Pulmonary capillary hemangiomatosis associated with connective tissue disease: a report of 4 cases and review of the literature.

Pulmonary hypertension (PHTN) can be seen in patients with connective tissue disease (CTD). The typical pathology associated with CTD is interstitial fibrosis and hypertensive pulmonary arteriopathy. We describe 4 patients with CTD and PHTN unexpectedly found to have pulmonary capillary hemangiomatosis (PCH) at explant after lung transplantation or autopsy. Pulmonary capillary hemangiomatosis is defined as a proliferation of capillaries in alveolar walls and can clinically cause PHTN. We detail the pathologic findings of PCH, describe the differential diagnosis, and present a review of the literature on the possible association of PCH with CTD. Although PCH may present clinically as PHTN, it is critical to differentiate between the typical CTD-associated interstitial fibrosis with hypertensive pulmonary arteriopathy and PCH because the treatment is different. We provide the largest case series to date and highlight the need for pathologists to have a high level of suspicion for PCH in patients with CTD.

Cocaine-induced microangiopathic hemolytic anemia mimicking idiopathic thrombotic thrombocytopenic purpura: a case report and review of the literature.

Our understanding of the pathogenesis of idiopathic thrombotic thrombocytopenic purpura (TTP) has increased, but remains incomplete, particularly with respect to cases of suspected TTP that are either unresponsive to therapeutic plasma exchange (TPE) or have normal ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13) activity. A 53-year-old woman presented with severe anemia (hemoglobin 1.8 g/dL) and clinical and laboratory findings consistent with TTP in conjunction with acute cocaine use. The patient was treated with TPE until the pre-treatment ADAMTS13 activity was reported as normal without evidence of an inhibitor. TPE was stopped and the patient continued to improve without treatment. This patient's microangiopathic hemolytic anemia (MAHA) appeared to be secondary to cocaine use. The proposed pathogenesis is likely a combination of cocaine-induced vasoconstriction, vascular damage, platelet activation, and procoagulation. This is the fifth published report of cocaine-induced MAHA and to our knowledge the first with ADAMTS13 testing.

Primary gastric extra-uterine endometrial stromal sarcoma.

Endometrial stromal sarcoma (ESS) is an uncommon uterine neoplasm, but its occurrence as an extra-uterine primary (EESS) is exceedingly unusual, and the fine-needle aspiration (FNA) cytopathology of EESS is rarely described. We hereby present 2 women with primary gastric EESS whereby the FNA cytopathology of this rare entity showed a population of cytologically monotonous oval-spindle shaped cells. This cytopathology is correlated with the subsequent histopathology. EESS is another, albeit rare, diagnostic consideration along with gastrointestinal stromal tumor, schwannoma, glomus tumor, and leiomyoma of cytologically bland neoplasms of the stomach that can be encountered using endoscopic ultrasound-guided FNA biopsy.

Spindle cell neoplasms of the upper gastrointestinal tract, hepatobiliary tract, and pancreas by fine needle aspiration: A single institutional experience of 15 years with follow-up data.

BACKGROUND: The diagnosis of spindle cell neoplasms (SCN) of the upper gastrointestinal (GI) tract, hepatobiliary tract, and pancreas detected by fine needle aspiration (FNA) is challenging. We describe a single-center experience of these samples with follow-up data and characterization of the morphologic findings. METHODS: We retrospectively reviewed pathology records for all FNAs diagnostic for or suggestive of SCN on esophagus, stomach, small bowel, liver, and pancreas in a 15 year period. All cases with at least 6 month follow-up were included. Surgical material (biopsy or resection) was the diagnostic gold standard. All FNAs with subsequent surgical specimens were reviewed and assessed for cellularity, architectural features, and nuclear features. RESULTS: In 15 years, 5101 FNAs of the upper GI tract, hepatobiliary tract, and pancreas were performed. SCN was diagnosed in 98 (2%) patients. Seventy-two patients had definitive pathologic diagnoses: 68 were neoplastic and four were non-neoplastic. Cytomorphologic review in relationship to final diagnosis revealed three statistically significant features: low cellularity favors a benign process (P = .00544), epithelioid nuclear morphology favors malignancy (P = .00278), and identification of perinuclear vacuoles favors a diagnosis of GIST over non-GIST SCN (P = .04236). CONCLUSIONS: Among cases with follow-up, final pathologic diagnoses were SCN in 94% of cases diagnosed as SCN on FNA of upper GI, hepatobiliary tract, and pancreas. Although some cytomorphologic criteria are more suggestive of malignancy, arriving at a specific diagnosis relies on collaboration of clinical, radiologic, cytomorphologic, and immunohistochemical data.

Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia.

OBJECTIVE: In preclinical models of peripheral arterial disease the angiogenic response is typically robust, though it can be impaired in conditions such as hypercholesterolemia and diabetes where the endothelium is dysfunctional. Myoglobin (Mb) is expressed exclusively in striated muscle cells. We hypothesized that myocyte specific overexpression of myoglobin attenuates ischemia-induced angiogenesis even in the presence of normal endothelium. METHODS AND RESULTS: Mb overexpressing transgenic (MbTg, n=59) and wild-type (WT, n=56) C57Bl/6 mice underwent unilateral femoral artery ligation/excision. Perfusion recovery was monitored using Laser Doppler. Ischemia-induced changes in muscle were assessed by protein and immunohistochemistry assays. Nitrite/nitrate and protein-bound NO, and vasoreactivity was measured. Vasoreactivity was similar between MbTg and WT. In ischemic muscle, at d14 postligation, MbTg increased VEGF-A, and activated eNOS the same as WT mice but nitrate/nitrite were reduced whereas protein-bound NO was higher. MbTg had attenuated perfusion recovery at d21 (0.37+/-0.03 versus 0.47+/-0.02, P<0.05), d28 (0.40+/-0.03 versus 0.50+/-0.04, P<0.05), greater limb necrosis (65.2% versus 15%, P<0.001), a lower capillary density, and greater apoptosis versus WT. CONCLUSIONS: Increased Mb expression in myocytes attenuates angiogenesis after hind-limb ischemia by binding NO and reducing its bioavailability. Myoglobin can modulate the angiogenic response to ischemia even in the setting of normal endothelium.

Preoperative cytologic interpretation of noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a 1-year multi-institutional experience.

INTRODUCTION: Encapsulated follicular variant of papillary thyroid carcinoma (PTC) has an indolent behavior; hence, a change in terminology to "noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)" has been proposed. Data are scant on the fine-needle aspiration (FNA) diagnosis of nodules proven to be NIFTP upon resection. The aim was to evaluate the FNA diagnosis of nodules diagnosed as NIFTP upon resection. MATERIALS AND METHODS: The archives of 8 participating institutions were searched for thyroid resection specimens obtained in a 1-year period, and pertinent demographic and pathology data were recorded. RESULTS: 2226 thyroid surgeries were performed over the indicated time period. NIFTP was diagnosed in 6.3% of cases; 118 patients (119 nodules) with NIFTP and available preoperative thyroid FNA were included. Preoperative cytologic diagnosis were: non-diagnostic: 0.8%; benign: 5.9%; atypia of undetermined significance/follicular lesion of undetermined significance: 42.9%; follicular neoplasm/suspicious for a follicular neoplasm: 31.0%; suspicious for malignancy: 15.9%; malignant: 3.4%. Molecular data was available for 49 cases, either by Afirma or ThyGenX/ThyroSeq. Of the Afirma cases, 11% were classified as "benign", 2% as "indeterminate", and 87% as "suspicious"; of the ThyGenX/ThyroSeq cases, 50% had NRAS mutations, 20% demonstrated KRAS mutations, 20% showed HRAS mutations, and 10% showed a BRAF mutation (K601E). CONCLUSIONS: NIFTP are tumors demonstrating nuclear features similar to those seen in PTC. Our series shows that a preoperative diagnosis of "suspicious for malignancy" or "malignant" is uncommon in NIFTP, suggesting that there are sufficient cytomorphologic differences between PTC and NIFTP to allow for the suspicion of NIFTP on FNA specimens.

Current practice patterns in nongynecologic and fine-needle aspiration cytology.

INTRODUCTION: The American Society of Cytopathology Clinical Practice Committee in collaboration with the American Society of Cytotechnology surveyed cytology practitioners to better understand current practices related to nongynecologic (NGYN) cytology. While work practices in gynecologic (GYN) cytology are highly regulated with limited variation among specimens and processing techniques, practice patterns for NGYN cytology are less standardized among laboratories. MATERIALS AND METHODS: An NGYN cytology survey was created that consisted of 40 questions focusing on 6 main topic areas: (1) practice settings and demographic data; (2) NGYN non-fine-needle aspiration cytology; (3) fine-needle aspiration (FNA) cytology; (4) rapid on-site evaluation practices; (5) workload recording practices; and (6) expanding roles of the cytotechnologist (CT). The survey was sent to all American Society of Cytopathology and American Society of Cytotechnology members and remained available for 40 days. RESULTS: There were 368 survey participants (14% response rate) with nearly equal participation among CTs, cytology general managers and/or supervisors, and pathologists representing a variety of practice types. Most laboratories (87%) are providing a rapid on-site evaluation service for FNA specimens. The role of CTs is expanding with the majority of respondents stating that CTs assist with both clinician-performed and pathologist-performed FNA acquisition (77% and 50%, respectively), telecytology (16%), and screening of ancillary studies, including special stains (64%), immunohistochemistry (23%), and fluorescence in situ hybridization (16%). CONCLUSIONS: Knowledge of NGYN cytology practice patterns among laboratories may contribute information to better define the future of cytotechnology, support reimbursement initiatives, and enhance quality and efficiencies in the cytology laboratory.

Squamous intraepithelial lesions and squamous cell carcinomas detected by endometrial sampling: Pap test correlation and outcome data.

INTRODUCTION: Squamous intraepithelial lesions (SIL) and squamous cell carcinomas (SCC) can rarely be detected in endometrial sampling. We reviewed all cases of SIL and SCC detected solely on endometrial biopsies and curettings to determine their significance and whether these findings were detected on prior or concurrent Papanicolaou (Pap) test. MATERIALS AND METHODS: Endometrial samples with detached fragments of SIL and SCC over a 13-year period were reviewed, along with prior and/or concurrent Pap tests, human papillomavirus status, and subsequent pathology results. Cases with concurrent cervical or endocervical sampling that showed SIL or SCC were excluded. RESULTS: Fifty patients had endometrial biopsies and/or curettings with SIL or SCC. Thirty-six patients (72%) had concurrent or previous Pap tests within 1 year prior to the endometrial sampling. The Pap test was negative for intraepithelial lesion or malignancy in 44% of patients (16/36) and atypical squamous cells of undetermined significance in 22% of patients (8/36). The source of the SIL and SCC in endometrial sampling was cervical SIL in 18 patients, cervical SCC in 14 patients, endometrioid carcinomas in 3 patients, metastatic carcinoma in 1 patient, and not definitively identified in 14 patients. CONCLUSIONS: The majority of SIL and SCC in endometrial samples are from the cervix. Prior and concurrent Pap tests were often negative for intraepithelial lesion or malignancy in patients with SIL and SCC detected by endometrial samples. This suggests that SIL and SCC detected on endometrial sampling may detect a subset of cervical SIL/SCC that are more proximal in the endocervical canal and are not sampled with conventional Pap tests.

Solid tumor metastases to the pancreas diagnosed by FNA: A single-institution experience and review of the literature.

BACKGROUND: Pancreatic fine-needle aspiration (FNA) is useful for diagnosing pancreatic masses. This article describes the experience of a single institution with metastases to the pancreas sampled by FNA and provides a review of the literature. METHODS: Medical records were retrospectively searched for pancreatic FNA that showed metastatic disease. Data were gathered for the tumor size, focality, and time period between the primary tumor and the metastasis. A literature search using PubMed was performed. RESULTS: Pancreatic FNA was performed 2327 times in 14 years at the authors' institution. Twenty-two cases showed metastatic disease. The average size of the metastatic lesions in their greatest dimension was 3.7 cm (range, 1.5-6.5 cm). The majority of the tumors were unifocal (16 of 22 or 73%). A rapid onsite adequacy evaluation was performed for 13 patients (4 were diagnostic of metastasis, 3 were positive for malignant cells, 6 were atypical, and none were negative). There were 14 renal cell carcinomas, 2 colonic adenocarcinomas, 1 urothelial carcinoma, 1 non-small cell lung carcinoma, 1 ovarian serous carcinoma, 1 prostatic adenocarcinoma, 1 papillary thyroid carcinoma, and 1 mesenchymal chondrosarcoma. The median time between the diagnosis of the primary tumor and the initial pancreatic metastasis was 9 years (range, concurrent diagnosis to 21 years). A literature review yielded 12 case series with a variety of metastases to the pancreas diagnosed by FNA and surgical pathology specimens. CONCLUSIONS: In agreement with prior series, the most common metastasis to the pancreas was renal cell carcinoma. A variety of other primary malignancies were also documented in this study and in the literature. Also, this article reports the first case of metastatic mesenchymal chondrosarcoma to the pancreas diagnosed by FNA.

Electromagnetic navigation bronchoscopy-guided fine needle aspiration for the diagnosis of lung lesions.

Many peripheral lung lesions are beyond the reach of conventional bronchoscopes, and require percutaneous CT-guided or open surgical biopsy, which carry increased risks to the patient. Electromagnetic navigation bronchoscopy (ENB) is a relatively new technique, which uses an image guided localization system to direct steerable bronchoscopic tools to predetermined points within the bronchial tree. This technology allows improved access to peripheral lesions in particular. We investigated the sensitivity and specificity of ENB-guided fine needle aspiration (FNA) in the diagnosis of lung lesions. All ENB-guided FNAs performed at one institution were included in the study. The superDimension i-Logic System™ was used in all cases. Pathologic reports of the ENB-guided FNAs, as well as all other pulmonary sampling performed simultaneously with the FNA and within 1 year of the ENB-guided FNA were reviewed. Patients with a positive ENB-guided FNA or malignancy within the same lobe within the follow-up period were considered positive for malignancy. Patients with an atypical diagnosis but no definitive malignancy were considered negative for malignancy for statistical purposes. Ninety-one patients underwent 95 ENB-guided FNAs over a 3-year period. Thirty-five patients (38%) were positive for malignancy. ENB-guided FNA had a sensitivity of 63% for the detection of malignancy. The sensitivity for the detection of malignancy using all ENB-guided sampling methods, including FNA, bronchoscopic biopsy, and bronchial brushing was 83%. Pathologists and cytotechnologists should be aware of ENB-guided FNA as an emerging technology with a relatively high sensitivity for the diagnosis of peripheral lung lesions.

Cytologic features of parathyroid fine-needle aspiration on ThinPrep preparations.

BACKGROUND: Previous studies have provided cytologic criteria that aid in the recognition of parathyroid tissue on aspirate smears, including high cellularity, the presence of naked nuclei, loose 2-dimensional clusters, and papillary architecture. However, to the authors knowledge, the cytomorphologic features of parathyroid fine-needle aspiration (FNA) on liquid-based preparations have not been previously described. METHODS: The authors retrospectively reviewed all parathyroid FNAs that had aspirate smears and a ThinPrep preparation performed over 10 years at 1 institution. The FNA smears and ThinPrep preparations from each case were deidentified and independently reviewed for cellularity, naked nuclei, architecture, and colloid-like material. RESULTS: Forty patients were included in the current study. When individual cases were compared, the ThinPrep preparation was more likely to have lower cellularity, lack papillary architecture, lack naked nuclei, and have areas with a microfollicular pattern compared with the FNA smear. CONCLUSIONS: The cytologic features of parathyroid tissue vary depending on preparation. Many of the common features of parathyroid aspirates are lost on ThinPrep preparations, and an increased percentage of parathyroid FNA specimens have a microfollicular pattern on ThinPrep. This may lead to difficulty in recognizing parathyroid origin on FNA.

Utility and morphologic features of granulomas on rapid on-site evaluation of endobronchial ultrasonography-guided fine-needle aspiration.

INTRODUCTION: Endobronchial ultrasonography (EBUS)-guided fine-needle aspiration (FNA) is increasingly used to sample central lung lesions and mediastinal lymphadenopathy. We investigate the utility of EBUS-guided FNA and concomitant rapid on-site evaluation (ROSE) to diagnose granulomas, the morphologic characteristics of granulomas on ROSE, and how the diagnosis of granulomas changed the clinical impression. MATERIALS AND METHODS: All pathologic reports and associated clinical records of patients who had EBUS-guided FNA of the lungs or mediastinal lymph nodes that yielded granulomas were reviewed with at least a 1-year follow-up after EBUS-guided FNA. All ROSE slides were rereviewed to evaluate granulomas for quantity, necrosis, and cohesion. RESULTS: Over a 3-year period, 882 EBUS-guided FNAs were performed. One hundred and twelve patients (49% male, average age 50.8 years, range 16-83) had 161 EBUS-guided FNAs that yielded granulomas (18%). The etiologies of the granulomas were as follows: sarcoidosis (54%), infection (12%), malignancy (5%), inflammatory bowel disease-related lymphadenopathy (1%), and no specific clinical etiology (28%). Of the patients with EBUS-guided FNAs, 98 had ROSE performed (87.5%) and granulomas were seen in 70 of these patients (71%). Granulomas associated with sarcoidosis were mostly well-formed and non-necrotizing (90%). The results of the EBUS-guided FNA changed or redefined the clinical diagnosis in 79 patients (71%). CONCLUSIONS: EBUS-guided FNA with concurrent ROSE is a useful technique for the diagnosis of granulomas. The quality and quantity of granulomas detected during ROSE may suggest an etiology and help direct ancillary testing.

Two cases of Cokeromyces recurvatus in liquid-based Papanicolaou tests and a review of the literature.

We present 2 cases of Cokeromyces recurvatus in routine, liquid-based Papanicolaou tests (ThinPrep). Patient 1 is a healthy, asymptomatic, 26-year-old woman with no pertinent past medical history. Patient 2 is a healthy, asymptomatic, 47-year-old woman with no pertinent past medical history. The Papanicolaou tests from both patients showed many fungal-like elements as globose, yeastlike forms measuring 10 to 30 µm in diameter with multiple, narrowly attached apparent "daughter" buds. This morphology was consistent with Paracoccidioides brasiliensis. However, broad-range fungal polymerase chain reaction and deoxyribonucleic acid sequence analysis performed with GenBank Basic Local Alignment Search Tool showed an exact match for C recurvatus. Our cases highlight the importance of molecular techniques to prevent misdiagnosis of C recurvatus as P brasiliensis, based on morphology alone. There have been 8 previously published cases of C recurvatus infection in humans, 3 of which were reported in the female genital tract.

Mouse model of erectile dysfunction due to diet-induced diabetes mellitus.

OBJECTIVES: To determine whether diet-induced diabetes mellitus (DM) in mice would reproduce the major features of human erectile dysfunction (ED) because DM is a significant risk factor in the development of ED. METHODS: In total, 150 C57BL6 (bl6) mice were divided into six groups of 25 mice each. Of these 150 mice, 125 were fed a high-fat (45% of total calories) diet for the final 4 (group 2), 8 (group 3), 12 (group 4), 16 (group 5), or 22 (group 6) weeks. Group 1 was fed a normal diet. The mice were 22 to 25 weeks old at study termination. The corporal tissues were harvested and studied for endothelium-dependent and endothelium-independent vasoreactivity, endothelial and smooth muscle cell content by immunohistochemistry, nitric oxide synthase expression by nicotinamide adenine dinucleotide-diaphorase staining, and apoptosis by terminal deoxynucleotidyl transferase biotin-D-UTP nick-end labeling staining. RESULTS: The blood glucose levels were greater in groups 2 to 6 compared with those in group 1. The vasoreactivity, endothelial cell content, and smooth muscle/collagen ratio were lower and apoptosis were greater in the DM mice (P = 0.0001, P = 0.10, P = 0.0002, P <0.001, and P <0.001, respectively). Significantly decreased nitric oxide synthase expression and significantly increased apoptosis (P <0.0001 each) was found in the high-fat diet mice. CONCLUSIONS: Corporal tissue from mice with diet-induced DM demonstrated many of the major functional, structural, and biochemical changes found in humans with ED. This model should serve as a valuable tool for advancing our understanding of the role DM plays in the pathogenesis of ED.

Intracavernosal basic fibroblast growth factor improves vasoreactivity in the hypercholesterolemic rabbit.

PURPOSE: We determined the effects of intracavernosal injection (ICI) of recombinant basic fibroblast growth factor (rbFGF) on corporal tissue in hypercholesterolemic rabbits. METHODS: Twenty New Zealand White rabbits were fed a 1% cholesterol diet for 6 weeks and were randomly divided into four groups. Group 1 (N = 5) received an ICI of phosphate buffered saline solution (PBS) once and again 3 weeks later. Group 2 (N = 4) received an ICI of 2.5 microg rbFGF once and PBS 3 weeks later. Group 3 (N = 6) received an ICI of 2.5 microg rbFGF once and again 3 weeks later. Group 4 (N = 5) received an ICI of 2.5 microg rbFGF once. All animals were maintained on the high cholesterol diet until sacrifice, 3 weeks after last injection. Strips of corporal tissue were submaximally contracted with norepinephrine, and dose-response curves were generated to evaluate endothelial-dependent (acetylcholine, ACH) and endothelial-independent (sodium nitroprusside, SNP) vasoreactivity. Protein levels of bFGF and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assay. Neuronal nitric oxide synthase (nNOS) protein and mRNA were detected by Western blot and semi-quantitative polymerase chain reaction, respectively. RESULTS: Vasoreactivity was improved by bFGF treatment as shown by higher ED50[-log(M)] of ACH and SNP in Groups 2, 3, and 4. The expression of bFGF protein, VEGF protein, nNOS protein, and mRNA were all increased after bFGF treatment. CONCLUSIONS: ICI of bFGF improved vasoreactivity in hypercholesterolemic rabbit corporal tissue, offering a new direction to explore for the treatment of erectile dysfunction.

An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb ischemia.

OBJECTIVE: Angiogenesis is the growth and proliferation of blood vessels from existing vascular structures, and therapeutic angiogenesis seeks to promote blood vessel growth to improve tissue perfusion. Vascular endothelial growth factor (VEGF) is a prototypic angiogenic agent that exists in vivo in multiple isoforms, and studies with VEGF to date had used single isoform therapy with disappointing results. We tested plasmid and adenoviral vectors encoding a zinc-finger DNA-binding transcription factor (ZFP-32E) that was designed to increase the expression of all major VEGF isoforms in a preclinical model of peripheral arterial obstructive disease (PAOD) in hypercholesterolemic (ApoE knock-out) mice. METHODS: Unilateral femoral artery ligation/excision was performed in 117 mice. At 7 days postoperatively, the ischemic tibialis anterior (TA) and gastrocnemius (GAS) muscles received either ZFP-32E treatment (125 microg of plasmid, 2.5 x 10(11) viral particle units [vpu] of adenovirus; some mice received a second plasmid injection 3 days later) or no-ZFP treatment (125 microg of beta-galactosidase [beta-gal], a plasmid-lacking insert, or an equal dose of adenoviral encoding beta-gal; some mice received a second plasmid injection 3 days later). Group 1 mice (n = 31) were euthanized 3 days later, and VEGF messenger RNA (mRNA) and protein levels were measured. Group 2 mice (n = 38) were euthanized 7 days later, and measures of capillary density, cell proliferation, and apoptosis were quantified. Group 3 mice (n = 48) were euthanized 28 days later, and changes in lower limb blood flow perfusion were measured. RESULTS: In group 1, VEGF mRNA and protein levels were significantly higher in those with ZFP-32E treatment vs beta-gal. In group 2, capillary density and proliferating cells were significantly greater and apoptosis was significantly lower in those with ZFP-32E treatment vs beta-gal. Finally, in group 3, changes in the perfusion ratio (ischemic/nonischemic limb) at 21 days after injection were significantly greater in those with ZFP-32E treatment vs no-ZFP treatment. CONCLUSION: The ability of this engineered zinc-finger VEGF-activating transcription factor to induce therapeutic angiogenesis in hypercholesterolemic mice suggests this approach warrants investigation as a novel approach to treat PAOD.