Prohibitin: targeting peptide coupled to ovarian cancer, luteinization and TGF-ß pathways.

BACKGROUND: Ovarian epithelial tumor (OET) is a silent disease of late diagnosis and poor prognosis. Currently treatment options are limited and patient response to treatment is difficult to predict so there is a serious need to delineate the real pathogenesis to predict tumour prognosis. Prohibitin (PHB) is an evolutionarily protein that regulates the cell cycle. TGF-ß has been shown to be a positive and negative regulator of cellular proliferation and differentiation. The present study provides an overview on the role played by PHB1, TGF-ß and LH in ovarian cancer. METHODS: The study was conducted on 60 patients with ovarian tumors (benign, borderline and malignant) and 20 healthy volunteers. LH and TGF-ß serum levels were measured by ELISA. Expression of prohibitin and LHR-mRNA were assessed by IHC and TaqMan® real time gene expression assay, respectively. RESULTS: Serum levels of LH and TGF-ß were significantly decreased among borderline and malignant groups. There was significant over-expression of LHRmRNA in malignant group. Prohibitin expression was significantly increased in malignant ovarian tissue. Strong negative correlations were found between LHR mRNA expression and serum LH levels, and between IHC score of prohibitin and serum levels of LH among patients with borderline ovarian tumors. CONCLUSION: Steady decline of LH and TGF-B serum levels, from benign cystadenoma to borderline tumor to carcinoma, suggests their inhibitory role against OET cell growth. Increased PHB1 expression in OET suggests its proliferative activity that can be regulated by luteinisation and/or TGF-ß. Furthermore increased LHR mRNA tissue expression can provide hope for using LH in treatment of some types of ovarian cancers.

Papillary cystadenoma of the epididymis and broad ligament: morphologic and immunohistochemical overlap with clear cell papillary renal cell carcinoma.

Papillary cystadenoma is an uncommon epithelial tumor, originating within the head of the epididymis and broad ligament. When the lesion is bilateral, it is associated with von Hippel-Lindau disease. Its resemblance to metastatic clear cell renal cell carcinoma (RCC) has been noted in the literature. Owing to the emergence of additional markers for RCCs, we have evaluated the immunohistochemical staining patterns of a series of 7 papillary cystadenomas using CK7, RCC, PAX8, carbonic anhydrase IX, and AMACR. Six of the cases involved the epididymis, and 1 involved the broad ligament. The patients ranged in age from 20 to 65 years old. All of the tumors were unilateral and not known to be associated with von Hippel-Lindau disease. The lesions were composed of cystic structures, which focally contained papillary fibrovascular cores lined by cuboidal to columnar bland-appearing cells with clear cytoplasm. Another component was the presence of tubules, which focally had elongated profiles. Reverse polarity, wherein the nuclei are oriented toward the luminal surface with subnuclear vacuoles, was present focally in 4 cases and more extensively in a fifth case. Features associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis, were not identified. All lesions were strongly positive for CK7 and negative for RCC. Carbonic anhydrase IX was positive in all tumors (diffusely positive in 6, patchy in 1) with lack of staining in the apical portion of the cytoplasm (ie, cup-shaped staining). PAX8 showed diffuse positivity in 6 of the 7 lesions, with one of the epididymal cases showing negative staining. AMACR staining was negative in 5 of the 7 cases and showed only focal, weak staining in the remaining 2 cases. The current study more specifically demonstrated that papillary cystadenoma does not resemble clear cell RCC. Rather, papillary cystadenomas of the epididymis and broad ligament have identical morphology and immunohistochemical staining to clear cell papillary RCC. The diagnosis of papillary cystadenoma can be established as clear cell papillary RCC to date has not exhibited metastatic behavior.

P63 expression in papillary cystadenoma and mucoepidermoid carcinoma of minor salivary glands.

OBJECTIVE: The aim of this study was to investigate the expression of p63 protein in mucoepidermoid carcinoma and papillary cystadenoma of the salivary glands, and to evaluate the usefulness of this protein in distinguishing these tumors. STUDY DESIGN: Immunoexpression of p63 protein was studied and quantified in 9 formalin-fixed paraffin-embedded mucous retention cysts, 4 papillary cystadenomas, and 19 low-grade and 9 high-grade mucoepidermoid carcinomas. RESULTS: All cases were positive for p63 immunoexpression; however, it was observed that p63 labeling in mucous retention cysts and papillary cystadenomas was limited to the basal layers of the cystic spaces, whereas in low-grade mucoepidermoid carcinomas, positive nuclear staining was also found diffusely in the suprabasal layers. Mucoepidermoid carcinoma presented increased immunoexpression of p63 compared with the other groups. CONCLUSIONS: P63 immunohistochemical expression pattern can be helpful in distinguishing low-grade mucoepidermoid carcinoma from papillary cystadenoma of the salivary glands.

An analysis of five clear cell papillary cystadenomas of mesosalpinx and broad ligament: four associated with von Hippel-Lindau disease and one aggressive sporadic type.

AIMS: Clear cell papillary cystadenoma (CCPC) is associated with von Hippel-Lindau disease (VHLD), but rarely involves mesosalpinx and broad ligament (M/BL). This study provides new data about its behaviour and immunophenotype. METHODS AND RESULTS: We performed an analysis of four benign cases of CCPC of M/BL with either characteristic clinical features or genetic markers [loss of heterozygosity (LOH)] of VHLD in patients ranging from 24 to 36 years and a sporadic case in a 52-year-old presenting with peritoneal metastases. All CCPCs were papillary but had solid and tubular areas. Haemorrhage, thrombosis and scarring were constant features and related to an unusual pattern of sub-epithelial vascularity. All clear or oxyphilic cells co-expressed cytokeratin 7 (CK7), CAM5.2 and vimentin, with strong apical CD10 and nuclear paired box gene 2 (PAX2) immunoreactivity. Three cases also showed positivity for VHL40, epithelial membrane antigen (EMA), Wilms' tumour suppressor gene (WT-1) and cancer antigen 125 (CA125) but only one expressed renal cell carcinoma (RCC) antigen. Vascular plexus overexpressed nuclear and cytoplasmic WT-1. CONCLUSION: The VHLD-associated cases appeared to be benign, but the sporadic case exhibited a low malignant potential. CCPCs show histological and immunophenotypical similarities with the recently reported clear cell papillary RCC, although the previously unreported apical CD10 and nuclear PAX2 expression may be related to their mesonephric origin. CCPC has a distinctive sub-epithelial vascular pattern that is consistent with its pathogenesis.

A detailed immunohistochemical analysis of 2 cases of papillary cystadenoma of the broad ligament: an extremely rare neoplasm characteristic of patients with von hippel-lindau disease.

We report 2 cases of papillary cystadenoma, a rare neoplasm characteristic of patients with Von Hippel-Lindau (VHL) disease, involving the pelvic soft tissues of women and probably arising within the broad ligament. In only one of the women was there a history of VHL disease. The other woman was investigated for VHL disease after the diagnosis of papillary cystadenoma and all tests were negative. There has been debate as to whether papillary cystadenomas in women are of mesonephric (Wolffian) or of Mullerian origin and to investigate this we undertook a detailed immunohistochemical analysis. Both tumors were positive with AE1/3, Ber EP4, epithelial membrane antigen, CK7, CD10, CA125, CA19.9, calretinin, and vimentin. One exhibited focal nuclear staining with WT1 and PAX8. The tumors were negative with estrogen receptor, progesterone receptor, androgen receptor, CK20, CEA, TTF1, inhibin, RCC marker, and hepatocyte nuclear factor 1ß. Although favoring a mesonephric origin, the immunohistochemical findings are essentially inconclusive and not definitive for either a mesonephric or a Mullerian origin. We believe that patients found to have papillary cystadenoma should be investigated for VHL disease if there is no history of this. This is the second reported example of papillary cystadenoma in a woman not known to have VHL disease and the first in which investigations have excluded this disease.

Intraductal papillary neoplasm arising from peribiliary glands connecting with the inferior branch of the bile duct of the anterior segment of the liver.

Intraductal papillary neoplasms of the bile duct are generally thought to arise from neoplastic papillary proliferation of epithelial cells lining the bile duct. We herein report a case with findings that strongly suggested that the biliary cystic tumor might have derived from a peribiliary gland. A 69-year-old female was found to have a cystic lesion with intracystic protrusions at the anterior segment of the right hepatic lobe and underwent hepatic anterior segment resection. Fluoroscopy of the resected specimen injected with contrast medium into the cyst revealed a connection between the cystic lesion and the bile ducts. The cyst was multilocular in appearance. On microscopic examination, the cyst was located within the portal tract of the inferior branch of the anterior segment and connected with the inferior branch of the bile duct. The wall of the hepatic cyst lacked an ovarian-like stroma. The tumor was composed of papillary and glandular components, and the tumor cells were similar to gastric foveolar and pyloric gland epithelia and regarded as adenoma. These tumor cells were positive for MUC 5AC, MUC6, and HIK1083. The tumor was finally diagnosed as an intraductal papillary neoplasm of the bile duct (adenoma, gastric type) arising from a peribiliary gland.

Papillary cystadenofibroma of epididymis: a case report.

We present the first reported case of papillary cystadenofibroma of the epididymis. The tumor occurred in a 46-year-old man. The mass was 3.7 cm and included a hemorrhagic fluid-filled cyst. Microscopically, stromal-filled papillae were lined by low cuboidal to columnar epithelium. Epithelial cells were reactive for cytokeratin 7, cytokeratins AE1/3, and focally in the apical cytoplasm for CD10. Focal CD10 reactivity was also noted in the stroma. The lesion was negative for alpha-fetoprotein. These findings ruled out other lesions, including metastatic renal cell carcinoma.

PDGF BB induces VEGF secretion in ovarian cancer.

We identified the platelet derived growth factor receptor (PDGFR) as a potential target in epithelial ovarian carcinoma (EOC). This led us to test whether inhibition of the PDGFR affects ovarian cancer cell proliferation and survival and regulates other processes critical to tumor growth and metastasis. We postulated that there is a correlation between the PDGF-PDGFR axis and the secretion of VEGF in EOC. VEGF secretion in ovarian tumors, cancer cells, serum and ascites fluid was measured by IHC, Western Blot and ELISA. We found increased VEGF expression and secretion in most ovarian tumors (by IHC), in EOC malignant ascites and in the conditioned media of primary ovarian cancer cells (quantified by ELISA). In malignant ascites, the levels of secreted PDGF BB and VEGF were strongly correlated (Pearson coefficient of correlation R = 0.728), suggesting that the two pathways interconnect. In PDGFR expressing immortalized ovarian cancer cells, PDGF potently induced VEGF secretion, while imatinib mesylate (Gleevec), a partially selective PDGFR inhibitor, reduced PDGF stimulated VEGF production to basal state. In ovarian cancer cells overexpressing constitutively active Akt, imatinib inhibited partially VEGF secretion, suggesting that the PI3K/Akt pathway is implicated in PDGF-stimulated VEGF secretion. In summary, these results suggest a correlation between the PDGF and VEGF networks in ovarian cancer cells and tumors. The effects of imatinib on VEGF secretion in tumor cells may affect the tumor microenvironment in a manner detrimental to tumor progression.

Evaluating patients with mildly elevated transaminase levels.

CASE STUDY: S.B. is a 52-year-old woman with recurrent stage IV ovarian cancer. She initially presented three and a half years ago with complaints of abdominal pain, increased abdominal girth, and abdominal bloating. A CA-125 blood test was elevated, and a computed tomography scan of the abdomen and pelvis revealed bilateral ovarian masses highly suspicious for malignancy. She was taken to surgery for a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and suboptimal tumor reduction. Pathology revealed poorly differentiated papillary serous ovarian cancer. Metastatic disease was noted in the rectosigmoid area and vaginal apex. Postoperatively, she received six cycles of paclitaxel and carboplatin. At completion, her CA-125 normalized and imaging studies showed no evidence of disease. However, within three months, her CA-125 was elevated and a palpable mass at the vaginal apex was proven by biopsy to be recurrent disease.

Loss of cell-adhesion molecule complexes in solid pseudopapillary tumor of pancreas.

Solid pseudopapillary tumor of pancreas (SPT) is a rare neoplasm that occurs most often in young females with the two distinct features, the 'solid-cystic' gross appearance, and the 'solid-pseudopapillary' microscopic pattern. It has been reported that almost all SPT tumors contain a mutation in the beta-catenin gene; however, the histogenetic origin of this tumor remains largely a mystery. E-cadherin is a cell adhesion molecule that links to catenins to form cell adhesion junctions, which is associated with the cytoskeleton formation. In this study, we examined the expression of E-cadherin and beta-catenin from SPT in an attempt to determine the molecular basis for the unusual morphology of this tumor. Nine cases of SPT were retrieved from Surgical Pathologic Archives of three institutions, including one male and eight females. H&E slides of each case were reviewed to confirm the diagnosis. The beta-catenin gene was sequenced in one case. E-cadherin and beta-catenin immunostains, were performed on all nine cases. Sequencing analysis on one case showed a point mutation of the beta-catenin gene, confirming previous findings that almost all SPT tumors contain mutation in the beta-catenin gene. Immunostains showed that, in both solid and pseudopapillary areas, all the tumor cells lost expression of E-cadherin, and beta-catenin nuclear expression was observed in all cases. Our findings suggest that loss of cytoplasmic beta-catenin protein in the cell adhesion complex due to beta-catenin gene mutation, results in instability of the complex, loss of E-cadherin in cell membrane, and eventually dissociation of the tumor cells to form the pseudopapillary pattern.

Non-cystic solid-pseudopapillary tumor of the pancreas showing nuclear accumulation and activating gene mutation of beta-catenin.

Solid-pseudopapillary tumor (SPT) is an unusual pancreatic neoplasm that is characterized by a mixture of solid and cystic components and a fibrous capsule. Recently, the tumorigenesis of SPT has been reported to be associated with gene mutations of beta-catenin, which is a molecule participating in the Wnt signaling pathway. Reported herein is the case of a 53-year-old woman with SPT. The tumor, approximately 3 cm in diameter in the pancreas body, had a clear margin and central calcification but had neither a cystic component nor fibrous capsule. Several lines of pathological findings in the surgically resected specimen indicated SPT: (i) pseudopapillary proliferation of eosinophilic polygonal cells with oval nuclei; (ii) positive expression of several marker molecules indicating differentiation into acinar and endocrine cells; and (iii) zymogen granule-like structures in the cytoplasm on electron microscopy. Further, the tumor cells had intense nuclear accumulation of beta-catenin and an activating mutation, (34)Gly(GGA) to Arg(AGA), in exon 3 of the beta-catenin gene, as previously reported in most SPT. These findings suggest that association of the beta-catenin phenotype with development of the rare phenotype of SPT, a non-cystic and unencapsulated tumor, is unlikely.

Human pancreatic mucinous cystadenoma is characterized by distinct mucin, cytokeratin and CD10 expression compared with intraductal papillary-mucinous adenoma.

AIMS: To examine cytokeratin, epithelial glycoprotein (mucin) and glycoprotein CD10 expression in benign mucinous cystdenomas (MCAs) in comparison with intraductal papillary mucinous adenomas (IPMAs). METHODS AND RESULTS: Thirty MCAs of the pancreas were analysed for immunohistochemical expression of cytokeratin (CK) 7, CK20, MUC1, MUC2, MUC5AC and CD10 and were compared with 16 IPMAs. CK7 was expressed in all neoplasms. CK20 was significantly more frequent in MCAs compared with IPMAs (56.66% versus 18.75%, P = 0.027). MUC1 was more frequent in MCAs (40% versus 12.5%, P = 0.0915), whereas MUC5AC was significantly less frequent in MCAs (33.33% versus 100%). MUC2 was expressed in goblet cells of seven MCAs. In MCAs, CD10 was observed both in epithelial cells and in the ovarian-type stromal cells (24/30). Epithelial expression of CD10 was significantly lower in IPMAs (66.66% versus 6.25%, p = 0.0001). CONCLUSIONS: MCA is characterized by a significantly greater frequency of expression of CK20 and CD10 when compared with IPMA, which preferentially expresses MUC5AC.

Malignant solid and pseudopapillary tumor of the pancreas--clinicohistological, immunohistochemical, and flow cytometric evaluation.

BACKGROUND/AIMS: Solid and pseudopapillary tumor of the pancreas is a benign and low malignant potential tumor. Prognosis is good after surgical resection but its malignant potential is usually defined after metastasis. We compared benign and malignant cases with clinicopathological, immunohistochemical and DNA flow cytometric studies. METHODOLOGY: From January 1991 to July 2004, seven patients were found to have solid and pseudopapillary tumor of the pancreas at Taipei Veterans General Hospital. The paraffin sections were reevaluated with hematoxylin & eosin stain, immunohistochemical stains, and DNA flow cytometric studies. RESULTS: It included 6 benign and one malignant case. The progesterone receptor, vimentin, neuron-specific enolase, and chromogranin A showed diffused positive stain in all cases. Estrogen receptor and P53 stain were negative in all 7 patients. Synaptophysin stain was negative in 6 no recurrence patients, but was positive only in the patient who suffered from recurrence. DNA flow cytometry showed diploid results in six non-malignant tumors. In the malignant patient, the tumor in the first operation showed diploid result, but tumors in second and third operations showed aneuploidy. CONCLUSIONS: Solid and pseudopapillary tumor of the pancreas should be considered as a potentially malignant disease in all patients and regular follow-up is mandatory.

Paratesticular cysts with benign epithelial proliferations of wolffian origin.

Paratesticular cysts with benign epithelial proliferations (BEPs) are rare. Only 10 cases were found in a series of 431 paratesticular cysts and were classified as follows: cystadenoma, 5; papilloma, 2; and hamartoma, 3. Four cystadenomas showed multiple papillae lined by CD10+ epithelial cells with hyperchromatic nuclei. The remaining lesion showed areas with a microcystic, glandular, cribriform pattern, with small, benign glands without atypia. Urothelial papilloma presented BEPs with cytokeratin (CK) 7+ and CD10+ and CK20- umbrella-like cells. The mural papilloma was lined by proliferative cylindrical cells exhibiting strong CK7 and CD10 expression. The 3 Wolffian hamartomas were characterized by strongly CD10+ epithelium surrounded by smooth muscle cells. The consistent CD10 expression in BEPs of paratesticular cysts suggests a Wolffian origin. The differential diagnosis of paratesticular cysts with BEP vs metastatic prostatic and primary borderline or malignant tumors is discussed.

Comparative analysis of K-ras point mutation, telomerase activity, and p53 overexpression in pancreatic tumours.

K-ras point mutation, p53 over-expression, and telomerase activity have been proposed as molecular markers for clinical diagnosis of pancreatic carcinoma. To evaluate the clinical usefulness of these markers, we performed comparative analysis in 61 resected pancreatic samples including 15 intraductal papillary-mucinous tumours (IPMTs), 4 mucinous cystic tumours, 37 ductal adenocarcinomas, and five chronic pancreatitis samples. K-ras point mutation, telomerase activity, and p53 overexpression were analyzed using mutant allele specific amplification, the telomeric repeat amplification protocol, and immunohistochemical staining, respectively. In malignant tumours, K-ras mutation, telomerase activity, and p53 overexpression were detectable in 76, 91, and 46%, respectively, while in benign tumours, these alterations were detectable in 38, 0, and 0%, respectively. Among 15 IPMTs, K-ras mutation was detectable in 4 (80%) of 5 IPMT-adenomas, 4 (80%) of 5 IPMT-carcinomas and 2 (66%) of 3 papillary-mucinous carcinomas, which are invasive carcinomas derived from IPMTs. Telomerase activity was not detectable in IPMT-adenomas, but was detected in all 5 IPMT-carcinomas and 3 papillary-mucinous carcinomas. p53 overexpression was not detected in IPMTs, but was detected in 2 (66%) of 3 papillary-mucinous carcinomas, indicating that telomerase is likely to be activated concomitant with carcinogenesis. These results suggest that telomerase activity is the most useful as a differential diagnostic marker between malignant and benign pancreatic tumours.

Quantitative analysis of follicle-stimulating hormone receptor in ovarian epithelial tumors: a novel approach to explain the field effect of ovarian cancer development in secondary mullerian systems.

The role of FSHR expression in ovarian cancer development is not clear. We examined quantitative expression of FSHR in different types of OET, presumed precursor lesions and peritoneal implants and further discussed FSH as a key growth-promotion factor for the process of ovarian epithelial tumorigenesis. Thirty-five primary OET specimens, including 5 serous cystadenomas, 4 papillary serous cystadenomas, 9 SBTs and 17 serous carcinomas, were examined for quantitative FSHR expression. Ten paired samples (3 benign cystadenomas, 5 SBTs and 2 carcinomas) were obtained from several morphologically different areas, including benign-looking, borderline and cancerous areas in the same OETs, and from the remaining ovarian tissue and contralateral ovaries. Competitive RT-PCR was performed to measure the quantitative expression of FSHR in each tissue sample. FSHR expression levels were compared among nonpaired samples and within paired samples. We found that OSE had the lowest FSHR expression, whereas antral follicles had the highest level. Within benign OETs, papillary serous cystadenomas have 4.9-fold higher FSHR levels than nonpapillary serous cystadenomas. SBTs had the highest level of FSHR expression, which was 12.8-fold, 2.7-fold and 2.4-fold higher than that of serous cystadenomas, papillary serous cystadenomas and grade 1 carcinomas, respectively. A similarly high level of FSHR mRNA was found in peritoneal implants, which were associated with SBTs. FSHR levels among serous carcinomas decreased with an increase in carcinoma grade. Grade 3 carcinomas had the lowest FSHR level, which was similar to that of serous cystadenomas, while grade 1 carcinomas had 6.5-fold higher FSHR levels than those in serous cystadenomas. Our results suggest that not only serum FSH but also FSHR in ovarian epithelium may play important roles in ovarian OET development. Both the receptor and ligand may act in a synergistic way to promote tumor growth. The observation that high FSHR levels are present in peritoneal implants suggests that FSH may also play a similar role in the development of peritoneal serous tumors. From this perspective, circulating FSH may be considered a driving force in the field effect theory for the development of both ovarian neoplasms and their associated peritoneal implants. However, the exact role of FSH and/or FSHR in the development of epithelial tumors arising in both the ovary and peritoneum needs further investigation.

Expression of laminin-5-gamma-2 chain in intraductal papillary-mucinous and invasive ductal tumors of the pancreas.

The laminin-5-gamma-2 chain is expressed in various invasive carcinoma cells. To clarify the relationship between laminin-5 expression and the development of intraductal papillary-mucinous tumors (IPMTs), we performed an immunohistochemical study of 26 IPMTs and 30 invasive ductal adenocarcinomas. Cases were classified into five groups: intraductal papillary-mucinous adenoma (Group A; n = 8), adenocarcinoma without invasion (Group B; n = 3), adenocarcinoma with minimal invasion (Group C; n = 5), adenocarcinoma with macroscopically evident invasion (Group D; n = 10), and invasive ductal adenocarcinoma (conventional type; Group E; n = 30). In the invasive components of Groups D and E, laminin-5 was expressed in 80% and 100% of cases, respectively. In the intraductal components of IPMTs, expression of laminin-5 was not seen in Groups A and B, whereas they were seen in one case in Group C (20%) and in seven in Group D (70%). Most of the staining patterns of the intraductal components were focal and scattered. Laminin-5-gamma-2 expression in the intraductal components of IPMTs tends to increase as tumors develop and may be a indicator of the potential invasiveness of the tumor cells.

Solid-pseudopapillary tumor of the pancreas (Frantz tumor) in children: report of four cases and review of the literature.

BACKGROUND: Solid-pseudopapillary tumor of the pancreas (SPT) is an exceptionally rare neoplasm in children. Its origin remains enigmatic. It is of low malignant potential and occurs most frequently in young females. PATIENTS AND METHODS: A cumulative review of the tumor's clinicopathological characteristics from the world's literature is presented. The clinical course, pathohistologic data and outcome of surgery of four Austrian children treated at the general hospital of Vienna are analyzed. RESULTS: Between 1987 and 1999, four girls (age: 12--16 years) with SPT were diagnosed at our institution. All patients presented with an abdominal mass and uncharacteristic abdominal pain. Two tumors were located in the tail, one in the body and tail and one in the head of the pancreas (diameter: 7--15 cm). Surgical procedures included three distal pancreatectomies and one partial duodenopancreatectomy (Whipple procedure). One patient had two recurrences with metastases that could only be partially resected. Chemotherapy was initiated for this patient. In the follow-up period (range: 6 months to 12 years) all patients are alive with no evidence of recurrence. CONCLUSIONS: SPT is a rare differential diagnosis of a pancreatic mass in children. It is mandatory to establish this diagnosis since complete surgical removal of the tumor even in case of metastases or local invasion offers an excellent prognosis.