For a tumor classification scheme to be useful, it must be reproducible and it must show clinical significance. Classification of neuroendocrine lung tumors is a difficult problem with little ...information about interobserver reproducibility. We sought to evaluate the classification of typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell carcinoma (SCC) tumors as proposed by W.D. Travis et al (Am J Surg Pathol 15:529, 1991). Forty neuroendocrine tumors were retrieved from the Armed Forces Institute of Pathology (AFIP) files and independently evaluated by five lung pathologists and classified as TC, AC, LCNEC, or SCC (pure SCC, mixed small cell/large cell, and combined SCC). A single hematoxylin and cosin—stained slide from each case was reviewed. Each participant was provided a set of tables summarizing the criteria for separation of the four major categories. Agreement was regarded as unanimous if all five pathologists agreed, a majority if four agreed, and a consensus if three or more pathologists agreed. The kappa statistic was calculated to measure the degree of agreement between two observers. A consensus diagnosis was achieved in all 40 cases (100%), a majority agreement in 31 of 40 (78%), and unanimous agreement in 22 of 40 (55%) of cases. Unanimous agreement occurred in seven of SCC (70%), seven of TC (58%), four of AC (50%), and four of LCNEC (40%). A majority diagnosis was achieved in 11 of 12 (92%) of TC, 9 of 10 (90%) of SCC, 6 of 8 (75%) of AC, and 5 of 10 (50%) of LCNEC. Most of the kappa values were 0.70 or greater, falling into the substantial agreement category. The most common disagreements fell between LCNEC and SCC, followed by TC and AC, and AC and LCNEC. The highest reproducibility occurred for SCC and TC, with disagreement in 8% and 10% of the diagnoses, respectively. For TC, 10% of the diagnoses rendered were AC. For AC, 15% of the diagnoses were rendered as TC, with 2.5% called LCNEC and 2.5% called SCC. For LCNEC, 18% and 4% of the diagnoses were called SCC and AC, respectively. For SCC, 4% of the diagnoses were called AC and 4% were called LCNEC. Thus, using the classification scheme tested, a consensus diagnosis can be achieved for virtually all neuroendocrine lung tumors with substantial agreement between experienced lung pathologists. Classification of NE tumors is most reproducible for classification of TC and SCC but less reproducible for AC and LCNEC. These results indicate a need for more careful definition and application of criteria for TC versus AC and SCC versus LCNEC.
Pulmonary neuroendocrine tumors (NE) include a spectrum of tumors from typical carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). ...Little is known about prognostic predictors for AC because of its rarity. Survival analysis was performed on 106 ACs with clinical follow-up from the AFIP and the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2 mm
2 of viable tumor or coagulative necrosis. Multiple clinical and histologic features were analyzed by Kaplan-Meier and Cox regression analysis. Of the clinical features, higher stage (
P = .003) and a tumor size of 3.5 cm or greater (
P = .003) were associated with a worse prognosis. Features that were histologically unfavorable by univariate analysis were mitotic rate (
P = .002), pleomorphism (
P = .018), and aerogenous spread (
P = .007). Histologically favorable features by univariate analysis were the presence of palisading (
P = .008), papillary (
P = .039), pseudoglandular (
P = .026), and rosette (
P = .022) patterns. Female gender showed a trend toward a poorer prognosis (
P = .085) and was included in the multivariate model. Multivariate analysis stratified for stage showed mitoses (
P < .001), a tumor size of 3.5 cm or greater (
P = .017), and female gender (
P = .012) to be the only negative independent predictors of prognosis and the presence of rosettes (
P = .016) to be the only independent positive predictor. We further divided the AC into subgroups of low (2 to 5 mitoses/2 mm
2) and high (6 to 10 mitoses/2 mm
2) mitotic rate and compared the survival with TC and with LCNEC. Within the category of AC, the patients with a higher mitotic rate had a significantly worse survival than those with a lower mitotic rate (
P < .001) stratified for stage. Five- and 10-year survival rates for AC (61% and 35%, respectively) stratified for stage were significantly worse than for TC and better than that for LCNEC and SCLC. Chemotherapy or radiation therapy was given in 12 of 52 and 14 of 52 cases, respectively, but the data were insufficient to evaluate tumor response. We conclude that AC is an aggressive neuroendocrine neoplasm with survival intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor size of 3.5 cm or greater, female gender, and presence of rosettes are the only independent predictors of survival. Surgical resection remains the treatment of choice, and the role of chemotherapy and radiation therapy remains to be proven. H
UM P
ATHOL 31:1255-1265. This is a US Government work. There are no restrictions on its use.
Abstract only
Changes in sex hormones with weight loss might have implications for breast cancer prevention and have not been examined extensively, particularly in African‐American (AA) women. We ...conducted a longitudinal study of 278 overweight/obese postmenopausal women (38% AA), not taking hormone therapy, who lost at least 4 kg after a 6‐month weight‐loss program. During the next 12 months, participants attempted to sustain weight loss. We evaluated percent change in serum estrone (E1), total estradiol (E2), testosterone, androstenedione, dehydroepiandrosterone sulfate and sex hormone‐binding globulin (SHBG) across the two phases using GEE. During the weight‐loss program, mean weight loss was 7.7 kg: E1 (−5.7%, P=0.006) and E2 (−9.9%, P< 0.001) decreased, SHBG (16.2%, P< 0.001) increased. During weight maintenance, weight increased on average 2.2 kg: E1 (−6.4%, P=0.003) and SHBG (−8.0%, P<0.0001) decreased. AA women experienced less change in estrogens (E1 0.6% vs. 1.2%, p‐interaction= 0.10, E2 1.1% vs. 1.9%, p‐interaction=0.04) and SHBG (0.9% vs. 1.6%, p‐interaction=0.006) per kg weight change than non‐AA. AA women also had significantly higher estrogen concentrations, independent of adiposity. Overweight/obese postmenopausal women who successfully lose and maintain weight have reductions in estrogens which may reduce breast cancer risk. The racial differences merit investigation.
Abstract 1169
Inherited bone marrow failure syndromes (IBMFS) are characterized by progressive bone marrow failure (BMF) and increased risk of myelodysplastic syndrome (MDS), acute leukemia and solid ...tumors. Previous studies have reported inconsistent data on the levels of serum immunoglobulins, relative number of lymphocyte subpopulations, and inflammatory cytokines in patients with Fanconi anemia (FA). To systematically investigate these parameters we evaluated immune function in 157 well-characterized individuals: 25 FA patients, 29 FA relatives; 33 DC patients, 38 DC relatives; 22 Diamond-Blackfan anemia (DBA) patients, 10 DBA relatives. We examined immunoglobulin levels, lymphocyte subsets, and serum levels of 18 cytokines, including T-helper (Th1)-type (IL-7, IL-17, IL-12p70, IFN-g, TNF-a, G-CSF, GM-CSF), Th2 type (IL-4, IL-6, IL-10), inflammatory cytokines (IL-1a, IL-1b, IL-8, MIP-1a, MCP-1, IP-10, eotaxin, and RANTES), as well as a hematopoietic marker (FLT3-ligand), using Millipore bead assay kits. We compared patients with the three syndromes with each other and with their respective unaffected relatives. Statistical analyses were performed using Excel, STATA or SAS software; p value ≤ 0.05 was significant. One or more serum immunoglobulins were decreased below the normal range in 5/22 (23%) FA, 4/32 (13%) DC, and in 1/22 (5%) DBA patients vs. none of the relatives. In addition, one or more lymphocyte subsets were abnormally low in 9/10 (90%) FA, 7/26 (27%) DC, and 0/9 DBA patients vs. none of the relatives. In FA, low levels of lymphocytes included CD4 in 4 patients, CD19 in 5, and NK-cells in 5; in DC, the low levels of CD4 in 3 patients, CD8 in 3, CD19 in 4, and NK-cells in 4. In all, 10/22 (45%) FA, 10/32 DC (31%) and 1/22 DBA (5%) patients had low immunoglobulins and/or lymphocyte subsets; FA and DC were similar. Among FA patients, 6/10 with decreased immune parameters had solid tumors vs. 1/12 with no immune abnormalities (p=0.02). In DC, 9/10 patients with immune abnormalities had a severe hematological and/or clinical phenotype vs. 6/22 with normal immune studies (p=0.002).
To go beyond clinical immune parameters, we examined the large number of candidate inflammatory and hematopoietic cytokines listed above. Levels of IL-4, IL-7, IL-10 and IL-12p70 were undetectable in most samples and not analyzed further. IFN-g was decreased in all patient groups compared with their relatives, and RANTES was significantly reduced in DC compared with relatives and with FA or DBA patients. Compared with their relatives, FLT-3 was increased in all patient groups, IP-10 was increased in FA and DC, and eotaxin was decreased in DC patients. MIP-1α was higher in FA than in DBA patients. TNF-a, FLT3-ligand, IL-8 and G-CSF were highest in FA patients followed by DC and DBA patients High FLT3-ligand values significantly correlated with multilineage cytopenias in FA and DC, and in those patients with DBA who had anemia and neutropenia. The following cytokines were similar in FA, DC and DBA patients and their relatives: IL-1a, IL-1b, IL-6, GM-CSF, MCP-1, IL-17 and eotaxin. Unadjusted values for all parameters were similar to those following adjustment for age, gender and sample handling methods. In conclusion, we identified significant immunoglobulin and lymphocyte abnormalities in FA and DC, but not in DBA patients, and these correlated with the presence of malignancies or severe aplastic anemia. Except for RANTES, the inflammatory cytokine profile was also similar in patients with FA and DC. This is intriguing, since FA and DC have similar cumulative incidences of BMF and similar types of cancers by age 50. In contrast, several cytokine levels were higher in FA and DC than in DBA, a syndrome with only anemia and a lower incidence of cancer. These abnormalities in immunoglobulins, lymphocyte subsets, and cytokine levels may have prognostic value with regard to disease progression, marrow failure and carcinogenesis.
No relevant conflicts of interest to declare.
Background Congenital Cytomegalovirus (CMV) is a very common intrauterine infection which can cause severe mental and hearing impairments. Notably, only 40% of primarily infected women transmit CMV ...to the fetus. CMV-specific T-cell response has a role in CMV disease but individual immune heterogeneity precludes reliable correlation between measurable T-cells response and intrauterine transmission. Study Aim To establish a correlation between maternal T-cells response and fetal CMV transmission using an individual normalized immune response. Methods We analyzed IFN-gamma secretion upon whole blood stimulation from primary CMV-infected pregnant women, with either CMV-peptides or PHA-mitogen. Results We established a new normalization method of individual IFN-gamma response to CMV by defining the ratio between specific-CMV response and non-specific mitogen response (defined as IFN-gamma relative response, RR), aiming to overcome high person-to-person immune variability. We found a unique subpopulation of women with low IFN-gamma RR strongly correlated with absence of transmission. IFN-gamma RR lower than 1.8% (threshold determined by ROC analysis) reduces the pre-test probability of transmission from 40% to 8%, revealing an unexpected link between low IFN-gamma RR and non-transmission. Conclusion In pregnant women with primary CMV infection, low IFN-gamma RR is associated with low risk of transmission.
We previously reported from a case-control analysis that T-cell non-Hodgkin's lymphoma (NHL) was strongly associated with human T-lymphotropic virus type I (HTLV-I) infection in Jamaica and Trinidad ...and that the relative risk for HTLV-I infection was very high in younger patients.
The objective of this study was to estimate the age-specific incidence rates of NHL among HTLV-I-infected and HTLV-I-uninfected adults in Jamaica and Trinidad.
Population rates of HTLV-I infection were calculated from available census reports and serosurvey data. Incidence rates for NHL were calculated from all incident cases in Jamaica during 1984-1987 (n = 135) and from all incident cases in Trinidad during 1986-1990 (n = 117). Using biopsy material, we determined whether the immunophenotype of the tumor cells was T cell, B cell, or other. NHL incidence rates were computed according to HTLV-I status, age, sex, and tumor phenotype for each country separately and for both countries combined by weighting to the relative population size of each country.
The age-standardized NHL incidence rate (mean +/- SE) in Jamaica was 1.9 +/- 0.2 per 100,000 person-years (PY). In Trinidad, the rate was 2.9 +/- 0.4 per 100,000 PY. Overall, the incidence of NHL increased with age and was higher in males than in females. In the HTLV-I-infected population, the incidence of NHL was inversely related to age, and age-specific rates were higher in males than in females. The NHL incidence in those estimated to have acquired HTLV-I infection in childhood, however, showed no sex difference, and one in 1300 such carriers (95% confidence interval: one in 1100 to one in 1600) per annum were estimated to be at such risk. For T-cell NHL, as proxy for adult T-cell lymphoma/leukemia, incidence was highest in those patients infected with HTLV-I early in life (perinatally or via breast milk), with high, sustained risk from early adulthood in both sexes.
While overall NHL incidence rates reveal that HTLV-I endemicity does not impose an exaggerated lymphoma burden on these populations, the risk for lymphoma among carriers who acquire infection early in life is dramatic and is consistent with the hypothesis that virus exposure early in life is most important for lymphoma-genesis.
Studies of HTLV-I carriers known to be infected in childhood may provide insight into markers intermediate in the lympho-magnetic process. Strategies to disrupt early-life transmission of HTLV-I, notably mother-infant transmission, may be critical in reducing the burden of lymphoreticular disease in these populations.
Data were analyzed from a case-control interview study of malignant mesothelioma in Louisiana, which gathered information on usual diet and on lifetime occupational exposure to asbestos. Thirty-seven ...patients with malignant mesothelioma of the pleura (n = 32) or peritoneum (n = 5) were matched to controls according to age, sex, race, and factors related to case ascertainment (hospital and date of diagnosis, or parish and date of death). Twenty-one of the 37 cases were judged by masked occupational review to have been exposed to asbestos (57%), compared to seven of 37 controls (19%). Seven additional cases and 10 additional controls had occupational histories suggestive of asbestos exposure. With regard to usual diet before illness, cases reported less frequent consumption of homegrown produce (p = 0.005), cruciferous vegetables (p = 0.005), and all vegetables combined (p = 0.09) than did the controls. An estimate of usual carotene intake was also significantly lower in cases (p = 0.03). Dose-dependent reductions in risk were seen with increasing consumption of vegetables, especially cruciferous vegetables (p for trend = 0.013). These associations were not explained by differences in asbestos exposure as measured by the occupational review. The results indicate that consumption of vegetables or some vegetable-related constituent may have a protective effect on developing mesothelioma.
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