Pathologic assessment in diagnosis, management, prognosis of lung cancer
Ki–67 and coagulative tumor necrosis as predictors of outcome for patients with clear cell renal cell carcinoma
Relationship between symptoms of prostatitis and histological inflammation
Utility of Van Nuys Prognostic Index for managing ductal carcinoma in situ
Differential expression of TRAF1 aids in the distinction of cutaneous CD30-positive lymphoproliferations
Characterization of muscle layers and lamina propria of urinary bladder by systematic histologic mapping
Senescence and apoptosis in carcinogenesis of cervical squamous cell carcinoma
The American College of Chest Physicians conducted a study to provide evidence-based background and recommendations for developing guidelines for the diagnosis and management of lung cancer. A systematic search of medical and scientific literature from 1990 to 2006 was performed using Medline, Midconsult, UpToDate, Cochrane Library, NCCN guidelines, and NCI/NIH search engines to identify evidence-based and consensus guidelines. The search was limited to literature on humans and articles in the English language. The pathologic assessment of lung cancer is based on 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 grossly and microscopically because these lesions may be multifocal and represent multi-step carcinogenesis and may be amenable to therapy. Cytologic assessment of people with no symptoms is of little clinical benefit in screening for 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 part of protocol studies. Enhanced pathologic and molecular techniques may identify 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. The authors concluded that 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 modalities for evaluating lung cancers.
Schwartz AM, Henson DE. Diagnostic surgical pathology in lung cancer: evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132:78S–93S.
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Ki-67 is a cell proliferation protein associated with aggressive clear cell renal cell carcinoma. A recent report suggests that Ki-67 may represent a surrogate marker for coagulative tumor necrosis. Consequently, the authors conducted a study to determine whether Ki-67 and necrosis convey similar or distinct information for the prognostic assessment of clear cell renal cell carcinoma (ccRCC). They evaluated tumor specimens from 741 patients treated consecutively who underwent surgery for ccRCC between 1990 and 1999. The authors assessed tumor specimens for various clinicopathologic features, including levels of tumor cell Ki-67 expression. Associations of these features with death from renal cell carcinoma were evaluated using Cox proportional hazards regression models. The authors found at last followup that 396 patients had died, including 238 who died from ccRCC at a median of 2.1 years after surgery. Although tumor cell Ki-67 expression and coagulative tumor necrosis were highly correlated, the prognostic information conveyed by these two markers failed to overlap. For the subset of patients with necrotic tumors, high levels of Ki-67 more than doubled the risk of death from renal cell carcinoma (risk ratio, 2.18; 95% confidence interval [CI], 1.52–3.11; P<0.001). For patients with tumors lacking necrosis, high levels of Ki-67 expression were similarly correlated with an increased risk of death from renal cell carcinoma (risk ratio, 2.50; 95% CI, 1.66–3.77; P<0.001). The authors concluded that the prognostic information conveyed by Ki-67 and coagulative tumor necrosis is not interchangeable. Therefore, Ki-67 and coagulative tumor necrosis should not be treated as surrogates for one another, and both features should be evaluated when generating outcome predictions for patients with ccRCC.
Tollefson MK, Thompson RH, Sheinin Y, et al. Ki-67 and coagulative tumor necrosis are independent predictors of poor outcome for patients with clear cell renal cell carcinoma and not surrogates for each other. Cancer. 2007;110:783–790.
Reprints: Dr. Eugene D. Kwon, Departments of Urology and Immunology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email@example.com
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Symptoms of abacterial chronic prostatitis/chronic pelvic pain syndrome are associated with prostate inflammation. The ongoing Reduction by Dutasteride of Prostate Cancer Events trial is a four-year, phase III, placebo-controlled study to determine whether 0.5 mg of dutasteride daily decreases the risk of biopsy-detectable prostate cancer. All male study participants underwent biopsy before entering the study, which allowed for review of the relationship between histological prostate inflammation and prostatitis symptoms. Eligible men were 50 to 75 years old and had a serum prostate-specific antigen level of 2.5 ng/mL or greater and 10 ng/mL or less (ages 50 to 60 years), or 3.0 ng/mL or greater and 10 ng/mL or less (older than 60 years), and an International Prostate Symptom Score of less than 25, or less than 20 if already on α-blocker therapy. Acute prostatitis was an exclusion criterion. The National Institutes of Health Chronic Prostatitis Symptom Index was used to assess prostatitis-like symptoms. Spearman rank correlations were used to assess the relationship between acute and chronic inflammation and Chronic Prostatitis Symptom Index scores for pain, urinary symptoms, and quality of life domains, as well as average pain, total score, and prostatitis-like symptoms. Data were available on 5,597 patients. The distribution of inflammation status was similar for those with and without chronic prostatitis-like symptoms. Significant correlations were found between average chronic inflammation and total Chronic Prostatitis Symptom Index score and subscores for urinary symptoms and quality of life, but the magnitude of these correlations was small. The authors concluded that there was a lack of clinically meaningful association between prostatitis-like pain symptoms and histological inflammation in the Reduction by Dutasteride of Prostate Cancer Events population. Consequently, the viewpoint that symptoms of chronic prostatitis/chronic pelvic pain syndrome and prostate inflammation are associated needs further scrutiny.
Nickel JC, Roehrborn CG, O’Leary MP, et al. Examination of the relationship between symptoms of prostatitis and histological inflammation: baseline data from the REDUCE chemoprevention trial. J Urology. 2007;178(3):896–901.
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The Van Nuys Prognostic Index purports to predict the risk of ipsilateral breast tumor recurrence after excision of ductal carcinoma in situ. It is a simple scoring scheme based on a retrospective evaluation of data from a single group of investigators. Various versions of the Van Nuys Prognostic Index (VNPI), using such clinical and pathologic features as tumor size, tumor grade, margin width, and patient age, have been proposed. Despite common use of the VNPI for clinically managing patients with ductal carcinoma in situ (DCIS), independent validation is lacking. The authors conducted a study in which they retrospectively analyzed 222 patients with mammographically detected DCIS who were treated with surgical excision alone. Wire-localized excisional biopsy was performed and surgical specimens measured and inked to help assess the margin. Multiple sections of each specimen were evaluated for histopathologic subtype, histologic and nuclear grade, presence of necrosis, maximum dimension of the lesion, and margin width. Each patient was prospectively evaluated by a multidisciplinary management team and presented with adjuvant treatment options, including whole breast radiotherapy or tamoxifen, or both. All patients in this cohort declined radiotherapy. Thirty-one percent of patients received tamoxifen. Patients were followed clinically every three to six months and mammographically every six to 12 months. Ipsilateral breast tumor recurrence (IBTR) was confirmed by biopsy. Wilcoxon regression analysis was used to evaluate risk groups according to three proposed VNPI classification schemes: VNPI group one (margin, grade, and size), VNPI group two (margin, grade, size, and patient age), and VNPI group three (margin only). With a median followup of 4.6 years, the crude rate of IBTR was 8.6 percent for the entire cohort. Of the patients who developed IBTR, 73.7 percent had a lesion with a maximum dimension of up to 15 mm, 47.4 percent had a margin of 10 mm or more, and 36.8 percent had grade one histology. At five years, IBTR was statistically indistinguishable for the three VNPI models. The five-year freedom from IBTR for low-risk, intermediate-risk, and high-risk groups according to VNPI group one was 96 percent, 84 percent, and 100 percent, respectively (P=0.20). Similarly, the five-year freedom from IBTR for low-risk, intermediate-risk, and high-risk groups according to VNPI group two was 95 percent, 83 percent, and 100 percent, respectively (P=0.19). Taking into account margin status only (VNPI group three), the five-year freedom from IBTR for low-risk, intermediate-risk, and high-risk groups was 92 percent, 91 percent, and 91 percent, respectively (P=0.98). Tamoxifen use did not appear to affect the five-year rate of IBTR (95% versus 94%; P=1.0). The results of this study suggest that VNPI and margin width alone are not valid tools for helping to stratify patients after excision alone for their risk of IBTR at five years. Further followup may strengthen the predictive utility of the various VNPI classification schemes.
MacAusland SG, Hepel JT, Chong FK, et al. An attempt to independently verify the utility of the Van Nuys Prognostic Index for ductal carcinoma in situ. Cancer. 2007;110:2648–2653.
Reprints: Dr. David E. Wazer, Dept. of Radiation Oncology, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111; firstname.lastname@example.org
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Lymphomatoid papulosis (LyP), primary cutaneous anaplastic large T-cell lymphoma (cALCL), and cutaneous infiltrates of systemic anaplastic large cell lymphoma (sALCL) are CD30-positive lymphoproliferative disorders of the skin that overlap clinically, histopathologically, immunophenotypically, and genetically but differ considerably in their prognosis. In particular, lesions of LyP regress spontaneously, whereas those of cALCL and sALCL persist and may progress and spread to extracutaneous sites. In contrast to patients with cALCL, LyP patients do not benefit from an aggressive radiotherapeutic or chemotherapeutic approach, or both. The authors generated a novel tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) antibody that recognizes a formalin-resistant epitope (Ber-TRAF1A). They also investigated the expression of TRAF1, an intracellular component of TNFR signaling, in LyP and ALCL. They showed strong TRAF1 expression in the tumor cells of most LyP cases (42 of 49, 84%). In contrast, tumor cells of primary and secondary cALCL revealed TRAF1 expression in only a few cases (3 of 41, 7%), as shown for sALCL without skin manifestation. The authors concluded that TRAF1 expression distinguishes LyP from primary or secondary cALCL. This may be of crucial diagnostic importance and have a strong impact on treatment decisions for patients with cALCL and LyP.
Assaf C, Hirsch B, Wagner F, et al. Differential expression of TRAF1 aids in the distinction of cutaneous CD30-positive lymphoproliferations. J Invest Dermatol. 2007;127:1898–1904
Correspondence: Dr. Horst Dürkop, Institute of Pathology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Hindenburgdamm 30, D 12200 Berlin, Germany; email@example.com
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The muscularis mucosae and muscularis propria are important landmarks for pathologic tumor staging of urinary bladder cancer. The authors have occasionally noted, in their routine practice, patterns of muscularis mucosae that do not always conform to the originally described configuration of thin slender bundles arranged in a single layer of interrupted, dispersed, or continuous muscle. The authors evaluated the characteristics of lamina propria, muscularis mucosae, and muscularis propria in 35 urinary bladder resection specimens with systematic sampling from the dome, trigone, anterior, posterior, right, and left lateral walls. Among the subsites, the trigone had a relatively flatter surface and attenuated lamina propria depth (0.46 to 1.58 mm)—about half of the thickest region was the dome (0.98 to 3.07 mm). The muscularis mucosae was typically in individual or small groups of slender and wavy fascicles or wispy fibers. Muscularis mucosae also had a focal to rarely extensive hyperplastic appearance (53%, most common in dome) with two recognizable patterns. The first was aggregates of hyperplastic muscularis mucosae with haphazard outlines (33%) distinct from that of muscularis propria. The second was hyperplastic compact muscularis mucosae with parallel muscle fibers and a regular outline arranged singly or in small groups (45%) that occasionally strongly resembled muscularis propria muscle but was distinguishable from it based on location in the lamina propria. By distribution, these muscle bundles were more typically dispersed or formed a discernable layer (41%) as a discontinuous or infrequently near-continuous layer. The lamina propria vascular plexus was present in every section, most often in association with the muscularis propria muscle; however, variations in distribution were observed. The muscularis propria most commonly had a relatively regular interface with the lamina propria. A distinctive pattern was noted in the trigone, where occasionally there was gradual diminution of size of the muscularis propria muscle bundles as they extended to almost a suburothelial location. In 22 percent, isolated or small groups of compact regular hyperplastic muscularis mucosae muscle bundles were noted in deep lamina propria situated between the more typical slender muscularis mucosae layer and the muscularis propria. The authors concluded that there are additional patterns of muscularis mucosae other than previously described. Awareness of the occasionally hyperplastic appearance of muscularis mucosae muscle is important to prevent overstaging of invasive urothelial carcinoma. In transurethral resection specimens, lack of orientation may preclude distinguishing hyperplastic muscularis mucosae from true muscularis propria in these rare situations. Isolated muscle bundles immediately adjacent to the urothelium would favor the hyperplastic pattern of muscularis mucosae over muscularis propria muscle. Topographical variations exist among the subsites. The more superficial location of the muscularis propria and the rarity of muscularis mucosae in the trigone, relative abundance of hyperplastic muscularis mucosae in the dome, and presence of the more superficial ureteral muscularis propria at its insertion in the bladder complicate the traditional pathologic tumor stage evaluation of invasion in these regions. The inconsistency of a distinct muscularis mucosae layer and variations in the lamina propria vascular plexus indicate that substaging of pT1 would be problematic. This further supports the 1998 World Health Organization/International Society of Urological Pathology and 2004 World Health Organization recommendations against implementing such staging at this time.
Paner GP, Ro JY, Wojcik EM, et al. Further characterization of the muscle layers and lamina propria of the urinary bladder by systematic histologic mapping: implications for pathologic staging of invasive urothelial carcinoma. Am J Surg Pathol. 2007;31:1420–1429.
Reprints: Dr. Mahul B. Amin, Dept. of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite 8728, Los Angeles, CA 90048; firstname.lastname@example.org
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Senescence and apoptosis protect against cancer. Many cell cycle regulators, including p14ARF, p15INK4b, and p16INK4a, are important in G1 cell cycle arrest and oncogene-induced senescence. The bcl-2 protein is a key component in controlling apoptosis, and the p53 protein plays key roles in both mechanisms. The genes of these key regulator proteins are often mutated or deleted in various malignancies. It is unknown how senescence and apoptosis are regulated in one of the most common tumors of the female genital tract, cervical squamous cell carcinoma (SCC). The authors conducted a study in which they characterized the expression of senescence, apoptosis, and proliferation markers in normal cervical epithelium, cervical intraepithelial neoplasia (CIN), and SCC via immunohistochemical staining for p14ARF, p15INK4b, p16INK4a, bcl-2, p53, and Ki-67 in tissue microarray blocks. The blocks contained 20 samples each of normal cervix, moderate-to-severe cervical dysplasia (CIN II-III), and invasive SCC. Samples were derived from 60 cases of cervical biopsies and cervical conizations. Results showed that the proliferation marker Ki-67 is markedly increased and the senescence markers p15INK4b, p16INK4a, and p14ARF are overexpressed in dysplasia and carcinoma. P53 immunostain is negative in all normal cervical tissue and positive in dysplasia and carcinoma. Although the expression of bcl-2 is increased in dysplasia, the marker is negative in about half of SCC cases. These results suggest that some senescence pathways are activated and are still maintained in cervical dysplasia and carcinoma. However, proliferation is increased and carcinogenesis is not thwarted, leading to the eventual development of cervical cancer. Other mechanisms, such as those that account for the apparent overexpression of p53 and paradoxical loss of bcl-2 expression in some SCC cases, as well as additional senescence and apoptotic pathways, may play key roles in the carcinogenesis of cervical SCC.
Feng W, Xiao J, Zhang Z, et al. Senescence and apoptosis in carcinogenesis of cervical squamous carcinoma. Mod Pathol. 2007;20:961–966.
Reprints: Dr. W. Feng, Dept. of Pathology and Laboratory Medicine, Houston Medical School, University of Texas, 6431 Fannin St., MSB 2.262, Houston, TX 77030; email@example.com
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Dr. Cibull is professor of pathology and laboratory medicine and direct of surgical pathology, University of Kentucky Medical Center, Lexington. Dr. Kesler is hematopathology fellow, University of Texas Southwestern Medical Center at Dallas.