BLI from the Japanese Society for Cancer of the Colon and Rectum (JSCCR). In the second cohort, all pathologists used the JSCCR diagnostic criterion. The authors found that in the first cohort, diagnostic concordance was moderate for the U.S./Canadian and European pathologists. They noted no differences in consistency compared with results from the Japanese pathologists and no improvement in diagnostic concordance based on using the JSCCR criterion. However, in the second cohort the JSCCR criterion decreased the consistency of BLI diagnosis in the U.S./Canadian and European pathologists. The level of decreased consistency in assessing BLI varied between the U.S./Canadian and European pathologists. The authors concluded that a uniform criterion strongly influences the diagnostic consistency of BLI but may not always improve concordance. Additional study is required to achieve an objective diagnosis of BLI in colorectal cancer. The varying effects of diagnostic criteria on the pathologists from Japan, U.S./Canada, and Europe might reflect varied interpretations of the criteria. An internationally accepted criterion should be developed.
Kojima M, Puppa G, Kirsch R, et al. Blood and lymphatic vessel invasion in pT1 colorectal cancer: an international concordance study. J Clin Pathol. 2015;68:628–632.
Correspondence: Dr. Atsushi Ochiai at aochiai@east.ncc.go.jp