Case of lung fine needle aspiration showing mucinous cells and extracellular mucin.

Mucinous neoplasm with extracellular mucin can be challenging to interpret on fine needle aspiration and core biopsies. Determining the biologic origin of the mucin/mucinous cells, that is, benign/incidental versus neoplasm, invasive versus in situ, and primary versus metastatic tumors, requires a thorough multidisciplinary evaluation. The work up of these lesions includes morphologic analysis with ancillary immunohistochemical and/or molecular studies and correlation with clinical and imaging studies. This review outlines a practical approach to the diagnosis of mucinous lesions in the lung with comprehensive review of literature.

Incidental intra-adrenal splenule.

Splenules can be found in the adrenals and should be considered in the differential diagnosis of adrenal incidentalomas.

ALK Gene Rearrangements in Lung Adenocarcinomas: Concordance of Immunohistochemistry, Fluorescence In Situ Hybridization, RNA In Situ Hybridization, and RNA Next-Generation Sequencing Testing.

INTRODUCTION: The 2018 updated molecular testing guidelines for patients with advanced lung cancer incorporated ALK immunohistochemistry (IHC) analysis as an equivalent to fluorescence in situ hybridization (FISH) method recommended in 2013. Nevertheless, no specific recommendation for alternative methods was proposed owing to insufficient data. The aim of this study was to compare the results of ALK IHC, FISH, RNA next-generation sequencing (NGS), and RNA in situ hybridization (ISH) with available clinical data. METHODS: A search for lung carcinomas with ALK testing by greater than or equal to one modality (i.e., ALK IHC, FISH, NGS) was performed; a subset underwent RNA ISH. When available, clinical data were recorded. RESULTS: The results were concordant among all performed testing modalities in 86 of 90 cases (95.6%). Of the four discordant cases, two were ALK positive by FISH but negative by IHC, RNA NGS, and RNA ISH. The remaining two cases failed RNA NGS testing, one was IHC negative, FISH positive, RNA ISH negative and the second was IHC positive, FISH positive, RNA ISH equivocal. RNA NGS identified one rare and one novel ALK fusion. Sufficient therapy data were available in 10 cases treated with tyrosine kinase inhibitors; three had disease progression, including one with discordant results (FISH positive, RNA NGS negative, IHC negative, RNA ISH negative) and two with concordant ALK positivity among all modalities. CONCLUSIONS: Our results reveal high concordance among IHC, RNA NGS, and RNA ISH. In cases of discordance with available RNA NGS, FISH result was positive whereas IHC and ISH results were negative. On the basis of our data, multimodality testing is recommended to identify discrepant results and patients (un)likely to respond to tyrosine kinase inhibitors.

Pulmonary small cell carcinoma: Review, common and uncommon differentials, genomics and management.

Lung cancer is the leading cause of cancer-related death worldwide. It is divided into sub-categories based upon morphology, immunostaining pattern, biology, molecular profile, and/or treatment options. Up until the early 2000s when driver mutations with targeted therapies were identified in a subset of adenocarcinomas, the most critical distinction of lung carcinomas was driven by differences in treatment between small cell carcinoma (SCC) and nonsmall cell lung carcinoma (NSCLC). The distinction between SCC and NSCLC remains critical in the 21st century for management, especially for advanced stage cancer. In the vast majority of cases, morphological features are sufficient to separate SCC from other types of lung cancers. In some instances, however, cytomorphological features and immunohistochemical overlap with other tumors, limited sample availability, and/or crush artifact pose diagnostic challenges. The aim of this review is to highlight salient features of SCC and ancillary studies to distinguish it from common and uncommon potential mimickers, as well as provide updates in genomics and management.

Lung cancer cytology and small biopsy specimens: diagnosis, predictive biomarker testing, acquisition, triage, and management.

In the 21st century, there has been a dramatic shift in the management of advanced-stage lung carcinoma, and this has coincided with an increasing use of minimally invasive tissue acquisition methods. Both have had significant downstream effects on cytology and small biopsy specimens. Current treatments require morphologic, immunohistochemical, and/or genotypical subtyping of non-small cell lung carcinoma. To meet these objectives, standardized classification of cytology and small specimen diagnoses, immunohistochemical algorithms, and predictive biomarker testing guidelines have been developed. This review provides an overview of current classification, biomarker testing, methods of small specimen acquisition and triage, clinical management strategies, and emerging technologies.

Synchronous Pulmonary Adenocarcinomas.

OBJECTIVES: To determine concordance/discordance between morphology and molecular testing (MT) among synchronous pulmonary carcinomas using targeted next generation sequencing (NGS), with and without comprehensive molecular review (CMR), vs analyses of multiple singe genes (non-NGS). METHODS: Results of morphologic and MT assessment were classified as concordant, discordant, or indeterminate. For discordant cases, comprehensive histologic assessment (CHA) was performed. RESULTS: Forty-seven cases with 108 synchronous tumors were identified and underwent MT (NGS, n = 23 and non-NGS, n = 24). Histology and MT were concordant, discordant, and indeterminate in 53% (25/47), 21% (10/47), and 26% (12/47) of cases, respectively. CHA of the 10 discordant cases revised results of three cases. CONCLUSIONS: There is discordance between histology and MT in a subset of cases and MT provides an objective surrogate for staging synchronous tumors. A limited gene panel is sufficient for objectively assessing a relationship if the driver mutations are distinct. Relatedness of mutations require CMR with a larger NGS panel (eg, 50 genes).

The Role of Endoscopic Ultrasound-Guided Ki67 in the Management of Non-Functioning Pancreatic Neuroendocrine Tumors.

BACKGROUND/AIMS: The management of small, incidentally discovered nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) has been a matter of debate. Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) is a tool used to identify and risk-stratify PNETs. This study investigates the concordance rate of Ki67 grading between EUS-FNA and surgical pathology specimens in NFPNETs and whether certain NF-PNET characteristics are associated with disease recurrence and disease-related death. METHODS: We retrospectively reviewed the clinical history, imaging, endoscopic findings, and pathology records of 37 cases of NFPNETs that underwent pre-operative EUS-FNA and surgical resection at a single academic medical center. RESULTS: There was 73% concordance between Ki67 obtained from EUS-FNA cytology and surgical pathology specimens; concordance was the highest for low- and high-grade NF-PNETs. High-grade Ki67 NF-PNETs based on cytology (p=0.028) and histology (p=0.028) were associated with disease recurrence and disease-related death. Additionally, tumors with high-grade mitotic rate (p=0.005), tumor size >22.5 mm (p=0.104), and lymphovascular invasion (p=0.103) were more likely to have poor prognosis. CONCLUSION: NF-PNETs with high-grade Ki67 on EUS-FNA have poor prognosis despite surgical resection. NF-PNETs with intermediate-grade Ki67 on EUS-FNA should be strongly considered for surgical resection. NF-PNETs with low-grade Ki67 on EUSFNA can be monitored without surgical intervention, up to tumor size 20 mm.

Cell block alone as an ideal preparatory method for hemorrhagic thyroid nodule aspirates procured without onsite cytologists.

OBJECTIVE: To study diagnostic efficacy of direct smears (DS) vs. cell block (CB) alone in hemorrhagic thyroid fine needle aspirations (FNAs) performed without a cytotechnologist or cytopathologist. STUDY DESIGN: Ultrasound-guided thyroid FNAs from an offsite location were retrospectively searched during a 53-month period. Aspirates in the initial 13 months were submitted as air-dried DSs. Subsequent specimens were submitted as CBs. Each case was classified into 1 of 4 categories: (1) nondiagnostic, (2) nonneoplastic, (3) follicular lesions and (4) papillary thyroid carcinoma (PTC). RESULTS: There were 77 aspirates: DS = 20 (26%) and CB = 57 (74%). Two cases had both DSs and CBs. Diagnoses of DS: nondiagnostic = 12 (60%); nonneoplastic = 7 (35%); follicular lesion = 1 (5%). Diagnoses of CB cases: nondiagnostic = 4 (7.0%); nonneoplastic = 43 (75.4%); follicular lesion, including 1 Hürthle cell neoplasm = 7 (12.3%), PTC = 3 (5.3%). Repeat FNAs on 4 nondiagnostic cases (3 DSs, 1 CB) utilizing the CB-only technique were diagnostic and included nodular goiter, follicular neoplasm, PTC, and reactive lymph node. CONCLUSION: Without onsite assessment, CB alone is superior to DSs for hemorrhagic thyroid FNAs. It shows increased diagnostic efficacy and slide reduction and obviates repeat FNAs.

Cytologic features of needle aspiration of ovarian sex cord tumor with annular tubules: Report of two cases and literature review.

Sex cord tumor with annular tubules (SCTAT) is a rare ovarian tumor with characteristic microscopic morphologic features. Diagnosis most often is based on examination of tissue specimens. Cytologic features of this tumor rarely have been described in the English literature. Herein, we report cytologic findings of cyst aspiration fluid in two cases of SCTAT, with cyto-histologic correlation.

Adult exogenous lipoid pneumonia: A rare and underrecognized entity in cytology - A case series.

BACKGROUND: Exogenous lipoid pneumonia (ELP) is a rare benign entity without specific clinical or imaging presentation. Although cytological studies - either bronchoalveolar lavage (BAL) or fine-needle aspiration (FNA) - may be pursued in patients with ELP, a definitive diagnosis is frequently rendered only on histology. The aim of this study is to highlight the cytological features of ELP. METHODS: A search of cytopathology (CP) and surgical pathology (SP) diagnoses of ELP was conducted. The corresponding clinical and imaging features were obtained, and the morphology, particularly the presence and size of the intracytoplasmic vacuoles and background, was assessed. RESULTS: Nine cases of ELP were identified, including eight with corresponding CP and SP. A neoplasm was suspected in three based on imaging, but ELP was not in the differential clinically or radiographically in any. Among the cases, six patients had BALs and three FNAs. All of the samples showed multiple large vacuoles within macrophages with at least some equal to or larger than the size of the cell nucleus. Similar vacuoles were noted extracellularly on smears. CONCLUSIONS: ELP is typically described in case reports in the clinical or radiological literature. To the best of our knowledge, this represents the largest series of adult ELP in CP. When large vacuoles are present in macrophages in cytology specimens, at least a suspicion of ELP can be suggested to initiate appropriate therapy, identify/remove the inciting agent, and preclude a more invasive procedure.

Molecular testing on endobronchial ultrasound (EBUS) fine needle aspirates (FNA): Impact of triage.

BACKGROUND: Endobronchial ultrasound (EBUS)-guided fine needle aspiration (FNA) is performed to diagnose and stage lung cancer. Multiple studies have described the value of Rapid On-Site Evaluation (ROSE), but often the emphasis is upon diagnosis than adequacy for molecular testing (MT). The aim was to identify variable(s), especially cytology-related, that can improve MT. METHODS: A search for EBUS-FNAs with ROSE was conducted for lung adenocarcinomas or when this diagnosis could not be excluded. All such cases underwent reflex MT on cell blocks. The impact of cytology-related variables [i.e., number of pass(es), dedicated pass(es) directly into media, cytotechnologist (CT), laboratory technician (LT) and triage with 1 or >1 cytologist] was evaluated. The latter category was divided into Group A [ROSE, triage and slide preparation by cytopathologist (CP) and CT at start of the procedure] and Group B (ROSE only by CT or by CT/CP after start of procedure; triage and slide preparation by CT or clinical staff). The impact of all these variables on MT was assessed. RESULTS: A total of 100 cases were identified, and 79 had sufficient tissue for MT. Of all variables evaluated, MT was positively affected by performing a direct dedicated pass (P = 0.013) and ROSE by Group A (P = 0.033). CONCLUSIONS: ROSE with appropriate triage, including performing a dedicated pass and proper slide preparation, improves MT, and this is enhanced by having >1 cytologist at the start of the procedure. In the era of personalized medicine, "adequate" should denote sufficient tissue for diagnosis and MT.

Endoscopic ultrasound-guided biopsies of pancreatic masses: comparison between fine needle aspirations and needle core biopsies.

Endoscopic ultrasound-guided fine needle aspiration (EUS-guided FNA) is a highly sensitive and specific method for diagnosing pancreatic masses. Alternatively, EUS-guided needle core biopsies (NCB) have also been introduced. We sought to determine efficacies of pancreatic EUS-guided FNAs and NCBs. Records of consecutive EUS-guided FNAs received over a 24-mo-period were reviewed. Cases with concurrent NCBs were selected for the study. The diagnoses from the two modalities were compared and designated concordant (CC) or discordant (DC). Of 252 cases, 52 had concurrent NCBs. The final diagnoses included primary and secondary tumors. Of the 52 cases, 29/52 (55.8%) were CC and 23/52 (44.2%) were DC. The sensitivities for FNAs and NCBs were 95.0% and 67.6%, respectively. Both modalities were 100% specific. Direct comparison between EUS-guided FNAs and NCBs demonstrated that the former are more sensitive for diagnosing pancreatic neoplasms, both primaries and metastases. There was no correlation between CC/DC cases and type of neoplasm.

Cytomorphologic features distinguishing Bethesda category IV thyroid lesions from parathyroid.

BACKGROUND: Thyroid follicular cells share similar cytomorphological features with parathyroid. Without a clinical suspicion, the distinction between a thyroid neoplasm and an intrathyroidal parathyroid can be challenging. The aim of this study was to assess the distinguishing cytomorphological features of parathyroid (including intrathyroidal) and Bethesda category IV (Beth-IV) thyroid follicular lesions, which carry a 15%-30% risk of malignancy and are often followed up with surgical resection. METHODS: A search was performed to identify "parathyroid" diagnoses in parathyroid/thyroid-designated fine-needle aspirations (FNAs) and Beth-IV thyroid FNAs (follicular and Hurthle cell), all with diagnostic confirmation through surgical pathology, immunocytochemical stains, Afirma® analysis, and/or clinical correlation. Unique cytomorphologic features were scored (0-3) or noted as present versus absent. Statistical analysis was performed using R 3.3.1 software. RESULTS: We identified five FNA cases with clinical suspicion of parathyroid neoplasm, hyperthyroidism, or thyroid lesion that had an eventual final diagnosis of the parathyroid lesion (all female; age 20-69 years) and 12 Beth-IV diagnoses (11 female, 1 male; age 13-64 years). The following cytomorphologic features are useful distinguishing features (P value): overall pattern (0.001), single cells (0.001), cell size compared to red blood cell (0.01), nuclear irregularity (0.001), presence of nucleoli (0.001), nuclear-to-cytoplasmic ratio (0.007), and nuclear chromatin quality (0.028). CONCLUSIONS: There are cytomorphologic features that distinguish Beth-IV thyroid lesions and (intrathyroidal) parathyroid. These features can aid in rendering correct diagnoses and appropriate management.

PD-L1 expression in non-small cell lung carcinoma: Comparison among cytology, small biopsy, and surgical resection specimens.

BACKGROUND: One immunotherapeutic agent for patients with advanced non-small cell lung carcinoma, pembrolizumab, has a companion immunohistochemistry (IHC)-based assay that predicts response by quantifying programmed death-ligand 1 (PD-L1) expression. The current study assessed the feasibility of quantifying PD-L1 expression using cytologic non-small cell lung carcinoma specimens and compared the results with those from small biopsy and surgical resection specimens. METHODS: PD-L1 expression was quantified using the IHC-based 22C3 pharmDx assay, with "positivity" defined as staining in ≥50% viable tumor cells; ≥ 100 tumor cells were required for test adequacy. For cytology specimens, IHC was performed on cell block sections. RESULTS: A total of 214 specimens were collected from 188 patients, 206 of which (96%) were found to be adequately cellular, including 36 of 40 cytology (90%) and 69 of 72 small biopsy (96%) specimens. There was no significant difference noted with regard to the feasibility of PD-L1 IHC on small biopsy specimens compared with surgical resection specimens (P = .99), or between the percentage of PD-L1-positive cytology and histology (including surgical resection and histologic small biopsy) specimens (P = .083). PD-L1 expression was found to be concordant among samples from 21 of 23 patients from whom > 1 specimen was collected (91%). There also was no significant difference observed with regard to rates of PD-L1 positivity when comparing age, sex, diagnosis, and specimen site. CONCLUSIONS: Quantification of PD-L1 expression is feasible on cytology specimens, and the results are comparable to those obtained from surgical resection and small biopsy specimens, including in matched specimens and using a single predictive IHC marker. Future studies will be necessary to determine the comparative value of other antibodies and their ability to predict response to immunotherapy. Cancer Cytopathol 2017;125:896-907. © 2017 American Cancer Society.

Fine-needle aspiration of renal angiomyolipoma: cytological findings and diagnostic pitfalls in a series of five cases.

Diagnosis of renal angiomyolipoma (AML) by fine-needle aspiration (FNA) may be difficult because cytological and radiological findings sometimes overlap with renal cell carcinoma (RCC) and liposarcoma. Five FNAs of AMLs were studied. Epithelioid and spindle stromal cells were arranged in loosely cohesive clusters and singly. The chromatin was evenly distributed and bland. Occasionally nuclear atypia was identified. Nuclei were oval to elongated, nucleoli were inconspicuous or absent, naked nuclei were present in three specimens, and intranuclear inclusions were present in two specimens. The cytoplasm was delicate and sometimes finely vacuolated. Adipose tissue was observed in two specimens. Thick-walled vessels, mitoses, and necrosis were absent. Corresponding surgical material showed typical features of AML. In FNA, bland chromatin and inconspicuous nucleoli distinguish renal AML from RCC and liposarcoma. Adipose tissue is not universally present. Cellular atypia in conjunction with overlapping radiological findings with RCC and liposarcoma are potential diagnostic pitfalls. Immunocytochemical (ICC) stains may elucidate the correct diagnosis.

Fine-needle aspiration cytology of pleomorphic hyalinized angiectatic tumor: A case report.

Pleomorphic hyalinized angiectatic tumor (PHAT) of soft parts is a neoplasm characterized by spindle and pleomorphic cells associated with an angiectatic vasculature. We describe the cytological findings of a fine-needle aspiration biopsy (FNAB) from the right medial knee of a 45-yr-old woman. The aspirate material was entirely submitted in Cytolit solution. The specimen was moderately cellular and was comprised of spindle cells in a background of fibrinous material. The cells varied from small, bland spindle cells with a fine chromatin pattern and inconspicuous nucleoli to larger pleomorphic cells with coarser chromatin and occasional intranuclear inclusions. Most of the cells were arranged singly with sporadic small cluster formation with indistinct cell borders. Rare mononuclear inflammatory cells morphologically compatible with mast cells were identified. The differential diagnosis include solitary fibrous tumor (SFT) and ancient schwannoma, which also shows fibrous-like material and spindle cells that may have intranuclear inclusions.

FNA, core biopsy, or both for the diagnosis of lung carcinoma: Obtaining sufficient tissue for a specific diagnosis and molecular testing.

BACKGROUND: Increasingly, minimally invasive procedures are performed to assess lung lesions and stage lung carcinomas. In cases of advanced-stage lung cancer, the biopsy may provide the only diagnostic tissue. The aim of this study was to determine which method-fine-needle aspiration (FNA), core biopsy (CBx), or both (B)--is optimal for providing sufficient tissue for rendering a specific diagnosis and pursuing molecular studies for guiding tumor-specific treatment. METHODS: A search was performed for computed tomography-guided lung FNA, CBx, or B cases with rapid onsite evaluation. Carcinomas were assessed for the adequacy to render a specific diagnosis; this was defined as enough refinement to subtype a primary carcinoma or to assess a metastatic origin morphologically and/or immunohistochemically. In cases of primary lung adenocarcinoma, the capability of each modality to yield sufficient tissue for molecular studies (epidermal growth factor receptor, KRAS, or anaplastic lymphoma kinase) was also assessed. RESULTS: There were 210 cases, and 134 represented neoplasms, including 115 carcinomas. For carcinomas, a specific diagnosis was reached in 89% of FNA cases (33 of 37), 98% of CBx cases (43 of 44), and 100% of B cases (34 of 34). For primary lung adenocarcinomas, adequate tissue remained to perform molecular studies in 94% of FNA cases (16 of 17), 100% of CBx cases (19 of 19), and 86% of B cases (19 of 22). No statistical difference was found among the modalities for either reaching a specific diagnosis (p = .07, Fisher exact test) or providing sufficient tissue for molecular studies (p = .30, Fisher exact test). CONCLUSIONS: The results suggest that FNA, CBx, and B are comparable for arriving at a specific diagnosis and having sufficient tissue for molecular studies: they specifically attained the diagnostic and prognostic goals of minimally invasive procedures for lung carcinoma.

Cytomorphological features of ALK-positive lung adenocarcinomas: psammoma bodies and signet ring cells.

BACKGROUND: Correlation between histology and genotype has been described in lung adenocarcinomas. For example, studies have demonstrated that adenocarcinomas with an anaplastic lymphoma kinase (ALK) gene rearrangement may have mucinous features. The objective of the current study was to determine whether a similar association can be identified in cytological specimens. METHODS: A retrospective search for ALK-rearranged cytopathology (CP) and surgical pathology (SP) lung carcinomas was conducted. Additional ALK-negative (-) lung adenocarcinomas served as controls. For CP and SP cases, the clinical data (i.e., age, sex, and smoking history), architecture, nuclear features, presence of mucin-containing cells (including signet ring cells), and any additional salient characteristics were evaluated. RESULTS: The search yielded 20 ALK-positive (+) adenocarcinomas. Compared with patients with ALK(-) lung adenocarcinomas (33 patients; 12 with epidermal growth factor receptor [EGFR]-mutation, 11 with Kristen rat sarcoma [KRAS]-mutation, and 10 wild-type adenocarcinomas), patients with ALK(+) adenocarcinoma presented at a younger age; and there was no correlation noted with sex or smoking status. The most common histological pattern in SP was papillary/micropapillary. Mucinous features were associated with ALK rearrangement in SP specimens. Signet ring cells and psammoma bodies were evident in and significantly associated with ALK(+) SP and CP specimens. However, psammoma bodies were observed in rare adenocarcinomas with an EGFR mutation. Both the ALK(+) and ALK(-) groups had mostly high nuclear grade. CONCLUSIONS: Salient features, including signet ring cells and psammoma bodies, were found to be significantly associated with ALK(+) lung adenocarcinomas and are identifiable on CP specimens. Recognizing these may be especially helpful in the molecular triage of scant CP samples.

Cytology of low-grade endocrine neoplasms involving liver: a series of 24 specimens, including 4 with hepatoid or glandular features.

Low-grade endocrine neoplasms (LGENs) involving the liver usually show typical endocrine features. Occasionally these tumors display cytologic characteristics that mimic hepatocellular carcinoma (HCC) or adenocarcinoma (ACA). Twenty-four liver FNABs from 22 patients were reviewed. Twenty specimens showed cytologic characteristics typical of LGENs, including small to medium-sized cells with salt-and-pepper or granular chromatin, moderate to high N/C ratios, and inconspicuous or absent nucleoli. Plasmacytoid cells were observed in 19 cases. Immunocytochemical stains (ICCs) confirmed endocrine differentiation in 9 cases. 4 FNABs were comprised of larger tumor cells that displayed cytologic features that overlapped with HCC or ACA, including transgressing or wrapping endothelium, moderate to abundant cytoplasm, and conspicuous nucleoli. LGENs involving the liver typically demonstrate characteristic cytologic features. Cases comprised of larger cells with abundant cytoplasm, conspicuous nucleoli, and transgressing or wrapping endothelium may pose diagnostic difficulties. ICCs and plasmacytoid morphology are beneficial in classifying the endocrine origin of these tumors.