Fine-needle aspiration of malignant mesothelioma with unusual morphologic features: a case report

Malignant mesothelioma is an aggressive neoplasm linked to asbestos exposure. Most mesothelioma patients present with pleural effusion and the fluid is typically sent for cytological examination. Therefore, cytopathologists are most familiar with features of mesothelioma in fluid preparations. We present here a case of malignant mesothelioma with unusual cytological features diagnosed on FNA. The diagnosis was confirmed by immuno-histochemical and electron microscopic studies. In addition, we compare the cytomorphological features observed in malignant effusion versus fine-needle aspiration.     

Pleuramesotheliom

The definitive diagnosis of malignant mesothelioma (MM) in effusion cytology is often avoided or reluctantly made by cytology alone. The most probable reason for this skepticism is the lack of expertise in cytology among many pathologists and clinicians. When an effusion specimen is composed of cells with unequivocal cytological features of malignancy that have the morphology and immunophenotype of mesothelial cells, the cytological diagnosis of MM is straightforward. However, in the daily routine difficult cases of atypical mesothelial cells are often encountered and additional methods are required to establish an accurate diagnosis. In contrast to reactive mesothelial cells cells of MMs often harbor chromosomal aberrations, most frequently a polysomy in combination with a 9p21 deletion. These chromosomal aberrations can easily be detected by multitarget fluorescence in situ hybridization (FISH); therefore, FISH allows a reliable distinction between reactive mesothelial cells and MM cells. In order to be able to discriminate between MM and adenocarcinoma, an immunocytochemical panel consisting of different mesothelial and epithelial markers is very helpful. In most inconclusive cases of atypical mesothelial cells the combination of morphology, immunocytochemistry and FISH allows a better distinction between reactive mesothelial cells and MM in effusion cytology.     

用免疫细胞化学鉴别胸腹水脱落细胞在肿瘤诊断中的价值

探讨免疫细胞化学鉴别胸腹水中上皮来源恶性肿瘤细胞和间皮源性细胞的价值。应用免疫细胞化学方法,检测80例患者胸腹水恶性肿瘤细胞和间皮细胞的细胞学形态及ESA、CEA、CK、D2-40、CR、Mesothlial、KI67、Vimentin等8种蛋白的表达情况。结果表明：胸腹水脱落细胞学检测和这8种蛋白联合检测可鉴别上皮来源恶性肿瘤细胞和间皮细胞。两种方法联合检测胸腹水,提高了脱落细胞学疑难病例诊断的准确率。     

Scoring system for differential diagnosis of malignant mesothelioma and reactive mesothelial cells on cytology specimens

Cytology is the only useful tool in the detection of malignant mesothelioma (MM) at an early stage. No other methods, such as immunocytochemistry or electron microscopy, are available to distinguish MM from reactive mesothelial cells (RMC). Some objective analysis of cytology specimens is necessary. On the basis of our case review and cytological features described in previous articles, we developed a scoring system for malignant mesothelioma (SSMM) of effusion cytology to distinguish MM cells from RMC. Mesothelioma cells in effusions from 22 patients (20 pleural and 2 peritoneal mesotheliomas) were compared with RMC from 20 patients without obvious tumor cells and 50 effusions containing metastatic carcinoma cells. The SSMM is based on characteristic features of mesothelial and malignant cells. The total achievable score is 10 points: one point each is given for variety of cell size, cyanophilic cytoplasm with villosity/windows/bleb, sheet‐like arrangement, mirror‐ball‐like cell clusters, nuclear atypia, and cannibalism, respectively. Further two points each are ascribed for acidophilic large nucleoli and multinucleated cells with more than eight nuclei. The total score for each of the 22 mesotheliomas was more than 5 points. On the other hand, all RMC and the 50 metastatic carcinoma cases scored less than 3 points, aside from two cases that were treated with OK432. No single characteristic feature was observed to be consistent within the 22 mesotheliomas analyzed. Ancillary use of immunocytochemistry, such as podoplanin (D2‐40) and calretinin, supported the diagnostic accuracy of the SSMM. SSMM is useful for the differential diagnosis of MM. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Fluoreszenz-in-situ-Hybridisierung

Fluorescence in situ hybridization (FISH) is a powerful method for the identification of chromosomal aberrations to improve the diagnostic performance of cytology. FISH is applicable to almost any type of cytological specimen irrespective of cell type, staining or fixation modality. Multi-target tests for the simultaneous analysis of four chromosomes or chromosomal loci improves the sensitivity of cytological diagnosis in bladder and lung cancer and is most helpful in equivocal cytology. FISH also allows a reliable distinction between malignant mesothelioma and reactive mesothelial cells. Specific translocations can easily be detected by FISH for precise diagnosis of lymphomas and sarcomas. Testing for HER-2 amplification has become a standard method to select patients with breast cancer for therapy with trastuzumab. Co-analysis of HPV and selected genes could become a useful approach in gynecological cytology. The spectrum of diagnostic FISH applications is continuously growing.     

Thoracic and abdominal mesothelioma in a dog: a cytologist��s view

Mesothelioma is an uncommon tumour in dogs, whose diagnosis can be a challenge to the veterinary cytologist. This paper aims to report a case of mesothelioma in a dog, obtained from the cytological analysis of pleural and abdominal fluid, which allowed an in vivo diagnosis. A 4.10-year-old-boxer dog was presented for clinical care with abdominal distension, difficulty in breathing and loss of appetite. Laboratorial and imaging tests were performed, and the cytology of abdominal and pleural effusions suggested the presence of mesothelioma. The cytology was ratified later by a histopathology of the lungs, ovaries, liver, spleen, peritoneum and omentum.     

Diagnosis of pleural malignant mesothelioma in life--a practical approach

This review documents a practical approach to the pathological diagnosis of pleural malignant mesothelioma based on the closed needle biopsy and effusion cytology, thus avoiding the need to resort to open surgery. Tissue diagnosis is often difficult, and the pathologist's opinion may be influenced by a consideration of three factors: the clinical setting; the adequacy and availability of specimens; and the criteria for assessment and interpretation of these. The level of confidence with which a tissue diagnosis of mesothelioma can be established using limited material depends on there being an appropriate clinical background including a history of asbestos exposure. Without this, the diagnosis should be a qualified or tentative one. For an adequate tissue sample to be obtained, the closed needle biopsy procedure is best performed by an experienced operator. All aspirated pleural effusions should be forwarded for cytological evaluation. In addition to conventional morphological studies, adequate samples permit ancillary tests to be carried out. A combined interpretive approach utilizing both histopathology and cytology is recommended in order to increase the accuracy of the diagnosis.     

Fine‐needle aspiration of a well‐differentiated papillary mesothelioma in the inguinal hernia sac: A case report and review of literature

Well‐differentiated papillary mesothelioma (WDPM) is an uncommon subtype of epithelioid mesothelioma. In contrast to malignant epithelioid mesothelioma, WDPM has a low malignant potential and an indolent clinical course. WDPM may be difficult to diagnose and differentiate from benign reactive mesothelial cells and other malignant neoplasm on cytology specimens due to the presence of papillary or tubulopapillary clusters of tumor cells. We report a case of a 63‐year‐old Asian male with a slowly growing left inguinal hernia mass for several years and a concurrent 8 cm mass in the peritoneal wall. The cytology of ultrasound‐guided fine‐needle aspiration (FNA) of the left inguinal hernia and peritoneal masse reveal cellular specimens with numerous individual and tubulopapillary clusters of epithelioid mesothelial cells in a background of scant hyalinized material. Tumor cells show minimal cytological atypia. The differential diagnoses are broad and include reactive mesothelial cells, WDPM, and other malignant neoplasm. The follow‐up surgical resection of masses reveals features of WDMP. It is important to recognize this entity in the differential diagnosis, because the clinical management of WDPM is quite different from that of malignant neoplasm. On the basis of the published data in the literature, it suggests that in male patients, the WDPM occurs predominantly in pleural cavity of older men in their 50s, and about half of the patients have history of asbestos exposure. However, the data is limited and insufficient for a definitive conclusion. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Exfoliative cytology of diffuse mesothelioma

The exfoliative cytology of 14 diffuse mesothelioma (11 pleural and three peritoneal) is described. Malignant cells were identified in 10 patients; in eight malignant cells still retaining the characteristics of mesothelial cells were found. It is suggested that only if malignant cells of this type are recognized should the probable diagnosis of diffuse mesothelioma be made.     

Diffuse malignant mesothelioma of the pleura: A clinicopathological study of six patients with a prolonged symptom-free interval or extended survival after biopsy and a review of the literature of long-term survival

Diffuse malignant mesothelioma of the pleura generally proceeds rapidly with clinical deterioration soon after the initial histopathological diagnosis of the tumor. We encountered six patients in whom the symptom-free interval after biopsy was surprisingly prolonged. Histopathologically, the tumor in each case was epithelioid with prominent myxoid stroma and formation of tubules and micropapillae. Cytologically, the malignant cells had relatively regular nuclei with bland chromatin. As individual findings, these histological and cytological features are common in diffuse malignant mesothelioma. However, the combination of (1) bland cytology of epithelioid cells, (2) formation of tubular and micropapillary patterns, (3) a myxoid stroma and (4) an absence of sclerosing desmoplasia, as observed in these six cases, might indicate indolent disease at the outset in a few patients. It is possible that these features are related to early stage of disease rather than having discriminatory value in their own right. We do not conclude that initially restrained disease necessarily presages a longer mean survival because the follow-up in these patients has not been long enough. We present these observations because, to date, this malignancy has proven so refractory to clinical management.     

Lymphohistiocytoid mesothelioma of the pleura: A case report with cytological findings

Lymphohistiocytoid malignant mesothelioma is an infrequent variant of sarcomatoid mesothelioma representing approximately 0.5–3.3% of malignant mesotheliomas. It has been related to asbestos exposure. The tumor is characterized by a diffuse large histiocyte‐like cells proliferation mixed with an inflammatory infiltrate of lymphocytes and plasma cells. Its cytological diagnosis is difficult. We present a case of a 67‐year‐old female with lymphohistiocytoid mesothelioma involving the left pleura. The cytological, histological, and immunohistochemical features are discussed. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

Desmoplastic small round cell tumor with sphere‐like clusters mimicking adenocarcinoma

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive neoplasm that predominantly affects young men. DSRCT often presents as multiple nodules on the serosal surface and is histologically categorized as a small round cell tumor. However, the cytological spectrum of DSRCT is not fully understood because of its rarity. Here, we report an unusual case of DSRCT that showed spheres of cells without stromal cores in pleural fluid cytology material, a finding that is typically associated with metastatic adenocarcinoma and mesothelioma. The specimen from a simultaneous needle biopsy showed the classic histology of DSRCT, comprising nests of small round cells set in desmoplasia. The diagnosis of DSRCT was further supported by immunohistochemical coexpression of cytokeratin and desmin, as well as Ewing sarcoma breakpoint region 1 gene rearrangement, which was determined by fluorescence in situ hybridization. The unusual cytological finding in this case illustrates a potential pitfall of the cytological diagnosis of pleural fluid or ascites. DSRCT should not be excluded from the differential diagnosis when sphere‐like round cell clusters are observed in pleural or abdominal effusion, particularly in young male patients. Diagn. Cytopathol. 2015;43:214–217. © 2014 Wiley Periodicals, Inc.     

Use of p16 FISH for differential diagnosis of mesothelioma in smear preparations

Because most of malignant pleural mesothelioma (MPM) patients first present with pleural effusion, detection of mesothelioma cells on effusion smears is critical for early diagnosis. Recently, accumulating evidence indicating that the cytological diagnosis of MPM supported by ancillary techniques is as reliable as that based on histopathology has led to new guidelines for the cytopathologic diagnosis of MPM. Based on the guidelines, a combination of cytomorphological criteria and verification by ancillary techniques is required for the cytologic diagnosis of MPM. Detection of p16 homozygous deletion by fluorescence in situ hybridization (FISH) is the most reliable ancillary technique for differentiating MPM from reactive mesothelial cells (RMC) because of its relatively high sensitivity and extremely high specificity. We showed that the p16 deletion status of MPM cells in pleural effusions reflected that of the underlying invasive MPM tissues, indicating the usefulness of p16 FISH in effusion smear cytology for MPM diagnosis. Thus, for differentiating MPM from RMC, we propose to perform p16 FISH as often as possible. A positive p16 homozygous deletion supports the diagnosis of MPM. However, a negative result does not rule out the possibility of MPM. In such cases, a morphological assessment is critical. Therefore, we analyzed the morphological characteristics of p16 deletion‐positive mesothelioma cells using a combination of virtual microscopy and p16 FISH, and identified three morphological characteristics useful for the differentiation, including cell‐in‐cell engulfment with or without hump formation, multinucleate cells, and larger berry‐like cell aggregates. Diagn. Cytopathol. 2016;44:774–780. © 2016 Wiley Periodicals, Inc.     

“Signet‐ring” cells—A caveat in the diagnosis of a diffuse peritoneal mesothelioma occurring in a lady presenting with recurrent ascites: An unusual case report

A diffuse peritoneal mesothelioma is a rare tumor. Exfoliative cytology forms the first step in the diagnosis of mesothelioma, since most of these cases presented with effusion. Despite well established cytomorphological features, a challenge exists in differentiating mesothelial cells, including reactive and malignant types from carcinoma cells and macrophages. Presence of “signet‐ring” cells increases the diagnostic challenge as these can be forms of benign and malignant cells. Ancillary techniques like immunohistochemical (IHC) markers and ultrastructural analysis form useful adjunct in substantiating exact diagnosis. We report an unusual case study of a diffuse peritoneal mesothelioma in a 57‐years‐old lady, with no history of asbestos exposure, presenting with recurrent ascites, diagnosed on ascitic fluid cytology and on histology as an adenocarcinoma, based upon the presence of “signet‐ring” cells. On review, clinicopathological correlation with IHC was helpful in forming correct diagnosis. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

Image cytometry: an aid for cytological diagnosis of pleural effusions

The conventional cytology rate for identification of neoplastic cells in effusions is about 60%. The rate of diagnostically equivocal effusions in routine cytology is dependent on the volume of effusion examined, type of preparation and staining, experience of the examiner, and application of ancillary methods. The aim of our study was to confirm the role of image cytometry analysis (DNA-ploidy) on pleural effusions. In this retrospective study based on 42 available cases with a histological diagnosis, we have examined 13 reactive mesothelial proliferations and 29 cases of malignant tumors (adenocarcinoma [ACA] or mesothelioma). The smears collected were submitted to the image analysis following a-three step protocol (smears stained with the Papanicolaou method were destained and then restained with Feulgen staining and finally analysed using image analysis cytometry). The results have shown that nonmalignant cases (reactive mesothelial proliferation) were all diploid and in contrast all aneuploid cases corresponded to malignant tumors. Only three mesotheliomas showed a diploid profile. In conclusion, these results confirm data from literature and indicate that cytometric analysis of nuclear content is a useful marker for identification of malignant cells in equivocal effusions and can be used to increase the cytological sensitivity in doubtful mesothelial proliferations.     

The value of ThinPrep and cytospin preparation in pleural effusion cytological diagnosis of mesothelioma and adenocarcinoma

The diagnosis of malignant mesothelioma requires an integration of the clinical presentation, radiological studies, and immunohistochemical stain of histological sections. Cytological diagnosis on pleural effusions of mesothelioma and pulmonary adenocarcinoma is highly desirable but debatable. A spectrum of cytological features has been found to be associated more commonly with malignant mesothelioma (e.g., peripheral cytoplasmic skirt, bubbly cytoplasm, cyanophilic cytoplasm, and scalloped border of cell balls) vs. adenocarcinoma (e.g., two-cell population, inspissated cytoplasmic material, cytoplasmic vacuole, angulated and indented nuclei, and smooth border of cell balls) to only name a few. The current study is designed to assess whether the introduction of a liquid-based technology such as ThinPrep (TP) can provide additional diagnostic value in addition to the conventional cytospin Diff-Quik (DQ) preparations. Pleural effusion specimens were prepared with split samples for DQ-stained cytospin and Papanicolaou-stained liquid-based TP. Fifteen pleural effusion samples with immunohistologically confirmed malignant mesothelioma and 13 pleural effusion samples of immunohistologically confirmed pulmonary adenocarcinomas were retrieved from our files. Both DQ cytospin- and Papanicolaou-stained TP slides were evaluated for the known cytological features associated with malignant mesothelioma (25 cytological features) and adenocarcinoma (22 cytological features) without knowledge of the original cytological and histological diagnoses. The McNemar test was used to compare these two cytological preparations for both malignant mesothelioma and pulmonary adenocarcinoma. In the malignant mesothelioma group, 4 of 25 cytological features evaluated, bubbly cytoplasm (P = 0.002), vacuolated cytoplasm (P = 0.005), cell-in-cell arrangement (P = 0.007) and irregular nuclear contour (P = 0.083), were seen more frequently in the DQ cytospin preparation, as opposed to only one feature, nuclear size enlargement (P = 0.008), more readily seen using TP. In the pulmonary adenocarcinoma group, only 1 of 22 cytological features evaluated, presence of angulated or indented nuclei (P = 0.025), was seen more frequently in DQ as opposed to two features, presence of two- cell population (P = 0.04) and presence of micropapillary structures (P = 0.1), were seen more readily in TP. All other cytological features evaluated distinguishing mesotheliomas (20 features) and pleural adenocarcinomas (19 features) were seen equally readily in both types of specimen preparation techniques. This study suggests that the liquid-based TP preparation of pleural effusions does not appear to provide additional diagnostic value when compared with the DQ cytospin preparation in the cytological distinction between mesothelioma and adenocarcinoma in pleural effusions. Most cytological features evaluated, 20 of 25 (mesothelioma) and 19 of 22 (adenocarcinoma), can be seen in both preparation techniques.     

Primary angiosarcoma of the thyroid gland with recurrence diagnosed by fine needle aspiration: A case report

Angiosarcoma of the thyroid is a rare and aggressive primary malignant tumor of the thyroid originally reported in patients from the Swiss Alpine region. Diagnosis of this tumor rests mainly on characteristic histopathological features of a malignant vascular tumor supported by immunopositivity for vascular markers e.g., CD31, Factor VIII, and CD34. Its cytological features, however, are not well‐defined. We describe a case of primary angiosarcoma of the thyroid in a 48‐year‐old female, who presented with a rapidly enlarging neck mass associated with compressive symptoms. She had a history of hypothyroidism. The initial fine needle aspiration cytology of the neck mass was negative. She then underwent left hemithyroidectomy. Histologically, the tumor showed poorly differentiated malignant cells with eccentrically‐placed nuclei, prominent nucleoli, and intracytoplasmic vacuoles admixed with mixed inflammatory cells. These showed immunopositivity for CD31 but were negative for CD34, Factor VIII, CK5/6, EMA, TTF‐1, Thyroglobulin, Calcitonin, Melan A, and Calretinin. A diagnosis of poorly differentiated malignant tumor consistent with angiosarcoma was made. The patient was treated with radiation therapy but developed recurrence of the tumor. Second aspiration cytology of the recurrent tumor yielded hypocellular smears containing singularly dispersed atypical cells having eccentrically‐placed nuclei with prominent macronucleoli and intracytoplasmic vacuoles within a background of inflammatory cells, consistent with recurrent angiosarcoma. Chemotherapy was started but she succumbed to the disease 7 months after diagnosis. The cytological, histopathological, immunohistochemical findings, and the clinical course are discussed. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Value of p53 immunostaining in pancreatico-biliary brush cytology specimens

Brush cytology is routinely used in the assessment of pancreatico-biliary strictures but the technique has limited diagnostic sensitivity in malignant lesions. It has been suggested that ancillary techniques, such as the identification of p53 immunoreactivity, might improve diagnostic accuracy. p53 protein expression was examined in 143 consecutive brush cytology specimens from patients with pancreatic or bile duct strictures and correlated with conventional cytological assessment and clinicopathologic follow-up data. Sixty-three of 89 (70.8%) malignant strictures were identified cytologically while 45 cases (50.6%) were p53 immunoreactive. One case of bile duct adenoma with high-grade dysplasia was reported as consistent with adenocarcinoma cytologically and was p53 negative. There was one false-positive diagnosis with conventional cytology and, in a separate case, with p53 immunostaining. Nineteen specimens (13.3%) were considered atypical cytologically and p53 expression proved accurate in only 12 cases (four immunopositive carcinomas and eight negative benign strictures). In conclusion, p53 immunostaining proved less sensitive than conventional cytology in this series and its routine diagnostic use could not be supported.