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Introduction: The Japan Lung Cancer Society (JLCS) and the Japanese Society of Clinical Cytology (JSCC) have proposed a new four-tiered cytology reporting system for lung carcinoma (JLCS-JSCC system). Prior to the proposal, the Papanicolaou Society of Cytopathology (PSC) had proposed a revised reporting system (PSC system), which comprises the “neoplastic, benign neoplasm, and low-grade carcinoma” category (N-B-LG category), in addition to the 4 categories of the JLCS-JSCC system. This study aimed to evaluate the interobserver agreement of the JLCS-JSCC system with an additional dataset with more benign lesions in comparison with the PSC system. Methods: We analyzed 167 cytological samples, which included 17 benign lesions, obtained from the respiratory system. Seven observers classified these cases into each category by reviewing one Papanicolaou-stained slide per case according to the JLCS-JSCC system and PSC system. Results: The interobserver agreement was moderate in the JLCS-JSCC (k = 0.499) and PSC (k = 0.485) systems. Of the 167 samples, 17 samples were benign lesions: 7 pulmonary hamartomas, 5 sclerosing pneumocytomas, 2 squamous papillomas, one solitary fibrous tumor, one meningioma, and one lymphocytic proliferation. There were diverse sample types as follows: 11 touch smears, 3 brushing smears, 2 aspirations, and one sputum sample. Fourteen samples (82.3%) were categorized into “negative” or “atypical” by more than half of the observers in the JLCS-JSCC system. Conversely, 3 samples were categorized as “suspicious” or “malignant” by more than half of the observers in the JLCS-JSCC system. On the other hand, 11 samples (64.7%) were categorized into the N-B-LG category by more than half of the observers in the PSC system. Conclusions: The concordance rate in the JLCS-JSCC system was slightly higher than that in the PSC system; however, the interobserver agreement was moderate in both the JLCS-JSCC and PSC systems. These results indicate that both the JLCS-JSCC and PSC systems are clinically useful. Therefore, both systems are expected to have clinical applications. It may be important to integrate the 2 systems and construct a universal system that can be used more widely in clinical practice.

Introduction: The classification of lung carcinoma is based on small biopsies and/or cytology in 80% of patients with non-small cell carcinoma. However, there is no widely accepted classification system for respiratory cytology. The Japan Lung Cancer Society (JLCS) and Japanese Society of Clinical Cytology (JSCC) have proposed a new four-tiered cytology reporting system for lung carcinoma with the following categories: (1) “negative for malignancy,” (2) “atypical cells,” (3) “suspicious for malignancy,” and (4) “malignancy.” Objective: The aim of this work was to perform an interobserver reproducibility study to confirm the utility of the four-tiered reporting system on respiratory cytological samples. Methods: We analyzed 90 cytological samples obtained with bronchoscopy. Seven observers classified these cases into each category by reviewing one Papanicolaou-stained slide per case according to the three-, four-, and five-tiered reporting systems. Results: The interobserver agreement was fair in the three- (κ = 0.50), four- (κ = 0.45), and five-tiered (κ = 0.45) reporting systems. However, the four-tiered reporting system provided more precise information than the three-tiered reporting system in patient management. The risk of malignancy in the four-tiered reporting system was also stratified well: 19.3% for “negative for malignancy,” 45.6% for “atypical cells,” 74.7% for “suspicious for malignancy,” and 88.1% for “malignancy.” Conclusions: The reporting system proposed by the JLCS and JSCC was designed to enhance the communication between clinicians and pathologists and among different institutions. It is simple and applicable to cytological diagnosis of any respiratory diseases. We propose establishing an international classification for respiratory cytology, harmonizing the reporting systems proposed by different countries.

Ciliated muconodular papillary tumors (CMPTs) of the lung are rare, likely benign neoplastic lesions. Here we describe a case of a CMPT, focusing on its cytologic features, which to our knowledge have not been reported previously. Owing to dull back pain, a 69-year-old male non-smoker underwent CT, which revealed a 1.3 × 1.3-cm solid nodule in the peripheral field of the left lower lung lobe. A wedge resection of the nodule was performed, with the provisional diagnosis being primary lung cancer. Macroscopic examination of a resected specimen showed a 1.2-cm grayish nodule. Touch imprint smear cytology revealed ciliated columnar cells and mucous cells, as well as abundant extracellular mucin on inflammatory background of lymphocytes and histiocytes. Histologic examination revealed a nodular papillary tumor composed of ciliated columnar cells, mucous cells, and basal cells surrounded by a mucin pool. No nuclear atypia or mitotic figures were identified. The final diagnosis was CMPT. The postoperative course was uneventful, with no recurrence at 8 months after surgery. Although a CMPT is a rare lung tumor, it should be considered when cytological or histological examination of a solitary peripheral lung nodule shows non-atypical ciliated cells and mucous cells surrounded by mucin.

Objective: Morphological discrimination between malignant mesothelioma (MM) and reactive mesothelium (RM) is often difficult. Stereological analysis of nuclear luminance using centrifuged smear samples from coelomic fluid and discriminant analysis based on Mahalanobis distance may help to more accurately discriminate between MM and RM. In the present study, discriminant analysis was conducted on cytological specimens using the auto-smear method in a blinded manner with regard to histological results. Study Design: Coelomic fluid samples of 28 cases, cytologically diagnosed using the auto-smear method, were analyzed to determine pixel counts, the number of focus layers, 3-dimensional variation in the coefficient of variation of nuclear luminance between the focus layers as well as roundness in about 30-50 atypical cell nuclei per case. These measurements were employed to determine malignancy based on Mahalanobis distance. Results: Discrimination rates were as high as 91.7% for MM and 82.7% for RM. The discrimination rates of MM with histology were >80% in 8 of 10 suspicious cases with the initial cytology. Conclusion: Our method allowed accurate discrimination between MM and RM and provides a useful alternative for the diagnosis of suspicious cases where morphological diagnosis of malignancy is difficult.

Objective: The aim of this study was to evaluate whether the immunocytochemical expression of cell proliferation markers, such as minichromosome maintenance protein 7 (MCM 7), geminin, topoisomerase II alpha (topo IIα) and Ki-67, which are different types of cell proliferation markers, could be useful for their differential diagnosis in reactive mesothelial cells and malignant mesothelioma cells obtained from body cavity fluids. Study Design: Samples diagnosed and later histologically confirmed as reactive mesothelial cells (39 cases) or malignant mesothelioma (32 cases) in body cavity fluids were examined. Immunocytochemical staining of MCM 7, geminin, topo IIα and Ki-67 was performed with the immunoperoxidase polymer method. Results: Labeling indices (LIs) of MCM 7 (cutoff value 20.0%; sensitivity 100%; specificity 100%), geminin (cutoff value 4.5%; sensitivity 88.0%; specificity 70.0%), topo IIα (cutoff value 11.0%; sensitivity 88.0%; specificity 92.0%) and Ki-67 (cutoff value 15.3%; sensitivity 78.0%; specificity 79.0%) of malignant mesothelioma cells were significantly higher than those of reactive mesothelial cells. Conclusion: LIs of MCM 7, geminin and topo IIα can be reliable tools for the differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells.

The prognosis of urothelial carcinoma, micropapillary variant (MPV), of the bladder has been shown to be worse than that of the conventional urothelial carcinoma (UC). However, it remains to be clarified why the MPV is more aggressive. We therefore here focused on the correlation between clinical features and histological, immunohistochemical and molecular findings for eight MPV and 35 UC, evaluating expression of MUC1, Ki-67, p53, CD147, CD34, D2-40, and extracellular matrix proteins. The Ki-67 labeling index was significantly higher in UC than in MPV but densities of venous and lymphatic tumor emboli were significantly higher in the MPV cases and lymph node metastasis was more frequent, with a poorer prognosis. Tenascin-C and fibronectin also showed significantly greater expression in MPV than in UC at the epithelial-mesenchymal interfaces. Direct sequencing showed point mutations of KRAS exon 1 in three MPV with significantly more frequency compared to UC. Occupation rate of the MPV area in the tumor showed significant inverse correlation with overall survival. Thus our histopathological findings provide clues to explaining why prognosis is poorer in the MPV than UC.

目的: 子宮内膜細胞診において, Thinlayer 標本と従来の塗抹標本 (Conventional 標本) の診断成績を比較し, Thinlayer 標本の特性を明らかにする.方法: 内膜組織診とエンドサイトによる内膜細胞診を同一日に施行した 96 例を対象とした. 塗抹後のエンドサイトから Thinlayer 標本を作製し, 従来の診断基準で Thinlayer 標本も診断した. 組織診の結果を基に, 両細胞診標本の感度および特異度を求め, 細胞塗抹量, 鏡検時間, 細胞像について検討した.成績: Conventional 標本の感度/特異度は 87.0%/89.4%, Thinlayer 標本は 73.9%/70.2%であり, 後者が低かったがいずれも有意差は認めなかった. Thinlayer 標本は重積性が軽減され, 背景の赤血球や炎症細胞が大きく減少していた. 鏡検時間は Thinlayer 標本で有意に短縮された. しかし Conventional 標本とは異なる細胞像を示す傾向があった.結論: Thinlayer 標本による内膜細胞診標本は Conventional 標本と同程度の感度/特異度であり, Thinlayer 標本の特性を十分理解したうえで臨床応用は可能と思われる.

BACKGROUND Clear cell adenocarcinoma (CCA) of the minor salivary gland accounts for < 1% of all tumors of the salivary gland. CASE A 32-year-old woman with a history of papillary carcinoma of the thyroid 1 year earlier complained of pain on the left side of the neck. After a detailed examination, the patient underwent the resection of a tumor located at the palate. Imprint cytology of the tumor revealed cohesive tumor cells of uniform size containing an abundant clear cytoplasm and round nuclei with extra but fine granular chromatin and conspicuous nucleoli. A basement membrane-like substance (BMS) was stained in light green with Papanicolaou staining and was positive for laminin with immunohistochemical staining. Histopathologic analysis confirmed the trabecular or nest-like arrangement of the cells with the clear cytoplasm and BMS substance surrounded by tumor cells, which were positive for laminin and AE1 immunohistochemically. CONCLUSION Although CCA of the palate is extremely rare, an accurate cytologic diagnosis can be made if the characteristic findings of CCA, including BMS, are imaged.

背景:まれな卵巣甲状腺腫性カルチノイドを経験した. 細胞所見, 組織像と免疫組織化学, 特に二重染色結果を報告する.症例:59歳, 女性.下腹部痛, 腹部膨満感, 便秘を主訴として来院し, 左卵巣に腫瘍を認めた.捺印細胞像では, 均一な小型細胞が軽度重積性を示す集塊, 索状集塊あるいは散在性に出現し, 一部にはコロイド様無構造物質も認めた. 細胞質はライトグリーンに淡染し, 核は大小不同に乏しく, クロマチンは粗顆粒状に増量していた. 組織学的には甲状腺腫, カルチノイドおよびそれらの移行部分から構成されていた.thyrogloblin, thyroid transcriptional factor-1は甲状腺腫と移行部分の小濾胞構造に, chromogranin Aは甲状腺腫, カルチノイドの両者に陽性を示した. peptide YYはカルチノイド部分に陽性を示した.結論:診断には, カルチノイドに特徴的な細胞配列と甲状腺腫に特徴的な濾胞構造の両者に着目することが大切であった. 免疫組織化学より, 甲状腺腫部分が神経内分泌細胞としての性格を有していることから, 本腫瘍は甲状腺腫濾胞上皮からカルチノイドが発生していると考えた.

BACKGROUND Large cell neuroendocrine carcinoma (LCNEC) of the lung has been proposed as a new disease entity. To establish diagnostic features, bronchial brush cytologic findings were evaluated. METHODS Bronchial brush cytology material of 20 LCNECs was evaluated by light microscopy and stained immunocytochemically with protein gene product 9.5 (PGP9.5), neuron-specific enolase, and neural cell adhesion molecule antibodies. The findings were compared with those for 19 poorly differentiated adenocarcinomas (ACs), 18 poorly differentiated squamous cell carcinomas (SCCs), and 20 small cell lung carcinomas (SCLCs). RESULTS Frequently observed characteristic cytologic findings of LCNECs were necrotic background (90.0%), large tumor cell size (90.0%), naked nuclei (90.0%), and nuclear streaking (90.0%). Nuclei in all LCNECs showed a fine granular chromatin pattern and possessed one or a few nucleoli. Indian-filing and rosette arrangements were observed in less than one-half of the LCNECs. In poorly differentiated ACs and SCCs, these features were less frequent, whereas thick nuclear membranes were observed more often. In SCLCs, tumor cell adhesions and Indian-filing or nuclear molding were observed more frequently than in LCNECs, whereas a necrotic background, tumor cell clusters, large tumor cells, and nucleoli were less prominent. The majority of LCNECs (80.0%) had a positive immunocytochemical reaction for PGP9.5, in contrast to the low positive reactions for ACs (42.1%) and SCCs (30.8%). CONCLUSIONS Large cell neuroendocrine carcinomas can be diagnosed preoperatively by bronchial brush cytology using reliable parameters, including tumor cell size, naked nuclei, thin nuclear membranes, nuclear streaking, high PGP9.5 positivity, and a necrotic background. Cancer (Cancer Cytopathol) 2003;99:247–54. © 2003 American Cancer Society.

本邦においても子宮体癌は増加傾向にあるが, 内膜増殖症はその前癌病変として注目されている.また, 早期体癌は高率に内膜増殖症を合併していることから, 前癌状態での発見のみならず, 体癌の早期発見のためには, この増殖症を細胞診断する意義はきわめて高い.一方, 1996年に改訂された子宮体癌取り扱い規約で, 子宮内膜増殖症は単純型, 複雑型, 単純型異型, 複雑型異型の4型に分類されることとなった.そこで, この複雑型増殖症と複雑型異型増殖症の細胞所見について検討したところ, 複雑型増殖症では (1) 背景に出血はあっても壊死物質は出現しない,(2) 多くの場合正常増殖期内膜の共存を認めるが, 正常増殖期よりは集塊の出現数が多い,(3) 細胞集塊辺縁の乳頭状突出, 半島状突出を認める,(4) 有端集塊, 分枝集塊の頻度が高い,(5) 腺細胞の重層化・腺管の増生back to back,(6) 集塊辺縁の柵状配列の乱れが特徴的であった.複雑型異型増殖症ではさらに,(7) 重層性の強化,(8) 核の大小不同・著明な核小体を伴っていた.

The prognosis of urothelial carcinoma, micropapillary variant (MPV), of the bladder has been shown to be worse than that of the conventional urothelial carcinoma (UC). However, it remains to be clarified why the MPV is more aggressive. We therefore here focused on the correlation between clinical features and histological, immunohistochemical and molecular findings for eight MPV and 35 UC, evaluating expression of MUC1, Ki-67, p53, CD147, CD34, D2-40, and extracellular matrix proteins. The Ki-67 labeling index was significantly higher in UC than in MPV but densities of venous and lymphatic tumor emboli were significantly higher in the MPV cases and lymph node metastasis was more frequent, with a poorer prognosis. Tenascin-C and fibronectin also showed significantly greater expression in MPV than in UC at the epithelial-mesenchymal interfaces. Direct sequencing showed point mutations of KRAS exon 1 in three MPV with significantly more frequency compared to UC. Occupation rate of the MPV area in the tumor showed significant inverse correlation with overall survival. Thus our histopathological findings provide clues to explaining why prognosis is poorer in the MPV than UC.

The aim of this study was to evaluate the significance of abnormal squamous cells (ASCs) in urinary cytology to clarify whether finding of ASCs could improve diagnostic accuracy. A total of 3,812 urine specimens were reviewed. We focused on three parameters of ASCs, necrotic debris, and ASC clusters, and linked them to histological diagnosis and clinical information. ASCs were identified in 34 (0.9%) specimens from 21 different patients. The incidence of ASCs was higher in females than in males. The 34 urine specimens were categorized as voided urine (16 cases), bladder-catheterized urine (17 cases), and bladder-washed fluid (1 case). Six (28.6%) of 21 patients were histologically diagnosed as having combined urothelial carcinoma and squamous cell carcinoma (SCC). Eight patients (38.1%) were histologically diagnosed as having SCC originating from sites other than the urinary tract; those urine specimens showed ASCs that were likely to have been exfoliated from malignant lesions. Necrotic debris and ASC clusters were identified in 12 specimens (35.3%) from 11 patients and 4 specimens (11.8%) from 4 patients, respectively, from a total of 34 specimens. Our results indicate that a great amount of care is needed for cytological diagnosis when attempting to recognize ASCs in urine specimens because ASCs were identified in not only SCC of the bladder but also in carcinoma or nonmalignant lesions of nonurinary tracts. Necrotic debris was found not only in patients who had malignant bladder tumors but also in those who had malignant lesions in locations other than the bladder.

Clear cell adenocarcinoma (CCA) of the minor salivary gland accounts for1% of all tumors of the salivary gland.A 32-year-old woman with a history of papillary carcinoma of the thyroid 1 year earlier complained of pain on the left side of the neck. After a detailed examination, the patient underwent the resection of a tumor located at the palate. Imprint cytology of the tumor revealed cohesive tumor cells of uniform size containing an abundant clear cytoplasm and round nuclei with extra but fine granular chromatin and conspicuous nucleoli. A basement membrane-like substance (BMS) was stained in light green with Papanicolaou staining and was positive for laminin with immunohistochemical staining. Histopathologic analysis confirmed the trabecular or nest-like arrangement of the cells with the clear cytoplasm and BMS substance surrounded by tumor cells, which were positive for laminin and AE1 immunohistochemically.Although CCA of the palate is extremely rare, an accurate cytologic diagnosis can be made if the characteristic findings of CCA, including BMS, are imaged.

To clarify whether the 3 parameters of cell clusters, cell cannibalism and nucleus-fragmented cells could improve diagnostic accuracy for grade 1 urothelial carcinoma (G1UC).A total of 52 voided urine samples from 31 patients histologically diagnosed as having G1UC were reviewed. In addition, 10 voided urine samples from cases with grade 3 demonstration urothelial carcinoma (G3UC) and 30 voided urine samples from 25 patients with a histologic diagnosis of chronic inflammation of the bladder were evaluated for comparison. Areas of tumor cells with cannibalism were measured.Cell cannibalism was evident in 12 of 31 G1UC cases (38.7%), significantly less often than with G3UC, but never identified in the control group. Mean areas of tumor cells featuring cannibalism were significantly smaller in G1 UC than in G3UC cases. Nucleus-fragmented cells were also less frequent in G1UC than in G3UC, but more common than in the control group.Cell cannibalism and nucleus-fragmented cells in voided urine with special attention to areas of tumor cell with cannibalism could be applied as a parameter to improve diagnostic accuracy for G1UC.

To objectively evaluate the difference in cytologic findings between specimens of voided and catheterized urine by using a comparative image analysis device, CAS200.Cells in voided and catheterized urine from 13 patients with transitional cell carcinoma (TCC), including 3 with grade 1, 6 with grade 2 and 4 with grade 3, were compared cytologically. The cellular area, nuclear area, nuclear/cytoplasmic ratio and nuclear density of both types of cytologic specimen were measured using CAS200.Cell area and nuclear area of grade 1 TCCs were significantly greater in voided urine than in catheterized urine. In contrast, cell area and nuclear area of grade 3 TCCs were significantly smaller in voided urine than in catheterized urine (P.01), and nuclear density of grade 3 TCCs was higher in the latter than in the former.The cellular findings in voided urine were different from those in catheterized urine from the same patient. Thus, the method selected for obtaining urine specimens will affect the findings in urinary cytology.