The spectrum of malignant diagnoses in cerebrospinal fluid cytology from an adult population: a multi-institutional retrospective review.

INTRODUCTION: Limited updated literature exists about the prevalence and spectrum of malignancies involving cerebrospinal fluid (CSF). In this multi-institutional study, we review our experience with focus on first time malignancy diagnosis in CSF samples of adults. MATERIALS AND METHODS: Institutional databases at 4 academic centers were queried retrospectively for CSFs over a 10-year period. The following data elements were collected: total # of CSFs, total # of CSFs with a malignant diagnosis; for each patient with a first time CSF diagnosis of malignancy: age, gender, diagnosis, prior history of malignancy, and ancillary studies. RESULTS: Twenty-four thousand one hundred forty-two CSFs were collected with a positive for malignancy rate of 2.3% (n = 551). Out of 347 (1.4%) adults with a first-time diagnosis of CSF malignancy 182 (52%) were female (age range: 19-89/mean: 57) and 165 (48%) were male (age range: 20-95/mean: 60). Hematolymphoid malignancies (48%, n = 168) were overall the most common neoplasm. In women, metastatic carcinomas (63%, n = 114) were the leading malignancy, of which the majority were breast primaries. In men, lymphomas/leukemias (64%, n = 106) were the leading malignancy, of which the majority were B-cell lymphomas. Ancillary studies aided the final diagnosis in 110 (32%) cases. For 286 (82%) cases, a prior history of malignancy was available to correlate CSF findings. CONCLUSIONS: A malignancy diagnosis in the CSF of adults is rare. The most common malignancies in females and males are metastatic breast carcinoma and hematolymphoid malignancies, respectively. Metastatic neoplasms account for the majority, with primary central nervous system neoplasms being quite uncommon. History of malignancy and ancillary tests can be helpful.

DNA Methylation Profiling Distinguishes Adamantinoma-Like Ewing Sarcoma From Conventional Ewing Sarcoma.

Adamantinoma-like Ewing sarcoma (ALES) has traditionally been considered a variant of Ewing sarcoma because it generally harbors EWSR1::FLI1 fusions despite showing diffuse positivity for keratins and p40. However, it has become increasingly recognized that different tumors can have identical translocations, including shared fusions between carcinomas and sarcomas, raising questions as to whether ALES might represent a separate entity. Using methylation profiling, we further explored the relationship between Ewing sarcoma and ALES. The archives of multiple institutions were searched for candidate cases of ALES. DNA methylation profiling was performed and results were compared to corresponding data from conventional Ewing sarcoma. Twelve cases of ALES (5 previously reported) were identified in 10 men and 2 women (aged 20-72 years; median age, 41.5 years). Cases included tumors arising in the parotid gland (3), sinonasal cavity (2), submandibular gland (2), thyroid gland (1), neck (1), gingiva (1), hypopharynx (1), and mandible (1). Histologic review consistently showed sheets and nests of basaloid cells within a fibromyxoid or hyalinized stroma. All tumors were positive for at least 1 keratin and CD99 expression, whereas all 10 cases tested were positive for p63 or p40; S100 protein expression was noted in 2 cases. Cases harbored either EWSR1::FLI1 fusions (n = 6), FUS::FLI1 fusions (n = 1), and/or EWSR1 rearrangements (n = 6). Methylation profiling was successful in 11/12 cases evaluated. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) of DNA methylation data revealed a distinct methylation cluster for all 11 cases, including the tumor with the FUS::FLI1 fusion, which clearly segregated them from the conventional Ewing sarcoma. Follow-up (n = 11, 1-154 months) revealed that 4 patients experienced recurrence and 6 developed metastatic disease. ALES demonstrates a distinct methylation signature from conventional Ewing sarcoma. This finding adds to the distinctive immunoprofile of ALES, suggesting that these 2 tumors should be considered distinct entities rather than histologic extremes of the same disease.

Nasopharyngeal cancer: Incidence and prognosis of human papillomavirus and Epstein-Barr virus association at a single North American institution.

BACKGROUND: The prognostication of Epstein-Barr virus (EBV) and human papillomavirus (HPV) status in nasopharyngeal cancer (NPC) is unclear. METHODS: This retrospective study analyzed NPC from 2000 to 2019. RESULTS: Seventy-eight patients were included: 43 EBV+ , 12 HPV+ , 23 EBV- /HPV- , and 0 EBV+ /HPV+ . All p16+ tumors were also positive for HPV-CISH. Baseline characteristics were not different between groups except age, N-classification, and Karnofsky Performance Scale (KPS) (p < 0.05). For EBV+ , HPV+ , and EBV- /HPV- respectively, 3-year overall survival (OS) was 89.9%, 69.8%, and 52.5% (p = 0.006). EBV- /HPV- status was significantly associated with worse OS but not freedom from progression (FFP) on univariate analysis, and did not remain a significant predictor of OS after adjusting for KPS, age, and group stage. CONCLUSIONS: EBV+ NPC tumors were seen in younger, healthier patients than HPV+ and EBV- tumors, and there were no cases of coinfection. The association of viral status with OS was insignificant after adjusting for KPS and age.

Squamoglandular Variant of Acinic Cell Carcinoma: A Case Report of a Novel Variant.

While salivary gland tumors have considerable plasticity, juxtaposition of the morphologies of two named tumor types is rare. Tumors with both mucoepidermoid and serous acinar components, dubbed "mucoacinar" carcinomas were recently characterized, and based on morphologic and molecular features, considered variants of mucoepidermoid carcinoma. Here we describe a unique case of a 59-year-old male with a 0.9 cm right parotid mass with a similar blend of mucoepidermoid-like and acinar elements that instead has a molecular phenotype of acinic cell carcinoma, essentially the reverse of mucoacinar carcinoma. The tumor was fairly well circumscribed with a prominent tumor associated lymphoid response. It consisted of a predominant bland but basaloid squamoid proliferation with scattered pockets of serous acinar differentiation as well as rare mucous cells and tubules. The tumor showed diffuse cytokeratin and DOG1 reactivity as well as p40 expression in the squamoid components. Immunostaining for NR4A3 was diffusely positive, and an NR4A3 rearrangement was noted on fluorescence in situ hybridization, while testing for MAML2 and MSANTD3 rearrangements were negative. Based on these findings, this tumor is best considered a "squamoglandular variant of acinic cell carcinoma." Morphologic and clinical evidence argues against this representing a form of high-grade transformation. While overall bland, the differential diagnosis may include various basaloid tumors in the parotid gland, both primary and metastatic.

Oro- and Nasopharyngeal Papillomas with Squamous and Respiratory Features: A Case Series of Schneiderian-Like Papillomas of the Pharynx.

There is limited literature detailing the histology of pharyngeal papillomas. Herein, we report our experience with papillomas occurring in the oro-and nasopharynx that have both squamous and respiratory features akin to the sinonasal Schneiderian papilloma. We retrospectively reviewed pharyngeal papillomas that were composed of both squamous and respiratory epithelium received at our institution between 2010 and 2020. Cases of sinonasal papillomas directly extending into the pharynx were excluded. Immunohistochemistry for p16 as well as RNA in situ hybridization to evaluate for 6 low-risk and 18 high-risk HPV genotypes were performed on all cases. Thirteen cases were included. Mean age was 61 with 12 males and 1 female. While often incidentally found, presenting symptoms included globus sensation, hemoptysis, and hoarseness of voice. Histologically, all tumors consisted of squamous and respiratory epithelium with neutrophilic infiltrates arranged in an exophytic/papillary architecture that was reminiscent of the exophytic type of Schneiderian papilloma. Immunohistochemistry for p16 was negative in all papillomas. 85% were positive for low-risk human papillomavirus (HPV) subtypes and all were negative for high-risk HPV subtypes. A well-differentiated, invasive squamous cell carcinoma was associated with two of the cases. Papillomas with squamous and respiratory features similar to the sinonasal exophytic Schneiderian papilloma can arise in the oro- and nasopharynx and like their sinonasal counterparts show an association with HPV. While many in this series were benign, they can be harbingers for invasive squamous cell carcinoma.

SMARCB1 (INI-1)-Deficient Adenocarcinoma of the Sinonasal Tract: A Potentially Under-Recognized form of Sinonasal Adenocarcinoma with Occasional Yolk Sac Tumor-Like Features.

The classification of sinonasal adenocarcinoma (SNAC) is complex. The high-grade, non-intestinal SNAC group is particularly heterogeneous, with tumors showing widely variable morphology. SMARCB1 (INI-1)-deficient sinonasal carcinoma is a newly described, aggressive tumor that usually resembles sinonasal undifferentiated carcinoma (SNUC) or non-keratinizing squamous cell carcinoma; however, glandular differentiation has been rarely reported and this feature may be under-recognized. We present a dedicated series of 12 SMARCB1-deficient SNACs. All tumors had an oncocytoid/plasmacytoid cytomorphology with variable degrees of glandular differentiation consisting of tubules and cribriform structures with foci of intracellular or intraluminal mucin. Three of 12 tumors exhibited foci of yolk sac tumor-like histologic features. The tumors were uniformly high-grade, with nuclear pleomorphism, elevated mitotic rates and frequent necrosis. By immunohistochemistry, all tumors were entirely SMARCB1-deficient, and 10 of 12 were CK7-positive. Occasional expression of CDX2 (4 of 12), CK20 (3 of 12), and p40 (3 of 10) was seen. Expression of yolk sac markers was variably present in tumors that harbored yolk sac-like areas but also tumors that did not: glypican-3 (10 of 11), SALL4 (6 of 11), HepPar-1 (4 of 11), PLAP (1 of 10), and AFP (1 of 11). SMARCB1-deficient sinonasal carcinoma, particularly the oncocytoid/plasmacytoid form, can demonstrate variable degrees of glandular differentiation. This unexpected morphology combined with variable immunohistochemical results may lead to misdiagnoses of high-grade intestinal or non-intestinal SNAC, myoepithelial carcinoma, or even yolk sac tumor or metastatic hepatocellular carcinoma.

Malignancy risk for solitary and multiple nodules in Hürthle cell-predominant thyroid fine-needle aspirations: A multi-institutional study.

BACKGROUND: Hürthle cell metaplasia is common in hyperplastic nodules, particularly within the setting of lymphocytic thyroiditis (LT). The Bethesda System for Reporting Thyroid Cytopathology indicates that it is acceptable to classify Hürthle cell-predominant fine-needle aspiration (HC FNA) specimens as atypia of undetermined significance (AUS) rather than suspicious for a Hürthle cell neoplasm (HUR) within the setting of multiple nodules or known LT. The goal of the current study was to address whether this approach is justified. METHODS: HC FNA specimens were identified and correlated with ultrasound and surgical pathology reports if available. Multinodularity was determined based on findings on macroscopic examination if imaging results were unavailable. RESULTS: A total of 698 HC FNA specimens were identified, including 576 resected nodules, 455 of which (79%) were benign. The overall risk of malignancy for HUR was 27%, whereas the risk of malignancy for AUS was 10%. The mean size of the benign nodules was 2.1 cm on surgical resection specimens, with multiple nodules noted in 293 cases (64%) and histologic LT noted in 116 cases (25%). The mean size of the malignant nodules was 2.8 cm, with multiple nodules and histologic LT noted in 74 cases (61%) and 22 cases (18%), respectively. The malignancy rate did not differ between solitary or multiple nodules (P = .52) or in the presence or absence of LT (P = .12). However, size did significantly differ between malignant and benign nodules (P < 0.01). CONCLUSIONS: The malignancy rate did not differ significantly in the presence of multiple nodules or LT, although the latter demonstrated a statistical trend. A diagnosis of AUS over HUR based solely on the presence of multinodularity is not warranted.

Primary salivary gland-type tumors of the tracheobronchial tree diagnosed by transbronchial fine needle aspiration: Clinical and cytomorphologic features with histopathologic correlation.

BACKGROUND: Primary salivary gland-type tumors of the tracheobronchial tree are rare; their cytologic features have been seldom reported. We aim to describe the clinical and cytomorphologic features of tracheobronchial salivary gland-type tumors diagnosed by transbronchial fine needle aspiration (TBNA) at our institution, and correlate the findings with a corresponding surgical specimen. METHODS: We searched our laboratory information system to identify patients with a primary salivary gland-type neoplasm of the tracheobronchial tree diagnosed by TBNA and with a corresponding surgical pathology specimen, over 10 years. RESULTS: The study cohort consisted of 11 patients (7F/4M; mean age 58 years, range 41-78). Presenting symptoms included hemoptysis (4), cough (3), dyspnea (1), stridor (1), and shoulder pain (1). Most had a tracheal mass (5), while 3 had mainstem bronchi masses and 3 had lung masses. Radiographically, the masses were lobulated, rounded, or polypoid in six patients. All underwent TBNA with a 21- or 22-gauge needle and endobronchial biopsy. The most frequent diagnosis was adenoid cystic carcinoma (4/11, 36%), followed by mucoepidermoid carcinoma (3/11, 27%), epithelial-myoepithelial carcinoma (2/11, 18%), oncocytoma (1/11, 9%), and hyalinizing clear cell carcinoma, salivary gland type (1/11, 9%). The surgical pathology specimens confirmed the diagnosis in all cases. CONCLUSIONS: To our knowledge, this is one of the largest cytomorphologic studies of primary salivary gland tumors of the tracheobronchial tree in the literature. Salivary gland tumors of the tracheobronchial tree are rare, and recognizing cytomorphologic changes that occur in salivary gland-type tumors is important for establishing a definitive diagnosis.

Fine-needle aspiration of adrenal lesions: A 20-year single institution experience with comparison of percutaneous and endoscopic ultrasound guided approaches.

BACKGROUND: Historically, sampling of adrenal lesions has been performed by percutaneous image-guided fine-needle aspiration (FNA) biopsy. Endoscopic ultrasound guided (EUS)-FNA of the adrenals was first employed at Cleveland Clinic ~10 years ago. We report a two-decade experience of adrenal FNA in our institution. METHODS: An electronic retrieval identified adrenal FNAs from 1997 to 2017. Data points from each case (diagnosis, method of FNA, age, sex, laterality, needle gauge, size of lesion, adequacy of sample, and histologic follow up) were analyzed. RESULTS: Our retrieval confirmed 198 adrenal FNAs performed over 20 years. Of these, 90% (179/198) were percutaneous, and the remaining 10% (19/198) were collected by EUS. Of the 179 CT guided FNAs, 93% (162/179) yielded an adequate specimen as compared with an adequacy rate of 89% (17/19) for EUS-FNAs, with no significant difference in adequacy rates by collection method, P = .64 (Fisher's exact). Of all adrenal FNAs, 53% (105/198) confirmed metastases, 33% (65/198) showed adrenal cells or primary adrenal neoplasms (85% cortical cells, 14% cortical neoplasia, 1% pheochromocytoma), 8% were inadequate (15/198), 3% were atypical (7/198), and 2% were suspicious for malignancy (5/198). CONCLUSION: FNA of the adrenal glands can be useful in the diagnosis and staging of metastatic neoplasms, as well as in distinguishing primary adrenal cortical from medullary neoplasms and characterizing hematolymphoid and mesenchymal neoplasms. Overall adequacy rates for adrenal cytology are high (92%) with no statistically significant difference between CT-guided (93%) and EUS-FNA adequacy (89%). The majority of our procedures confirmed metastases, sparing patients unnecessary surgery.

Early squamous cell carcinoma of the oral tongue with histologically benign lymph nodes: A model predicting local control and vetting of the eighth edition of the American Joint Committee on Cancer pathologic T stage.

BACKGROUND: The eighth edition of the American Joint Committee on Cancer staging manual (AJCC8) added depth of invasion to the definition of pathologic T stage (pT). In the current study, the authors assess pT stage migration and the prognostic performance of the updated pT stage and compare it with other clinicopathologic variables in patients with early squamous cell carcinoma of the oral tongue (OTSCC; tumors measuring ≤4 cm) with histologically benign lymph nodes (pN0). METHODS: A multi-institutional cohort of patients with early OTSCC was restaged as per AJCC8. Primary endpoints were local recurrence (LR) and locoregional recurrence (LRR). Influential variables were identified and an LR/LRR prediction model was developed. RESULTS: There were a total of 494 patients, with 49 LR and 73 LRR. AJCC8 pT criteria resulted in upstaging of 37.9% of patients (187 of 494 patients), including 34.5% (64 of 185 patients) from pT2 to pT3, without improving the prognostication for LR or LRR. Both LR and LRR were found to be similar for patients with AJCC8 pT2 and pT3 disease. On multivariate analysis, LR was only found to be associated with distance to the closest margin (hazard ratio, 0.36; 95% CI, 0.20-0.64 [P = .0007]) and perineural invasion (hazard ratio, 1.92; 95% CI, 1.10-0.64 [P = .046]). Based on these 2 predictors, a final proportional hazards regression model (which may be used similar to a nomogram) was developed. The proposed model appeared to be superior to AJCC pT stage for estimating the probability of LR and LRR for individual patients with early OTSCC. CONCLUSIONS: AJCC8 pT criteria resulted in pT upstaging of patients with pN0 disease without improved LR or LRR prognostication. The proposed model based on distance to the closest margin and perineural invasion, status outperformed pT as a predictor of LR and LRR in patients with early OTSCC.

Consistent LEF-1 and MYB Immunohistochemical Expression in Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma: A Potential Diagnostic Pitfall.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a distinct, newly-described sinonasal tract neoplasm characterized by a salivary gland tumor-like appearance with myoepithelial and ductal cells, frequent surface squamous dysplasia, and relatively indolent behavior. When considering a diagnosis of HMSC, aggressive high-grade salivary gland carcinomas, particularly those with a basaloid morphology such as basal cell adenocarcinoma and adenoid cystic carcinoma, enter the differential diagnosis. The full morphologic and immunophenotypic profile of HMSC continues to be unraveled. In this series of ten cases, we demonstrate that this tumor has consistent, strong immunohistochemical expression of LEF-1 yet lacks nuclear expression of ß-catenin, and also has consistent yet variable expression of MYB protein. While LEF-1 expression may be a useful diagnostic adjunct, it can also be a pitfall, as other salivary tumors such as basal cell adenocarcinoma have been previously shown to express LEF-1. Additionally, MYB protein expression is not a discriminatory marker when trying to separate HMSC from adenoid cystic carcinoma.

Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma: A Case Report Documenting the Potential for Very Late Tumor Recurrence.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma is a peculiar sinonasal tract tumor that demonstrates features of both a surface-derived and salivary gland carcinoma. Implicit in its name, this tumor has a consistent association with high-risk HPV, particularly type 33. It was first described in 2013 under the designation of HPV-related carcinoma with adenoid cystic carcinoma-like features. However, since its initial description additional cases have emerged which demonstrate a wide morphologic spectrum and relatively indolent clinical behavior. Herein we report our experience with a case of HPV-related multiphenotypic sinonasal carcinoma that was initially classified as adenoid cystic carcinoma in the 1980s. The patient recurred after a 30-year disease free interval. RNA in situ hybridization confirmed the presence of high-risk HPV in both her recurrence and her initial tumor in the 1980s, which allowed for reclassification as HPV-related multiphenotypic sinonasal carcinoma. Our case adds to the literature of this relatively newly described entity and supports the indolent clinical behavior of this neoplasm but also demonstrates a potential for very late local recurrence.

Hyalinizing Clear Cell Carcinoma of the Lung: Case Report and Review of the Literature.

OBJECTIVES: Hyalinizing clear cell carcinoma (HCCC) is common in head and neck sites but extremely rare in the lung. This case report describes an HCCC in the lung of a 54-year-old female patient. METHODS: We summarize the histomorphologic, immunophenotypic, and molecular features for our and three previously reported HCCCs of the lung with emphasis on potential diagnostic pitfalls. RESULTS: Sections of a well-circumscribed 3.5-cm lung mass were characterized by a bronchocentric tumor growing in sheets, nests, and cords in a background of hyalinized stroma. Tumor cell appearance was clear to eosinophilic, lacking significant pleomorphism or mitotic activity. By immunohistochemistry, the tumor cells were strongly positive with antibodies to pan-keratin, p63, and CK5/6 while negative for CK7, CK20, thyroid transcription factor 1, napsin A, chromogranin, and synaptophysin. Next-generation sequencing demonstrated an EWSR1-ATF1 fusion transcript. CONCLUSIONS: Awareness of key morphologic features of pulmonary HCCC is crucial for the recognition of this rare entity in the lung. Ancillary studies, including immunohistochemistry and molecular testing, are essential for the distinction from its mimics.

Fine Needle Aspiration Cytology of Diffuse-Type Tenosynovial Giant Cell Tumors.

BACKGROUND: Tenosynovial giant cell tumor (TSGCT), also known as giant cell tumor of tendon sheath or pigmented villonodular synovitis, is the most common benign tumor of the tendon and synovium. The intra-articular diffuse type can present as a large infiltrative mass involving adjacent soft tissue and sometimes causes secondary destruction of bone, which leads to radiographic and clinical concern for malignancy. The tumor may also be purely extra-articular. CASE: Here, we report the fine needle aspiration cytology findings of 2 cases of diffuse-type TSGCT with large mononuclear cells with eccentric nuclei, finely granular cytoplasm, and a peripheral well-defined cytoplasmic rim of hemosiderin ("ladybird cells"). CONCLUSION: Although the presence of ladybird cells has been described in tissue sections of TSGCT, their identification in cytological specimens has not been reported to our knowledge. When observed, their presence may aid in differentiating TSGCT from other lesions with multinucleated osteoclast-type giant cells occurring at or near joints.

Thyroid sclerosing mucoepidermoid carcinoma with eosinophilia: a clinicopathologic and molecular analysis of a distinct entity.

Sclerosing mucoepidermoid carcinoma with eosinophilia is a rare thyroid neoplasm of uncertain pathogenesis that resembles salivary gland mucoepidermoid carcinoma. This multi-institutional study characterizes the clinicopathologic and molecular features of this tumor by utilizing next-generation sequencing to assess common mutations and gene fusions involved in thyroid carcinogenesis as well as fluorescence in-situ hybridization for MAML2 translocations typical of salivary gland mucoepidermoid carcinoma. Nine cases (6 females and 3 males, mean age: 59 years, range 30-77 years) were identified. All cases were comprised of nests and strands of tumor cells with both squamous and mucinous differentiation embedded in a fibrohyaline stroma with an inflammatory infiltrate replete with eosinophils. All cases were p63 positive, thyroglobulin negative and showed variable expression of TTF-1. All nine cases were negative for MAML2 rearrangements. Five cases successfully tested by next-generation sequencing (ThyroSeq v.2 assay) were negative for mutations and translocations commonly involved in thyroid carcinogenesis. NTRK1 showed overexpression but no evidence of translocation. On follow-up, one patient died of persistent disease, whereas one of four remaining patients with available follow-up (mean: 7.3 years, range 4-11 years) demonstrated recurrence at 4 years. Thus, we show that sclerosing mucoepidermoid carcinoma with eosinophilia appears molecularly and morphologically distinct from follicular and C-cell-derived thyroid tumors as well as from salivary gland mucoepidermoid carcinoma. The overall and recurrence-free survival for these patients may be lower than for other well-differentiated thyroid cancers.