The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei.

The vermiform appendix is the primary site of several distinctive benign and malignant neoplasms. Some can produce the clinical syndrome of pseudomyxoma peritonei (PMP). A consensus on their terminology was reached by an international panel of pathologists and clinicians working under the auspices of the Peritoneal Surface Oncology Group International (PSOGI), and this review discusses the application of the PSOGI classification to routine reporting. We discuss diagnosis and differential diagnosis together with implications for patient management, covering low-grade appendiceal mucinous neoplasms, high-grade appendiceal mucinous neoplasms, serrated polyps, adenomas and adenocarcinomas. We do not cover goblet cell tumours or neuroendocrine neoplasms in this paper.

A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated Appendiceal Neoplasia: The Results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process.

Pseudomyxoma peritonei (PMP) is a complex disease with unique biological behavior that usually arises from appendiceal mucinous neoplasia. The classification of PMP and its primary appendiceal neoplasia is contentious, and an international modified Delphi consensus process was instigated to address terminology and definitions. A classification of mucinous appendiceal neoplasia was developed, and it was agreed that "mucinous adenocarcinoma" should be reserved for lesions with infiltrative invasion. The term "low-grade appendiceal mucinous neoplasm" was supported and it was agreed that "cystadenoma" should no longer be recommended. A new term of "high-grade appendiceal mucinous neoplasm" was proposed for lesions without infiltrative invasion but with high-grade cytologic atypia. Serrated polyp with or without dysplasia was preferred for tumors with serrated features confined to the mucosa with an intact muscularis mucosae. Consensus was achieved on the pathologic classification of PMP, defined as the intraperitoneal accumulation of mucus due to mucinous neoplasia characterized by the redistribution phenomenon. Three categories of PMP were agreed-low grade, high grade, and high grade with signet ring cells. Acellular mucin should be classified separately. It was agreed that low-grade and high-grade mucinous carcinoma peritonei should be considered synonymous with disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis, respectively. A checklist for the pathologic reporting of PMP and appendiceal mucinous neoplasms was also developed. By adopting the classifications and definitions that were agreed, different centers will be able to use uniform terminology that will allow meaningful comparison of their results.

A Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project.

The Genotype-Tissue Expression (GTEx) project, sponsored by the NIH Common Fund, was established to study the correlation between human genetic variation and tissue-specific gene expression in non-diseased individuals. A significant challenge was the collection of high-quality biospecimens for extensive genomic analyses. Here we describe how a successful infrastructure for biospecimen procurement was developed and implemented by multiple research partners to support the prospective collection, annotation, and distribution of blood, tissues, and cell lines for the GTEx project. Other research projects can follow this model and form beneficial partnerships with rapid autopsy and organ procurement organizations to collect high quality biospecimens and associated clinical data for genomic studies. Biospecimens, clinical and genomic data, and Standard Operating Procedures guiding biospecimen collection for the GTEx project are available to the research community.

Improving the TNM classification: findings from a 10-year continuous literature review.

The Union for International Cancer Control's (UICC) TNM classification is a globally accepted system to describe the anatomic extent of malignant tumors. Since its development seventy years ago, the TNM classification has undergone significant revisions to reflect the current understanding of extent of disease and its role in prognosis. To ensure that revisions are evidence-based, the UICC implemented a process for continuous improvement of the TNM classification that included a formalized system for submitting proposals for revisions directly to the UICC and an annual review of the scientific literature on staging that assessed, criticized or made suggestions for changes. The process involves review of the proposals and literature by a group of international, multidisciplinary Expert Panels. The process has been in place for 10 years and informed the development of the 7th edition of the TNM classification published in 2009. The purpose of this article is to provide a description of the annual literature review process, including the search strategy, article selection process and the roles and requirements of the Expert Panels in the review of the literature. Since 2002, 147 Expert Panel members in 11 cancer sites have reviewed over 770 articles. The results of the annual literature reviews, Expert Panel feedback and documentation and dissemination of results are described.

'Evidence-based medicine: the time has come to set standards for staging'. Is a radical overhaul really needed?

This Invited Response addresses concerns and opinions expressed in an Invited Commentary, 'Evidence-based medicine: the time has come to set standards for staging', by Quirke et al., published in this issue of The Journal of Pathology.

A distinctive novel epitheliomesenchymal biphasic tumor of the stomach in young adults ("gastroblastoma"): a series of 3 cases.

This report describes 3 cases of a distinctive, hitherto unreported gastric epitheliomesenchymal biphasic tumor that differs from other biphasic tumors of the stomach and elsewhere: carcinosarcoma, biphasic synovial sarcoma, teratoma, and mixed tumor. The tumors occurred in young adults, 2 males and 1 female, of ages 19, 27, and 30 years. Two tumors were located in the greater curvature in the gastric body and one in the antrum. The tumors measured 5, 6, and 15 cm in maximum diameter, and their mitotic rates were 0, 4, and 30 mitoses per 50HPF. There were 2 components: uniform oval or spindled cells in diffuse sheets, and clusters or cords of epithelial cells occasionally forming glandular structures with small lumens. The epithelial elements were positive for keratin cocktail AE1/AE3, keratin 18, and partly for keratin 7, but were negative for keratins 5/6, 20 and epithelial membrane antigen. The spindle cells were positive for vimentin and CD10. All components were negative for CD34, CD99, estrogen receptor, KIT, smooth muscle actin, desmin S100 protein, p63, calretinin, chromogranin, synaptophysin, CDX2, and thyroid transcription factor 1. In situ hybridization for SS18 rearrangement was negative in all cases separating this tumor from synovial sarcoma. All 3 patients were alive after follow-up of 3.5, 5, and 14 years. Because these tumors have some resemblance to blastomas of other organs, we propose the term "gastroblastoma" for this distinctive, at least low-grade malignant epitheliomesenchymal tumor of the stomach.

Plexiform fibromyxoma: a distinctive benign gastric antral neoplasm not to be confused with a myxoid GIST.

A great majority of gastric mesenchymal tumors are gastrointestinal stromal tumor (GIST). A rare group of non-GISTs include myxoid mesenchymal neoplasms. In this report, we describe 12 cases of a distinctive gastric tumor, named here as plexiform fibromyxoma. These tumors occurred in 5 men and 7 women of ages 7 to 75 years (median, 41 y). All tumors were located in the gastric antrum and 6 of them also extended into extragastric soft tissues or into the duodenal bulb. The tumors measured from 3 to 15 cm (median, 5.5 cm). Histologically typical was a plexiform intramural growth with multiple micronodules containing paucicellular to moderately cellular myxoid to collagenous and fibromyxoid neoplastic elements. A prominent, sometimes plexiform capillary pattern was typically present. Extramural components included subserosal nodules, and sometimes more cellular, solid nonplexiform spindle cell proliferation. The tumor cells varied from oval to spindled and had limited atypia and mitotic activity < 5/50 high-power fields. Frequent ulceration, mucosal invasion, and vascular invasion (4 cases) had no adverse significance in these tumors. Immunohistochemically, the tumor cells were positive for alpha smooth muscle actin, and variably for CD10, and were consistently negative for KIT, DOG1, CD34, desmin, and S100 protein. No KIT or platelet-derived growth factor receptor alpha mutations were present in the 3 examined cases. None of the 4 patients who were followed from 9 to 20 years (median, 19 y) developed recurrences or metastases. Additional 3 patients survived 14 to 25 years with unknown tumor status. Review of large numbers of mesenchymal tumors in the esophagus and intestines did not reveal similar tumors. Plexiform fibromyxoma is a distinctive benign gastric antral neoplasm that should be separated from GIST, nerve sheath tumors, and other fibromyxoid neoplasms.

A uniform residual tumor (R) classification: integration of the R classification and the circumferential margin status.

BACKGROUND: Since the introduction of the TNM residual tumor (R) classification, the involvement of resection margins has been defined either as a microscopic (R1) or a macroscopic (R2) demonstration of tumor directly at the resection margin ("tumor transected"). METHODS: The recognition of the importance of the circumferential resection margin (CRM) in patients with rectal cancer patients raises the need for an alternative definition of resection margin involvement, namely, the importance of delineating tumor with a minimal distance from the CRM of

Gastrointestinal stromal tumors presenting as omental masses--a clinicopathologic analysis of 95 cases.

Gastrointestinal stromal tumors (GISTs), generally KIT-positive and KIT/PDGFRA mutation-driven mesenchymal neoplasms, most commonly originate from the stomach or small intestine, but in rare examples they involve the omentum. In this study, we analyzed 95 GISTs surgically designated as the omental masses. These tumors occurred in 49 males and 46 females with a median age of 60 years (range: 27 to 88 y). They formed single (n=51) or multiple masses (n=39); 5 cases were equivocal in this respect. Of the single tumors, 21 had no evidence of gastrointestinal tract involvement, 25 were attached to stomach, and 3 were attached to small intestine. Clinicopathologic parameters and prognosis of the 2 former groups were similar. Single tumor cases showed a median mitotic count of 2/50 HPFs and median tumor size was 14 cm. Their histologic features were similar to gastric GISTs in 22 cases, and to small intestinal GISTs in 6 cases. These tumors were KIT positive 38/41, CD34 positive 20/33, 8 had PDGFRA mutations, and 6 had KIT exon 11 mutations. The median survival was 129 months (range: 0 to 397 mo) and 14 patients were alive at the end of follow-up. Multiple tumor cases showed median mitotic count of 14/50 HPFs and the main tumor median size was 16 cm. The histologic features were similar to small intestinal GISTs in 21 cases and to gastric GISTs in 7 cases; small intestinal attachment or history of a previous small intestinal GIST were noted in 5 cases, whereas no tumor was attached to stomach. The multiple GISTs were KIT positive 23/24, CD34 positive 7/21, and 5 had KIT exon 11 mutations, 3 had KIT exon 9 mutations, and 2 had PDGFRA mutations. The median survival was for 8 months and all patients died. Omental GISTs are clinicopathologically heterogenous. Patients with solitary tumors usually have gastric GIST-like morphology and a better prognosis than those with multiple tumors, whose tumor usually has small intestinal GIST-like histology. Omental GISTs unattached to gastrointestinal tract often resemble gastric GISTs suggesting that they may be gastric GISTs directly extending or parasitically attached into the omentum, whereas multiple omental GISTs more often resemble small intestinal GISTs suggesting that they may be metastatic or detached from this source. KIT positive Cajal cells were not found in normal omental tissues failing to support the presence of these ancestral cells for GIST in the omentum.

Primary melanomas of the esophagus and anorectum: epidemiologic comparison with melanoma of the skin.

The objective of this study was to use recently available data to describe the epidemiology of melanomas of the esophagus and the anorectum in contrast to melanoma of the skin. The methods used include descriptive epidemiology using cases reported to the Surveillance Epidemiology and End Results registry, 1973-2003. All rates were age adjusted. We found 46 759 cutaneous melanomas, 170 anorectal melanomas and 20 esophageal melanomas, corresponding to age-adjusted rates of 70.1, 0.27, and 0.03 per million population, respectively. Median age of patients with melanoma of the skin was less than those with melanoma of the anorectum or esophagus (55 years vs. 71 years and 69 years, respectively). Rates of melanoma of the skin were 1.5-fold higher for men than for women (87.1 vs. 58.1 per 10); in contrast, rates of anorectal melanoma were 1.6-fold higher for women than for men (0.324 vs. 0.199 per 10). Rates of cutaneous melanoma for whites were 13-fold higher than for blacks (80.6 vs. 6.1 per 10, P<0.001), whereas the rates of anorectal melanoma were 1.7-fold higher among whites than blacks (0.273 vs. 0.173 per 10). Comparing the period 1973-1987 with 1988-2003, the rate of cutaneous melanoma increased 1.4-fold (56.0-80.1 per 10), whereas the rate of anorectal melanoma similarly increased 1.8-fold (0.182 to 0.329 per 10).In conclusion, anorectal melanomas, and especially, esophageal melanomas remain rare malignancies. This is the first report where temporal trends in anorectal melanoma are following the increased incidence of cutaneous melanomas, but it is unclear whether immunohistochemical diagnostic practices have influenced this trend. As gastrointestinal melanomas represent melanocytic transformation in the absence of sunlight, their epidemiology may provide etiologic clues to alternative or systemic transformative factors also operant in cutaneous melanoma.

Gain-of-function PDGFRA mutations, earlier reported in gastrointestinal stromal tumors, are common in small intestinal inflammatory fibroid polyps. A study of 60 cases.

The inflammatory fibroid polyp is a rare benign lesion occurring throughout the digestive tract. It usually forms a solitary mass, characterized by a proliferation of fibrovascular tissue infiltrated by a variable number of inflammatory cells. The etiology of this lesion is unknown and conflicting histogenetic theories have been proposed. Recently, mutations in platelet-derived growth factor receptor (PDGFRA) and PDGFRA expression were reported in gastric inflammatory fibroid polyps. In this study, PDGFRA exons 12, 14, and 18 were screened for activating mutations in 60 small intestinal inflammatory fibroid polyps. In addition, the PDGFRA expression was evaluated immunohistochemically. Mutations in PDGFRA were identified in 33 of 60 (55%) cases, whereas 95% expressed PDGFRA. There were 26 deletions, three deletion-insertions, duplication, and single nucleotide substitution in exon 12, and a single nucleotide substitution and deletion in exon 18. The majority (n=23) of exon 12 deletions were 1837_1851del leading to S566_E571delinsR. However, 1835_1852delinsCGC leading to the same S566_E571delinsR, were found in two tumors. Three inflammatory fibroid polyps had 1836_1850del leading to S566_E571delinsK. A complex deletion-insertion affecting a similar region (1837_1856delinsGATTGATGATC) and leading to S566_I573delinsRIDDL was identified once. In addition, duplication and single nucleotide substitution were found 5' to the common inflammatory fibroid polyp mutational 'hot spot'. These mutations consist of 1808_1828dup leading to I557_E563dup, and 1821T>A resulting in 561V>D substitution. A 2664A>T and 2663_2674del leading to 842D>V and D842_H845del, respectively, were identified in exon 18. Similar gain-of-function PDGFRA mutations reported in gastrointestinal stromal tumors have been considered to be a driving pathogenetic force. This study showed consistent expression and common mutational activation of PDGFRA in small intestinal inflammatory fibroid polyps as in their gastric counterparts, and these lesions should be considered PDGFRA-driven benign neoplasms. We also suggest that these polyps may develop from earlier described PDGFRA-positive mesenchymal cells distributed along the villus membrane after oncogenic PDGFRA activation.

Secondary tumors and tumorlike lesions of the peritoneal cavity: imaging features with pathologic correlation.

Tumors and tumorlike lesions that secondarily involve the mesothelial or submesothelial layers of the peritoneum are a diverse group of disorders that range in biologic behavior from benign to highly malignant. The anatomy of peritoneal ligaments and mesenteries and the normal circulation of peritoneal fluid dictate location and distribution of these diseases within the peritoneal cavity. Peritoneal carcinomatosis is the most common secondary tumor to affect the peritoneal cavity. When it arises from carcinomas of the gastrointestinal tract or ovary, the prognosis is grave. However, when low-grade mucinous adenocarcinoma of the appendix spreads to the peritoneal cavity, the consequence is typically pseudomyxoma peritonei, which is a clinical syndrome, characterized by recurrent and recalcitrant voluminous mucinous ascites due to surface growth on the peritoneum without significant invasion of underlying tissues. Carcinomas from elsewhere in the body, as well as lymphomas and sarcomas, may also produce diffuse peritoneal metastasis. Granulomatous peritonitis is the consequence of disseminated infection such as tuberculosis or histoplasmosis, foreign materials, or rupture of a tumor or hollow viscus. Finally, a group of benign miscellaneous conditions that range from common disorders such as endometriosis and splenosis to very rare conditions such as gliomatosis peritonei and melanosis may also affect the peritoneum diffusely. Secondary tumors and tumorlike lesions of the peritoneum have overlapping imaging features when compared with each other and primary peritoneal tumors. Knowledge of peritoneal anatomy, normal fluid circulation within the peritoneal cavity, and clinical and pathologic features of secondary peritoneal lesions is essential for identification of these lesions.

True smooth muscle tumors of the small intestine: a clinicopathologic, immunhistochemical, and molecular genetic study of 25 cases.

Gastrointestinal stromal tumors (GISTs) comprise a great majority of small intestinal mesenchymal tumors previously designated as smooth muscle tumors (SMTs), but true SMTs occur with a low-frequency encompassing both leiomyomas and leiomyosarcomas (LMSs). In this study, we analyzed 25 tumors in the spectrum of primary SMTs of the small intestine. Metastatic tumors and those with external attachment only were excluded. These tumors occurred in 15 men and 10 women of median age of 62 years (range: 18 to 80 y). There were 9 well-differentiated SMTs with no atypia and low mitotic activity [< or = 5/50 high-power fields (HPFs)] and these were considered leiomyomas. All 6 tumors examined were positive for SMA and desmin, and negative for KIT; all 3 tumors in female patients that were tested were negative for estrogen receptor. Two leiomyomas, a 5 mm, and another, 2 cm tumor, were examples of a muscularis mucosae leiomyomas. The other 7 were considered intramural leiomyomas; their median diameter was 4.5 cm (range: 0.8 to 9 cm). No patient with these tumors experienced recurrences or metastases, and 6 patients were alive with a median follow-up of 16 years (range: 9 to 28 y). Sixteen tumors had atypia and mitotic activity warranting the designation of LMS. One of these tumors, a 16 cm diverticular tumor, had mitotic activity of only 1/50 HPFs, and this tumor recurred 4 times. All other LMSs had > or =35 mitoses/50 HPFs. Four of 5 such LMSs with follow-up recurred or metastasized, and at least 3 patients died of disease; several others had a short survival but cause of death could not be determined. One patient, an 18-year-old woman, who died of LMS, was a survivor of a Wilms tumor radiated in infancy. All 6 LMSs studied for GIST-specific KIT and platelet-derived growth factor receptor alpha mutations showed wild-type sequences. This series demonstrates that primary small intestinal SMTs are rare (estimated frequency 1 SMT for 36 GISTs). A majority of these are mitotically active tumors with atypia warranting the diagnosis of LMS, and have a high malignant potential. The number of LMS cases is too small for stratification for risk assessment. True SMTs of small intestine should be separated from GISTs because of different pathogenesis and treatment.

t(11;18)(q21;q21) in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in stomach: a study of 48 cases.

Gastric extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MZL-MALT) is speculated to be immune mediated and is notable for responding to treatment by Helicobacter pylori eradication. However, the gastric MZL-MALT with t(11;18)(q21;q21) has been shown to be resistant to treatment by H. pylori eradication. We studied the molecular, immunohistochemical, and histological aspects of 48 cases of gastric MZL-MALT and used a reverse transcription real-time PCR assay to assess the presence of a t(11;18)(q21;q21) in formalin-fixed, paraffin-embedded tissue. Florescence in situ hybridization for t(11:18)(q21;q21) was used to confirm the real-time PCR results. Three distinct morphological subtypes were recognized: monocytoid, small lymphocytic, and plasmacytoid. Morphology, immunophenotype, and immunoglobulin heavy chain (IgH) gene rearrangement were correlated with the results of the t(11:18)(q21;q21) assay. Of the 48 analyzed cases, 15 (31%) were positive for t(11;18)(q21;q21) and 33 (69%) were monoclonal for IgH gene rearrangement. Of the 15, 13 (87%) cases with t(11;18)(q21;q21) translocation showed IgH gene rearrangement by PCR. Of the 33 t(11;18)(q21;q21)-negative cases tested, 20 cases (61%) showed IgH gene rearrangement. The 15 t(11;18)(q21;q21) translocation-positive cases had either monocytoid (12 of 15) or small lymphocytic morphology (3 of 15). Aberrant expression of CD43 was observed in 8 of 15 (53%) t(11;18)(q21;q21)-positive cases and 21 of 31 (68%) t(11;18)(q21;q21)-negative cases. Our data show that t(11;18)(q21;q21)-positive MZL-MALTs frequently show monocytoid morphology, less often small lymphocytic morphology, and not purely plasmacytoid morphology. Identification of a t(11;18)(q21;q21) by reverse transcription real-time PCR is highly specific for MZL-MALT and helps in the diagnosis of MZL-MALT. Studying the correlation between this translocation and morphological features may increase our understanding of the role of this translocation in the pathogenesis and the clinical behavior of gastric MZL-MALT.

Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix.

Appendiceal tumors exhibiting both neuroendocrine and glandular differentiation are uncommon and have caused difficulty in pathologic classification, prediction of prognosis, and clinical management. Previously, such lesions have been variously designated as adenocarcinoid, goblet cell carcinoid (GCC), and mixed adenocarcinoma carcinoid. In this study, we undertook a retrospective investigation of 63 such cases and classified them as typical GCC (group A) and adenocarcinoma ex GCC on the basis of the histologic features of the tumor at the primary site. The adenocarcinoma ex GCC group was further divided into signet ring cell type (group B) and poorly differentiated adenocarcinoma type (group C). The clinical characteristics and prognosis were compared within these groups and with conventional de novo appendiceal adenocarcinomas. Both groups A and B tumors shared a similar immunoprofile, which included generally focal immunoreactivity for neuroendocrine markers, and a normal intestinal type mucin glycoprotein profile (negative MUC1 expression and preserved MUC2 immunoreactivity). The proliferative index was relatively low in these tumors and slightly increased from groups A to B tumors (11% to 16%). Both beta-catenin and E-cadherin exhibited a normal membranous staining pattern in groups A and B tumors. The poorly differentiated adenocarcinomas ex GCC (group C) demonstrated abnormal p53 and beta-catenin immunoreactivity. The mean follow-up time was 49+/-5 (SE) months. The overall disease-specific survival for all subtypes was 77%, with 46% of patients without evidence of disease and 31% alive with disease. The mean survival was 43+/-7 months. All the patients with clinical stage of I or IIA disease had a favorable outcome after appropriate surgery with or without chemotherapy. Although most patients (63%) with GCC presented at an advanced clinical stage, their clinical outcome could be differentiated by subclassification of tumors. The stage IV-matched 5-year survival was 100%, 38%, and 0% for groups A, B, and C, respectively. In conclusion, GCC is a distinctive appendiceal neoplasm that exhibits unique pathologic features and clinical behavior. They display a spectrum of histologic features and possess the potential to transform to an adenocarcinoma phenotype of either signet ring cell or poorly differentiated adenocarcinoma types. Careful evaluation of the morphologic features of GCCs and appropriate pathologic classification are crucial for clinical management and prediction of outcome. Surgical management with right hemicolectomy is recommended after appendectomy for most cases, particularly those with an adenocarcinoma component (groups B and C).

Genetic variants in T helper cell type 1, 2 and 3 pathways and gastric cancer risk in a Polish population.

Host immune responses are known determinants of gastric cancer susceptibility. We previously reported an increased gastric cancer risk associated with common variants of several T helper type 1 (Th1) cytokine genes in a population-based case-control study in Warsaw, Poland. In the present study, we augmented our investigation to include additional Th1 genes as well as key genes in the Th2 and Th3 pathways. Analysis of 378 cases and 435 age- and sex-matched controls revealed associations for polymorphisms in the Th1 IL7R gene and one polymorphism in the Th2 IL5 gene. The odd ratios (ORs) for IL7R rs1494555 were 1.4 [95% confidence interval (CI), 1.0-1.9] for A/G and 1.5 (95% CI, 1.0-2.4) for G/G carriers relative to A/A carriers (P = 0.04). The ORs for IL5 rs2069812 were 0.9 (95% CI, 0.7-1.3) for C/T and 0.6 (95% CI, 0.3-1.0) T/T carriers compared with C/C carriers (P = 0.03). These results suggest that IL5 rs2069812 and IL7R rs1389832, rs1494556 and rs1494555 polymorphisms may contribute to gastric cancer etiology.

The staging of cancer: a retrospective and prospective appraisal.

The tumor-node-metastasis (TNM) classification describes the anatomic extent of cancer. The ability to separately classify the individual T, N, and M elements and then group them into stages differs from other cancer staging classifications, which are primarily concerned with summarized groups. The objectives of the TNM system are to aid clinicians and investigators in planning treatment, assessing prognosis, stratifying patients for therapeutic studies, evaluating the results of treatment, and facilitating communication. The most important challenge facing TNM is how to interface the current taxonomy with the numerous nonanatomic prognostic factors currently in use or under study. As nonanatomic prognostic factors become widely used, TNM will remain a solid foundation on which to build prognostic classifications. There is, however, a risk that this system will be corrupted by a variety of irrelevant prognostic data. An anatomic extent of disease classification is needed to provide a standard against which to measure the importance of nonanatomic factors. Methods are needed to express overall prognosis without losing the vital anatomic content of TNM. These methods should be able to integrate multiple prognostic factors, including TNM, yet permit TNM to remain intact and distinct.