RET,a targetable driver of pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease, affecting about 40,000 individuals in the United States annually. We aimed to characterize the role of RET as a co-driver of pancreas tumorigenesis. To assess the role of RET as a co-driver of PDA, we generated a novel triple mutant transgenic mouse based on the cre-activated p53^R172H gene and a constitutively active RET ^M919T mutant (PRC). Survival analysis was performed using Kaplan–Meier analysis. Study of human PDA specimens and Pdx-1-Cre/Kras^G12D /p53^R172H (KPC) mice revealed that RET is upregulated during pancreas tumorigenesis, from inception through precursor lesions, to invasive cancer. We demonstrated that activation of RET is capable of inducing invasive pancreatic carcinomas in the background of the P53 inactivation mutation. Compared to KPC mice, PRC animals had distinct phenotypes, including longer latency to tumor progression, longer survival, and the presence of multiple macrometastases. Enhanced activation of the MAPK pathway was observed as early as the PanIN 2 stage. Sequencing of the exonic regions of KRAS in PRC-derived PDA cells revealed no evidence of KRAS mutations. RET can be an essential co-driver of pancreatic tumorigenesis in conjugation with KRAS activity. These data suggest that RET may be a potential target in the treatment of PDA.     

Autoimmune pancreatitis misdiagnosed as a tumor of the head of the pancreas

Autoimmune pancreatitis can mimic pancreatic cancer in its clinical presentation, imaging features and laboratory parameters. Differentiating between those two entities requires implementation of clinical judgment and experience along with objective parameters that may suggest either condition. Few strategies have been proposed for the surgeon to implement when facing borderline cases. The following case is an example of a clinical scenario compatible with an accepted algorithm for diagnosis of pancreatic cancer, which eventually proved wrong. We present a 75-year-old patient who was admitted for obstructive jaundice. Imaging features were highly suggestive for pancreatic cancer as was the carbohydrate antigen 19-9 (CA 19-9) level, leading to a decision for surgery. Pathological examination revealedautoimmune pancreatitis. Though no frank carcinoma was found, premalignant ductal changes of pancreatic intraepithelial neoplasia (PanIN)Ⅰand PanIN Ⅱ were discovered throughout the pancreatic duct. Caution is advised when relying on the combination of highly suggestive radiology features and elevated levels of CA 19-9 in the diagnosis of pancreatic cancer. When the tissue diagnosis is not conclusive, obtaining IgG4 and antinuclear Ab levels is advised, to rule out the rare possibility of autoimmune pancreatitis. Patients with autoimmune pancreatitis should be followed carefully as precancerous lesions may accompany the benign disease and the correlation of these two entities has not been ruled out.     

Primary intraspinal primitive neuroectodermal tumor treated with autologous stem cell transplantation: case report and review of the literature

The authors describe the case of a 19-year-old female patient with a primary primitive neuroectodermal tumor (PNET) of the thoraco-lumbar spinal cord, who presented with acute urinary retention and back pain for 2 months. Magnetic resonance imaging revealed an intradural extramedullary tumor, 6.5 cm long, in the region of the conus medullaris. Histological examination disclosed a small round cell tumor with immunohistochemical characteristics of a peripheral PNET. Metastatic workup showed no evidence of an intracranial tumor or metastases outside the neuroaxis. The patient received multidisciplinary treatment, including surgical excision, irradiation of the entire cranio-spinal axis, and high-dose chemotherapy with autologous stem cell rescue. Presently, 24 months after diagnosis, the patient remains in complete remission.     

Rheumatoid lung nodulosis and osteopathy associated with leflunomide therapy

Background Leflunomide (LEF) is indicated in adults for the treatment of active rheumatoid arthritis (RA). LEF inhibits dehydroorotate dehydrogenase, a key enzyme of the pyrimidine synthesis in activated lymphocytes. Among rare adverse effects, fatal interstitial lung disease has been recently reported during treatment of RA with LEF in Japan. Clinical trials outside Japan do not suggest that LEF causes an excess of pulmonary adverse effects. Development and increase of peripheral rheumatoid nodules in typical sites of RA patients following LEF therapy has been recently reported. Objectives Two cases with new and accelerated development of rheumatoid lung nodulosis during LEF therapy were described in this study. Methods LEF treatment was administered to two male patients (77 and 66 years old) with long-standing active seropositive nodular RA with failure of multiple second line drugs and without lung involvement. Clinical and laboratory assessment using the American College of Rheumatology response criteria, chest computed tomography (CT), quantification of serum rheumatoid factor (RF), and monocyte count of peripheral blood along with routine laboratory follow up were performed on both patients before and during therapy. In case 1, a bone scan was performed due to sustained limbs pain. Open lung biopsy was performed in case 1 and core lung biopsy in case 2. Results Both patients achieved full clinical remission during 2 months of LEF therapy. In case 1, the first complaints were limbs pain after 10 months of treatment associated with intensive bone uptake on a bone scan consistent with hypertrophic pulmonary osteopathy. Productive cough developed after 3 months of the therapy in case 2. Initially, these complaints were not attributed to therapy. New lung disease was present on CT with cherry-like progressive cavitary nodules, predominantly involving the basal segments of the right lung. The first lung lesions were found by CT 13 months (case 1) and 7 months (case 2) after the beginning of therapy and were erroneously related to bronchiectasia in case 2. In both cases, the lung biopsy showed necrosis surrounded by epithelioid mononuclear inflammation with giant cells, consistent with rheumatoid lung node. The time that elapsed between the beginning of the first symptoms to LEF discontinuation was very long: 13 months in case 1 and 24 months in case 2. Discontinuation of LEF therapy was followed by an arrest in growth of lung nodules, resolution of limb pain, and gradual improvement of bone scan. A significant decrease of monocyte count and RF level in peripheral blood was observed during LEF therapy in both cases. Conclusion For the first time, we described rheumatoid lung nodulosis as complication of successful LEF therapy for RA. Hypertrophic pulmonary osteopathy with severe limbs pain and dry cough were the first manifestations of the lung nodulosis. Monocytopenia during LEF therapy is proposed to be involved in pathogenesis of this rare complication of LEF therapy.     

KRAS mutation positive mucinous adenocarcinoma originating in mature ovarian teratoma: Case report and review of literature

Mature ovarian teratomas rarely undergo transformation into malignancy. Carcinomas, mostly squamous cell carcinoma, are the most common malignancy arising in mature cystic teratoma. In the present report we describe a 13‐year‐old girl who developed a large mass in her ovary. Fine needle biopsy identified intestinal type mucinous adenocarcinoma, which was also identified in the full surgical specimen. Extensive sampling of the surgical specimen also identified areas of mature cystic teratoma. Interestingly, molecular analysis of DNA extracted from various components of the lesion identified KRAS mutation in the carcinoma, borderline mucinous tumor and benign intestinal‐type epithelium but not in the epidermal component of the teratoma. To the best of our knowledge this is the first report of KRAS mutation in mucinous carcinoma originating in mature cystic teratoma. We discuss the importance of extensive tissue sampling to differentiate between carcinoma originating in teratoma and metastatic colorectal carcinoma to the ovary. Additionally, the identification of KRAS mutation in the morphologically benign intestinal‐type epithelium indicated that it is an early event in the carcinogenic sequence and that the molecular pathway of carcinogenesis in teratoma is similar to that in the carcinogenic process of somatic tissue.     

Sonographically guided percutaneous needle biopsy of soft tissue masses with histopathologic correlation.

OBJECTIVE: The purpose of this study was to evaluate the accuracy of sonographically guided percutaneous core biopsy of soft tissue masses. METHODS: We retrospectively reviewed the medical records of patients who underwent sonographically guided biopsy of soft tissue masses at our institution during a 50-month period. Core biopsy histopathologic results were compared with surgical or clinical follow-up. RESULTS: One hundred eighty-three patients, 76 male and 107 female, with a mean age of 48.5 years were included in the study. Thirteen patients had more than 1 biopsy, and the total number of biopsies performed was 196. Five patients were lost to follow-up. Biopsy results were diagnostically accurate in 174 (91%) cases. Thirteen biopsies were inconclusive. No complications occurred. The overall sensitivity, specificity, positive predictive value, and accuracy in separating malignant from benign lesions were 97%, 99%, 99%, and 98%, respectively. CONCLUSIONS: Sonographically guided core needle biopsy is an accurate and safe means to obtain tissue samples for the histopathologic diagnosis of soft tissue masses. It obviates the need for open biopsy and should be performed routinely for treatment planning.     

Gliosarcoma arising in oligodendroglial tumors ("oligosarcoma"): a clinicopathologic study

Gliosarcomas are morphologically biphasic tumors composed of glial and sarcomatous elements. Only rare examples of gliosarcoma with oligodendroglial components have been reported. Seven patients with oligodendroglial tumors and a sarcomatous component were identified. Fluorescence in situ hybridization for 1p/19q was sought in glial and sarcomatous regions in all cases. Their mean age at diagnosis of gliosarcoma was 48 years (range 36 to 68) (F:M ratio=5:2). At first resection, the tumors included grade II oligodendroglioma (n=3), grade III oligodendroglioma (n=1), grade II oligoastrocytoma (n=1), and grade III oligoastrocytoma (n=2). The sarcomatous component developed in recurrent/progressive tumors in 6 cases but was a focal finding at first tumor resection in 1 and included fibrosarcoma (n=5), leiomyosarcoma (n=1), or pleomorphic myogenic sarcoma (n=1). Rhabdoid change was a focal finding in the sarcomatous component of 1 tumor. The glial component expressed both glial fibrillary acidic protein and S-100 in all cases, whereas the sarcomatous component at least focally showed smooth muscle actin (n=6), CD34 (n=4), S-100 protein (n=3), and epithelial membrane antigen (n=2) reactivity. Fluorescence in situ hybridization studies demonstrated 1p/19q codeletion in 5 cases, showed no evidence of deletion in 1 case, and technically failed in 1 case. Three of the 5 cases demonstrated 1p/19q codeletion in the sarcomatous component as well. Gliosarcomas with oligodendroglial elements are rare. The relatively frequent presence of 1p/19q codeletion in both glial and sarcomatous components supports the notion that the sarcomatous component represents a metaplastic change occurring in the glial element, the same mechanism active in classic astrocytic gliosarcomas.