Incidental finding of non-Hodgkin's lymphoma in a patient affected by castration-sensitive prostate cancer: A case report.

RATIONALE: This article describes the case of a patient with 2 simultaneous malignant diseases: Follicular lymphoma and 'castration sensitive prostate cancer. Patients with multiple cancers are not easy to manage and it is difficult to find the appropriate approach and resources to use with them. We focused our attention on how to choose the correct strategy to face 2 different neoplasms and control the adverse reactions related to the corresponding treatments. PATIENT CONCERNS: We present a case of a 71-year-old man who came to us complaining about an abnormal difficulty in urinating associated with an interrupted flow and excessive urination at night. Clinical examination detected multiple enlarged superior and inferior diaphragmatic lymph nodes. DIAGNOSIS: Prostate biopsy revealed an acinar adenocarcinoma (Gleason 4+3, Grade group 3). Clinical staging by bone scan was negative but computed tomography scan (CT) detected multiple enlarged superior and inferior diaphragmatic, and inguinal lymph nodes. This type of lymph node involvement pattern is unusual for an acinar adenocarcinoma prostate cancer therefore we suspected the simultaneous presence of a lymphatic neoplasm. Fluorodeoxyglucose positron emission tomography scan. The exam showed one of the left inguinal lymph nodes had the highest standardized uptake value (13.0) so a biopsy was taken. The sample analysis confirmed the diagnosis of a follicular non-Hodgkin lymphoma of Grade 3a. INTERVENTIONS: We used a multidisciplinary clinical approach based on Rituximab+CHOP administered every 21 days. Simultaneously, the patient underwent androgen deprivation therapy with triptorelin monthly and bicalutamide administered just during the first month of treatment. When we obtained a complete response for the lymphoma, the patient continued the therapy with Rituximab once every 2 months for the next 2 years. Then we added volumetric modulated arc therapy (VMAT) radiotherapy with simultaneous integrated boost (SIB) to androgen deprivation therapy for the duration of 1 month. OUTCOMES: After 1 year and 6 months since the conclusion of therapy for prostate cancer and Follicular lymphoma, patient's conditions are good and he is in complete remission for both diseases. Gut toxicity is reduced with a mean number of 2 to 3 discharges daily and an increased body weight. LESSONS: The presence of diffuse lymphadenopathy and urinary symptoms in the same patients must induce the suspect of 2 contemporary cancer diseases. Parallel treatments of follicular lymphoma and prostate cancer should consider the increased risk of severe adverse effects related to the treatment and their management. We describe our therapeutic strategy to highlight the importance to balance benefits and disadvantages to get the best possible response and maintain a good quality of life in this complex setting.

Immunohistochemical profile of ductal adenocarcinoma of the prostate.

Ductal adenocarcinoma of the prostate (DAC) is considered to be an aggressive subtype of prostate cancer with greater risk of progression than acinar adenocarcinoma (AC). It has been debated whether DAC is a distinct subtype or a morphological variant of AC. Our aim was to examine the protein expression of DAC and to compare the results with AC. A tissue microarray was constructed from 60 DAC and 46 AC matched by Gleason score. The slides were stained for 28 immunomarkers (estrogen, progesterone and androgen receptor, prolactin, PSA, prostein, PSMA, PSAP, CDX2, lysozyme, villin, monoclonal CEA, CK7, CK20, HMWCK, p63, p504s, c-myc, EGFR, Ki-67, p16, p21, p27, p53, PTEN, ERG, PAX-2, and PAX-8). HMWCK was positive in 8.5 % of DAC, but negative in all cases of AC (p = 0.045). p16 was positive in 53.3 % of DAC and in 26.1 % of AC (p = 0.005). p53 was positive in 42.4 % of DAC and 26.7 % of AC (p = 0.031). A distinct patchy positivity of CK20 was seen in 23.7 % of DAC, and this pattern was also seen in 9.1 % of AC (p = 0.047). Villin was positive in 3.4 % of DAC while expression was negative in AC. Ki-67 labeling index was significantly higher in DAC than in AC (mean 9.2 % [95 % CI 6.4-12.0] and 2.6 % [1.9-3.4], p < 0.001). While there is some overlap in the immunohistochemical expression of DAC and AC, the differences between these two morphotypes of prostatic carcinoma are consistent with DAC having a more aggressive phenotype than AC.

Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation.

OBJECTIVES: Emerging evidence from mouse models suggests that mutant Kras can drive the development of pancreatic ductal adenocarcinoma (PDA) precursors from acinar cells by enforcing ductal de-differentiation at the expense of acinar identity. Recently, human genome-wide association studies have identified NR5A2, a key regulator of acinar function, as a susceptibility locus for human PDA. We investigated the role of Nr5a2 in exocrine maintenance, regeneration and Kras driven neoplasia. DESIGN: To investigate the function of Nr5a2 in the pancreas, we generated mice with conditional pancreatic Nr5a2 deletion (PdxCre(late); Nr5a2(c/c)). Using this model, we evaluated acinar differentiation, regeneration after caerulein pancreatitis and Kras driven pancreatic neoplasia in the setting of Nr5a2 deletion. RESULTS: We show that Nr5a2 is not required for the development of the pancreatic acinar lineage but is important for maintenance of acinar identity. Nr5a2 deletion leads to destabilisation of the mature acinar differentiation state, acinar to ductal metaplasia and loss of regenerative capacity following acute caerulein pancreatitis. Loss of Nr5a2 also dramatically accelerates the development of oncogenic Kras driven acinar to ductal metaplasia and PDA precursor lesions. CONCLUSIONS: Nr5a2 is a key regulator of acinar plasticity. It is required for maintenance of acinar identity and re-establishing acinar fate during regeneration. Nr5a2 also constrains pancreatic neoplasia driven by oncogenic Kras, providing functional evidence supporting a potential role as a susceptibility gene for human PDA.

Induction of p21 and nuclear accumulation of TAp73alpha and c-abl during apoptosis of cisplatin-treated primary pancreatic acinar cells.

To understand the role of endogenous p53 and related proteins in pancreatic injury responses, we established primary pancreatic acinar cultures from wild-type and p53-deficient mice and investigated the relationship between apoptosis, proliferation and underlying molecular events in cells exposed to the DNA cross-linking agent cisplatin. This treatment led to a time-dependent elevation in p53 levels, accompanied by phosphorylation at key serine residues. Despite this apparent activation of p53, acinar cells entered growth arrest unaffected by p53 deficiency. Moreover, p53-null cells exhibited only a temporal delay in engaging apoptosis, compared to wild-type counterparts. Whilst p53-proficient cells rapidly accumulated nuclear p21, the kinetics of p21 accumulation in p53-null cells were delayed, correlating with the execution of p53-independent apoptosis. During the course of treatment, c-abl and TAp73alpha, a p53 homologue, accumulated in acinar cell nuclei, irrespective of genotype, indicating that they are induced upon DNA damage and that they may act in parallel or in concert with p53 for the eradication of damaged acinar cells. We also report the nuclear accumulation of c-abl and TAp73alpha in cells, treated with the nuclear export inhibitor leptomycin B, suggesting that these proteins undergo constant nucleocytoplasmic shuttling in normal culture conditions, possibly reflecting a role for TAp73alpha-mediated transactivation or repression in the regulation of in vitro acinar cell growth.

Acinic cell carcinoma of the sublingual gland accompanied by bone formation.

A rare case of acinic cell carcinoma of the sublingual gland accompanied by bone formation is reported. The patient is a 79-year-old male who was referred to Yokohama Minami Kyosai Hospital with sublingual swelling. A tumor mass, 20 x 10 mm in diameter, was detected on the right side of the floor of the mouth. Computed tomography (CT) revealed a mass lesion with calcification in the sublingual gland. The patient underwent total sialadenectomy of the sublingual gland with conservation of the lingual nerve. Histologically, the lesion showed amylase-positive atypical cells with thyroid gland-like arrangement, and mature bone tissue in the stroma. Based on these findings, the tumor was diagnosed as acinic cell carcinoma accompanied by bone formation. Postoperative recovery was uneventful, and two years after surgery, there are no signs of distant metastases or recurrence.

Stimulation of both CCK-A and CCK-B receptors activates MAP kinases in AR42J and receptor-transfected CHO cells.

It was recently found that cholecystokinin (CCK) activates mitogen-activated protein kinases (MAPK) in isolated rat pancreatic acini. The present study evaluates whether one or both types of CCK receptors are capable of MAPK activation in pancreatic AR42J acinar cells as well as CHO cells transfected with CCK-A or CCK-B receptors. CCK significantly increased p44 MAPK and p42 MAPK activities in AR42J cells. Minimal, half-maximal, and maximal responses were observed at 30 and 500 pM and 10 nM, respectively, after CCK-8 stimulation and at 100 pM and 1.5 and 30 nM, respectively, after gastrin stimulation. Glycine-extended gastrin had no effect at 100 nM and a small but significant effect at 1 microM. The CCK-B receptor antagonist L365,260 almost totally blocked MAPK activation in AR42J cells after stimulation with gastrin and glycine-extended gastrin and substantially reduced the activation of both kinases by CCK-8, while the CCK-A receptor antagonist L364,718 was much less effective. The CCK-A-selective agonist A71376, however, was an effective stimulant of MAPK activity. In an alternative approach, stably transfected CHO cells bearing either CCK-A or CCK-B receptors were stimulated with CCK-8. Each receptor induced a time-dependent increase in activity of both MAPKs by five- to sixfold in CCK-A- and CCK-B-bearing cells. In conclusion, both CCK-A and CCK-B receptors activate MAPK in AR42J cells and in transfected CHO cells.

Atypical adenomatous hyperplasia of the prostate: a critical review.

AIMS: The aim of this report is to review the literature concerning atypical adenomatous hyperplasia (AAH) with specific regard to evidence in support of or refuting its role as a precursor lesion for prostatic adenocarcinoma. METHODS: The available literature was collected and critically reviewed. In addition, recently reported (abstract) but as yet unpublished data were included. Particular attention was focused on biological studies. RESULTS: There is considerable morphologic evidence suggesting that AAH is associated with low-grade (Gleason patterns 1 and 2) adenocarcinoma arising in the transition zone. Only limited biologic studies have been performed. There is weak and limited data to indicate that AAH has a proliferation rate higher than hyperplasia but lower than adenocarcinoma. AAH is diploid, as are most examples of low-grade adenocarcinoma. A few markers (blood group antigens, peanut agglutinin) show similar patterns of expression in AAH and adenocarcinoma while others (carbohydrate D-galactose-N-acetyl-D-galactosamine) do not. Recent cytogenetic analyses have detected abnormalities of chromosome 8 in a very small proportion (4-6%) of cases of AAH studied. CONCLUSIONS: Presently, the only strong evidence linking AAH to adenocarcinoma is morphologic. The few biologic and molecular/cytogenetic studies performed have not provided convincing evidence to support or refute this possibility. Additional studies are required. Finally, in comparative studies of AAH with adenocarcinoma, the latter should include low-grade transition zone tumors.