A Case of Primary Mammary Analog Secretory Carcinoma (MASC) of the Thyroid Masquerading as Papillary Thyroid Carcinoma: Potentially More than a One Off.

We present the second reported mammary analog secretory carcinoma (MASC) apparently arising in the thyroid and propose a potential close relationship to ETV6-NTRK3 fusion papillary thyroid carcinoma. The patient, a 36 year old woman, presented with a neck mass of 1 year's duration. Imaging studies showed a tumor involving most of the thyroid with enlarged regional lymph nodes. FNA biopsy yielded a diagnosis of "papillary thyroid carcinoma". Resection revealed a 4.5 cm infiltrative tumor. Final diagnosis was "papillary thyroid carcinoma (PTC) consistent with diffuse sclerosing variant" with positive lymph nodes (2+/4) and margins. Histologic features included mixed microcystic, solid, follicular and papillary architecture, prominent nucleoli, abundant nuclear grooves and rare nuclear pseudo-inclusions. Despite radioactive iodine, radiotherapy and multiagent chemotherapy, the patient progressed over 6 years with local recurrence and additional lymph node involvement finally developing widespread distant metastases. Prompted by the breast carcinoma-like histopathology of a metastasis, immunohistochemical staining was performed and revealed strong expression of GATA3 and mammaglobin with no reactivity for thyroglobulin or TTF-1. The original tumor was then tested and showed the same immunoprofile. RT-PCR confirmed the presence of an ETV6-NTRK3 fusion consistent with a diagnosis of MASC. Our patient's clinical, imaging and morphologic features remarkably mimicked papillary thyroid carcinoma. At the molecular level, the ETV6-NTRK3 fusion in this patient involved exons reported in the rare "papillary thyroid carcinoma" with this translocation. Given the immunophenotype of this case, it is possible that at least some ETV6-NTRK3 fusion positive PTC are actually MASC masquerading as papillary thyroid carcinoma.

Phase IB study of the combination of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen.

BACKGROUND: To assess the response of patients with soft tissue sarcoma (STS) to the combination of docetaxel, bevacizumab, and gemcitabine. Vascular endothelial growth factor (VEGF)-A levels and expression of VEGF-A and VEGF receptors 1 and 2 were evaluated. PATIENTS AND METHODS: Thirty-eight chemotherapy-naive patients with STS were enrolled. A dose-finding study for gemcitabine from 1000, 1250, then 1500 mg/m(2) was done in nine patients (three cohorts), followed by an expansion cohort of 27 patients. Dose of docetaxel was 50 mg/m(2), bevacizumab was 5 mg/kg, and gemcitabine was 1500 mg/m(2), every 2 weeks. Serum VEGF-A was measured by enzyme-linked immunosorbent assay and tissue VEGF-A and its receptors by immunohistochemistry. RESULTS: The median follow-up was 36 months. The overall response rate observed was 31.4%, with 5 complete and 6 partial responses, and 18 stable diseases lasting for a median of 6 months. There was no significant hematologic toxicity. The adverse events with the highest grade were attributed to bevacizumab. There was no correlation of VEGF pathway biomarkers with outcome. CONCLUSIONS: The combination of gemcitabine, docetaxel, and bevacizumab is safe and effective in patients with STS. The most concerning adverse events were consequences of bevacizumab administration. The benefit of bevacizumab in this patient population remains unclear.

Predicting gene promoter methylation in non-small-cell lung cancer by evaluating sputum and serum.

The use of 5-methylcytosine demethylating agents in conjunction with inhibitors of histone deacetylation may offer a new therapeutic strategy for lung cancer. Monitoring the efficacy of gene demethylating treatment directly within the tumour may be difficult due to tumour location. This study determined the positive and negative predictive values of sputum and serum for detecting gene methylation in primary lung cancer. A panel of eight genes was evaluated by comparing methylation detected in the primary tumour biopsy to serum and sputum obtained from 72 patients with Stage III lung cancer. The prevalence for methylation of the eight genes in sputum (21-43%) approximated to that seen in tumours, but was 0.7-4.3-fold greater than detected in serum. Sputum was superior to serum in classifying the methylation status of genes in the tumour biopsy. The positive predictive value of the top four genes (p16, DAPK, PAX5 beta, and GATA5) was 44-72% with a negative predictive value for these genes > or =70%. The highest specificity was seen for the p16 gene, and this was associated with a odds ratio of six for methylation in the tumour when this gene was methylated in sputum. In contrast, for serum, the individual sensitivity for all genes was 6-27%. Evaluating the combined effect of methylation of at least one of the four most significant genes in sputum increased the positive predictive value to 86%. These studies demonstrate that sputum can be used effectively as a surrogate for tumour tissue to predict the methylation status of advanced lung cancer where biopsy is not feasible.

Extracutaneous angiosarcomas metastatic to the lungs: clinical and pathologic features of twenty-one cases.

Angiosarcomas are rare malignant vascular tumors with a high rate of metastasis involving lungs (most commonly), liver, regional lymph nodes, bone, and other sites. In this study, we have reviewed the clinical presentation and histopathology of 21 cases of extracutaneous angiosarcoma metastatic to the lungs. Tumors with exclusively pleural involvement were excluded. Patients presented with dyspnea, chest pain, and/or hemoptysis lasting a few weeks to months. Radiologically, the most common finding comprised multiple peripheral lung nodules (57%), often accompanied by infiltrates. For 11 cases (52%), the primary tumor was not identified at the time of presentation. Vasoformative areas were identified in 15 cases (71%). Nine cases comprised spindle cells (43%), two contained epithelioid cells (9.5%), and 10 consisted of both spindle and epithelioid cells (48%). Nuclear pleomorphism was at least moderate in all cases. However, five tumors contained regions of minimal nuclear atypia. Hemorrhage, siderophages, and fibrosis were commonly present. Immunohistochemical staining (IHS) was performed on 14 cases. Thirteen tumors showed reactivity for vascular markers. Tumor cells reacted for Von Willebrand factor in 13 of 14 cases, and CD31 and CD34 were each positive in 2/2 cases. Two cases (of nine examined) also expressed cytokeratins. Because the tumor often first presented in the lungs before the primary sarcoma was identified, the clinical impression included both benign and malignant entities. For patients with primary cardiac tumors, symptoms referable to the primary tumor complicated the clinical presentation, and radiologic evaluation supported a clinical diagnostic impression of non-neoplastic pericarditis. Thus, angiosarcoma in the lung may elude diagnosis until histopathologic evaluation of the lung biopsy.

The XRCC1 399 glutamine allele is a risk factor for adenocarcinoma of the lung.

Defects in the repair and maintenance of DNA increase risk for cancer. X-ray cross-complementing group 1 protein (XRCC1) is involved with the repair of DNA single-strand breaks. A nucleotide substitution of guanine to adenine leading to a non-conservative amino acid change was identified in the XRCC1 gene at codon 399 (Arg/Gln). This change is associated with higher levels of aflatoxin B1-adducts and glycophorin A somatic mutations. A case-control study was conducted to test the hypothesis that the 399Gln allele is positively associated with risk for adenocarcinoma of the lung. XRCC1 genotypes were assessed at codon 399 in 172 cases of lung adenocarcinoma and 143 cancer-free controls. Two ethnic populations were represented, non-Hispanic White and Hispanic. The distribution of XRCC1 genotypes differed between cases and controls. Among cases, 47.7% were Arg/Arg, 35.5% were Arg/Gln, and 16.9% were Gln/Gln. Among controls, XRCC1 allele frequencies were 45.5% for Arg/Arg, 44.8% for Arg/Gln, and 9.8% for Gln/Gln. Logistic regression analysis was used to assess the association between lung adenocarcinoma and the G/G genotype relative to the A/A or A/G genotypes. In non-Hispanic White participants, the lung cancer risk associated with the G/G genotype increased significantly after adjustment for age (OR=2.81; 95% CI, 1.2-7.9; P=0.03) and increased further after adjustment for smoking (OR=3.25; 95% CI, 1.2-10.7; P=0.03). Among all groups, a significant association was found between the G/G homozygote and lung cancer (OR=2.45; 95% CI, 1.1-5.8; P=0.03) after adjustment for age, ethnicity, and smoking. This study links a functional polymorphism in the critical repair gene XRCC1 to risk for adenocarcinoma of the lung.

Fine needle aspiration cytology of follicular dendritic cell sarcoma. Report of a case with cytologic detection in an extranodal site.

BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare malignancy of accessory immune cells that can present in both nodal and extranodal sites. Previous cytologic case reports of FDCS have focused on fine needle aspiration (FNA) findings in nodal sites with low grade morphology and indolent clinical courses. CASE: A 33-year-old female presented with a three-month history of abdominal distention, early satiety and nausea. Initial imaging studies showed a large abdominal mass, with subsequent studies showing lung, liver and lymph node metastases. Examination of primary and metastatic tumors by a combination of conventional histology, immunohistochemistry and FNA demonstrated an extranodal intraabdominal follicular dendritic cell sarcoma. CONCLUSION: FDCS demonstrates a characteristic cytologic picture on FNA, with important cytologic features, including both syncytial and discohesive large epithelioid to spindled malignant cells with intranuclear inclusions, nuclear grooves and a prominent, mature, lymphocytic inflammatory component. No evidence of morphologic tumor progression was noted in comparison of primary and metastatic tumors. To aid in the cytologic distinction of FDCS from other similar-appearing neoplasms, we recommend acquisition of material for immunohistochemical studies, recognition of diverse clinical presentations (including extranodal and aggressive) and acknowledgment of the range of tumor morphologic grades.

Solitary fibrous tumor of the orbit with a t(9;22)(q31;p13).

Solitary fibrous tumors are well-described neoplasms found predominantly in the subpleural region but also in many other body sites. They generally behave in a benign fashion, although a few cases that exhibit a malignant course have been reported. Genetic information on solitary fibrous tumors is sparse. This case illustrates a previously unreported finding of a tumor-specific t(9;22)(q31;p13) in a solitary fibrous tumor of the orbit of a 58-year-old man.

Specimen fine-needle aspiration cytology of littoral cell angioma with histologic and immunohistochemical confirmation.

We performed a specimen fine-needle aspiration biopsy (FNAB) of a littoral cell angioma (LCA) from a 33-yr-old male who underwent elective splenectomy due to thrombocytopenia secondary to Wiscott-Aldrich syndrome. Gross examination revealed a 420-g, diffusely enlarged spleen which contained two moderately well-circumscribed, soft brown lesions measuring 0.3 and 1.0 cm, respectively. Benchtop aspiration of the lesions following splenectomy yielded a cellular sample composed predominantly of dispersed single cells, which ranged from columnar to spindle to circariform in shape. Nuclei were round to oval with even chromatin, and many contained single longitudinal grooves. A majority of the cells contained abundant, granular hemosiderin pigment, a key cytologic feature. Immunohistochemical staining revealed reactivity for antibodies to CD68 and factor VIII-related antigen with no reactivity for S-100 protein and CD8. Littoral cell angioma must be differentiated from splenic hamartoma, hemangioma, angiosarcoma, littoral cell angiosarcoma, and epithelioid and spindle cell hemangioendothelioma. A combination of cytologic features and immunohistochemical results should enable an accurate diagnosis.

Fine needle aspiration cytology of plexiform fibrohistiocytic tumor. A case report.

BACKGROUND: Plexiform fibrohistiocytic tumors are rare lesions of proposed myofibroblastic origin occurring primarily in infants and children. While the histologic, immunohistochemical and ultrastructural findings have been well described, cytologic description has been limited. CASE: An 8-month-old, male infant presented with a posterior chest wall mass and decreased use of his left arm. Fine needle aspiration biopsy showed a spectrum of plump fibroblastic spindle cells and histiocytelike cells within a finely granular myxoid background. Osteoclastlike giant cells were also noted. CONCLUSION: We report here the cytologic findings of a plexiform fibrohistiocytic tumor from fine needle aspiration biopsy studied using Papanicolaou, Ultrafast Papanicolaou and Diff-Quik stain, with the cytologic differential diagnosis of other spindled and histiocytelike tumors.

Primary lung tumors infiltrated by osteoclast-like giant cells.

Six primary lung tumors with numerous multinucleated osteoclast-like giant cells (OLGCs) and no osteogenic component were evaluated histologically and immunohistochemically to examine pulmonary lesions inciting an OLGC response. The patients comprised four women and two men ranging in age from 61 to 80 years (average age, 69 years). The tumors consisted of one adenocarcinoma, two sarcomatoid carcinomas, and three giant cell variants of malignant fibrous histiocytoma. One tumor was endobronchial in location, while five were situated peripherally. Tumor diameter spanned from 1 to 6.5 cm (average, 2.7 cm). In addition to the giant cells, common characteristics included the malignant nature of the neoplasms and, in five of six cases, histologically malignant mesenchyme. This array of cases exemplifies the variability of lung lesions which may elicit an OLGC inflammatory response resulting in areas resembling the giant cell variant of malignant fibrous histiocytoma. The results of this study suggest that OLGCs occur preferentially in malignant rather than benign nonosteogenic lung tumors and that sarcomatoid regions of malignant tumors are more likely to be infiltrated by OLGCs than epithelial regions.

Fine-needle aspiration biopsy of large-cell undifferentiated carcinoma of the salivary glands: presentation of two cases, literature review, and differential cytodiagnosis of high-grade salivary gland malignancies.

Primary undifferentiated carcinoma of the salivary glands is a rare, high-grade neoplasm which accounts for a very small number (1-5.5%) of malignant salivary gland tumors. The large-cell variant (LCU) is less well-characterized than the small-cell form. We report on the fine-needle aspiration (FNA) biopsy findings of 2 cases of LCU, one arising in the parotid gland, and the other in a buccal mucosa accessory salivary gland. The 2 cases were similar in composition: isolated and loosely cohesive large cells with abundant cytoplasm, and variability pleomorphic nuclei with prominent nucleoli. One case also featured multinucleated tumor giant cells and macrophage polykaryons; the latter has not previously been described in FNA biopsies of LCU. There was no evidence of squamous, myoepithelial, or widespread mucinous differentiation by morphological, cytochemical, or immunohistochemical analyses (focal rare mucin production identified on special stains in one case). The differential diagnosis is lengthy and consists of other high-grade primary salivary gland malignancies as well as metastatic lesions, including melanoma. The pattern of immunohistochemical reactivity (positive keratin, negative S-100, and HMB-45 antigens), and lack of conspicuous mucin production of significant lymphoidinfiltrate, were useful in establishing the correct diagnosis.

Signet-ring squamous cell carcinoma: a case report.

A-50-year-old Hispanic man presented to the dermatology clinic with a 0.6-cm eroded, erythematous, scaly plaque on the left side of his neck. On shave biopsy, the lesion was composed of intra-epidermal and invasive dermal cells characterized by a signet-ring appearance. One area suggestive of typical squamous cell carcinoma prompted the inclusion of that entity in the differential diagnosis. Mucicarmine stains were negative, while the extra-vacuolar cytoplasm focally reacted with periodic acid-Schiff staining, the positive reaction for which was abolished by diastase, consistent with glycogen. Malignant cells expressed keratins by reacting to antibodies, Mak6, AE1/AE3, Ker 903, and CAM5.2. Additionally, weak reactivity occurred with antibodies to CEA and EMA. Tumor cells did not express S-100, HM-B45, Leu M1, or actin. By ultrastructural examination, the large vacuoles corresponded to markedly dilated endoplasmic reticulum. A diagnosis of signet-ring squamous cell carcinoma, a rare form of cutaneous squamous cell carcinoma which has been described in only one case report in the last 10 years, was made. Immunohistochemical staining provided information useful in differentiating this lesion from other clear cell and signet-ring cell tumors which involve the skin.

Intra-abdominal lymphangiomas in children and adults. Assessment of proliferative activity.

OBJECTIVE: Intra-abdominal lymphangiomas are rare in children and even more exceptional in adults. Because these lesions occasionally progressively enlarge, we analyzed seven adult and four pediatric cases for evidence of proliferative activity. DESIGN: Immunohistochemical analysis was performed retrospectively on representative tissue sections using antibodies to the following antigens: Ki-67, proliferating cell nuclear antigen, and p53 gene product (eight cases). DNA ploidy was examined in five cases. PATIENTS: The study group consisted of seven adult women (aged 24 to 73 years), a 3.5-year-old girl, and two boys, aged 3.5 and 9 years, the last with a recurrence at age 15. The lymphangiomas ranged from 1.7 to 23 cm in maximum size. RESULTS: Ranges of percentages of cells staining for proliferating cell nuclear antigen, Ki-67, and p53 were similar between the pediatric and adult cases. Antibody to Ki-67 stained from 0.5% to 17% of the stromal and endothelial components of the lymphangiomas. Proliferating cell nuclear antigen activity was noted in 16% to 52% of lesional cells. Reactivity was noted almost exclusively in areas of inflammation and fibroplasia. For comparison, 10% to 50% of intermixed lymphocytes stained for Ki-67 and proliferating cell nuclear antigen. There was no labeling with p53. DNA content was uniformly diploid. CONCLUSIONS: The scant staining for Ki-67 in the majority of the lesions, combined with proliferative rates that were only focally elevated, suggests that lymphangiomas in children and adults are quiescent lesions whose enlargement is due to engorgement by chyle and localized secondary inflammation rather than primary tumoral growth.

Ameloblastic fibroma: a fine-needle aspiration case report.

Fine-needle aspiration biopsy of an ameloblastic fibroma, an unusual odontogenic tumor related to ameloblastoma, was performed on a 38-yr-old man with a slowly enlarging left facial mass. Aspiration of the tumor yielded a cellular sample composed of a mixture of mesenchymal and epithelial cells, arranged, respectively, in thick mats and complex solid structures outlined by columnar cells with central regions reminiscent of stellate reticulum. A diagnosis of odontogenic tumor was conferred, and the lesion was surgically biopsied and then resected. The key cytologic feature distinguishing this lesion from other odontogenic tumors was fragments of hypercellular stroma. The differential diagnosis includes ameloblastoma, ameloblastic fibrosarcoma, other odontogenic tumors, intraosseous adenoid cystic carcinoma, trabecular adenoma, and basal-cell carcinoma.

Tall cell variant of papillary thyroid carcinoma: cytologic features and differential diagnostic considerations.

The cytologic features of the tall cell variant (TCV) of papillary thyroid carcinoma may be confused with those of other thyroid neoplasms with different prognoses and treatment modalities. Elucidation of the cytomorphology of this variant would be useful in planning treatment for this fairly aggressive variant of papillary carcinoma. The cytologic features of 20 cases of TCV were compared with those of 23 cases of the usual variant (UV) of papillary thyroid carcinoma and of 10 Hürthle-cell neoplasms (HCN). After a set of features was defined, the efficacy of employing it to distinguish TCV from UV and HCN was assessed by three cytopathologists (J.D.T., I.R., and M.O.), was independently examined 15 unknown cases selected by the first author. Aspirates of TCV showed some specific cytologic features which included large cell size with abundant granular cytoplasm and variably sized nuclei with granular chromatin. The cells were sometimes columnar, but more often were polygonal, and prominent cytoplasmic borders were present in 50% of cases. Intra-nuclear inclusions were more prominent in TCV than in UV. There was some overlap in the cytomorphology of some TCV and UV cases, and variable numbers of cells with UV features were encountered in TCV cases. Employing the cytologic features of TCV listed above, three cytopathologists examined the unknown cases, which included 7 cases of TCV, 4 cases of UV, and 4 cases of HCN. TCV was recognized as such by all three cytopathologists in 6 of 7 cases, and all UV and HCN were correctly typed by all three examiners. The cytologic features of TCV are sufficiently distinctive to enable separation from HCN and most cases of UV. Although the diagnosis of TCV may be rendered employing fine-needle aspiration biopsy, material, this diagnosis should be limited, in our opinion, to specimens which contain at least 30% of cells with typical TCV features.

Aspiration cytology features of the warthin tumor-like variant of papillary thyroid carcinoma. A report of two cases.

BACKGROUND: Warthinklike tumor of thyroid is a recently described variant of papillary thyroid carcinoma characterized histologically by a papillary architecture, oxyphilic tumor cells and extensive, chronic inflammation. CASES: Fine needle aspiration was performed on solitary thyroid nodules in two females aged 19 and 35 years. Both patients complained of neck lumps, and the older one noted several months of fatigue and weight gain. The specimens were cytologically similar and were characterized by two distinct sets of features, one suggesting the tall cell or oxyphilic variant of papillary thyroid carcinoma and the other suggesting chronic lymphocytic (Hashimoto's) thyroiditis. Neoplastic follicular cell nuclei were divided into those with grooves, pseudoinclusions and hyperlobation consistent with papillary thyroid carcinoma, while other tumor nuclei exhibited a uniform, round contour; hypergranular chromatin; and relatively prominent nucleoli reminiscent of Hürthle cells. Chronic inflammation was abundant and intimately associated with neoplastic cell groups. CONCLUSION: Warthinlike tumor of the thyroid possesses cytoplasmic and nuclear features with overlap with several other thyroid lesions. Although a definitive diagnosis at aspiration biopsy may be very difficult, the lesions are recognizably neoplastic and identifiable as probable or definite papillary thyroid carcinoma.

Force sensor for laparoscopic Babcock.

UNLABELLED: GENERAL: A force sensor has been designed and fabricated that will fit to existing laparoscopic grasping forceps (Babcocks) from Ethicon Endosurgery Inc. The goal of the sensor development is to provide tool-tissue force information to the surgeons so that surgeons can regain the sense of touch that has been lost through laparoscopy. Eventually, force sensing will provide feedback for robotic laparoscopic surgical platforms. OBJECTIVE: We have developed a prototype force sensor system with ATI Industrial Automation. This tool is provided as an in-line transducer with six degrees of freedom that can retrofit current Babcocks. The sensor is currently being used in clinical trials with animals to determine the benefits. The sensor system utilizes industry proven technology in combination with a custom transducer and user interface. A GUI is part of the system and provides resolved force magnitude data in a graphical format for case of interpretation. Sterilization, size, and ease of use are addressed by the current design. Operating room reliability and safety are currently being investigated. CLINICAL TRIAL: A three phase experimental trial using a porcine model is being completed that will test the hypothesis that force information can be used to minimize tissue trauma during laparoscopic surgery. RESULTS: Based on our research, there is strong evidence that surgeons would benefit from information regarding the levels of force applied to tissues. In the future, robotic surgery will require force sensing. Surgical simulators could provide force feedback during simulated surgical procedures by using a sensor platform such as this. In addition, tool tip design in the future will benefit from the application of this technology and data base.

p53 PCNA, and Ki-67 in hydropic molar and nonmolar placentas: an immunohistochemical study.

Sixty molar and nonmolar placentas with hydropic features [23 complete moles, 14 partial moles, 8 moles-not further classified, and 15 hydropic, nonmolar placentas] were evaluated immunohistochemically for expression of Ki-67, proliferating cell nuclear antigen (PCNA), and p53, and the results were compared with DNA ploidy and S-phase fractions derived from flow cytometric analysis. The data were evaluated to determine if proliferation marker staining could aid in distinguishing mole from non-mole and partial from complete mole. PCNA and p53 expression did not discriminate between moles and non-moles. However, the percentage of rimming villous cytotrophoblast nuclei reactive for Ki-67 differed significantly between moles and non-moles (p < 0.001). All molar specimens contained at least one medium-sized villus with > 70% Ki-67-positive cells, whereas the maximum percentage of reactive cells in hydropic abortuses was 22%. These results suggest that percentage Ki-67 positivity in rimming cytotrophoblast nuclei may aid in distinguishing a mole from a nonmolar, hydropic abortion.

Unusual mesenchymal and mixed tumors of the salivary gland. An immunohistochemical and flow cytometric analysis of three cases.

Histological, immunohistochemical, and flow cytometric characteristics of three unusual parotid gland tumors are described. The patients were adult white men with carcinoma ex pleomorphic adenoma, true malignant mixed tumor, and primary parotid gland chondrosarcoma. The carcinoma ex pleomorphic adenoma showed evidence of simultaneous epithelial, myoepithelial, and mesenchymal differentiation by immunohistochemistry. The true malignant mixed tumor exhibited variable positivity for two keratins, vimentin, proliferating cell nuclear antigen, Ki67, and p53. The chondrosarcoma initially stained for vimentin, S100, muscle-specific actin, proliferating cell nuclear antigen, and Ki67, but it lost actin expression in its first recurrence, accompanied by more extensive Ki67 staining. DNA ploidy varied from diploid to aneuploid with intratumoral variation in the carcinosarcoma. S-phase fractions ranged from 2.43% to 13.9%. The findings underscore the diversity of tumors that may be pathogenetically related to, and at times derived from, pleomorphic adenoma.