Extent of High-Grade Prostatic Adenocarcinoma in Multiparametric Magnetic Resonance Imaging-Targeted Biopsy Enhances Prediction of Pathologic Stage.

CONTEXT.­: Multiparametric magnetic resonance imaging (mpMRI) of prostate with targeted biopsy has enhanced detection of high-grade prostatic adenocarcinoma (HG PCa). However, utility of amount of HG PCa (Gleason pattern 4/5) in mpMRI-targeted biopsies versus standard 12-core biopsies in predicting adverse outcomes on radical prostatectomy (RP) is unknown. OBJECTIVE.­: To examine the utility of amount of HG PCa in mpMRI-targeted biopsies versus standard 12-core biopsies in predicting adverse RP outcomes. DESIGN.­: We performed a retrospective review of prostate biopsies that had corresponding RP, 1 or more mpMRI-targeted biopsy, and Grade Group 2 disease or higher. For the 169 cases identified, total millimeters of carcinoma and HG PCa and longest length HG PCa in a single core were recorded for 12-core biopsies and each set of mpMRI-targeted biopsies. For RP specimens, Gleason grade, extraprostatic extension, seminal vesicle involvement, and lymph node metastasis were recorded. The main outcome studied was prostate-confined disease at RP. A logistic regression model was used to test which pre-RP variables related to this outcome. RESULTS.­: Univariate analysis showed significant associations with adverse RP outcomes in 5 of 8 quantifiable variables; longest millimeter HG PCa in a single 12-core biopsy, highest Grade Group in any core, and total millimeter HG in mpMRI-targeted biopsies showed no statistical association (P = .54, P = .13, and P = .55, respectively). In multivariate analysis, total millimeter carcinoma in all cores, highest Grade Group in any core, and longest millimeter HG PCa in a single mpMRI-targeted core provided additional predictive value (P < .001, P = .004, and P = .03, respectively). CONCLUSIONS.­: Quantitation of HG PCa in mpMRI-targeted biopsies provides additional value over 12-core biopsies alone in predicting nonorgan confined prostate cancer at RP. Linear millimeters of HG PCa in mpMRI-targeted biopsies is a significant parameter associated with higher pathologic stage and could be of value in risk models.

The Importance of Tumor Length in Needle Biopsies of the Prostate.

OBJECTIVES: To form a composite predictor variable that combines the effects of tumor length, serum prostate-specific antigen (PSA), and International Society of Urologic Pathologists (ISUP) grade on the observation of adverse prostatectomy pathology. METHODS: Logistic regression analysis was used to demonstrate how tumor length, serum PSA, and ISUP grade related to adverse prostatectomy results and to derive weighting factors for a composite variable, cx. RESULTS: The composite variable, cx, relates closely to adverse prostatectomy results as well as to observed PSA failure. CONCLUSIONS: The composite variable cx uses preoperative information that may allow the sorting of patients into low, intermediate, and high risk for adverse outcomes after prostatectomy.

Adverse Histopathologic Characteristics in Small Clear Cell Renal Cell Carcinomas Have Negative Impact on Prognosis: A Study of 631 Cases With Clinical Follow-up.

Tumor size has been used for decision making in the management of patients with renal masses. Active surveillance in selected patients is now increasingly common in tumors ≤4 cm in size. Clear cell renal cell carcinoma (CCRCC) is the most common type of renal malignancy. Adverse histopathologic characteristics that correlate with worse prognosis have been described in CCRCCs. The aim of our study was to determine the frequency and extent of adverse histopathologic characteristics in CCRCCs ≤4 cm and their association with patient outcome. A search of a single institution for nephrectomies performed for CCRCC identified 631 consecutive cases. Cases were reviewed for the following morphologic features: high nuclear grade, necrosis, lymphovascular invasion, and rhabdoid or sarcomatoid histology. Relationships between the variables were examined by Kruskal-Wallis test, Wilcoxon test, χ test, and logistic regression. We found adverse tumor histopathologic characteristics were significantly related to size: In CCRCCs >4 versus ≤4 cm, there were more high nuclear grade (45% vs. 15%, P<0.01), necrosis (46% vs. 21%, P<0.01), and lymphovascular invasion (17% vs. 3%, P<0.01). Although adverse histologic features are less commonly seen in CCRCCs ≤4 cm, their presence was associated with lower disease-free survival (P<0.01). Adverse histopathologic characteristics in CCRCCs ≤4 cm correlated with worse prognosis and identification of these features through needle core biopsy examination may guide clinical management, especially in patients for whom active surveillance is considered.

The Calculus of Serum PSA.

OBJECTIVES: To review the mathematics of kinetic changes in serum prostate-specific antigen (PSA) and to use a compartmental model to derive a new kinetic measure, alpha. METHODS: The calculus of kinetic measures of PSA changes with time is presented, and a compartmental model is then used to derive alpha of serum PSA. Alpha is then tested for prognostic importance in 119 men who underwent prostatectomy. RESULTS: The percentage of tumor in the prostate is closely related to alpha and to tumor length in diagnostic needle biopsies, but not to tumor grade. The presence of adverse pathology in the prostatectomy specimens (positive margins or T3 stage) is significantly associated with alpha, but not to tumor length or grade. CONCLUSIONS: The derived kinetic parameter, alpha, shows promise as a preoperative prognostic parameter, and may help sort patients into those with low vs high probability for adverse pathology features in the prostatectomy specimens.

A review of the incidence of adenocarcinoma detected during surveillance for Barrett's esophagus.

The objective of this study is to provide an up-to-date estimate of the incidence of adenocarcinoma detected during surveillance of Barrett's esophagus. Fifty-five longitudinal studies involving approximately 61 000 patients were reviewed. A general linear model analyses with Poisson link function was used to study how the number of cancer cases detected depended on study details. The studies seemed to follow the same statistical model, and the probability of developing Barrett's carcinoma during surveillance was found to depend on the following variables: how Barrett's metaplasia was defined, the number of patients studied, the mean time of follow-up, and the fraction of patients followed up for at least 5 years. The model derived from all the studies predicted that the per-person probability of developing cancer in 5 years of complete follow-up is approximately .0012.

Serum Prostate-Specific Antigen (PSA) Concentration, PSA Mass, and Obesity: A Mathematical Analysis.

OBJECTIVES: To provide a mathematical background for understanding the phenomenon of analyte hemodilution using a kinetic analysis. METHODS: The first assumption for this analysis is that change in concentration of any analyte, such as prostate-specific antigen (PSA), is due to the flux of the analyte from an organ into the blood minus its flux from the blood. What results is a relatively simple differential equation that emphasizes the importance of plasma volume, organ mass, and two rate constants. RESULTS: The analyses demonstrate how serum PSA can be affected by plasma volume as well as body mass and how hemodilution due to obesity can be at least partly corrected for by expressing PSA in units of total mass or total mass density. CONCLUSIONS: At a time when obesity is prevalent, expressing analytes in units of total mass may make them relate more closely to disease status and prognosis.

Defining Papillary Carcinoma of the Thyroid: A Short Review and Analysis.

OBJECTIVES: To review how changes in the pathologic definitions for papillary tumors of the thyroid during recent decades have affected outcomes for patients with these tumors. METHODS: Forty-nine previous reports or studies involving collectively 53,606 patients were reviewed, and new analyses were performed on the data to include analyses of agreement, incidence, survival, and diagnostic categories. RESULTS: The past emphasis on cytologic features to define papillary tumors has not resulted in ideal pairwise agreement between pathologists and has produced incidence and survival data suggesting overdetection and overdiagnosis. Most recently, tissue patterns have been reemphasized. CONCLUSIONS: With the recent reemphasis on diagnostic tissue patterns (over cytologic criteria), agreements between pathologists for the diagnosis of papillary tumors should improve, and the incidence of papillary carcinoma should decline. Nevertheless, updated survival analyses demonstrate excellent long-term survival for most of those diagnosed with papillary carcinomas.

Gleason Grading, Biochemical Failure, and Prostate Cancer-Specific Death.

OBJECTIVES: To examine the relationship between the recently defined Gleason grade groups and prostate cancer-specific mortality. METHODS: If the probability of prostate cancer-specific death is symbolized as P(PSD), the probability of biochemical failure is symbolized as P(BF), and the probability of prostate cancer-specific death after biochemical failure is symbolized as P(PSD | BF), then the rules of probability provide a way to estimate P(PSD) as P(PSD) = P(PSD | BF) * P(BF) Using this model and data from the literature for P(PSD | BF) and P(BF), I estimate here values of P(PSD) for the five newly described Gleason grade groups. RESULTS: The expected probability of prostate cancer- specific death is closely related to the new Gleason grade groups and ranges from a low of 0.014 for grade group 1 to a high of 0.15 for grade group 5. CONCLUSIONS: Although using the original study patient population may require years of additional follow-up to examine prostate cancer-specific mortality, the evidence available now indicates that these new Gleason grade groups relate to prostate cancer-specific mortality.

A Review of Outcomes for Colorectal Adenomas.

OBJECTIVES: Using data from former reports, this study reviews and analyzes the outcomes of tumor recurrence, tumor progression, and tumor-specific survival of patients with colorectal adenomas. METHODS: Data were collected from 32 longitudinal studies of outcomes after the first diagnosis of colorectal adenoma and collected as individual patient results, that is, as failure times from the first tumor to the three outcomes. Altogether, there were 45,286 patients, including 22,148 for the outcome of additional adenomas, 23,796 for the outcome of progression to invasive carcinoma, and 2,602 for the outcome of disease-specific survival (some patients were available for more than one outcome). RESULTS: In these data, the mean time to additional adenomas was 6 years, the mean time to invasive carcinoma was 15.9 years, and the mean tumor-specific survival time was 21.9 years. CONCLUSIONS: Although greater than 50% of those with colorectal adenomas will have additional adenomas, few progress to invasive tumor or die of colorectal cancer.

A Review of Outcomes for Stage Ta Bladder Tumors.

OBJECTIVES: Using data from former reports, this study reviews and analyzes the outcomes of tumor recurrence, tumor progression, and tumor-specific survival of patients with stage Ta bladder tumors. METHODS: Data were collected from 19 longitudinal studies of outcomes after the first diagnosis of tumor and collected as individual patient results, that is, as failure times from the first tumor to any of the three outcomes. Altogether, there were 14,252 patients, including 4,050 for the outcome of tumor recurrence, 2,937 for the outcome of tumor progression, and 11,595 for the outcome of disease-specific survival (some patients were available for more than one outcome). RESULTS: In these data, the mean time to additional tumors was 7.8 years, the mean time to an invasive tumor was 19.5 years, and the mean tumor-specific survival time was 27.2 years. All three outcomes were significantly related to the 2004 World Health Organization (WHO) tumor grades. CONCLUSIONS: Although greater than 50% of those with stage Ta bladder tumors have additional bladder tumors, approximately 80% appear to follow a benign course without developing invasive tumors or dying of bladder cancer. The 2004 WHO grading scheme accounts for some but not all of the prognostic information.

Detection of Occult Micrometastases in Patients With Clinical Stage I Non-Small-Cell Lung Cancer: A Prospective Analysis of Mature Results of CALGB 9761 (Alliance).

PURPOSE: Outcomes after resection of stage I non-small-cell lung cancer (NSCLC) are variable, potentially due to undetected occult micrometastases (OM). Cancer and Leukemia Group B 9761 was a prospectively designed study aimed at determining the prognostic significance of OM. MATERIALS AND METHODS: Between 1997 and 2002, 502 patients with suspected clinical stage I (T1-2N0M0) NSCLC were prospectively enrolled at 11 institutions. Primary tumor and lymph nodes (LNs) were collected and sent to a central site for molecular analysis. Both were assayed for OM using immunohistochemistry (IHC) for cytokeratin (AE1/AE3) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for carcinoembryonic antigen. RESULTS: Four hundred eighty-nine of the 502 enrolled patients underwent complete surgical staging. Three hundred four patients (61%) had pathologic stage I NSCLC (T1, 58%; T2, 42%) and were included in the final analysis. Fifty-six percent had adenocarcinomas, 34% had squamous cell carcinomas, and 10% had another histology. LNs from 298 patients were analyzed by IHC; 41 (14%) were IHC-positive (42% in N1 position, 58% in N2 position). Neither overall survival (OS) nor disease-free survival was associated with IHC positivity; however, patients who had IHC-positive N2 LNs had statistically significantly worse survival rates (hazard ratio, 2.04, P = .017). LNs from 256 patients were analyzed by RT-PCR; 176 (69%) were PCR-positive (52% in N1 position, 48% in N2 position). Neither OS nor disease-free survival was associated with PCR positivity. CONCLUSION: NSCLC tumor markers can be detected in histologically negative LNs by AE1/AE3 IHC and carcinoembryonic antigen RT-PCR. In this prospective, multi-institutional trial, the presence of OM by IHC staining in N2 LNs of patients with NSCLC correlated with decreased OS. The clinical significance of this warrants further investigation.

Probabilistic issues with sentinel lymph nodes in malignant melanoma.

OBJECTIVES: To address issues of probability for sentinel lymph node results in melanoma and provide details about the probabilistic nature of the numbers of sentinel nodes as well as to address how these issues relate to tumor thickness and patient outcomes. METHODS: Analysis of the probability of observing sentinel node metastases uses the discrete exponential probability distribution to address the number of observed positive sentinel nodes. In addition, mathematical functions derived from survival analysis are used. Data are then chosen from the literature to illustrate the approach and to derive results. RESULTS: Observations about the numbers of positive and negative sentinel nodes closely follow discrete exponential probability distributions, and the relationship between the probability of a positive sentinel node and tumor thickness follows closely a function derived from survival analysis. Sentinel node results relate to tumor thickness as well as to the total number of nodes harvested but fall short of identifying all those who eventually develop metastatic melanoma. CONCLUSIONS: Probability analyses provide useful insight into the success and failure of the sentinel node biopsy procedure in patients with melanoma.

A review of survival in mycosis fungoides.

OBJECTIVES: The objectives of this study are to review prior publications of survival for patients with mycosis fungoides (MF), to perform some analyses on the consolidated data, and then to consider the implications of the results. METHODS: The data for this study comprise 18 survival curves derived from seven prior publications of long-term survival in relatively large series of patients with MF. Altogether, the study uses results from over 5,000 patients. To examine fatality, the study uses hazard functions derived from the survival curves. RESULTS: The analyses demonstrate significant variability in survival between different groups who have studied MF, and the results document that for most patients the diagnosis of MF has little impact on fatality. CONCLUSIONS: Although MF is considered a cutaneous lymphoma, that is, a malignancy, it may be time to reconsider low stages of MF as precursors to malignancy analogous to the precursors to malignancies of other types or organs.

A probabilistic analysis of mitotic counts in melanoma.

OBJECTIVES: Mitotic counts in melanoma are important and have now become part of the staging of this tumor. Yet, this change was largely based on studies that evaluated the mitotic counts in a limited fashion. Because counts of things with a microscope are often distributed as a Poisson random variable, the major goal of this study was to uncover the probabilistic nature of mitotic counts in melanoma. METHODS: Specifically, a general double Poisson model was applied to mitotic counts in 53 cutaneous melanomas representing both thin and thick tumors. RESULTS: The general double Poisson probability model fit the data well. A single Poisson function was sufficient for 46 of the 53 study cases, and two Poisson functions were required for seven cases because of tissue heterogeneity. Furthermore, the success of the model implied that there is a high probability for false-negative mitotic counts, especially in thin melanomas, and that the "hot" spot methodology introduces bias. CONCLUSIONS: Mitotic counts in melanomas are a probabilistic phenomenon closely related to the Poisson probability distribution, and this factor needs to be considered when using mitotic counts for staging and prognosis in melanoma.

Revisiting overdiagnosis and fatality in thyroid cancer.

OBJECTIVES: To examine the rates of incidence and fatality in cohorts of patients diagnosed with thyroid cancer from 1975 to 1999. METHODS: This study uses National Cancer Institute's Surveillance, Epidemiology and End Results data and derives hazard functions in order to examine the fatality in thyroid cancer. RESULTS: The study documents forms of rapidly evolving and fatal tumors as well as forms of tumor that evolve more slowly to cause death. It demonstrates that the incidences of nonfatal forms of thyroid cancer have risen dramatically in the years from 1975 to 1999-mostly due to papillary carcinomas-but that the incidences of fatal forms of thyroid cancer have remained nearly constant. CONCLUSIONS: The results of this study support the notion that many thyroid cancers are part of a reservoir of nonfatal tumors that are increasingly being overdetected and overdiagnosed.

Epidermal dynamics and patterns of intraepidermal melanoma.

BACKGROUND: Dermatopathologists know that the epidermis represents a dynamic compartment and that its cells mature from the basal layer to the skin surface in approximately 45 days. What may seem intuitive - but not obvious - is that the dynamics of the epidermis can affect the patterns of melanoma cells within the epidermis. Here this conjecture is explored with an abstract, theoretical model. METHODS: To control the independent effects of epidermal replacement velocity and thickness as well as rate of melanoma cell penetration of the epidermis, an abstraction of the epidermis was created and simulated via computer. RESULTS: Simulated plots of the epidermis show that the number and pattern of melanoma cells in the epidermis is affected by the probability of melanoma cells entering the epidermis, by the velocity of epidermal replacement and by epidermal thickness. CONCLUSION: This analysis suggests that the dynamics of the epidermis are sufficient to affect the patterns of melanoma cells within the epidermis.

Cross-validation analysis of the prognostic significance of mucin expression in patients with resected non-small cell lung cancer treated with adjuvant chemotherapy: results from IALT, JBR.10 and ANITA.

INTRODUCTION: CALGB 9633 was a randomized trial of observation versus adjuvant chemotherapy for patients with stage IB non-small cell lung cancer (NSCLC). In CALGB 9633, the presence of mucin in the primary tumor was associated with shorter disease-free survival (DFS; hazard ratio (HR) = 1.9, p = 0.002) and overall survival (OS; HR = 1.9, p = 0.004). METHODS: To validate these results, mucin staining was performed on primary tumor specimens from 780 patients treated on IALT, 351 on JBR.10 and 150 on ANITA. The histochemical technique using mucicarmine was performed. The prognostic value of mucin for DFS and OS was tested in a Cox model stratified by trial and adjusted for clinical and pathological factors. A pooled analysis of all 4 trials was performed for the predictive value of mucin for benefit from adjuvant chemotherapy. RESULTS: The cross-validation group had 48% squamous, 37% adenocarcinoma and 15% other NSCLC compared with 29%, 56%, and 15%, respectively in CALGB. Among 1262 patients with assessable results, mucin was positive in IALT 24%, JBR.10 30%, ANITA 22% compared with 45% in CALGB. Histology was the only significant covariate (p < 0.0001) in multivariate analysis with mucin seen more commonly in adenocarcinoma (56%) compared with squamous (5%) and other NSCLC (15%). Mucin was a borderline negative prognostic factor for DFS (HR = 1.2 [1.0-1.5], p = 0.06) but not significantly so for OS (HR=1.1 [0.9-1.4], p = 0.25). Prognostic value did not vary according to histology: HR = 1.3 [1.0-1.6] in adenocarcinoma vs. 1.6 [1.2-2.2] for DFS in other histology (interaction p = 0.69). Mucin status was not predictive for benefit from adjuvant chemotherapy (test of interaction: DFS p = 0.27; OS p = 0.49). CONCLUSIONS: Mucin was less frequent in the cross-validation group due to its higher percentage of squamous cell carcinomas. The negative impact of mucin was confirmed for DFS but not for OS. Mucin expression was not predictive of overall survival benefit from adjuvant chemotherapy.