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Calretinin (CR) is a valuable marker in the immunohistochemical distinction between malignant mesothelioma (MM) and adenocarcinoma (ACA) in tissue sections. However, there is limited and conflicting data regarding the utility of CR in this differential diagnosis on cytologic material, especially cell block preparations. Also, the possible role of CR in the distinction of papillary serous borderline tumor (SBT) cells from reactive mesothelial cells in peritoneal washings has not been examined. Formalin-fixed paraffin-embedded cell block specimens of cytologic fluids, washings, and aspirates with a suspicious or positive cytologic diagnosis and a confirmed diagnosis of MM (29 cases), ACA (39 cases), and SBT (10 cases) were used for CR immunohistochemistry (IHC). Moderate to strong staining in > 50% of tumor cells was noted in 26 of 29 (90%) MMs but in only 3 of 39 (8%) ACAs and 1 of 10 (10%) SBTs. Admixed reactive mesothelial cells (when present) were strongly positive in all fluid specimens, but the staining pattern of benign non-reactive mesothelial cells in washing specimens was less reliable. CR is both a sensitive and specific marker of reactive and neoplastic mesothelial cells in cytologic cell block preparations and is thus useful in the differential diagnosis of MM and metastatic ACA in malignant effusions. However, CR IHC does not appear to allow definitive identification of SBT in peritoneal washings. Cancer (Cancer Cytopathol) 2000;90:312–9. © 2000 American Cancer Society.

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BACKGROUND:This study was conducted to evaluate the reliability and role of cell block preparations in the diagnosis of neoplastic and preneoplastic lesions of the cervix and to improve the value of cell block preparations in diagnosing and predicting the prognosis of cervical lesions through immunostaining of p16INK4A p16, Ki67, and human papillomavirus HPV L1 capsid protein HPV L1.METHODS:In total, 138 specimens were diagnosed on liquidbased cytology LBC and cell block preparations, and 63 specimens were subjected subsequently to tissue followup and immunostaining for p16, Ki67, and HPV L1 on cell block sections.RESULTS:In 42 specimens that were diagnosed as lowgrade squamous intraepithelial lesion, highgrade squamous intraepithelial lesion HSIL, and squamous cell carcinoma SCC on cell blocks, 38 specimens 90.5 were confirmed by histopathologic reports, and there was slightly better than 81.6 agreement between LBC and tissue followup. Immunointensity and cells that were positive for p16 were enhanced according to increased pathologic grade and differed statistically between cervical intraepithelial neoplasia 1 CIN1 and CIN2CIN3 as well as SCC. The positive rates of HPV L1 decreased gradually according to the severity of cervical neoplasia, and HPV L1p16 expression patterns were related to the severity of cervical lesions.CONCLUSIONS:The cell block preparation technique was complementary to LBC, and the authors concluded that the application of LBC combined with cell block preparations may improve the diagnostic accuracy of cytology. Immunostaining for p16 and Ki67 on cell block preparations can help to improve the diagnostic accuracy of HSIL and SCC. A combined expression pattern of p16 and HPV L1 may serve as a valuable index for predicting prognosis and followup of cervical dysplastic lesions. Cancer Cancer Cytopathol 2010. © 2010 American Cancer Society.

Cell blocks can be prepared from residual thin‐layer cervicovaginal (ThinPrep) material and can be used in immunohistochemical staining assays for p16INK4a and Ki‐67, which are surrogate markers related to human papillomavirus infection and cell proliferation, respectively. The objectives of the current study were 1) to investigate the feasibility and the role of cell block preparations in identifying significant neoplastic and preneoplastic lesions of the uterine cervix and 2) to assess the feasibility of using p16INK4a and Ki‐67 immunohistochemical staining patterns on cell blocks to identify significant preneoplastic cervical lesions.Cervicovaginal cytology specimens from 85 patients were analyzed. Cytologic diagnoses based on ThinPrep Papanicolaou test results were as follows: squamous cell carcinoma was diagnosed in 3 specimens, high‐grade squamous intraepithelial lesions (HSIL) were diagnosed in 27 specimens, low‐grade squamous intraepithelial lesions (LSIL) were diagnosed in 20 specimens, and atypical squamous cells of uncertain significance (ASCUS) were diagnosed in 11 specimens. Diagnoses of negativity for intraepithelial lesions or malignancy (NILM) were made in 24 specimens. Cell block sections were stained with hematoxylin and eosin and were immunostained with antibodies against p16INK4a protein and Ki‐67 antigen.The cytomorphologic diagnoses made using cell block preparations were as follows: SCC in 2 specimens, HSIL in 20 specimens, LSIL in 30 specimens, NILM in 32 specimens, and no diagnosis in 1 specimen. In 62 cases (73%), the diagnoses made using cell block preparations were in agreement with the ThinPrep diagnoses. Immunostaining of cell blocks for p16INK4a and Ki‐67 exhibited a statistically significant association (P < 0.05) with the presence of significant lesions on either cell block or ThinPrep analysis.To the authors' knowledge, p16INK4a has not been analyzed previously in ThinPrep cell blocks, and the correlation between Ki‐67 expression and cell block diagnoses also has not been reported previously. The current results indicate that cell blocks prepared from residual ThinPrep material represent an additional reliable diagnostic tool in the evaluation of cervical samples. Furthermore, immunohistochemical studies may be helpful in differentiating significant preneoplastic changes from other cervical lesions, such as atrophy. Cancer (Cancer Cytopathol) 2004. © 2004 American Cancer Society.

It has been shown that detection of the Wilms tumor susceptibility gene 1 protein (WT1) has diagnostic utility in the distinction of mesothelioma from adenocarcinoma in tissue sections of pleural tumors. This immunohistochemical study evaluates the effectiveness of WT1 as a marker for malignant mesothelioma in paraffin sections of cell block preparations derived from effusion specimens.The authors evaluated 111 cell blocks for WT1 immunoreactivity, including 14 mesotheliomas and 97 metastatic adenocarcinomas from various sites.Nuclear reactivity for WT1 was observed in all samples of mesothelioma. However, only 22 of 97 samples (23%) of metastatic adenocarcinoma, nearly all of which were of ovarian origin (91%), exhibited nuclear reactivity for WT1. In 14 other samples (most of pulmonary derivation), WT1 staining restricted to the cytoplasm was observed for some tumor cells and was regarded as nonspecific.Based on this staining profile, WT1 represents an effective marker for mesotheliomas in cell block preparations and can aid in its distinction from pulmonary adenocarcinoma. In assessment of effusion specimens with metastatic carcinoma, nuclear reactivity for WT1 is highly suggestive of an ovary primary tumor. Cancer (Cancer Cytopathol) 2002;96:000–000. © 2002 American Cancer Society.

BACKGROUND:Paired box gene 8 PAX8, a member of the thyroidspecific transcription factors, has recently been investigated as a useful marker of thyroid epithelial neoplasms. To the authors knowledge, its utility in the immunohistochemistry of papillary thyroid carcinoma PTC has not been well studied to date. The goal of the current study was to compare the immunohistochemical expression of PAX8 with HBME1 and cytokeratin 19 CK19 expression on cell block preparations of PTC and benign thyroid nodules BTN.METHODS:Thirtytwo cases of PTC and 20 cases of BTN diagnosed on fineneedle aspiration were included. The cell blocks were immunohistochemically stained for PAX8, HBME1, and CK19.RESULTS:PAX8 demonstrated nuclear positivity in >90 of cases with PTC 31 of 32 cases; 96.9 and BTN 20 of 20 cases; 100, with a high sensitivity 0.97, but low specificity 0. HBME1 and CK19 were found to have high sensitivity 0.78 and 0.75, respectively and specificity 0.95 for both for PTC. Statistically significant differences in staining intensity and distribution were noted for the PAX8 antibody negative 1 of 32 cases to weakly positive 20 of 32 cases in 65.6 of PAX8positive PTCs, and intermediate to strong in 100 of BTNs.CONCLUSIONS:In contrast to PAX8, HBME1 and CK19 were found to have a high degree of both sensitivity and specificity for PTC. The results of the current study demonstrate that strong PAX8 staining appears to be typical of BTNs, whereas negative to weakly positive staining is noted in PTC. PAX8, HMBE1 and CK19 may all play a role, particularly as a panel; however, the interpretation of PAX8 should consider the intensity and distribution of staining. Cancer Cancer Cytopathol 2010. © 2010 American Cancer Society.

BACKGROUND:Thyroid fineneedle aspiration FNA samples that feature a follicularpatterned, monotonous Hurthle oncocytic cell population cannot be diagnosed reliably. The authors of this report recently identified cyclin D3 overexpression on histologic sections of Hurthle cell carcinoma. In this study, they assessed the diagnostic value of cyclin D3 immunohistochemistry added to routine cytology.METHODS:Fiftyone FNA samples that were suspicious for Hurtle cell neoplasia and that had histologic followup 19 malignant cases were examined. Cyclin D3 expression levels were evaluated in cell block preparations and were compared with levels of the closely related cyclin D1 protein.RESULTS:Greater than 25 positive cells were used as the cutoff point, as suggested by previous studies. Cyclin D1 and cyclin D3 were highly specific 100 for both and fairly accurate 75 and 92, respectively in distinguishing between benign and malignant oncocytic lesions; the positive predictive value PPV for each was 100. However, both cyclins D1 and D3 had low sensitivity 32 and 79, respectively and low negative predictive value NPV 71 and 89, respectively. In contrast, by adopting balanced receiver operating characteristicderived positive cutoff values, cyclin D1 ≥6.5 and cyclin D3 ≥7.5 were found to be highly sensitive 100 for both and accurate 90 and 94, respectively; and the NPV was 100 for both. In contrast, cyclins D1 and D3 had low specificity 84 and 91, respectively and a low PPV 79 and 86, respectively; however, these values improved in samples that were positive for both cyclins sensitivity, 100; specificity, 94; PPV, 90; NPV, 100; and accuracy, 96.CONCLUSIONS:Cyclin D3 increased the suspicion of malignancy in indeterminate oncocytic lesions; its diagnostic performance depended on the cutoff point used and was enhanced further when combined with cyclin D1. Cancer Cancer Cytopathol 2009. © 2009 American Cancer Society.

BACKGROUND:Cystic pancreatic endocrine tumors PETs are rare neoplasms with a preoperative diagnostic challenge. The aim of this study was to evaluate the preoperative diagnostic strategy for these tumors and to assess the clinical and pathologic characteristics.METHODS:Six cases of cystic PET were retrospectively enrolled. Endoscopic ultrasoundguided fineneedle aspiration biopsy EUSFNAB was performed in 4 cases. All cytomorphologic data from conventional smears, ThinPrep preparations, and cell block preparations were reported in detail.RESULTS:There were 3 male and 3 female patients with a mean age of 52.3 years. Tumor size ranged from 10 mm to 60 mm mean, 29.8 mm. EUSFNAB contributed to an accurate diagnosis in all cases. Cytologically, loosely cohesive aggregates and single cells were predominant. Cells were small and typically plasmacytoid, with occasional cytoplasmic vacuolization. Nuclei were round or oval, uniform, with finely and evenly distributed chromatin. Immunocytochemistry confirmed the endocrine differentiation. Histologic findings were typical for endocrine proliferation. All tumors were well differentiated.CONCLUSIONS:Cystic PET is an unusual finding that presents diagnostic challenges for both endoscopists and cytologists. EUSFNAB with the Thinprep preparation technique and cell block material were found to be helpful in improving diagnostic accuracy. Immunocytochemical staining with endocrine markers confirmed the diagnosis. Cancer Cancer Cytopathol 2009. © 2009 American Cancer Society.

It has been shown previously that detection of the epithelial membrane antigen using the mouse monoclonal antibody MOC‐31 has diagnostic utility in the distinction between mesothelioma and metastatic carcinoma in body fluids. The current immunohistochemical study confirmed the effectiveness of MOC‐31 as a marker for adenocarcinoma from a broad range of primary sites in body fluid cytology prepared as paraffin sections of cell blocks.The authors evaluated 112 cell blocks for MOC‐31 immunoreactivity, including 17 mesotheliomas, 86 metastatic adenocarcinomas from various sites, and 9 control fluids from patients with nonneoplastic conditions.Membranous reactivity for MOC‐31 was observed in 86 of 86 samples (100%) of metastatic adenocarcinoma, regardless of the specific primary site. Sixteen of 17 mesothelioma samples were negative. In all but 1 sample of adenocarcinoma, > 90% of tumor cells present showed reactivity, and the staining intensity consistently was strong. Staining of scattered, morphologically benign mesothelial cells was observed in nine samples but did not interfere with interpretation.On the basis of the staining profile, MOC‐31 represented an effective marker for metastatic carcinoma in cell block preparations and may aid in distinguishing between benign and malignant mesothelial cells in these tumors. Cancer (Cancer Cytopathol) 2006. © 2006 American Cancer Society.

The distinction of bronchioloalveolar carcinoma (BAC) from atypical adenomatous hyperplasia (AAH) or reactive alveolar cell hyperplasia (RAH) can be difficult on aspiration cytology, even when cell block preparations are available. The authors evaluated the usefulness of B72.3, carcinoembryonic antigen (CEA), and Leu M‐1 immunostains in differentiating BAC, AAH, and RAH.Immunostains for B72.3, CEA, and Leu M‐1 were performed on cell block sections from 11 lung lesions that were diagnosed cytologically as BAC (6 lesions) and “atypical cells, cannot exclude BAC” (5 lesions). Ten histologic sections of AAH and 8 histologic sections of RAH also were stained.Among the six lesions that had an unequivocal cytologic diagnosis of BAC, all sections were positive for two of three immunostains. Tissue follow‐up confirmed BAC in all six lesions. Among the five lesions that were diagnosed as “atypical cells, cannot exclude BAC,” four lesions were positive for two of three immunostains, and one lesion was negative for all three immunostains. Subsequent tissue follow‐up confirmed BAC in four of these lesions. Follow‐up histology of the wedge resection on the lesion in the atypical category that was negative for B72.3, CEA, and Leu M‐1 showed only AAH. All 10 lesions that had a histologic diagnosis of AAH and 8 lesions that had a histologic diagnosis RAH were negative for B72.3, CEA, and Leu M‐1.Positive staining for at least 2 immunostains among B72.3, CEA, and Leu M‐1 provided strong supportive evidence for the diagnosis of BAC, and a negative result for all 3 immunostains was helpful in excluding BAC and in differentiating BAC from AAH and RAH. Cancer (Cancer Cytopathol) 2005. © 2005 American Cancer Society.

Cholangiocarcinoma (CC) represents approximately 10% of primary liver malignancies and can mimic metastatic adenocarcinoma.The authors retrospectively reviewed the cytopathology files at the University of Texas Medical Brach to identify patients who were diagnosed with intrahepatic or extrahepatic CC by aspiration cytology between 1995 and 2004. Brush cytology specimens of extrahepatic CC were excluded. All diagnoses were confirmed as CC by clinical, imaging, and histopathologic findings and by chart review.Cytopathology files from 13 patients with CC diagnosed by FNA were retrieved. The male:female ratio was 5:8, and the patients ranged in age from 29 years to 74 years (mean age, 59 years). In 12 of 13 patients, aspirates were obtained by ultrasound guidance; and, in 1 patient, computed tomography guidance was used. Three patients had aspirates only, 10 patients also had core biopsies, and 1 patient had cell block preparations. The phenotypic distribution of CC according to the World Health Organization (WHO) histologic classification was 9 adenocarcinoma (intrahepatic), not otherwise specified (NOS) (69%); 2 gastric foveolar type (extrahepatic) CCs (15%); 1 intestinal type (extrahepatic) CC (8%); and 1 sarcomatous/spindle cell type (intrahepatic) CC (8%). One adenocarcinoma, NOS was well differentiated CC with bland tubular architecture, and one was pleomorphic. Ancillary histochemical and immunochemical stains were performed on 5 of 13 specimens, which included 4 core biopsies and 1 aspirate with Mucicarmine positivity (3 specimens), carcinoembryonic antigen positivity (3 specimens), and a cytokeratin 7 (CK7)‐positive/CK20‐negative pattern (2 specimens). The 1 sarcomatous/spindle cell type CC was chromogranin‐negative and low molecular weight keratin (cell adhesion molecule 5.2)‐positive, which excluded metastatic carcinoid.Classification of intrahepatic and extrahepatic CC in aspiration cytology specimens was achieved in a reliable manner concordant with the WHO histologic classification. Special types of CC with bland nuclear features posed a diagnostic challenge on cytologic evaluation, particularly the well differentiated CC with tubular architecture and the gastric foveolar type CC with mucin‐producing tumor cells. The addition of core biopsy and/or ancillary studies, such as histochemical and immunochemical stains, were helpful in reaching the correct diagnosis. Cancer (Cancer Cytopathol) 2005. © 2005 American Cancer Society.

Cytology plays a pivotal role in the diagnosis of pleural effusions. In many cases, immunocytochemistry (ICC) is required to elucidate the etiology of the atypical cells. Effusions are samples that present unique problems for ICC. To date there is no standardization of ICC methods for effusions and cytology in general.The authors review the most commonly used cytologic preparations, fixatives, and antibodies used in effusion ICC.Through the utilization of cell block preparations and a panel of antibodies appropriate for the differential diagnosis in question, ICC conditions utilized in surgical pathology can be most closely replicated.ICC may provide reliable insights into various diagnostic dilemmas in effusion cytology, provided that laboratory standardization practices are followed. Cancer (Cancer Cytopathol) 2001;93:293–308. © 2001 American Cancer Society.

Tyrosinase, the rate-limiting enzyme in melanin synthesis, is a melanoma associated antigen that is recognized by both CD4+ and CD8+ T-cells in an HLA-restricted fashion. Peptides derived from the tyrosinase antigen currently are being utilized as a target for T-cells in several immunotherapy protocols for metastatic malignant melanoma (MMM) at the National Institutes of Health/National Cancer Institute. Serial fine-needle aspirations of metastatic lesions are performed to monitor the antigen expression of tyrosinase during treatment by immunostaining cytologic preparations with the monoclonal antibody T311. In the current study, 62 samples of MMM were evaluated for tyrosinase immunoreactivity on air-dried, acetone fixed cytospins and the corresponding formalin fixed, paraffin embedded cell block using an avidin-biotin immunoperoxidase method. Positive immunoreactivity revealed a granular cytoplasmic staining in melanocytic cells. The current study results showed that 92% of samples (57 of 62) were T311 immunoreactive on cell block preparations, whereas only 61% (38 of 62) were immunoreactive on cytospin preparations. In 66% of samples (41 of 62) immunoreactivity for T311 was greater in the cell block sample than in the corresponding cytospin, whereas in only 3% of samples (2 of 62) was it greater in the cytospins. In 31% of samples (19 of 62) there was no significant difference in immunoreactivity between the 2 sample types. The results of the current study show that tyrosinase is a sensitive marker for the detection of MMM; however, the optimal method of sample preparation for immunoperoxidase staining appears to be formalin fixation and paraffin embedding as tyrosinase immunoreactivity is diminished significantly in air-dried cytospin samples despite subsequent acetone fixation. Cancer (Cancer Cytopathol) 2000;90:252–7. © 2000 American Cancer Society.

The differentiation between malignant mesothelioma and adenocarcinoma based on morphology alone can be a diagnostic challenge. The majority of the available antibodies recognize molecules expressed by adenocarcinoma whereas to the authors' knowledge specific markers for mesothelial cells are lacking. Calretinin, a calcium-binding protein, has been reported to be a selective marker for mesothelioma and largely is absent from adenocarcinoma on histologic material. The results with cytologic preparations have been inconsistent. To evaluate the specificity of calretinin in differentiating mesothelioma from adenocarcinoma in cytologic preparations, 21 paraffin embedded cells blocks of serous effusions from 15 patients with metastatic adenocarcinoma and 16 cell blocks from 9 patients with malignant mesothelioma were stained with a monoclonal antibody against calretinin. The immunoreactivity was evaluated blindly by two observers. Positive staining was defined as nuclear and cytoplasmic staining with or without intense membranous decoration. The former resulted in a characteristic “fried egg” appearance. Calretinin staining was positive in all but 2 cases of mesothelioma (14 of 16 cases; 87.5%). The latter contained predominantly spindle-shaped neoplastic mesothelial cells in the cell block preparations. All adenocarcinoma specimens were classified as negative for calretinin staining; 9 (42.9%) lacked any immunoreactivity and 12 (57.1%) showed weak, sparse, coarse, granular cytoplasmic staining without nuclear or membranous staining. Benign reactive mesothelial cells, when observed in association with adenocarcinoma, also showed the characteristic “fried egg” appearance. The difference in the staining pattern of calretinin between cells of mesothelial origin and adenocarcinoma cells was statistically significant. Calretinin is a useful marker in differentiating mesothelioma of the epithelial type from adenocarcinoma in serous effusions. The “fried-egg” appearance or cytoplasmic and nuclear staining pattern is characteristic of cells of mesothelial origin. Cancer (Cancer Cytopathol) 2000;90:194–200. © 2000 American Cancer Society.

Clear cell tumors (CCTs) occur as primary neoplasms in a number of anatomic sites. Due to their overlapping morphologic features, these tumors can be challenging for the cytologist, particularly when they present as metastatic lesions. Forty-nine fine-needle aspirations (FNA) of metastatic CCTs from 46 patients (age range, 29–87 years; mean, 64 years) were reviewed retrospectively. In addition to the routine smears and cell block preparations, ancillary studies were performed in selected cases. Clinical and/or histologic follow-up was obtained for all patients. The sites of the 49 FNAs were the lung (12 cases), lymph nodes (9 cases), liver (7 cases), bone (7 cases), soft tissue (4 cases), pelvis (2 cases), adrenal gland (2 cases), pancreas (1 case), thyroid (2 cases), peritoneum (2 cases), and vagina (1 case). Twenty-seven patients had a previous history of a CCT and the FNA material in these cases was consistent with a metastasis. The primary anatomic sites in these cases were the kidney (20 cases), ovary (2 cases), salivary gland (1 case), and cervix (1 case). On light microscopy, these tumors had a similar appearance and often were indistinguishable. Nineteen patients did not have a prior history of malignancy; 12 of these patients had a concurrent renal mass and the diagnosis of metastatic renal cell carcinoma was made. The anatomic site of origin of seven of the ten remaining tumors (kidney [2 cases], lung [2 cases], ovary [1 case], germ cell [1 case], and endometrium [1 case]) was established through immunocytochemical studies of cytologic material and clinical follow-up. FNA plays an important role in the diagnosis of metastatic CCT. Cytologic examination, ancillary studies, and clinical information can establish the anatomic site of origin in the majority (95%) of cases, precluding the necessity of obtaining additional tissue. Cancer (Cancer Cytopathol) 1999;87:380–9. © 1999 American Cancer Society.