The importance of the early appropriate management of foot and ankle soft tissue sarcomas - experiences of a regional sarcoma service.

INTRODUCTION: Soft tissue sarcomas (STS) are a group of rare malignant tumours that can occur at almost any anatomical location in patients of any age, which often present to health care professional working outside a recognised sarcoma service. A review of foot and ankle STSs was conducted, reporting on patient and tumour characteristics, and patient outcome following surgery performed within and outside our sarcoma service. PATIENTS AND METHODS: A retrospective review of all foot and ankle STSs managed by our sarcoma service over a 14 year period was performed. Patient demographics, tumour characteristics, management and patient outcomes including recurrence rates and survival were analysed. RESULTS: Twenty-six patients were analysed (16F:10M) with a mean age of 57.7 years (range 17-87). The mean follow-up was 6.3 years (range 1-16). Sixteen tumours involved the foot, nine the ankle, and one spanned the foot and ankle. Mean tumour size was 4.3 cm (range 0.8-15), although 61% of cases were smaller than 4 cm, and almost one third of cases smaller than 1 cm. Seven of 26 (27%) cases were diagnosed after an unplanned excision performed by non sarcoma surgeons. These patients were more likely to undergo an incomplete tumour excision (p < 0.001), suffer local recurrence (p = 0.001), and eventually undergo a secondary amputation (p = 0.034) than those patients managed exclusively by a sarcoma service. Overall, 12 (46%) patients died of their disease during follow up, equating to a five-year survival rate of 69%. CONCLUSION: Our data shows that unplanned excisions continue to be performed on foot and ankle STSs, and that these have detrimental effects on patients. Despite this, our results also show that these complex patients can be managed successfully when referred appropriately to a sarcoma service, prior to any surgical treatment. This highlights the importance of vigilance amongst all health care professionals managing any foot or ankle lumps, regardless of their size.

Overlapping morphological, immunohistochemical and genetic features of superficial CD34-positive fibroblastic tumor and PRDM10-rearranged soft tissue tumor.

Superficial CD34-positive fibroblastic tumor (SCD34FT) is a recently recognized soft tissue tumor that is considered to be of borderline malignancy. The pathogenesis of this tumor remains incompletely understood, but it has been suggested that SCD34FT overlaps with tumors showing fusions involving the PRDM10 gene. Previous analyses of PRDM10-rearranged tumors have demonstrated that they have a distinct gene expression profile, resulting in high expression of CADM3 (also known as SynCam3), which can be detected immunohistochemically. Here, we investigated a series (n = 43) of SCD34FT or PRDM10-rearranged tumors and potential mimics (n = 226) with regard to morphological, genetic, and immunohistochemical features. The results show that SCD34FT and PRDM10-rearranged tumor are morphologically indistinguishable; 41 of 43 tumors of both entities are CADM3-positive. Hence, we suggest that they constitute a single entity, preferably referred to as SCD34FT. Expression of CADM3 was only rarely seen in other soft tissue tumors, except in tumors with Schwann cell differentiation. Thus, IHC for CADM3, in combination with the characteristic morphological features, is a valuable adjunct in the diagnosis of SCD34FT.

Collecting Duct Carcinoma With Cardiac Metastases: A Case Report & Literature Review.

Collecting duct carcinoma (CDC), is a rare and aggressive form of renal cell carcinoma (RCC) accounting for around 1% of all renal malignancy. It affects younger patients and is associated with rapid progression, distant spread and poor prognosis. Cardiac metastases from all types of RCC, without involvement of the inferior vena cava are very rare. We present the case of a 54 year old man with a history of CDC, who presents with collapse and ventricular tachycardia secondary to multifocal cardiac metastases. We are not aware of any other reports in the literature of CDC and cardiac metastases.

Remote conditioning or erythropoietin before surgery primes kidneys to clear ischemia-reperfusion-damaged cells: a renoprotective mechanism?

Acute kidney injury is common, serious with no specific treatment. Ischemia-reperfusion is a common cause of acute kidney injury (AKI). Clinical trials suggest that preoperative erythropoietin (EPO) or remote ischemic preconditioning may have a renoprotective effect. Using a porcine model of warm ischemia-reperfusion-induced AKI (40-min bilateral cross-clamping of renal arteries, 48-h reperfusion), we examined the renoprotective efficacy of EPO (1,000 iu/kg iv.) or remote ischemic preconditioning (3 cycles, 5-min inflation/deflation to 200 mmHg of a hindlimb sphygmomanometer cuff). Ischemia-reperfusion induced significant kidney injury at 24 and 48 h (χ(2), 1 degree of freedom, >10 for 6/7 histopathological features). At 2 h, a panel of biomarkers including plasma creatinine, neutrophil gelatinase-associated lipocalin, and IL-1ß, and urinary albumin:creatinine could be used to predict histopathological injury. Ischemia-reperfusion increased cell proliferation and apoptosis in the renal cortex but, for pretreated groups, the apoptotic cells were predominantly intratubular rather than interstitial. At 48-h reperfusion, plasma IL-1ß and the number of subcapsular cells in G2-M arrest were reduced after preoperative EPO, but not after remote ischemic preconditioning. These data suggest an intrarenal mechanism acting within cortical cells that may underpin a renoprotective function for preoperative EPO and, to a limited extent, remote ischemic preconditioning. Despite equivocal longer-term outcomes in clinical studies investigating EPO as a renoprotective agent in AKI, optimal clinical dosing and administration have not been established. Our data suggest further clinical studies on the potential renoprotective effect of EPO and remote ischemic preconditioning are justified.

Acute renal failure, microangiopathic haemolytic anemia, and secondary oxalosis in a young female patient.

A 29-year old female presented with a one-week history of vomiting, diarrhoea, abdominal pain, and headache. On admission, she had acute renal failure requiring dialysis. Tests revealed a hemolytic anemia with thrombocytopenia. An initial diagnosis of thrombotic thrombocytopenic microangiopathy was made and plasma exchange was instigated. However, renal biopsy did not show thrombotic microangiopathy but instead revealed acute kidney injury with mild tubulointerstitial nephritis and numerous oxalate crystals, predominantly in the distal tubules. The patient had been taking large doses (>1100 mg daily) of vitamin C for many months. She also gave a history of sclerotherapy using injections of an ethylene glycol derivative for superficial leg veins. The patient completed five sessions of plasma exchange and was able to discontinue dialysis. She eventually achieved full renal recovery. She has now discontinued sclerotherapy and vitamin supplementation.

Quantitative RT-PCR analysis of estrogen receptor gene expression in laser microdissected prostate cancer tissue.

BACKGROUND: Real-time quantitative RT-PCR analysis of laser microdissected tissue is considered the most accurate technique for determining tissue gene expression. The discovery of estrogen receptor beta (ERbeta) has focussed renewed interest on the role of estrogen receptors in prostate cancer, yet few studies have utilized the technique to analyze estrogen receptor gene expression in prostate cancer. METHODS: Fresh tissue was obtained from 11 radical prostatectomy specimens and from 6 patients with benign prostate hyperplasia. Pure populations of benign and malignant prostate epithelium were laser microdissected, followed by RNA isolation and electrophoresis. Quantitative RT-PCR was performed using primers for androgen receptor (AR), estrogen receptor beta (ERbeta), estrogen receptor alpha (ERalpha), progesterone receptor (PGR) and prostate specific antigen (PSA), with normalization to two housekeeping genes. Differences in gene expression were analyzed using the Mann-Whitney U-test. Correlation coefficients were analyzed using Spearman's test. RESULTS: Significant positive correlations were seen when AR and AR-dependent PSA, and ERalpha and ERalpha-dependent PGR were compared, indicating a representative population of RNA transcripts. ERbeta gene expression was significantly over-expressed in the cancer group compared with benign controls (P < 0.01). In contrast, PGR expression was significantly down-regulated in the cancer group (P < 0.05). There were no significant differences in AR, ERalpha or PSA expression between the groups. This study represents the first to show an upregulation of ERbeta gene expression in laser microdissected prostate cancer specimens. CONCLUSIONS: In concert with recent studies the findings suggest differential production of ERbeta splice variants, which may play important roles in the genesis of prostate cancer.

Analysis of the oestrogen response in an angiomyolipoma derived xenograft model.

Angiomyolipomas are benign mesenchymal tumours of smooth muscle, blood vessels and fat which occur sporadically or associated with tuberous sclerosis and lymphangioleiomyomatosis (LAM), a rare cystic lung disease. Angiomyolipoma and LAM are caused by loss of function of either the tuberous sclerosis-1 or -2 genes resulting in activation of p70S6kinase (S6K1) and uncontrolled cellular proliferation. LAM and angiomyolipoma can be exacerbated by oestrogens but how this occurs is not understood. To address this question, we created a xenograft tumour system in nude mice using immortalised angiomyolipoma cells. Angiomyolipoma xenografts had active S6K1, p38, p42/44 MAPK and Akt; they grew more rapidly and had greater Akt phosphorylation after oestrogen treatment of tumour-bearing mice. Transcriptional profiling showed oestrogen induced 300 genes including extracellular matrix proteins, proteases, cell cycle regulatory proteins and growth factors including platelet derived growth factor-C (PDGF-C). Biologically active PDGF-C was produced by primary angiomyolipoma cells in culture and PDGF-C protein was present in the neoplastic smooth muscle cells of 5/5 human angiomyolipoma and 4/5 LAM tissues examined by immunohistochemistry. These findings suggest that the response to oestrogen in this model is mediated by activation of Akt and transcriptional events. This model may prove useful for studying the biology and effect of drugs on angiomyolipoma and diseases related to TSC.

Identification of a novel prostate cancer-associated tumor antigen.

BACKGROUND: The identification of antigens that distinguish cancer cells from normal cells is of major importance for the definition of therapeutic targets in human malignancies. Using sera from cancer patients, we have previously reported on the identification of immunologically recognized proteins that belong to the family of cancer testis antigens (CTAs). METHODS: A normal testicular cDNA library was screened with pooled allogeneic sera from patients with prostate cancer using a modified SEREX approach. Subsequently we have identified and characterized a novel antigen, T21, with an expression pattern similar to that of CTAs. mRNA expression of T21 was determined using a panel of whole tissues and prostate cell lines using Q-RT-PCR. For laser microdissection, fresh prostate cancer and benign tissue was obtained using our novel validated harvesting technique. Protein expression and cellular localization of T21 were assessed in prostate cell lines using Western blotting, confocal microscopy and flow cytometry. RESULTS: T21 showed tissue-restricted mRNA expression in gastric, kidney and prostate cancers, and in normal testis and prostate tissues. Following laser microdissection, T21 was significantly over-expressed in malignant compared to benign prostatic epithelium. We have demonstrated expression of T21 at the protein level and confocal microscopy on PC3 cells probed with a T21-monospecific antibody revealed cytoplasmic localization of T21 protein. CONCLUSIONS: The highly restricted expression pattern of T21 makes it an attractive vaccine target for prostate cancer. Several CTAs reportedly induce cytotoxic T-lymphocyte responses, therefore it is reasonable to assume that T21 will be a valuable target for cancer immunotherapy.

Obtaining fresh prostate cancer tissue for research: a novel biopsy needle and sampling technique for radical prostatectomy specimens.

BACKGROUND: Fresh or fresh-frozen tissue samples are preferred for molecular profiling as formalin fixation degrades intracellular nucleic acids. Radical prostatectomy (RP) specimens are a valuable source of prostate cancer tissue, but the reliance on whole-organ pathological processing for prognostication limits sampling opportunities. Few studies have addressed specific harvesting techniques using prostatectomy specimens. MATERIALS AND METHODS: Ex vivo biopsies were performed on 23 consecutive fresh RP specimens using a purpose-designed needle. A standard sextant approach was used with an additional lateral biopsy on each side. Cores from each lobe were snap-frozen together and sections assessed by a pathologist blinded to the RP and pre-operative biopsy pathology. Comparison with pre-operative biopsies was performed using the t-test and chi(2) statistical tests. Eleven randomly selected RP specimens were further evaluated for the effects of needle tracks and margin perforation. RESULTS: Cancer was detected in 19 of 23 specimens, giving a sensitivity of 83.6%. The average tumor involvement was 28.3% per section compared with 15.6% for pre-operative biopsies (P < 0.02). There was no statistically significant difference between the groups for either Gleason sum score concordance or tumor location concordance. In 3 of 11 cases, needle margin perforation was identified; in none of the cases did it compromise pathological assessment, although in one case a deeper block resection was required. CONCLUSIONS: Ex vivo biopsy is a useful technique for retrieving fresh tissue whilst preserving organ morphology in RP specimens. The purpose-designed needle and harvesting technique provide good yields of cancer tissue from a high proportion of sampled prostatectomy specimens.

Malignant perivascular epithelioid cell tumour ("PEComa") of soft tissue: a unique case.

Tumours of perivascular epithelioid cells (PEComas) are being increasingly reported at visceral and somatic sites. Both benign and malignant variants have been identified, although clinical follow-up is often limited, which prevents meaningful predictions of behavior. We report the case of a malignant soft tissue PEComa with histologically confirmed regional lymph node metastases and radiologically confirmed pulmonary metastases. The light microscopic appearance and immunohistochemical profile (HMB-45, smooth muscle actin positive) and electron microscopic appearance support perivascular epithelioid cell differentiation.

Oligomeganephronia: an unexpected cause of chronic renal failure.

Oligomeganephronia represents a distinct subgroup of renal hypoplasia in which there is a marked reduction in the number of nephrons with hypertrophy of those that are present. It can only be recognised on renal biopsy. We describe a 14-year-old boy who presents with a history of dysuria and some blood in his pants. Urinalysis showed no hematuria but persistent heavy proteinuria. The size of the kidneys on ultrasound was between -1 to -2 SD for height (right 9.3; left 9.6cm) and both kidneys showed a diffuse increase in echogenicity. The pathological features were diagnostic with a reduced number of greatly enlarged glomeruli indicating oligomeganephronia. No focal segmental glomerulosclerosis was identified but there was subcapsular fibrosis. Hyperfiltration in the small number of nephrons initially maintains the glomerular filtration rate at an acceptable level but by adolescence these children typically have progressive proteinuria, glomerulo-sclerosis and renal failure.