Clonality of combined tumors: a molecular genetic study.Understanding the mechanisms of molecular pathogenesis for different types of tumors is very important for designing treatment and prevention strategies. As a result, many studies have focused on correlating phenotypes with genotypes. Various oncogenes and tumor suppressors have been studied in different cancers, and some specific relationships have been revealed. For example, an RB mutation has been found to be responsible for retinoblastoma Retinoblastoma Definition Retinoblastoma is a malignant tumor of the retina that occurs predominantly in young children. Description The eye has three layers, the sclera, the choroid, and the retina. , and a hereditary form of breast cancer results from BRCA BRCA One of two genes (designated BRCA1 and BRCA2) that help repair damage to DNA, but when inherited in a defective state increase the risk of breast and ovarian cancer. 1 mutation. It is now widely accepted that phenotypic manifestations of cancer are determined by alterations at the molecular level. A phenomenon often observed by pathologists is that a single tumor may contain areas of different morphologies, and these tumors are therefore termed combined tumors. An interesting question to ask is whether the different components are genetically related; the answer to this question may shed light on the mechanism of histogenesis histogenesis /his·to·gen·e·sis/ (-jen´e-sis) the formation or development of tissues from the undifferentiated cells of the germ layers of the embryo.histogenet´ic his·to·gen·e·sis n. and biologic behavior of the tumor cells. In the past, studies on combined tumors have addressed the issue of cell of origin by clonality analysis. (1-7) X-chromosome inactivation inactivation /in·ac·ti·va·tion/ (in-ak?ti-va´shun) the destruction of biological activity, as of a virus, by the action of heat or other agent. has been the most popular technique for such analyses. (1,3,7-11) With this method, many of these tumors, such as uterine and mammary mammary /mam·ma·ry/ (mam´ah-re) pertaining to the mammary gland, or breast. mam·ma·ry adj. Of or relating to a breast or mamma. mammary pertaining to the mammary gland. carcinosarcomas, have been found to be monoclonal, (6,7) which indicates a common cell of origin for the carcinomatous and sarcomatous areas. A limitation of this technique is that only tumors from female patients can be studied, and some patients are homozygous ho·mo·zy·gous adj. Having the same alleles at one or more gene loci on homologous chromosome segments. Homozygous Identical genes controlling a specified inherited trait. for the particular locus being amplified. In recent years, many researchers have used microdissection to obtain nearly pure populations of cells from archival, formalin-fixed, paraffin-embedded tissue. (12) Well-preserved DNA DNA: see nucleic acid. DNA or deoxyribonucleic acid One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. can be extracted from these cells and used for genetic studies. Loss of heterozygosity Loss of heterozygosity (LOH) in a cell represents the loss of one parent's contribution to part of the cell's genome. LOH can arise via several pathways, including deletion, gene conversion, mitotic recombination and chromosome loss. (LOH LOH Loss of Heterozygosity LOH Ladies Of Harley LOH Line Overhead LOH Light Observation Helicopter LOH Legion of Honor LOH Lay on Hands (Paladin ability; Everquest game) LoH Loop of Henle (kidney nephron) ) analysis involves amplification of selected genes or chromosomal loci by polymerase chain reaction (PCR PCR polymerase chain reaction. PCR abbr. polymerase chain reaction Polymerase chain reaction (PCR) ) using specific primers. This method has been used in many studies, and it has been shown that LOH of certain known tumor suppressor genes (such as RB and p53) is frequently associated with many tumors. (13-18) In addition, certain chromosomal regions, such as chromosomes 3p and 9p, often show LOH in neoplasms and are therefore considered to harbor unknown tumor suppressor genes. (12,19,20) To further understand the histogenesis of cells with different morphologies in combined tumors, we used microdissection/ LOH to study genetic alterations in these tumors. We studied multiple loci corresponding to known or suspected tumor suppressors and compared the genetic profiles in different cells to determine whether cells with different phenotypes have similar or different genotypes. METHODS Selection of Cases Six cases of combined tumors that contained enough microdissectable tumor cells in each of the morphologic areas were chosen for the study. Recuts recuts Surgical pathology Glass slides–GSs from paraffin-embedded tissue, obtained in addition to the original GSs, to either confirm the presence of a lesion identified on the first GSs or obtained for a second opinion, requested by the Pt or referring were made from the archival paraffin blocks and stained with hematoxylin-eosin, but they were not cover-slipped. They were used subsequently for microdissection. The clinical and pathologic data are summarized in Table 1. Immunohistochemical Analysis Mouse monoclonal antibody for p53 and mouse monoclonal antibody cocktail for cytokeratin (AE1/AE3) were purchased from BioGenex (San Ramon, Calif). Mouse monoclonal antibody for Rb was purchased from Oncogene Research Products (San Diego, Calif). All antibodies have been well characterized in our laboratory with standardized titrations and protocols. Biotinylated horse antimouse immunoglobulin G was used as the secondary antibody. Immunoreactivity was detected visually with use of the avidin-biotin complex--containing conjugated peroxidase enzyme. Microdissection and DNA Extraction Microdissection and DNA extraction were performed as previously described from non-cover-slipped, hematoxylin-eosin--stained slides. (12) Microdissection was performed under direct observation with an inverted microscope, using a microcapillary pipette that had been pulled to a fine tip by a micropipette mi·cro·pi·pette n. 1. A very small pipette used in microinjection. 2. A pipette used to measure very small volumes of liquids. micropipette a pipette for handling small quantities of liquids (up to 1 ml). puller. The tip was made slightly jagged to facilitate the scraping and adherence of dissected material. The tip was introduced into the field of view at an angle of approximately 30 [degrees] to 45 [degrees], and all the movements in the x, y, and z directions were controlled by a joystick-operated hydraulic manipulator (Nikon-Narishige, New York, NY). For each case studied, cells were dissected from each morphologic type and from normal stromal Stromal A type of tissue that is associated with the support of an organ. Mentioned in: Wilms' Tumor cells or lymphocytes. The scraped cells were allowed to adhere to the pipette tip and collected in a siliconized 0.5-mL microcentrifuge tube by breaking off the glass tip, and an estimate of the number of microdissected cells was recorded. The cells were pelleted by centrifugation at high speed (14 000 rpm) for l0 minutes. The DNA was extracted by digesting the cells in buffer consisting of tromethamine (pH 8.3), 50mM; EDTA EDTA: see chelating agents. , 1mM; 0.5% Tween 20; and proteinase K, 200 mg/mL, at 37 [degrees] C for 24 to 36 hours, followed by l0 minutes of incubation at 100 [degrees] C to destroy any remaining proteinase K activity. The insoluble material was pelleted by centrifugation, and aliquots of supernatant were used directly in the PCR reactions. DNA from at least 50 sectioned cells was used for each PCR reaction. Polymorphic DNA Markers and PCR Amplification To evaluate LOH and microsatellite See miniaturized satellite. alterations, we used primers flanking dinucleotide dinucleotide /di·nu·cleo·tide/ (di-nldbomack´le-o-tid?) one of the cleavage products into which a polynucleotide may be split, itself composed of two mononucleotides. di·nu·cle·o·tide n. and multinucleotide microsatellites repeat polymorphism located at the following genes or chromosomal locations: 3p12, 3p14.2 (FHIT FHIT Fragile Histidine Triad (gene) FHIT Farndon House Information Trust FHIT Fort Hare Institute of Technology (Alice, South Africa) FHIT Foundation for the Harmonization of Information Technology gene locus), 3p14.3-21, 3p21, 3p22-24.2, 9p21-22, 13q14 (RB gene) and 17p13.1 (p53 gene), and 18q (DCC (1) (Direct Cable Connection) A Windows 95/98 feature that allows PCs to be cabled together for data transfer. DCC actually sets up a network connection between the two machines. gene) and 5p (APC-MCC gene). Nested PCR methods were used to amplify dinucleotide and multinucleotide repeats from microdissected cells as described previously. (20) Water controls were included in all the experiments to rule out the possibility of false-positive bands. The first PCR was performed in 50 [micro]L reaction volume containing 20mM Tris (pH 8.3), 50mM potassium chloride, 1.5mM magnesium chloride, 200 [micro]M each of deoxynucleoside triphosphates (deoxyadenosine triphosphate, deoxycytidine triphosphate, deoxyguanosine triphosphate, and deoxythymidine triphosphate triphosphate /tri·phos·phate/ (tri-fos´fat) a salt containing three phosphate radicals. tri·phos·phate n. A salt or ester containing three phosphate groups. ), 0.5[micro]M each of primers, 0.25 units of AmpliTaq polymerase (GIBCO-BRL, Life Technologies, Gaithersburg, Md), and 5 [micro]L of the digested sample, which contained extracted DNA from at least 50 cells. The condition for the first PCR was 94 [degrees] C for 20 seconds, 55 [degrees] C for 20 seconds, and 72 [degrees] C for 20 seconds for 35 cycles. The first PCR product was then diluted 1:50 to 1:100 in distilled water. The second PCR reaction was performed in 10 [micro]L reaction mixture containing 50mM potassium chloride, 20mM Tris (pH 8.3), 1.5mM magnesium chloride, 100 [micro]M each of deoxynucleoside triphosphates (deoxyadenosine triphosphate, deoxycytidine triphosphate, deoxyguanosine triphosphate, and deoxythymidine triphosphate), 0.5 [micro]M each of primers, 0.25 units of AmpliTaq polymerase (GIBCO-BRL), 0.5 [micro]L of ([alpha]-[sup.32]P) deoxycytidine triphosphate (3000 Ci/mmol, 10 mCi/mL; Amersham Corp, Uppsala, Sweden), and 1 [micro]L of diluted first PCR product. The PCR condition was similar to that of the first PCR, except that 30 cycles of amplification were used. The amplified and labeled fragments were subjected to electrophoresis for 2 to 3 hours at 60 W in a 6% polyacrylamide gel containing 7M urea. The gel was dried on a filter paper and exposed to radiographic radiographic (rā´dēōgraf´ik), adj relating to the process of radiography, the finished product, or its use. film at room temperature for 12 to 24 hours. Loss of heterozygosity was scored by visual comparison of the intensity of alleles on autoradiograms. Microsatellite alterations (ie, changes in band size in tumor cells, reflecting changes in the number of repeats at 1 or both alleles) were noted by comparing the band positions in tumor cells and normal stromal cells. Constitutional heterozygosity heterozygosity /het·ero·zy·gos·i·ty/ (het?er-o-zi-gos´i-te) the state of possessing different alleles at a given locus in regard to a given character.heterozy´gous het·er·o·zy·gos·i·ty n. was determined by examination of normal stromal cells or lymphocytes. Because extra shadow bands above and below each intense principal allelic band are often seen in microsatellite studies, the most intense band(s) were considered the true allele(s). Detection of K-ras Mutations Using a PCR-Based Designed Restriction Fragment Length Polymorphism restriction fragment length polymorphism n. Abbr. RFLP Intraspecies variations in the length of DNA fragments generated by the action of restriction enzymes and caused by mutations that alter the sites at which these enzymes act, changing Method For detection of K-ras mutations, we used a modification of the designed restriction fragment length polymorphism method, using a nested PCR reaction, as previously described. (21) RESULTS Formalin-fixed, paraffin-embedded archival tissue from 6 cases of combined tumors was selected. The clinical and pathologic data are summarized in Table 1. Case 1 was a gastroesophageal junction combined tumor with an area of squamous carcinoma proximally and an area of adenocarcinoma distally (Figure 1). The metastatic tumor to the lymph node, however, was composed exclusively of adenocarcinoma. Immunohistochemical study of tumor suppressor genes RB and p53 showed that the 2 areas were both positive for Rb and negative for p53 (Table 2). Tumor cells from the 2 areas were microdissected, and an LOH assay was performed using normal stromal cells as control. In each case studied, multiple loci were informative. [FIGURE 1 OMITTED] Loss of heterozygosity assay revealed markedly different patterns of genetic alterations between the 2 areas (Table 3). Among the 13 informative loci, 7 were different between the 2 areas. Generally, areas of adenocarcinoma had more extensive genetic alterations, including LOH of Rb and p53, which was not present in squamous carcinoma. Case 2 was a combined tumor of the colon containing a neuroendocrine neuroendocrine /neu·ro·en·do·crine/ (-en´do-krin) pertaining to neural and endocrine influence, and particularly to the interaction between the nervous and endocrine systems. neu·ro·en·do·crine adj. carcinoma and a tubulovillous adenoma adenoma: see neoplasm. (Figure 2). Loss of heterozygosity assay showed that the 2 areas harbored identical genetic alterations in multiple informative loci (Table 3, Figure 3). In addition, mutational analysis of the K-ras gene showed that codon codon: see nucleic acid. 12 was mutated in cells from both areas (Figure 3). [FIGURES 2-3 OMITTED] Cases 3 and 4 were 2 combined tumors of the lung, each containing an area of squamous cell carcinoma squamous cell carcinoma n. A carcinoma that arises from squamous epithelium and is the most common form of skin cancer. Also called cancroid, epidermoid carcinoma. and an area of small cell carcinoma small cell carcinoma n. See oat cell carcinoma. small cell carcinoma Small cell undifferentiated carcinoma, undifferentiated carcinoma A highly aggressive malignancy, usually of lung, which arises in proximal bronchi . In both cases, cells from the squamous carcinoma and small cell carcinoma harbored identical patterns of LOH in multiple loci tested (Table 3). Cases 5 and 6 were both combined tumors of gallbladder with areas of squamous carcinoma and adenocarcinoma (Table 1). Loss of heterozygosity assay of multiple tumor suppressor genes and chromosomal loci showed identical patterns of genetic alteration in different histologic areas in both cases (Table 3). COMMENT We carefully analyzed the genetic changes in combined tumors containing different epithelial components and showed that in most of these tumors, the different histologic areas had identical genetic alterations in the chromosomal regions analyzed. These data are consistent with clonality assays in carcinosarcomas and other types of combined tumors studied. (1-7) Because multiple loci were tested, we feel it is reasonable to conclude that most of these tumors, although containing areas of different morphologies, are composed of genetically homogeneous populations of tumor cells. Therefore, these tumors are likely derived from a common precursor cell and are probably driven by the same carcinogens. Interestingly, cases 2, 3, and 4 were each composed of an area of small cell/neuroendocrine carcinoma and an area of either squamous carcinoma or tubulovillous adenoma. These tumors are known to possess very different histologic, ultrastructural, histochemical, and immunohistochemical features. We have provided evidence that these tumors, as different as they may appear morphologically and phenotypically, can have similar genetic profiles and may arise from a single cell under certain circumstances. This view is consistent with the recent observation that neuroendocrine neoplasms are often present in close proximity to dysplastic epithelium in inflammatory bowel disease inflammatory bowel disease n. Abbr. IBD Any of several incurable and debilitating diseases of the gastrointestinal tract characterized by inflammation and obstruction of parts of the intestine. , suggesting a common cell of origin. (22) It is worth noting that in case 2, in addition to LOH of the same chromosomal loci in both neuroendocrine carcinoma and tubulovillous adenoma, both areas also contain a K-ras mutation. Although the assay was not meant to be quantitative, the band representing mutant ras was much stronger in neuroendocrine carcinoma than in tubulovillous adenoma. Therefore, it is possible that different copy numbers of the mutant gene may be present in the 2 areas. It remains to be explained why cells containing similar genetic profiles display different morphologies with correspondingly different histochemical and immunohistochemical features. One possibility is that during malignant transformation, some of the progeny cells derived from a common precursor cell may convert to a different morphology under the influence of different host or environmental factors. Therefore, it cannot be entirely ruled out that additional undiscovered genetic alterations may have occurred, resulting in a different morphology. Alternatively, the clonal neoplastic neoplastic /neo·plas·tic/ (ne?o-plas´tik) 1. pertaining to a neoplasm. 2. pertaining to neoplasia. neoplastic pertaining to neoplasia or a neoplasm. cells may retain the ability to differentiate toward other morphologic phenotypes in response to different stimuli. This phenomenon has been well documented in cultured cells, such as HL60 cells (a promyelocytic leukemia cell line), which differentiate to different morphologies depending on growth conditions. In a minority of cases studied, however, different genetic profiles were observed in different morphologic areas. In case 1, the squamous carcinoma and adenocarcinoma areas contained different genetic changes in multiple loci studied, which suggests different ancestries for the 2 types of malignant cells. There can be several explanations for this observation. We favor the hypothesis that 2 different precursor cells were responsible for the 2 morphologic areas, since the LOH patterns were different in multiple loci and there was no trend of evolution from one area to the other If this hypothesis is correct, the 2 precursor cells were driven either by different carcinogens or by the same carcinogens due to a field effect. In support of this conclusion, a small portion of the combined hepatocellular cholangiocarcinomas probably contained 2 independent clones, (5) while the majority of these tumors, as well as many other types of combined tumors, (1-4,6,7) showed monoclonality. An interesting observation in our study was the discrepancy between immunohistochemical analysis and LOH assay seen in case 1. In this case, the 2 areas displayed similar patterns when immunohistochemical analysis was carried out using antibodies against Rb and p53. Many studies have shown that abnormalities of these tumor suppressors as detected by immunohistochemistry often correlate with malignant behavior. (15,23) However, in this particular case, immunohistochemical study failed to distinguish the 2 areas, while clinically the adenocarcinoma cells were much more aggressive, accounting for all the lymph node metastasis. Interestingly, the more aggressive behavior seen in adenocarcinoma cells correlated with the results of LOH study, which showed LOH of p53 and Rb only in adenocarcinoma cells. In fact, similar results were obtained by ploidy ploidy Number of sets of chromosomes in the nucleus of a cell. In normal human body cells, chromosomes exist in pairs, a condition called diploidy. During meiosis the cell produces sex cells (gametes), each containing half the normal number of chromosomes, a condition called assay, which showed aneuploidy aneuploidy /an·eu·ploi·dy/ (an?u-ploi´de) any deviation from an exact multiple of the haploid number of chromosomes, whether fewer or more. an·eu·ploi·dy n. in adenocarcinoma cells, but not in squamous carcinoma cells (data not shown). Therefore, it is worthwhile to explore the possibility that molecular genetic analysis may better predict the biologic behavior of tumors than immunohistochemical studies. Our results show that genetic study of combined tumors may yield useful information that cannot be obtained by histologic examination and immunohistochemical studies. The information thus obtained may be invaluable in our understanding of etiology and cells of origin of these tumors and tumors in general. Furthermore, these studies may be helpful in predicting the biologic behavior of tumors, thus directing treatment.
Table 1. Summary of Clinical and Pathologic Information
of Combined Tumors
Case No. Age, y/Sex Location Area A
1 62/M Gastroesophageal
junction Squamous carcinoma
2 51/M Colon Tubulovillous adenoma
3 68/M Lung Squamous carcinoma
4 69/F Lung Small cell carcinoma
5 58/F Gallbladder Adenocarcinoma
6 64/F Gallbladder Adenocarcinoma
Case No. Age, y/Sex Location Area B
1 62/M Gastroesophageal
junction Adenocarcinoma
2 51/M Colon Neuroendocrine carcinoma
3 68/M Lung Small cell carcinoma
4 69/F Lung Squamous carcinoma
5 58/F Gallbladder Squamous carcinoma
6 64/F Gallbladder Squamous carcinoma
Table 2. Special Studies of the Gastroesophageal
Junction Combined Tumor (Case 1) *
Squamous Adenocarcinoma
Carcinoma Area Area
Mucicarmine - +
Cytokeratin + +
CEA - +
EMA - +
p53 - -
Rb + +
* CEA indicates carcinoembryonic antigen; EMA,
epithelial membrane antigen.
Table 3. Summary of Loss of Heterozygosity (LOH) Study of Combined
Tumors *
Case 1 Case 2
Locus Probe A B A B
13q14 (RB gene) RB CA ** ** ** **
RB Tetra ** **** ** **
17p13.1 (p53 gene) P53 CA ** ***** ***** *****
p53 penta *** M ***** *****
APC-MCC gene 5q APC ** ** *** ***
9p21-22 9p IFNA ** ** ** **
D9S171 *** *** ** **
D9S1748 N N N N
3p12 D3S1274 N N *** ***
3p14-21 D3S1766 **** ***** M1 M1
3p14.2 FHIT gene D3S4103 N N N N
FHIT 1300 ***** **** N N
pH13 ** **** ** **
3p21 D3S1029 ** ** ** **
D3S1447 ***** ***** N N
D3S1478 **** **** ** **
ITIH-1 N N *** ***
KACA-1 N N N N
3p22-24.2 D3S2432 **** ** *** ***
D3S1351 ** ** *** ***
D3S1537 *** *** ** **
18Q DCC gene DCC N N *** ***
Case 3 Case 4
Locus Probe A B A B
13q14 (RB gene) RB CA *** *** **** ****
RB Tetra N N N N
17p13.1 (p53 gene) P53 CA M1 M1 *** ***
p53 penta **** **** ***** *****
APC-MCC gene 5q APC N N **** ****
9p21-22 9p IFNA *** *** ** **
D9S171 N N **** ****
D9S1748 ***** ***** **** ****
3p12 D3S1274 N N ***** *****
3p14-21 D3S1766 N N ***** *****
3p14.2 FHIT gene D3S4103 N N **** ****
FHIT 1300 N N N N
pH13 N N N N
3p21 D3S1029 N N ** **
D3S1447 *** *** ***** *****
D3S1478 **** **** ** **
ITIH-1 ** ** **** ****
KACA-1 N N ** **
3p22-24.2 D3S2432 **** **** ** **
D3S1351 *** *** *** ***
D3S1537 *** *** *** ***
18Q DCC gene DCC N N N N
Case 5 Case 6
Locus Probe A B A B
13q14 (RB gene) RB CA **** **** *** ***
RB Tetra N N N N
17p13.1 (p53 gene) P53 CA *** *** **** ****
p53 penta ***** ***** N N
APC-MCC gene 5q APC ** *** ** **
9p21-22 9p IFNA **** **** ***** *****
D9S171 ** ** **** ****
D9S1748 N N N N
3p12 D3S1274 N N N N
3p14-21 D3S1766 N N N N
3p14.2 FHIT gene D3S4103 N N N N
FHIT 1300 N N N N
pH13 N N N N
3p21 D3S1029 N N N N
D3S1447 N N N N
D3S1478 N N N N
ITIH-1 N N N N
KACA-1 N N N N
3p22-24.2 D3S2432 N N N N
D3S1351 N N N N
D3S1537 N N N N
18Q DCC gene DCC **** **** ***** *****
* ** indicates no LOH; ***, not informative; N, not done; ****, LOH,
lower allele lost; *****, LOH, upper allele lost; and M, microsatellite
alteration. A pair of M1s indicates identical patterns of
microsatellite alteration.
Accepted for publication October 19, 2001. This work was supported by a grant from Bristol-Myers Squibb, New York, NY (Dr Jagirdar). References (1.) Niho S, Yokose T, Kodama T, Nishiwaki Y, Mukai K. Clonal analysis of adenosquamous carcinoma of the lung. Jpn J Cancer Res. 1999;90:1244-1247. (2.) Puglisi F, Aprile G, Bruckbauer M, et al. Combined analysis of MIB-1 and thyroid transcription factor-1 predicts survival in non-small cell lung carcinomas. Cancer Lett. 2001 ;162:97-103. (3.) Thompson L, Chang B, Barsky SH. Monoclonal origins of malignant mixed tumors (carcinosarcomas): evidence for a divergent histogenesis. Am J Surg Pathol. 1996;20:277-285. (4.) Kersemaekers AM, van de Vijver MJ, Fleuren GJ. Comparison of the genetic alterations in two epithelial collision tumors of the uterine cervix: a report of two cases. Int J Gynecol Pathol. 2000;19:225-230. (5.) Fujii H, Zhu XG, Matsumoto T, Inagaki M, et al. Genetic classification of combined hepatocellular-cholangiocarcinoma. 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(15.) Gleich LL, Li YQ, Biddinger PW, et al. The loss of heterozygosity in retinoblastoma and p53 suppressor genes as a prognostic indicator for head and neck cancer. Laryngoscope. 1996; 106:1378-1381. (16.) Wistuba II, Gazdar AF, Roa I, Albores-Saavedra J. p53 protein overexpression in gallbladder carcinoma and its precursor lesion. Hum Pathol. 1996;27: 360-365. (17.) Yamaguchi T, Toguchida J, Wadayama B, et al. Loss of heterozygosity and tumor suppressor gene mutations in chondrosarcomas. Anticancer Res. 1996;16: 2009-2015. (18.) Yamamoto A, Virmani AK, Wistuba II, et al. Loss of heterozygosity and microsatellite alterations in p53 and RB genes in adenoid cystic carcinoma adenoid cystic carcinoma n. A carcinoma characterized by large epithelial masses containing round glandlike spaces or cysts, frequently containing mucus, that are bordered by layers of epithelial cells. Also called cylindromatous carcinoma. of the salivary glands. Hum Pathol. 1996;27:1204-1210. (19.) Kishimoto Y, Sugio K, Hung JY, et al. Allele-specific loss in chromosome 9p loci in preneoplastic lesions accompanying non-small-cell lung cancers. J Natl Cancer Inst. 1995;87:1224-1229. (20.) Wistuba II, Behrens C, Milchgrub S, et al. Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects. JAMA. 1988; 279:1554-1559. (21.) Sugio K, Kishimoto Y, Virmani AK, Hung JY, Gazdar AR K-ras mutations are a relatively late event in the pathogenesis of lung carcinomas. Cancer Res. 1994;54:5811-5815. (22.) Sigel JE, Goldblum JR. Neuroendocrine neoplasms arising in inflammatory bowel disease: a report of 14 cases. Mod Pathol. 1998;11:537-542. (23.) Sakata K. Alterations of tumor suppressor genes and the H-ras oncogene in oral squamous cell carcinoma. J Oral Pathol Med. 1996;25:302-307. From the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center The University of Rochester Medical Center (URMC), located in Rochester, New York, is one of the main campuses of the University of Rochester and comprises the university's primary medical education, research and patient care facilities. , Rochester, NY (Dr Huang); the Hamon Center for Therapeutic Oncology Research, Southwestern Medical Center, Dallas, Tex (Drs Behrens, Wistuba, and Gazdar); and the Department of Pathology, University of Texas Health Science Center at San Antonio UTHSCSA is the largest comprehensive health sciences university in South Texas. Located in the South Texas Medical Center, it serves San Antonio and all of the 50,000 square mile (130,000 km²) area of central and south Texas. , San Antonio, Tex (Dr Jagirdar). Reprints: Jaishree Jagirdar, MD, Department of Pathology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (e-mail: jagirda@uthscsa.edu). |
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