胃癌组织HLA－I类和DR分子免疫组化研究

本文应用免疫组化法对６４例胃癌、癌旁组织和６例胃溃疡大致正常胃粘膜冰冻和石蜡切片进行了染色．结果表明，正常胃粘膜和癌旁胃粘膜上皮细胞ＨＬＡ－Ｉ类分子表达阳性，其着色较均一，ＨＬＡ－ＤＲ染色均阴性．胃癌细胞Ｉ类分子表达缺失（２７／６４例），与癌旁上皮比较差异显著（Ｐ＜０．０１）。粘液细胞癌和低分化癌Ｉ类分子缺失率显著高于高分化癌（Ｐ＜０．０２５）．此外，发生肿瘤转移的病例Ｉ类分子缺失率（１２／１５例）显著高于无转移组（１／５例，Ｐ＜０．０２５）．ＤＲ分子在癌组织表达阳性，其阳性率高达５３．１％（３４／６４例）．低分化癌ＤＲ分子阳性率亦显著高于高分化癌和中分化癌，未分化癌ＤＲ分子阳性率亦显著高于高分化癌（Ｐ＜０．０１～０．０５）．提示（１）ＨＬＡ－Ｉ类分子表达缺失可能与癌细胞逃避宿主免疫监视发生润浸生长和转移有关；（２）分化程度不同的癌组织ＨＬＡ－Ｉ类分子表达差异显著，提示癌细胞分化可能影响Ｉ、Ⅱ类分子表达和肿癌抗原呈递；（３）ＨＬＡ－Ｉ类和ＤＲ分子表达异常可能是上皮恶性转变的标志之一．     

Major histocompatibility complex status in breast carcinogenesis and relationship to apoptosis

Major histocompatibility complex (MHC) molecules are of central importance in regulating the immune response against tumors. In this study we used immunohistochemistry to study human leukocyte antigen (HLA) class I and II antigen expression in normal breast tissues and benign, preneoplastic, primary, and metastatic breast lesions using antibodies against beta-2-microglobulin (beta2-m), heavy-chain, and HLA-DR antigens. Whereas all normal tissues and benign lesions were positive for beta2-m and HLA-A, -B, and -C antigens, total loss of HLA class I antigens was found in 37% (11 of 30) of in situ carcinomas, in 43% (56 of 131) of the primary tumors, and in 70% (31 of 45) of the lymph node metastases. HLA-DR was also underexpressed in breast cancer cells; thus 20% (6 of 30) of in situ carcinomas, 15% of invasive carcinomas (20 of 131), and only 1 metastatic case were positive for this antigen. Both HLA class I and II antigen expression were more frequently down-regulated in metastatic lesions than in primary breast lesions (P <0.05), and a tendency toward a simultaneous defective expression of HLA class I and II antigens was observed in primary carcinomas (P = 0.07). However, no correlation was found between the expression of any of the aforementioned molecules and pathological parameters or survival. Interestingly, HLA class I expression was expressed more frequently in tissues with high apoptotic activity and was significantly associated with the expression of the proapoptotic bax gene (P = 0.02), and was inversely associated with expression of the antiapoptotic bcl-2 gene (P = 0.03). We conclude that alterations in HLA class I and II antigen expression are early events in breast carcinogenesis and play significant roles in metastatic progression. In addition, their expression is correlated with apoptosis-regulating proteins, which may influence the cytotoxicity of T cells against HLA class I-specific tumor antigens.     

FAS and FAS-L expression by tumor cells and lymphocytes in breast carcinomas and their lymph node metastases

FAS receptor (FAS, CD95) and FAS ligand (FAS-L, CD95-L) are complementary members of a particular apoptotic pathway that plays a major role in immune regulation. The activation of FAS-L may trigger cytotoxic mechanisms leading to the death of FAS-expressing cells. Tumor cells and tumor-infiltrating lymphocytes (TIL) may express FAS and FAS-L in various proportions, and their interplay may affect tumor behavior. In the present study, we explored the expression of FAS and FAS-L in 28 mammary carcinomas (19 ductal and 9 lobular) and in their lymph node metastases. The expression of these mediators in immunostained sections was graded and evaluated comparatively between normal and neoplastic mammary epithelium, between tumor cells and TILs, and between mammary carcinoma cells and their lymph node metastases. We demonstrated the coexpression of FAS and FAS-L by breast carcinoma cells and TIL, with FAS expressed more strongly by normal epithelial cells and TIL than tumor cells. FAS-L was better stained on tumor cells than on TIL. There was equal or greater expression of FAS and FAS-L in the primary tumors and their TIL than in the metastatic counterparts. Comparing the expression of FAS with that of FAS-L, we recorded FAS equal or stronger than FAS-L in the primary mammary tumors and the reversal of their expression, FAS-L greater than FAS in the lymph node metastases. These results are consistent with reports of studies with other tumors, suggesting that the upregulated FAS-L indicates an increased ability of tumor cells to induce apoptosis in TIL and in the normal tissues invaded. However, it is understood that the FAS/FAS-L system, although essential for apoptosis, is only a contributing factor to the complex process of tumor invasion and antitumor defense.     

Prognostic significance of HLA-DR antigen in serous ovarian tumors

Abstract. The antigens encoded by the major histocompability complex (HLA-DR) are cell glycoproteins that play a fundamental role in the regulation of the immune response. The prognosis of ovarian cancer is dependent on the histological type and on the clinical stage at diagnosis. Our study reports the value of HLA-DR antigen as a prognostic marker of ovarian serous adenocarcinoma. We studied 31 cases of serous ovarian cystadenoma, 12 cases of serous ovarian borderline cystadenoma, and 39 cases of well-differentiated cystadenocarcinoma for HLA-DR monoclonal antigen. We also studied the T helper marker (CD4) in the tumor stroma of the relevant cases, given that it is now known that the dependence of immune responsiveness on the class II antigens reflects the central role of these molecules in presenting antigen to T helper cells. HLA-DR was expressed in 20 of 31 cystadenomas (64.5%), 4 of 12 borderline tumors (33.3%), and in 10 of 39 invasive carcinomas (25.6%). CD4 was expressed in 9 of 31 cystadenomas (29%), 5 of 12 borderline tumors (42%), and in 26 of 39 invasive carcinomas (67%). There was a statistically significant difference for the two examined antigens in cystadenomas (p<0.001) and invasive carcinomas (p<0.001), whereas there was no statistical difference in borderline tumors (p<0.5). The results showed decreased expression of HLA-DR and increased expression of CD4 as the lesion progressed to malignancy. The aberrant expression of HLA-DR by epithelial cells of cystadenomas, of borderline tumors, and of invasive adenocarcinomas agrees with the hypothesis of the adenoma/adenocarcinoma sequence. The immune attraction mechanism by low HLADR signaling seems to be of minor importance in the malignant and metastatic potential of serous ovarian tumors.     

Microtubule-associated protein-2: a new sensitive and specific marker for pulmonary carcinoid tumor and small cell carcinoma.

Microtubule-associated proteins (MAPs) are a major component of cytoskeleton family proteins associated with microtubule assembly. MAP-2 has been shown to be specifically expressed in neuronally differentiated cells. Pulmonary neuroendocrine carcinomas such as carcinoid tumors and small cell carcinomas are derived from neuroendocrine cells. We hypothesize that neuroendocrine cells may also express MAP-2, and therefore, MAP-2 may be used as a marker for pulmonary carcinomas of neuroendocrine differentiation. To investigate the utility of using MAP-2 expression to separate pulmonary neuroendocrine from non-neuroendocrine tumors, we examined the expression of MAP-2 immunohistochemically in 100 cases of pulmonary carcinomas. The immunoperoxidase method with antigen retrieval was used to characterize the expression of MAP-2, chromogranin, synaptophysin, and neuron-specific enolase in 25 small cell carcinomas, 25 carcinoid tumors, 25 adenocarcinomas, and 25 squamous cell carcinomas. All tumors were lung primaries. All 25 cases of carcinoid tumors (100%) as well as 23 of 25 cases (92%) of small cell carcinomas were positive for MAP-2. Four of 25 cases (16%) of adenocarcinomas were positive for MAP-2 and synaptophysin. Among the 25 squamous carcinomas, 4 cases (16%) were positive for MAP-2, 2 cases (8%) were positive for synaptophysin, 11 cases (44%) were positive for neuron-specific enolase, and none was positive for chromogranin. In conclusion, MAP-2 is a new sensitive and specific marker for the pulmonary tumors of neuroendocrine differentiation. We recommend that MAP-2 be added to immunohistochemical panels to separate non-neuroendocrine from neuroendocrine lung tumors.     

Human chorionic gonadotropin in esophageal carcinomas. An immunohistochemical study.

We have examined immunohistochemically the presence of human chorionic gonadotrophin (hCG) in 29 esophageal carcinomas: 24 squamous cell carcinomas, 2 adenocarcinomas, 2 adenoid cystic carcinomas and 1 adenosquamous carcinoma. In hCG-positive tumors, the presence of human placental lactogen (hPL) and pregnancy-specific beta-1 glycoprotein (SP-1) was also assessed. HCG immunoreactive cells were found in 5 squamous cell carcinomas (21%) and in none of 5 non-squamous cell tumors. The hCG positive cells were found in the most infiltrating areas of the tumors where poorly differentiated and pleomorphic cells predominated. The positive tumors were 4 poorly differentiated (31%) and one moderately differentiated carcinoma (12%). Four out of 10 cases (40%) with lymph node metastases had hCG in the primary tumor, whereas only one out of 11 cases (9%) without metastases was hCG positive. HPL and SP-1 were found in two cases. These placental proteins were detected in similar areas than hCG but the number of hPL and SP-1 immunoreactive cells was lower than hCG positive cells. SP-1 was also seen in areas of squamous cell differentiation negative for hCG. None of these two cases showed trophoblastic differentiation.     

Human chorionic gonadotropin in esophageal carcinomas. An immunohistochemical study.

We have examined immunohistochemically the presence of human chorionic gonadotrophin (hCG) in 29 esophageal carcinomas: 24 squamous cell carcinomas, 2 adenocarcinomas, 2 adenoid cystic carcinomas and 1 adenosquamous carcinoma. In hCG-positive tumors, the presence of human placental lactogen (hPL) and pregnancy-specific beta-1 glycoprotein (SP-1) was also assessed. HCG immunoreactive cells were found in 5 squamous cell carcinomas (21%) and in none of 5 non-squamous cell tumors. The hCG positive cells were found in the most infiltrating areas of the tumors where poorly differentiated and pleomorphic cells predominated. The positive tumors were 4 poorly differentiated (31%) and one moderately differentiated carcinoma (12%). Four out of 10 cases (40%) with lymph node metastases had hCG in the primary tumor, whereas only one out of 11 cases (9%) without metastases was hCG positive. HPL and SP-1 were found in two cases. These placental proteins were detected in similar areas than hCG but the number of hPL and SP-1 immunoreactive cells was lower than hCG positive cells. SP-1 was also seen in areas of squamous cell differentiation negative for hCG. None of these two cases showed trophoblastic differentiation.     

Expression of MHC class I and class II antigens in primary breast carcinomas and synchronous nodal metastases

Expression of the major histocompatibility (MHC) class I and class II antigens was studied by immunohistochemistry in a series of 70 primary breast carcinomas and in nodal metastases. In particular, the expression of class I (HLA A-B-C) and class II (DP, DQ and DR) molecules was compared in: a) primary breast cancers devoid of nodal metastases (n = 36) and tumors exhibiting metastatic deposits (n = 34) at the time of surgery, and b) primary breast carcinomas and their corresponding synchronous axillary nodal metastases. Reduced or absent HLA A-B-C antigen expression was seen in approximately 54.3% of primary breast carcinomas, whereas a partial or complete induction of class II products was observed in 18.5% (DQ), 30% (DP) or 48.5% (DR) of the same cases. An almost complete overlap of antigen expression was observed in breast tumors in which no metastases were found by histological examination of axillary nodes and in neoplasms showing histologically-diagnosed synchronous metastases. The reactivity for class I and class II antigens in nodal metastases roughly paralleled that exhibited by corresponding primary tumors. A discordant expression was seen in 11 cases (32%) stained for HLA A-B-C and in 8 (24%), 7 (21%) and 6 (18%) cases assayed for DP, DQ and DR products, respectively. When a discordant expression was detected, either decreased or increased staining patterns were observed in metastases. The finding of overlapping MHC antigenic profiles in the majority of primary breast tumors and nodal metastases casts doubts on the hypothesis that loss of MHC antigens can play an important role in the seeding and growth of metastatic breast carcinoma cells.     

Immunohistochemical study of the squamous epithelium antigen and the possibility of using it as a marker of squamous cell carcinoma

With the use of polyclonal antibodies to the squamous epithelium antigen it is demonstrated that small amounts of this marker are expressed in the cytoplasm of some cells in the prickle-cell layer of the epithelium. The amount of this antigen increases in the parabasal layer of squamous epithelium with the severity of the dysplastic process. Study of 115 specimens of various histological types of tumors, shows that the specificity of the antibodies for the squamous epithelium antigen is 97.4% for squamous cell carcinomas. Thus, this antigen can be used for the identification of squamous cell carcinomas from nondifferentiated tumors. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, N ^o 2, pp. 209–211, February, 1995 (Presented by V. I. Chissov, Member of the Russian Academy of Medical Sciences)     

P63 in pulmonary epithelium,pulmonary squamous neoplasms,and other pulmonary tumors

p63 is a p53-homologous nuclear protein that appears to play a crucial role in regulation of stem cell commitment in squamous and other epithelia. In this study, p63 expression was examined in benign lung and in neoplasms of pulmonary origin. Eighty sections from routinely fixed and processed archival bronchoscopic biopsy or lobectomy specimens were pretreated with citric acid (pH 6.0) for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained using a streptavidin-biotin kit and diaminobenzidine as chromagen, and were counterstained with hematoxylin. In normal lung, p63 intensely stained nuclei of bronchial reserve cells but did not stain ciliated cells, alveolar epithelial cells, or nonepithelial cells. The lower strata of squamous metaplastic bronchial epithelium stained positively. All squamous-cell carcinomas stained positively (n = 30). In some well-differentiated carcinomas, staining was found at the periphery of tumor nests but was negative in central zones showing squamous maturation. Poorly differentiated carcinomas showed very high proportions (80% to 100%) of p63-positive nuclei. All small-cell carcinomas were p63 negative (n = 9). Staining of bronchioloalveolar carcinomas (n = 7) and adenocarcinomas (n = 23) was variable: some tumors showed no detectable staining, others showed heterogeneously positive staining. Adenosquamous carcinomas (n = 5) displayed a unique basalar staining pattern. Carcinoid tumors were almost entirely negative (n = 5). We conclude that p63 is expressed in benign bronchial stem cells, in neoplastic cells with either squamous differentiation or squamous differentiating potential, and in a subpopulation of adenocarcinomas. p63 immunostaining may also aid in some histopathologic distinctions, such as in small biopsies where the differential diagnosis is poorly differentiated squamous carcinoma versus small-cell carcinoma. A stem cell biology-based classification system for squamous carcinomas is proposed.     

The expression of histocompatibility antigen HLA-DR in cervical squamous epithelium infected with human papilloma virus

Uterine cervices with histologic changes suggestive of human papilloma virus (HPV) infection were examined for the presence of papilloma virus capsid antigens and the Class II histocompatibility antigen HLA-DR. The purpose of this study was to determine whether papilloma virus infection could induce HLA-DR expression by squamous cells. This expression would allow squamous epithelium to function as antigen-presenting cells and perhaps initiate the immune response. In 20 cases in which HPV capsid antigens were identified, no HLA-DR expression was noted. HLA-DR expression was noted on Langerhans cells within the squamous epithelium and on mononuclear cells in the underlying lamina propria. HLA-DR-positive cells were also noted between columnar epithelial cells of the endocervix. We conclude that HPV infection does not induce HLA-DR expression in the cells it infects.     

MHC class I and II antigens on gastric carcinomas and autologous mucosa

The expression of HLA class I and II antigens was analysed in 30 primary gastric carcinomas, 27 autologous lymph node metastases and 25 autologous gastric mucosae. We used an immune alkaline phosphatase technique on cryostatic sections and mAbs directed against HLA class I monomorphic determinants, HLA-B locus-specific products and HLA-DR, -DP and -DQ molecules. In addition HLA class I genes were analysed in tumour tissue and compared by Southern blots with the RFLP from autologous mucosa using locus-specific HLA probes. Finally the infiltrating mononuclear cells were studied on gastric tumours and adjacent mucosa with mAbs defining CD4, CD8 and CD11b differentiation antigens. The results obtained showed that three out of 27 primary gastric carcinomas completely lack HLA-ABC antigens (10%). In addition, two primary tumours presented a variable expression. The remaining 22 tumours presented a homogeneous positive HLA class I expression. Interestingly, when the autologous mucosa was analysed, only 12 out 25 specimens were homogeneously stained with mAbs against HLA class I antigens, suggesting that this tissue may lack the expression of HLA antigens before becoming malignant. Indeed, the majority of the gastric carcinomas studied presented a higher HLA-ABC antigenic expression than autologous mucosa. Finally, the HLA expression observed in the primary tumour was similar to that observed in autologous metastases. As a second part of the study we have found a direct relationship between the expression of HLA-DR antigens in mucosa and the intensity of inflammatory infiltration. This relationship was not maintained in the tumour tissue. In the mucosa the CD4-positive T cell was the predominant lymphocyte, while it was CD8 in the HLA-DR-positive tumours. Finally the RFLP of class I genes did not show any differences in any of the cases when compared with autologous mucosa. We included in these studies DNAs from HLA class I-negative tumours, HLA positive and HLA-B-negative ones.     

Human monoclonal antibodies as a tool for the detection of HLA class I allele-specific expression loss in head-and-neck squamous cell carcinoma and corresponding lymph node metastases

Human leukocyte antigen (HLA) expression is important for the elimination of tumor cells by the immune system and immunotherapy. Activated T cells directed against tumor-associated antigens are fully capable of recognizing and eradicating neoplastic cells. Therefore, HLA expression loss is considered to be a main factor in tumor development. We report for the first time HLA-A and HLA-B allele-specific expression analysis by immunohistochemical staining of fresh tumor tissue and 9 lymph node metastases of 15 patients with head-and-neck squamous cell carcinoma. Heterogeneous HLA expression and HLA expression loss was detected in 13 tumor patients. Approximately 50% of the tumors had allele-specific expression loss, which would have remained undetected using HLA monomorphic and locus-specific antibodies. In the majority of the patients with head-and-neck squamous cell carcinoma, HLA allele-specific expression loss differed between primary lesions and metastases. This is important for the efficacy of immunotherapy in these patients. It can be concluded that it is crucial to study HLA expression at the allele-specific level of primary lesions and metastases. It increases and refines our knowledge of HLA expression loss in tumorgenesis, which will improve the development of specific immunotherapy.     

Characterization of the specificity by immunohistology of a monoclonal antibody to a novel epithelial antigen of ovarian carcinomas

An immunohistological study, using the avidin-biotin-peroxidase complex method, was carried out to define the reactivity profile of a murine monoclonal antibody, MOv2, which recognizes a novel glycoprotidic antigen associated with ovarian epithelial tumors. Among the primary ovarian tumors tested, MOv2 immunostained 93% of mucinous and 75% of serous cystadenomas, 100% of mucinous, 81% of serous and 73% of endometrioid carcinomas. Undifferentiated and clear cell tumors revealed more limited reactivity with the antibody, whereas ovarian sex cord-stromal and germinal tumors were immunonegative. Positive reactions were also documented in omental metastases from primary ovarian carcinomas. No immunoreactivity was detected in normal ovarian epithelium, whereas the cells lining Walthard's nests adjacent to the fallopian tubes and a variety of normal epithelia were consistently immunolabeled. These included the lining epithelia of the gastrointestinal tract, bronchi and endocervix, and the epithelium of salivary, biliary and pancreatic ducts and sweat glands. To a lesser extent, positive reactions were detected in other surface epithelia, such as squamous and transitional epithelia. Among tumors other than ovarian, MOv2 consistently reacted with adenocarcinomas and squamous cell carcinomas from different sites, most notably breast, lung and gastrointestinal tract, and with transitional cell carcinomas. In contrast, no staining was demonstrated in non-epithelial malignancies. The antigen defined by MOv2 may be operationally useful as a marker of epithelial lineage in tumor histopathology. Its pattern of immunohistochemical distribution indicates that an antigenic phenotype shared by normal surface epithelia and non-ovarian carcinomas is strongly associated with common epithelial neoplasms of the ovaries.     

Simultaneous detection of genetic and immunological markers in non-small cell lung cancer: prediction of metastatic potential of tumor

The restriction fragment length polymorphism of c-Ha-ras-1 and L-myc genes and expression of cell surface effector molecules were studied to determine their potential utility as markers for assessing risk of metastasis in 84 lung cancer patients. We performed a comparative study of primary lung carcinomas, metastases, adjacent tissues and blood samples in a group of patients with lung cancer of different histological types, grade of differentiation and presence of regional and distant metastasis. No differences in the frequency of c-Ha-ras-1 rare alleles were found between lung cancer patients and unaffected controls. The detection of common a4-allele seems to be associated with metastasis and low differentiation of lung carcinomas. S-allele of L-myc was observed in 82.6% of patients with metastatic lesions. Homozygosity of L-allele patients was not evidence for distant metastasis and only 17.4% of these patients have metastatic lesions of the lymph nodes. The expression of HLA class I and receptor of transferrin (TrRec) were tested immunohistochemically in the same patients. In the group of squamous cell carcinomas with regional metastases the expression of HLA class I antigens was decreased [7/21 (33.3%) positive staining tumors versus 13/20 (65.0%) in the group without metastases]. The opposite situation was observed for TrRec. The data of restriction fragment length polymorphism of oncogenes and expression of two cell surface effector molecules, identified in the same patients, were combined. The registration of more than one poor marker, tested in individuals with squamous cell carcinoma, closely correlated with dissemination and advanced stage of the disease. Nearly 90% (20/22) of patients with well and moderately differentiated tumor revealed metastatic lesions versus 6.6% (1/15) of patients with manifestation of a single poor marker. Finally, proposals could be made for the development of a risk group that incorporates both clinical and molecular biology features in the prediction of metastasis.     

Immunomorphological (light and electron microscopic) diagnosis of human squamous cell cancer using monoclonal antibodies

It is shown with fluorescent and peroxidase labels for antibodies that the antigen to which the monoclonal antibody A-6/2 is directed, is a marker for cells of the basal stratified epithelium (basal-cell antigen). This antigen persists in squamous cell carcinomas of various sites and degrees of differentiation, but does not occur in tumors of other origins. With electron immunocytochemistry, the antigen was found to be located in tonofilaments and desmosomes of human squamous cell carcinoma. The A-6/2 monoclonal and basal-cell antigen may be used when developing immunomorphologic (light- or electronmicroscopic) procedures for histogenetic diagnosis of these carcinomas.     

Immunohistochemical detection of parathyroid hormone-related protein in a cutaneous squamous cell carcinoma causing humoral hypercalcemia of malignancy.

Humoral hypercalcemia of malignancy is a cancer-related hypercalcemia caused by production of humoral factors by malignant cells in patients without bone metastases. Squamous cell carcinomas are the tumors most frequently associated with humoral hypercalcemia of malignancy, and parathyroid hormone-related protein is the main humoral factor implicated. In spite of the fact that normal keratinocytes produce parathyroid hormone-related protein, it is highly unusual for patients with squamous cell carcinomas of the skin to present with humoral hypercalcemia of malignancy. We present a well-documented case of cutaneous squamous cell carcinoma complicated by hypercalcemia in a patient with high levels of plasma parathyroid hormone-related protein and immunohistochemical evidence of high parathyroid hormone-related protein production by the tumoral cells.     

Expression of the epithelial L1 antigen as an immunohistochemical marker of squamous cell carcinoma of the lung

The distribution of epithelial L1 antigen was evaluated in 139 bronchogenic carcinomas which had been classified by a panel of pathologists according to the WHO recommendation of 1981. L1 was not found in three large cell and 13 small cell carcinomas, but it was expressed by tumour cells in 67 of 69 squamous cell carcinomas (97%), in three of four adenosquamous carcinomas (75%), and in three of 49 adenocarcinomas (6%). The staining for L1 antigen was more diffusely distributed in the positive adenocarcinomas than in the squamous cell carcinomas. Its expression in squamous cell carcinomas was typically confined to relatively small tumour cell groups and never included a complete specimen. Semi-quantitative estimation of the immunostaining showed no clear relationship to the degree of differentiation and scores for proliferation, but L1 expression was negatively related to nuclear aberration (P less than 0.025) and malignancy scores (P less than 0.002). The good agreement between morphological classification and expression of L1 makes this a valuable marker in the diagnosis of lung carcinomas.