Kovatich A, Friedland D M, Druck T, Hadaczek P, Huebner K, Comis R L, Hauck W, McCue P A
Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Cancer. 1998 Sep 15;83(6):1109-17. doi: 10.1002/(sici)1097-0142(19980915)83:6<1109::aid-cncr9>3.0.co;2-2.
The origins of and interrelations between low grade and high grade neuroendocrine lung tumors, typical and atypical carcinoids, and small cell lung carcinoma (SCLC) have not been elucidated. Karyotypic and molecular genetic studies have demonstrated deletions in 3p in 100% of SCLCs and the candidate lung tumor suppressor gene, FHIT, at 3p14.2 is not expressed in the majority of SCLCs. Similar studies of typical and atypical carcinoids could clarify the interrelations among these tumors.
For molecular genetic analyses, archival carcinoids and paired normal cells were microdissected from paraffin sections, deparaffinized, and DNA prepared. Oligonucleotide primer pairs for 12 microsatellite markers mapping between 3p14.2 and 3p21.3 were used to amplify allelic DNA fragments from 13 typical and 6 atypical carcinoids. In addition, an independent series of archival sections of carcinoids and SCLCs was tested by immunohistochemistry for expression of Fhit protein.
Of the six atypical carcinoids examined, three had lost an allele at all informative markers, whereas one had lost alleles in two distinct regions and two showed allele loss in a subregion of the chromosome region tested. Of the 13 typical carcinoids, 3 showed allele loss at only 1 or 2 loci each. Typical carcinoids, similar to normal lung epithelia, were strongly positive for the cytoplasmic Fhit protein, SCLCs were uniformly negative, and atypical carcinoids appeared to express an intermediate level of Fhit protein.
Loss of heterozygosity at 3p14.2-p21.3 is significantly more extensive in all atypical carcinoids. Atypical carcinoids, which exhibit clinicopathologic features intermediate between typical carcinoids and small cell carcinomas and have been considered well differentiated neuroendocrine carcinomas, also are intermediate between typical carcinoids and SCLC on the basis of extent of loss of 3p alleles and reduced expression of Fhit protein.
低级别和高级别神经内分泌性肺肿瘤、典型类癌和非典型类癌以及小细胞肺癌（SCLC）之间的起源及相互关系尚未阐明。核型和分子遗传学研究表明，100%的SCLC存在3p缺失，位于3p14.2的候选肺肿瘤抑制基因FHIT在大多数SCLC中不表达。对典型类癌和非典型类癌进行类似研究可能会阐明这些肿瘤之间的相互关系。
为进行分子遗传学分析，从石蜡切片中显微切割存档的类癌和配对的正常细胞，脱石蜡处理后制备DNA。使用12个位于3p14.2和3p21.3之间的微卫星标记的寡核苷酸引物对，从13例典型类癌和6例非典型类癌中扩增等位基因DNA片段。此外，通过免疫组织化学检测存档的类癌和SCLC切片系列中Fhit蛋白的表达情况。
在所检测的6例非典型类癌中，3例在所有信息性标记处均丢失了一个等位基因，1例在两个不同区域丢失了等位基因，2例在检测的染色体区域的一个亚区域显示等位基因丢失。在13例典型类癌中，3例仅在1或2个位点显示等位基因丢失。典型类癌与正常肺上皮相似，细胞质Fhit蛋白呈强阳性，SCLC均为阴性，非典型类癌似乎表达中等水平的Fhit蛋白。
在所有非典型类癌中，3p14.2-p21.3的杂合性缺失明显更为广泛。非典型类癌在临床病理特征上介于典型类癌和小细胞癌之间，曾被认为是高分化神经内分泌癌，基于3p等位基因缺失程度和Fhit蛋白表达降低，其在典型类癌和SCLC之间也处于中间位置。
