Yaxia Zhang

Primary Pseudomyogenic Hemangioendothelioma of Bone.

Pseudomyogenic hemangioendothelioma (PMH) is a well-recognized neoplasm that usually arises in the soft tissue; concurrent bone involvement occurs in 24% of cases. PMH of bone without soft tissue involvement is rare. We describe the clinicopathologic findings of 10 such cases, the largest series reported to date. The study included 9 male and 1 female patient; their ages ranged from 12 to 74 years (mean 36.7 y). All patients had multiple tumors with a distinct regional distribution: 45% restricted to the lower extremity; 25% to the spine and pelvis; and 15% to the upper extremity. On imaging studies the tumors were well circumscribed and lytic. The neoplasms were composed of spindled cells arranged in intersecting fascicles with scattered epithelioid cells; epithelioid cells predominated in 3 cases. The neoplastic cells contained abundant densely eosinophilic cytoplasm and vesicular nuclei. There was limited cytologic atypia and necrosis, few mitoses (0 to 2/10 high-power fields), and inconspicuous stroma. Unique findings included abundant intratumoral reactive woven bone and hemorrhage with numerous osteoclast-like giant cells. Immunohistochemically, most tumors were positive for keratin, ERG, and CD31; CD34 was negative. The balanced t(7:19)(q22;13) translocation was documented in 3 cases. Follow-up is limited, but no patient developed documented visceral dissemination, and all have stable or progressive osseous disease. PMH exclusively involving bone is rare. It is multicentric, often involves the lower extremity, and has unusual morphology. The differential diagnosis includes epithelioid vascular neoplasms, giant cell tumor, bone forming neoplasms, and metastatic carcinoma. Because of its rarity, unusual presentation, and morphology, accurate diagnosis can be challenging.

Squamous cell carcinoma arising in dedifferentiated chondrosarcoma proved by isocitrate dehydrogenase mutation analysis.

Dedifferentiated chondrosarcoma is a primary bone tumor characterized by the presence of both low-grade cartilaginous and high-grade malignant noncartilaginous components. The high-grade noncartilaginous component is typically a pleomorphic fibroblastic spindle cell sarcoma. Dedifferentiation into a malignant epithelial component is extremely rare. In this report, we present a 74-year-old woman who developed a metastatic squamous cell carcinoma in the right inguinal area 1 year after wide resection of her right proximal femur for a dedifferentiated chondrosarcoma. The dedifferentiated component was composed of poorly differentiated epithelioid cells with foci of squamous cell carcinoma. Mutational analysis was performed, and the isocitrate dehydrogenase 1 R132C mutation was detected in the low-grade chondrosarcoma, dedifferentiated chondrosarcoma as well as the metastatic squamous cell carcinoma. And this mutation was not detected in patients normal tissue. Our study supports the theory that both the chondrosarcoma cells and dedifferentiated epithelioid tumor cells arose from the same clonal origin.

Solitary C1 spinal osteochondroma causing vertebral artery compression and acute cerebellar infarct

Osteochondroma is a common benign bone lesion, usually involving the long bones. Spinal involvement is rare. The clinical presentation of spinal osteochondroma varies according to the site of the lesion. The most common reported clinical presentation is secondary to encroachment of the lesion on the spinal canal or nerve roots. Less common presentations such as a palpable neck mass, dysphagia, sleep apnea, paralysis of left vocal cord or acute respiratory distress have been reported when the lesions compress the anatomic structures anteriorly. We describe a rare case of a young patient who presented with an emergent critical condition of acute cerebellar infarct as a result of vertebral artery compression caused by a solitary C1 spinal osteochondroma.

Bone-Forming Tumors

Bone-forming tumors are defined by neoplastic cells that differentiate along the lines of osteoblasts that deposit neoplastic bone. The morphology and biological spectrum of bone-forming tumors is broad, and their accurate diagnosis requires the careful correlation of their clinical, morphologic, and radiologic characteristics. Immunohistochemical and molecular analyses have an important role in select instances. At present, the identification of neoplastic bone largely depends on histologic analysis, which can be subjective. The major types of osteosarcoma are defined according to their morphology, origin within or on the surface of the bone, and their histologic grade.

Giant cell tumor of bone: imaging and histology changes after denosumab treatment

We read with interest the article BGiant cell tumor of the bone: aggressive case initially treated with denosumab and intralesional surgery^ by Dr von Borstel et al. [1]. The authors describe a patient with a giant cell tumor of bone (GCT) who was treated with denosumab, developed interval changes noted on imaging studies and biopsies, underwent Bintralesional treatment,^ and apparently developed recurrence. Approximately 7 weeks after denosumab was started, an MRI was interpreted as Bsuspicious for worsening disease with increased intralesional heterogeneity, perilesional fluid-like signal, and circumferential cortical/periosteal thickening and irregularity.^ The authors emphasize that the MRI was misinterpreted, and that the lesion was responding appropriately to denosumab. Curettage 3 weeks later showed Bno evidence of giant cell tumor^ and Babsence of proliferating giant cells and mononuclear cells,^ supporting a reactive lesion. The authors subsequently argue that the post-denosumab samples were Bnegative for tumor cells,^ although the lesion subsequently recurred. We suggest that the authors seem to havemisinterpreted the biological effects of denosumab treatment. On the one hand, we agree that the interval changes seen on MRI, including T2 signal heterogeneity, increased Bcalcification^ (actually ossification), and cortical thickening are expected consequence of denosumab, but the absence of multinucleated giant cells in the curettage specimen does not indicate the absence of tumor cells. As described in other publications [2–4], it is now thought that the mononuclear cells are neoplastic and clonal, harboring specific H3F3A driver mutations [5, 6]. These cells may show osteoblastic phenotype and express RANKL, which recruits the multinucleated giant cells to the lesion. In contrast to what the authors stated in the introduction, the giant cells themselves are not considered to be neoplastic. Although denosumab has proven to be effective for reducing the number of osteoclastic giant cells, as observed in this case, by interfering with osteoclastic recruitment and differentiation, it does not necessarily eliminate neoplastic stromal cells. For example, Girolami et al. demonstrated the same H3F3A-mutated mononuclear cell population after treatment with denosumab [7]. That the mononuclear cells appear to be of osteoblast phenotype further explains the common observation of bone formation in and around GCTs treated with denosumab. The fact that the size of the tumor increased during denosumab therapy, along with rapid recurrence of the tumor within 5 months of intralesional curettage in this patient further support that the tumor cells were still present and continued to proliferate. This phenomenon was also observed in in vitro experiments [8]. In summary, we agree that by reducing the osteoclastic giant cells and inducing local bone formation denosumab * Thomas W. Bauer Osteoclast@aol.com

Molecular Testing of Non–Small Cell Lung Carcinoma Diagnosed by Endobronchial Ultrasound–Guided Transbronchial Fine-Needle Aspiration

CONTEXT.— Given the increasing demand for molecular testing of non-small cell lung carcinoma specimens to guide therapeutic decision-making and the trend toward minimally invasive techniques for obtaining diagnostic tissue, cytopathology laboratories must devise strategies to maximize DNA yield for necessary molecular testing. OBJECTIVE.— To describe our experience at Cleveland Clinic with epidermal growth factor receptor (EGFR) mutation testing by next-generation sequencing and anaplastic lymphoma kinase (ALK) gene rearrangement testing by fluorescence in situ hybridization of non-small cell lung carcinomas diagnosed by cytology, with an emphasis on specimens obtained by endobronchial ultrasound-guided transbronchial fine-needle aspiration. DATA SOURCES.— Data sources include a review of the current literature, including published articles from our institution. CONCLUSIONS.— At our institution, liquid-based cytology specimens are the primary resource used for molecular testing of non-small cell lung carcinomas; in most instances, adequate DNA can be extracted from the residual cell pellet for next-generation sequencing, and ThinPrep slides can be used reliably for fluorescence in situ hybridization testing for ALK gene rearrangements. In occasional cases where the cell pellet material is not adequate for molecular testing, cell blocks and/or surgical pathology specimens are secondary options. The cytopathologists role in specimen handling and triage is essential to ensure that molecular testing can be carried out successfully.

CD4/CD8 Ratio in Mediastinal Lymph Nodes Involved by Sarcoidosis: Analysis of Flow Cytometry Data Obtained by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration.

Background:Despite mixed results in the literature, some clinicians continue to consider an elevated CD4/CD8 ratio in bronchoalveolar lavage (BAL) fluid to be supportive of a diagnosis of sarcoidosis. However, the CD4/CD8 ratio in mediastinal lymph nodes involved by sarcoidosis has not been extensively studied. The primary aim of this study was to evaluate the utility of the CD4/CD8 ratio in mediastinal lymph node aspirates obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosing sarcoidosis. Methods:Our archives were searched for EBUS-TBNAs in which mediastinal lymph node aspirates had been submitted for flow cytometry (n=160). Clinical and pathologic findings in these cases were reviewed retrospectively. Cases were included in the study if they had (1) a clinical diagnosis of sarcoidosis supported by cytopathologic confirmation of non-necrotizing granulomas in EBUS-TBNA–derived lymph node aspirates (23 cases), or (2) a pathologically confirmed non-neoplastic diagnosis other than sarcoidosis (7 cases). Cases that did not fulfil these criteria were excluded (130 cases). Results:The CD4/CD8 ratios in mediastinal lymph nodes and BAL fluid were compared. The CD4/CD8 ratio was elevated in mediastinal lymph nodes in 12/23 (52%) cases of sarcoidosis and 3/7 (43%) pathologically confirmed nonsarcoid cases. BAL fluid had been concurrently submitted for flow cytometry in 20/23 cases of sarcoidosis and 5/7 nonsarcoid cases. CD4/CD8 was elevated in BAL fluid in 9/20 (45%) cases of sarcoidosis and 2/5 (40%) nonsarcoid cases. Conclusion:As in BAL fluid, the CD4/CD8 ratio in mediastinal lymph nodes involved by sarcoid granulomas is highly variable and does not reliably confirm or exclude sarcoidosis.

Expression of MDM2 and p16 in angiomyolipoma

Angiomyolipoma (AML) arises primarily from the kidney but may grow into the retroperitoneal space mimicking a primary retroperitoneal tumor. Fine needle aspiration (FNA) and core needle biopsy of AML, particularly the fat-predominant variant, may be difficult to distinguish from retroperitoneal well-differentiated liposarcoma (WDLS) or lipoma. Commonly used immunomarkers, MDM2 and p16, have proven useful in diagnosing WDLS and dedifferentiated liposarcoma (DDLS), while HMB45 and Melan-A are melanocyte-related markers characteristically expressed in AML. In this study, we investigated the utility of MDM2 and p16 along with HMB45 and Melan-A immunohistochemical analysis in distinguishing AML from WDL/DDLS or lipoma. Immunohistochemically, AMLs demonstrated focal MDM2 expression (40% of cases) and focal/diffuse expression of p16 (60%). AMLs marked focally or diffusely with HMB45 (76% of cases) and Melan-A (96%). These latter two immunomarkers were not expressed in any of the WDLS/DDLSs or lipomas tested. WDLS/DDLSs showed focal/diffuse expression of MDM2 (91% of cases) and p16 (97%). While focal expression of MDM2 and p16 was observed in 14% and 67% of lipomas, respectively, no lipoma exhibited diffuse MDM2 positivity. In our hands, MDM2 expression by itself cannot exclude the diagnosis of AML or lipoma, and p16 alone is not helpful in separating AML and conventional lipoma from WDLS/DDLS. However, along with morphology, an immunohistochemical battery including HMB45, Melan-A, MDM2 and p16 are useful in distinguishing AML from WDLS/DDLS or lipoma. For equivocal cases, fluorescence in situ hybridization for MDM2 should be performed.

Diagnosis of primary peritoneal high-grade serous carcinoma in a man by cytology

Primary peritoneal serous carcinoma (PPSC) is a rare neoplasm histologically indistinguishable from ovarian serous carcinoma primarily occurring in the female population. To date, extremely rare cases of PPSC have been reported in men; however, diagnosis by cytology has yet to be described. Here we present the clinical, radiographic, cytomorphologic, histologic and immunohistochemical (IHC) findings of a high-grade (HG) PPSC in a 70-year-old man with a history of prostatic adenocarcinoma. Core needle biopsy (CNB) touch preparation smears showed pleomorphic, round, columnar and polygonal epithelioid cells present singly or arranged in loosely cohesive three-dimensional clusters. The tumor cells are characterized by enlarged nuclei containing prominent nucleoli, and variable scant to moderate, slightly dense cytoplasm. Scattered cells contained cytoplasmic vacuoles. Examination of CNB revealed an infiltrating tumor in sheets with focal papillary configuration. Tumor cells were morphologically consistent with HG carcinoma. IHC studies demonstrated diffuse positivity for CK7, PAX-8, ER, WT1, p53, p16 and BerEP4 with focal/weak staining for calretinin and CK5/6, which supporting the diagnosis of HG PPSC. The patient was treated with 6 cycles of carboplatin and paclitaxel with near resolution of the mass at 10 month follow-up. To the best of our knowledge, this is the first reported case in the literature of PPSC in a man diagnosed by cytology. This article is protected by copyright. All rights reserved.

Sensitivity of Cerebrospinal Fluid Cytology for the Diagnosis of Cryptococcal Infections

Objectives Cryptococcal meningoencephalitis is the most common fungal infection of the central nervous system diagnosed by cerebrospinal fluid cytology (CSF) studies. Existing literature suggests that routine CSF cytomorphologic evaluations are exquisitely specific; however, less is known about their sensitivity. Methods An electronic record review of the cytopathology and microbiology files was conducted for the 21-year interval from January 1, 1995, through December 31, 2015. Results In 21 years, 12,584 CSF samples were processed in the laboratory. Of these, 24 (0.2%) were reported positive for cryptococcal organisms by light microscopy, and 129 CSF fungal cultures were positive for Cryptococcus species. All cotested specimens with positive cytology results were positive on culture (15 specimens, 100% specificity). Twenty-four samples with positive culture results were negative by CSF cytology (sensitivity 39%). Conclusions When culture is used as a gold standard, CSF cytology is 100% specific and 39% sensitive, with a positive predictive value of 100% and a negative predictive value of 99.8%.