A prognostic system for epithelial ovarian carcinomas using machine learning.

INTRODUCTION: Integrating additional factors into the International Federation of Gynecology and Obstetrics (FIGO) staging system is needed for accurate patient classification and survival prediction. In this study, we tested machine learning as a novel tool for incorporating additional prognostic parameters into the conventional FIGO staging system for stratifying patients with epithelial ovarian carcinomas and evaluating their survival. MATERIAL AND METHODS: Cancer-specific survival data for epithelial ovarian carcinomas were extracted from the Surveillance, Epidemiology, and End Results (SEER) program. Two datasets were constructed based upon the year of diagnosis. Dataset 1 (39 514 cases) was limited to primary tumor (T), regional lymph nodes (N) and distant metastasis (M). Dataset 2 (25 291 cases) included additional parameters of age at diagnosis (A) and histologic type and grade (H). The Ensemble Algorithm for Clustering Cancer Data (EACCD) was applied to generate prognostic groups with depiction in dendrograms. C-indices provided dendrogram cutoffs and comparisons of prediction accuracy. RESULTS: Dataset 1 was stratified into nine epithelial ovarian carcinoma prognostic groups, contrasting with 10 groups from FIGO methodology. The EACCD grouping had a slightly higher accuracy in survival prediction than FIGO staging (C-index = 0.7391 vs 0.7371, increase in C-index = 0.0020, 95% confidence interval [CI] 0.0012-0.0027, p = 1.8 × 10-7 ). Nevertheless, there remained a strong inter-system association between EACCD and FIGO (rank correlation = 0.9480, p = 6.1 × 10-15 ). Analysis of Dataset 2 demonstrated that A and H could be smoothly integrated with the T, N and M criteria. Survival data were stratified into nine prognostic groups with an even higher prediction accuracy (C-index = 0.7605) than when using only T, N and M. CONCLUSIONS: EACCD was successfully applied to integrate A and H with T, N and M for stratification and survival prediction of epithelial ovarian carcinoma patients. Additional factors could be advantageously incorporated to test the prognostic impact of emerging diagnostic or therapeutic advances.

An algorithm for expanding the TNM staging system.

AIM: We describe a new method to expand the tumor, lymph node, metastasis (TNM) staging system using a clustering algorithm. Cases of breast cancer were used for demonstration. MATERIALS & METHODS: An unsupervised ensemble-learning algorithm was used to create dendrograms. Cutting the dendrograms produced prognostic systems. RESULTS: Prognostic systems contained groups of patients with similar outcomes. The prognostic systems based on tumor size and lymph node status recapitulated the general structure of the TNM for breast cancer. The prognostic systems based on tumor size, lymph node status, histologic grade and estrogen receptor status revealed a more detailed stratification of patients when grade and estrogen receptor status were added. CONCLUSION: Prognostic systems from cutting the dendrogram have the potential to improve and expand the TNM.

An Algorithm for Creating Prognostic Systems for Cancer.

The TNM staging system is universally used for classification of cancer. This system is limited since it uses only three factors (tumor size, extent of spread to lymph nodes, and status of distant metastasis) to generate stage groups. To provide a more accurate description of cancer and thus better patient care, additional factors or variables should be used to classify cancer. In this paper we propose a hierarchical clustering algorithm to develop prognostic systems that classify cancer according to multiple prognostic factors. This algorithm has many potential applications in augmenting the data currently obtained in a staging system by allowing more prognostic factors to be incorporated. The algorithm clusters combinations of prognostic factors that are formed using categories of factors. The dissimilarity between two combinations is determined by the area between two corresponding survival curves. Groups from cutting the dendrogram and survival curves of the individual groups define our prognostic systems that classify patients using survival outcomes. A demonstration of the proposed algorithm is given for patients with breast cancer from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute.

Cystadenomas of the liver and extrahepatic bile ducts: Morphologic and immunohistochemical characterization of the biliary and intestinal variants.

Cystadenomas of the liver and extrahepatic bile ducts (EHBD) are uncommon but distinctive neoplasms whose terminology and epithelial phenotype have been a source of controversy. We reviewed 20 cases, 16 arising in the liver and 4 in the EHBD. Eighteen patients were women, with a mean age of 36.5 years. Eighteen tumors were multiloculated and 2 were unilocular. The tumor size ranged from 4 to 29 cm (average, 11 cm). The cyst fluid in 13 tumors was described as serous, in 2 as clear, in 2 others as hemorrhagic, and in 1 as serous and mucinous. Only in 2 tumors was the fluid described as mucinous. In 18 cystadenomas, the predominant epithelial lining consisted of a single layer of cuboidal or low-columnar nondysplastic cells similar to those of the gallbladder or bile ducts. This epithelial lining was strongly positive for cytokeratins 7 and 19, and focally positive for MUC1. Only 2 cystadenomas showed predominant intestinal differentiation characterized by mature goblet cells and columnar absorptive cells. These cells expressed CDX2, MUC2, and cytokeratin 20. Admixed with the goblet and columnar cells, there were serotonin-containing cells and Paneth cells. These 2 tumors showed extensive areas of high-grade dysplasia and invasive adenocarcinoma with intestinal phenotype. A subepithelial ovarian-like stroma was present in all tumors. None of the patients died of the tumors. We believe that the term mucinous cystic tumor recommended by the World Health Organization for all cystadenomas of the liver and EHBD is a misnomer.

Association of urothelial carcinoma of the renal pelvis with papillary and medullary thyroid carcinomas. A new sporadic neoplastic syndrome?

We describe 2 adult women (72 and 54 years), 1 with a low-grade noninvasive papillary urothelial carcinoma of the renal pelvis, who 14 years later developed a papillary carcinoma in 1 thyroid lobe and a medullary carcinoma in the contralateral lobe. Both neoplasms were similar in size and appeared symmetrical. Despite its small size, the medullary carcinoma metastasized in multiple cervical lymph nodes. The second patient had a high-grade invasive papillary urothelial carcinoma of the renal pelvis that infiltrated the renal parenchyma and metastasized in one of the lungs. Five months later, a papillary carcinoma was discovered in the thyroid gland. The 2 papillary thyroid carcinomas were of the follicular variant. Adjacent to 1 papillary carcinoma, there was a dominant nodule of a colloid and adenomatous goiter. The medullary carcinoma contained stromal amyloid and was immunoreactive for calcitonin and carcinoembryonic antigen. There was no C-cell hyperplasia (medullary carcinoma in situ). The 2 patients are alive, 1 is living with pulmonary metastasis from the high-grade urothelial carcinoma. Twelve cases of this neoplastic association were registered in the Survey, Epidemiology, and End Results Program from 1980 to 2009. We believe that the combination of these unusual neoplasms in the same patient may represent a new sporadic neoplastic syndrome.

Mucinous cystadenoma of the pyelocaliceal system: a report of 3 examples and an analysis of 17 previously published cases.

We report 3 patients all men between 45 and 64 years of age with unilocular or multilocular mucinous cystadenomas of the kidney. One tumor arose from the renal pelvis, and 2 involved the entire pyelocaliceal system. The tumors measured between 2.4 and 37 cm in greatest dimension. Two patients were asymptomatic, and 1 had recurrent attack of acute pyelonephritis. Microscopically, the morphology and immunophenotype (CK20, MUC2, and CDX2 positive) of the tumors were similar to the colonic adenomas. Two patients were asymptomatic 24 and 64 months after surgery, including the patient with mucinous cystadenoma and intramucosal carcinoma. One patient died of acute myocardial infarction, and his tumor was an autopsy finding. Only 17 cases of mucinous cystadenomas and 5 cases of mucinous cystadenocarcinomas have been reported. Of the 17 mucinous cystadenomas, 2 arose in horseshoe kidneys. The mean size of these neoplasms was 15 cm (2.4-37 cm). Despite their large size, some patients with mucinous cystadenomas were asymptomatic. Sixty percent were associated with renal lithiasis. Thirty percent progressed to mucinous adenocarcinomas, and only 2 cases showed areas of intramucosal carcinomas. Two cases were associated with carcinoid tumors, similar to those reported in the appendix. Most patients were asymptomatic after surgery, and only 1 patient died by abdominal sepsis related to adenomucinosis. The 3 examples of mucinous cystadenomas of the pyelocaliceal system reported here, and those previously published indicate that they are very uncommon neoplasms with morphology and intestinal immunophenotype similar to the colonic adenomas.

Thyroid-like cholangiocarcinoma of the liver: an unusual morphologic variant with follicular, trabecular and insular patterns.

We report the case of a 26-year-old woman with a 19 cm malignant hepatic neoplasm with morphological features that closely resembled a follicular thyroid carcinoma. Despite this, it was interpreted as a cholangiocarcinoma due to the absence of a primary thyroid tumor and the lack of thyroglobulin and TTF-1 immunoreactivity by the hepatic tumor. The left hepatic lobectomy specimen showed an encapsulated and multinodular gray-white mass with cystic and hemorrhagic areas. Microscopically, it displayed predominant macro and microfolicullar patterns with focal solid, trabecular and insular areas. The small and distended follicles contained a colloid-like secretion and were lined by low cuboidal cells with scant cytoplasm, round or oval hyperchromatic nuclei with fine chromatin. The solid areas, trabecular and insular structures were similar to those of follicular or papillary thyroid carcinomas. In addition, some of the neoplastic cells had clear nuclei with occasional grooves. The tumor was positive for cytokeratin (CK) 7, CK 19 and CD138, and negative for TTF-1, thyroglobulin, Hepar-1, Glypican-3, alpha-fetoprotein and neuroendocrine markers. A thyroid neoplasm was excluded clinically and by ultrasound and computed tomography. Although, the residual hepatic parenchyma was initially not cirrhotic, the patient eventually developed cryptogenic cirrhosis. The patient received adjuvant chemotherapy and died of metastatic disease 18 months after surgery. The thyroid-like pattern broadens the morphologic spectrum of cholangiocarcinoma.

Second primary breast, endometrial, and ovarian cancers in Black and White breast cancer survivors over a 35-year time span: effect of age.

Breast cancer incidence increases with age and exhibits a Black-to-White crossover around age 45. Breast cancer survivors are at a significantly elevated risk of developing a second primary breast or gynecological cancer compared with the general population. The purpose of this study was to determine whether a similar crossover occurs in hormonally related second primary breast, endometrial, or ovarian cancers in Black and White women. The Surveillance, Epidemiology, and End Results' Registry 9 was used to follow 415,664 White and 39,887 Black female breast cancer survivors, diagnosed at age 19 or older, for a second primary breast, endometrial, or ovarian cancer between 1973 and 2007. Cumulative incidence curves were generated; Pepe and Mori's test was used to test for significance. Second primary breast cancer followed the incidence pattern of the first primary breast cancer in Black and White women diagnosed before age 45. It was opposite of the pattern of first primary breast cancer in Black and White women diagnosed at age 45 or later. Second primary endometrial and ovarian cancers paralleled the incidence pattern of first primaries of the same anatomic site among Black and White women, independent of the age at diagnosis of the first primary breast cancer. Despite the Black-to-White crossover of first primary breast cancer around age 40, the incidence of hormonally related second primaries does not appear affected by the age at diagnosis of the first primary.

Cutaneous angiosarcoma. Analysis of 434 cases from the Surveillance, Epidemiology, and End Results Program, 1973-2007.

Cutaneous angiosarcoma is an aggressive malignant mesenchymal vasoformative neoplasm that accounts for 1% of all soft tissue sarcomas. Using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program, we analyzed the demographics and survival of cutaneous angiosarcoma. The Surveillance, Epidemiology, and End Results program recorded 434 cases of cutaneous angiosarcoma from 1973 to 2007. The incidence was nearly the same in men (222 cases) and women (212 cases). Most patients were white (88%) with a mean age of 73 years. African Americans made up only 4% of the cases. Two hundred seventy (62%) cases were tumors of the head and neck, whereas 106 (24%) cases arose in the skin of the trunk. Grade was recorded in 194 cases (45%): 28 were grade I, 44 were grade II, 60 were grade III, and 62 were grade IV. Survival rates of cutaneous angiosarcoma correlated with age, anatomical site, and stage of disease. Patients younger than 50 years had a 10-year relative survival rate of 71.7%, whereas patients 50 years and older had a 36.8% 10-year survival rate. Tumors of the scalp and neck resulted in a 13.8% 10-year relative survival rate, whereas tumors arising in the trunk resulted in a 75.3% 10-year survival rate. Tumors localized to the skin had better prognosis (53.6% 10-year relative survival rate) than those with regional or distant stage (19.0% and 6.2%). Twenty-six percent of patients with angiosarcoma had a prior primary. Cutaneous angiosarcomas arise predominantly in the head and neck of white individuals older than 60 years.

Integrating additional factors into the TNM staging for cutaneous melanoma by machine learning.

BACKGROUND: Integrating additional factors into the TNM staging system is needed for more accurate risk classification and survival prediction for patients with cutaneous melanoma. In the present study, we introduce machine learning as a novel tool that incorporates additional prognostic factors to improve the current TNM staging system. METHODS AND FINDINGS: Cancer-specific survival data for cutaneous melanoma with at least a 5 years follow-up were extracted from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute and split into the training set (40,781 cases) and validation set (5,390 cases). Five factors were studied: the primary tumor (T), regional lymph nodes (N), distant metastasis (M), age (A), and sex (S). The Ensemble Algorithm for Clustering Cancer Data (EACCD) was applied to the training set to generate prognostic groups. Utilizing only T, N, and M, a basic prognostic system was built where patients were stratified into 10 prognostic groups with well-separated survival curves, similar to 10 AJCC stages. These 10 groups had a significantly higher accuracy in survival prediction than 10 stages (C-index = 0.7682 vs 0.7643; increase in C-index = 0.0039, 95% CI = (0.0032, 0.0047); p-value = 7.2×10-23). Nevertheless, a positive association remained between the EACCD grouping and the AJCC staging (Spearman's rank correlation coefficient = 0.8316; p-value = 4.5×10-13). With additional information from A and S, a more advanced prognostic system was established using the training data that stratified patients into 10 groups and further improved the prediction accuracy (C-index = 0.7865 vs 0.7643; increase in C-index = 0.0222, 95% CI = (0.0191, 0.0254); p-value = 8.8×10-43). Both internal validation using the training set and temporal validation using the validation set showed good stratification and a high predictive accuracy of the prognostic systems. CONCLUSIONS: The EACCD allows additional factors to be integrated into the TNM to create a prognostic system that improves patient stratification and survival prediction for cutaneous melanoma. This integration separates favorable from unfavorable clinical outcomes for patients and improves both cohort selection for clinical trials and treatment management.

Etiologic heterogeneity for cervical carcinoma by histopathologic type, using comparative age-period-cohort models.

BACKGROUND: Cervical carcinomas comprise two main histopathologic types, squamous cell carcinomas and adenocarcinomas. Human papillomavirus (HPV) infections are causative for both types but the respective tumors may have different carcinogenic pathways. METHODS: To assess potential etiologic heterogeneity of cervical cancer by histopathologic type, we examined invasive squamous cell carcinomas and adenocarcinoma cervical cancer incidence rates in the National Cancer Institute's Surveillance, Epidemiology, and End Results database. We complemented standard descriptive epidemiology with comparative age-period-cohort (APC) models fitted to each histopathologic type. RESULTS: Squamous cell tumors (n=25,219) were nearly 5-fold more common than adenocarcinomas (n=5,451). Age-adjusted incidence trends decreased for squamous cell carcinomas but increased for adenocarcinomas. Cross-sectional age-specific incidence rates increased more rapidly for squamous cell carcinomas than adenocarcinomas in adolescents and young adults then leveled off for both types. APC models confirmed that secular trends and age-specific rates differed for the two types (P=0 for the null hypothesis of no difference). For squamous cell carcinoma, the APC "fitted" age-at-onset rate curve peaked before age 40 years then declined; for adenocarcinoma, the fitted curve increased rapidly until age 40 years then rose more slowly. CONCLUSIONS: Despite the necessary role of HPV infection in both squamous cell carcinomas and adenocarcinomas of the cervix, secular trends and age-related natural histories differed for the two tumor types, consistent with etiologic heterogeneity. Future analytic and clinical studies should consider the interaction (effect modification) of HPV infection and other cervical carcinoma risk factors by histopathologic type, time, and age.

Cancers of the ampulla of vater: demographics, morphology, and survival based on 5,625 cases from the SEER program.

BACKGROUND: Cancers of the ampulla are unusual and morphologically heterogeneous. The NCI's SEER Program is now large enough so that unusual cancers can be studied. Based on pathologic and epidemiologic characteristics of cancer of the ampulla available in SEER, important clinicopathological correlations can be made. METHODS: All patients with cancer of the ampulla were identified between 1973 and 2005. Demographic features, distribution of histological types, age-specific incidence rates, and 5-year survival rates according to stage and histologic type were compared. RESULTS: There were 5,625 cases of ampullary cancer. Ampullary cancer has been increasing since 1973. In both African Americans and Caucasians, the disease is more common in men. Adenocarcinomas, NOS comprised 65% of all histological types. Survival depends on stage, grade, and histologic type. Papillary carcinomas had a more favorable survival than other types; carcinomas arising in adenomas had a more favorable survival than adenocarcinomas not associated with adenomas. Logarithmic transformation of age-related incidence data demonstrates that cancers having differing histopathologic phenotypes represent a single population of tumors. CONCLUSIONS: Prognostic factors include histologic type, grade, stage, and coexisting adenomas. These data should be included in pathology reports. Although certain histologic types exhibit morphologic differences, their pathogenesis appears to be similar.

Carcinoid tumors and small-cell carcinomas of the gallbladder and extrahepatic bile ducts: a comparative study based on 221 cases from the Surveillance, Epidemiology, and End Results Program.

Primary neuroendocrine tumors of the gallbladder (GB) and extrahepatic biliary ducts (EHBDs) include carcinoid tumors and small-cell carcinomas (SCCs). They are uncommon, and therefore, little is known about their demographics and clinical course. From National Cancer Institute's Surveillance, Epidemiology, and End Results program (1973-2005), we analyzed the demographics and 10-year relative survival rates of carcinoids and SCCs of the GB and EHBD according to histologic type and stage. There were 119 cases of carcinoid tumors and 54 cases of SCCs in the GB. There were 31 carcinoid tumors and 17 SCCs in the EHBD. The female/male ratios of carcinoids in the GB and EHBD were 2.4 and 1.6, respectively. The ratios for SCC in the GB and EHBD were 2.2 and 1.1, respectively. For the GB, the mean age of diagnosis for carcinoids was 64.5, and for SCC, it was 67.5. For the EHBD, the mean age was 58.2 for carcinoids and 68.4 for SCC. The 10-year survival rates were 36% for carcinoid tumors of the GB and 80% for carcinoid tumors of the EHBD. For SCC, the 10-year survival was 0% in the GB and EHBD. Carcinoid tumors and SCC of the extrahepatic biliary tree are uncommon neoplasms that differ in their demographics and biologic behavior, supporting the distinction of these 2 histopathologic types. Therefore, these tumors should be separately classified and not included in the single generic group of neuroendocrine carcinoma.

Paraneoplastic sensory neuropathy associated with small cell carcinoma of the gallbladder.

A small number of patients with carcinoma of the gallbladder can present with a variety of paraneoplastic syndromes, including the Cushing syndrome, hypercalcemia, acanthosis nigricans, bullous pemphigoid, dermatomyositis, and the Leser-Trélat sign. We report on what appears to be the first case of a patient, a 48-year-old woman, with anti-Hu paraneoplastic sensory neuropathy and small cell carcinoma of the gallbladder. The patient's neurologic symptoms preceded the diagnosis of small cell carcinoma by 11 months. These symptoms improved after surgical removal of the tumor and chemotherapy. The small cell carcinoma was relatively small and was not associated with gallstones. In spite of the small size of the tumor, it metastasized to a celiac lymph node and probably to the liver. Anti-Hu paraneoplastic sensory neuropathy should be added to the list of paraneoplastic syndromes associated with small cell carcinoma of the gallbladder.

Carcinomas of the Renal Pelvis, Ureters, and Urinary Bladder Share a Carcinogenic Field as Revealed in Epidemiological Analysis of Tumor Registry Data.

BACKGROUND: Urothelial carcinomas are the most common malignant tumors in the upper and lower urinary tract. Renal cell carcinomas (RCCs) have a different pathoepidemiologic incidence and characteristics. We describe a population-based approach of differentiating between urothelial and renal carcinomas as a basis to support shared morphologic phenotypes. MATERIALS AND METHODS: Data from 2000 through 2014 from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute were used to calculate the incidence rates for cancers of the kidney, renal pelvis, ureter, and urinary bladder. Graphic plots of the epidemiologic patterns were analyzed according to age frequency density and double logarithmic (log-log) plots of age-specific incidence rates and age of diagnosis. RESULTS: RCCs were initially more common than cancers of the urinary bladder, but after age 60, cancers of the bladder became more common with age-specific rates rapidly rising in all age groups. The age frequency density plot for RCC peaked earlier than for urothelial cancers indicating a different tumorigenic process. Log-log plots revealed near parallel proportional rate patterns for cancers of the renal pelvis, ureters, and urinary bladder, suggesting similar carcinogenic pathways among these tumors, whereas they were not parallel for RCCs. Similar slopes indicate that cancer incidence is increasing at similar rates regardless of the incidence of each cancer. CONCLUSION: Tumors that arise in the renal pelvis, ureters, and urinary bladder share a common carcinogenic field on the basis of pathoepidemiologic analysis. The definition of a carcinogenic field should expand to include epidemiological parameters as well as common morphologic and embryological patterns.

Creating prognostic systems for cancer patients: A demonstration using breast cancer.

Integrating additional prognostic factors into the tumor, lymph node, metastasis staging system improves the relative stratification of cancer patients and enhances the accuracy in planning their treatment options and predicting clinical outcomes. We describe a novel approach to build prognostic systems for cancer patients that can admit any number of prognostic factors. In the approach, an unsupervised learning algorithm was used to create dendrograms and the C-index was used to cut dendrograms to generate prognostic groups. Breast cancer data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute were used for demonstration. Two relative prognostic systems were created for breast cancer. One system (7 prognostic groups with C-index = 0.7295) was based on tumor size, regional lymph nodes, and no distant metastasis. The other system (7 prognostic groups with C-index = 0.7458) was based on tumor size, regional lymph nodes, no distant metastasis, grade, estrogen receptor, progesterone receptor, and age. The dendrograms showed a relationship between survival and prognostic factors. The proposed approach is able to create prognostic systems that have a good accuracy in survival prediction and provide a manageable number of prognostic groups. The prognostic systems have the potential to permit a thorough database analysis of all information relevant to decision-making in patient management and prognosis.

Histologic variants of papillary and follicular carcinomas associated with anaplastic spindle and giant cell carcinomas of the thyroid: an analysis of rhabdoid and thyroglobulin inclusions.

We describe the histologic variants of papillary and follicular carcinomas associated with 109 spindle and giant cell carcinomas (SGCC) of the thyroid and determine the incidence of rhabdoid and thyroglobulin inclusions in these tumors. In addition, we searched for rhabdoid and thyroglobulin inclusions in 120 papillary carcinomas (PC) (all 15 variants included), 23 differentiated follicular carcinomas (DFC), (6 with insular pattern), 6 poorly differentiated follicular carcinomas (PDFC) and 34 follicular adenomas (FA). The following differentiated thyroid carcinomas coexisted with SGCC: 51 (46.8%) PC, (34 conventional type, 14 tall cell variant and 3 follicular variant), 6 (5.5%) DFC, 1 follicular carcinoma with insular pattern (0.9%), and 3 oncocytic carcinomas (2.8%). Eleven SGCC (10%) and 2 (33%) PDFC showed rhabdoid features, but lacked thyroglobulin inclusions. Thyroglobulin inclusions were found in 10 FA (29%), 8 (17%) follicular variants of PC and in 7 (30.4%) DFC. There were no rhabdoid inclusions in any of these differentiated thyroid tumors. Our findings support the hypothesis that most SGCC result from dedifferentiation or anaplastic transformation although the mechanisms that underlie this transformation remain unknown. The finding that only 1 (0.9%) SGCC was associated with follicular carcinoma with insular pattern contradicts the opinion that this tumor occupies an intermediate position between differentiated and anaplastic carcinomas. Rhabdoid features are markers of PDFC and SGCC while thyroglobulin inclusions are markers of FA and differentiated thyroid carcinomas with follicular phenotype.

Adenomyomatous hyperplasia of the gallbladder with perineural invasion: revisited.

We report 9 examples of segmental adenomyomatous hyperplasia of the gallbladder with perineural invasion. Five patients were women and 4 men. Their ages ranged from 49 to 81 years (mean age 64 y). Eight patients had gallbladder calculi. The original pathologic diagnosis of adenocarcinoma was made in 5 patients and of "adenoma malignum" in one. Six patients are disease-free for 2 to 11 years following cholecystectomy, 1 patient died of unrelated causes and 2 were lost to follow-up. Histologically 2 types of adenomyomatous hyperplasia were recognized. The first one characterized by numerous Rokitansky-Aschoff sinuses (RASs) was accompanied by smooth muscle hyperplasia and an expanded subserosal layer containing numerous nerve trunks (6 cases). The second type was characterized by an extensively fibrotic gallbladder wall with numerous RASs but with few or no smooth muscle bundles and an expanded subserosal layer containing abundant nerve-trunks (3 cases). Perineural (7 cases) and intraneural invasion (2 cases) was identified only in the subserosal layer. The lack of p53 reactivity and the very low MIB-1-labeling index provide additional support to the non-neoplastic nature of the lesion. The pseudoinvasive pattern of the RASs, reactive epithelial atypia, and the perineural and intraneural invasion probably contributed to the erroneous diagnosis of adenocarcinoma or "adenoma malignum." The mechanism by which the epithelial structures "invaded" the perineural spaces and the nerves is unclear. We favor the hypothesis that the migration of the benign glandlike structures into the nerves is related to the production of chemotactic factors or signaling substances and the activation of cell receptors.

Diagnostic surgical pathology in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition).

OBJECTIVE: The objective of this study was to provide evidence-based background and recommendations for the development of American College of Chest Physicians guidelines for the diagnosis and management of lung cancer. METHODS: A systematic search of the medical and scientific literature using MEDLINE, MDCONSULT, UpToDate, Cochrane Library, NCCN guidelines, and NCI/NIH search engines was performed for the years 1990 to 2006 to identify evidence-based and consensus guidelines. The search was limited to literature on humans and articles in the English language. RESULTS: The pathologic assessment of lung cancers is based on a set of well-accepted findings, including histologic type, tumor size and location, involvement of visceral pleura, and extension to regional and distant lymph nodes and organs. Bronchial-based incipient neoplasia needs to be recognized both grossly and microscopically because these lesions may be multifocal and represent multistep carcinogenesis and may be amenable to therapy. Cytologic assessment of the individual with no symptoms is, as yet, of insufficient clinical benefit for screening of lung cancer. In challenging situations of pathologic differential diagnosis, additional studies may provide information that enables the separation of distinct tumor types. Pathobiological and molecular biological studies may yield prognostic and predictive information for clinical management and should be considered as part of protocol studies. Enhanced pathologic and molecular techniques may identify the presence of micrometastatic disease within lymph nodes; however, the clinical utility of these approaches is still unresolved. Intraoperative consultations have high diagnostic accuracy and may aid ongoing treatment and management decisions. CONCLUSIONS: Pathologic assessment is a crucial component for the diagnosis, management, and prognosis of lung cancer. Selective diagnostic techniques and decision analysis will increase diagnostic accuracy. Cytologic screening, molecular characterization of tumors, and micrometastatic analysis are potential but not yet proved modalities for the evaluation of lung cancers.