Low-grade lung adenocarcinoma of fetal lung type, which is well characterized by its unique clinicopathologic and molecular features, is recognized as a distinct variant of lung cancer. In contrast, high-grade lung adenocarcinoma with fetal lung-like morphology (HG-LAFM) has not been studied widely. To characterize this subset better, we analyzed 17 high-grade adenocarcinomas with at least focal component resembling a developing epithelium in the pseudoglandular phase of the fetal lung. These rare (ca. 0.4%) carcinomas occurred predominantly in elderly men with a heavy smoking history, who showed elevated serum α-fetoprotein in 4 of 5 cases tested. Histologic examination revealed a fetal lung-like component as a focal finding accounting for 5% to 60% of the total tumor volume. It was invariably admixed with tissues having a morphology not resembling that of a fetal lung. A coexisting non-fetal lung-like element was quite heterogenous in appearance, showing various growth patterns. However, clear-cell (88%), hepatoid (29%), and large cell neuroendocrine carcinoma (24%) histology seemed overrepresented. HG-LAFM was characterized immunohistochemically by frequent expression of α-fetoprotein (41%), glypican-3 (88%), SALL-4 (59%), neuroendocrine markers (82%), CDX-2 (35%), and p53 (65%). HG-LAFM was molecularly heterogenous in that EGFR or KRAS mutation was observed in 22% of cases tested for both. Our data indicate that HG-LAFMs might form a coherent subgroup of lung adenocarcinomas. However, the uniformly focal nature of the fetal lung-like element, widely diverse coexisting non-fetal lung-like histology, and inhomogenous molecular profiles lead us to believe that HG-LAFM is best regarded as a morphologic pattern showing characteristic association with several clinicopathologic parameters rather than a specific tumor entity.
Mutations of the epidermal growth factor receptor (EGFR), particularly deletional mutations (DEL) in exon 19 and L858R in exon 21, are reportedly correlated with clinical outcome in patients with non-small cell lung cancer (NSCLC) receiving the EGFR tyrosine kinase inhibitors gefitinib and erlotinib, suggesting that detection of EGFR mutations would have an important role in clinical decision making. We established and validated an easy, inexpensive, and rapid method for detecting DEL and L858R from cytologic material by high-resolution melting analysis (HRMA). Dilution for sensitivity studies revealed that DEL and L858R were detectable in the presence of at least 10% and 0.1% EGFR-mutant cells, respectively. We analyzed 37 archived cytological slides of specimens from 29 patients with advanced NSCLC and compared the results with direct sequencing data obtained previously. Of 37 samples, 34 (92%) yielded consistent results with direct sequencing, 2 were false negative, and 1 was indeterminate. The sensitivity of this analysis was 90% (19/21) and specificity, 100% (15/15). These results suggest that HRMA of archived cytologic specimens of advanced NSCLC is useful for detecting EGFR mutations in clinical practice.
(1,2) In some cases of PLS, a myxoid or small round cell area similar to the myxoid/round cell liposarcoma (MLS/ RC) is observed with various numbers of pleomorphic lipoblasts. In such a situation, we sometimes experience diagnostic difficulty in distinguishing PLS from MLS/RC. Cytogenetically, complicated abnormal karyotypes have been reported in many cases of PLS.(3-6) Recently FUS-CHOP fusion transcripts specific for MLS/RC were detected in some cases of PLS using the reverse transcription-polymerase chain reaction (RT-PCR) method. (7,8) In the present fluorescence in situ hybridization (FISH) analysis study, we thus investigated the CHOP rearrangement in morphologically different areas of PLS including an MLS/ RC-like myxoid or round cell area on histological sections. Material and MethodSample selection. The archival pathological files of the Laboratory of Pathology, National Cancer Center Hospital, Tokyo, Japan were searched for patients with a diagnosis of PLS. Seven cases of PLS were selected for the study, consisting of primary tumors in four cases, and recurrrent tumors in three. Three cases of MLS/RC were also chosen as the positive control group with CHOP slit signals. In addition, 13 non-PLS tumors (4 malignant peripheral nerve sheath tumors, 3 synovial sarcomas, 3 myxofibrosarcomas, and 3 leiomyosarcomas) were selected as the negative control.Pathological evaluation. We reviewed all hematoxylin and eosin (HE) sections containing whole parts of the maximum dimension in each tumor and reclassified the histological heterogeneity of the tumor areas into four patterns including the typical PLS area, myxoid area, round cell area, and nonlipogenic sarcoma area. The typical PLS area consisted of a high-grade sarcoma with a varing amount of pleomorphic lipoblasts (Fig. 1a,b). The myxoid area showed round to spindle cell sarcoma with abundant myxomatous background similar to MLS/RC or myxofibrosarcoma (Fig. 1c). The round cell area exhibited a proliferation of monotonous round cells which resembled round cell liposarcoma (Fig. 1d). The non-lipogenic sarcoma area was composed of high-grade spindle to pleomorphic sarcoma without an apparent lipogenic differentiation (Fig. 1e).Fluorescence in situ hybridization. The most representative sections of seven PLSs and three MLS/RCs were examined with the FISH assay. The CHOP FISH studies were performed using formalin-fixed, paraffin-embedded specimens sectioned into 4 μm-thick tissue slices. Briefly, after dewaxing and dehydration, the sections were immersed in 0.2 N HCl for 20 min followed by a pretreatment solution (Abbott Molecular International, 50 mL) at 80°C for 30 min. After digestion in protease for 60 min at 37°C, the sections were washed in phosphate-buffered saline for 5 min at room temperature, fixed in 10% formaldehyde for 10 min at room temperature, washed in phosphatebuffered saline for 5 min at room temperature, and placed into a prewarmed solution (Vysis) for 5 min at 72°C. They were then dehydrated in an ethanol series (70, 85 and 100%) at room temp...
We established our bio-repository in October 2002. One of the unique aspects of our bio-repository is that it is based on post-clinical test samples. Although the post-clinical test sample-based storage is beneficial because ample clinical information is available for each sample and samples are to be refreshed regularly, many bio-bankers are hesitant to store them because of the possible problems of de-identification procedures and sample quality. Currently, we have two different types of sample, not de-identified status and de-identified status. Most of the samples for storage are not de-identified status. A portion of the samples are transferred to new tubes before and after being frozen, without clinical patient identifications and the status is de-identified. This tube transfer is the only de-identification procedure in our bio-repository so far. After a procedure of de-identification, these samples are stored. The de-identified samples are collected under various project-based schemes. The quality standards of our samples are established by two factors: pre-analytical quality control efforts, and record keeping of sample history by sample tracking system. All the samples have been phlebotomized under strict control of pre-analytical requirements. By record keeping of sample history with the sample tracking system, we can tell the exact temperature and elapsed time in various situations since the phlebotomy procedure or on arrival at the clinical laboratory. In this article, we will disclose how we have dealt with the de-identification procedure and sample quality.
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