Multiple Tumor Nodules Research Articles

Hepatitis serology predicts tumor and liver-disease characteristics but not prognosis after resection of hepatocellular carcinoma

The impact of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on survival rates after resection of hepatocellular carcinoma (HCC) is controversial. The objective of this study was to determine whether serologic evidence of HBV or HCV infection ("hepatitis serology") can predict underlying liver disease, tumor factors, and survival rates in patients with HCC. Using a multicenter international database, we identified 446 patients with complete HBV and HCV serology. One hundred twenty-six patients were negative for HBV and HCV, 163 patients had HBV infection only, 79 patients had HCV infection only, and 78 patients had coinfection with HBV and HCV. Patients with hepatitis were more likely to have tumors smaller than 5 cm and bilateral HCC involvement. Hepatitis status (negative vs. HBV vs. HCV vs. coinfection with HBV and HCV) did not predict tumor grade or the presence of multiple tumor nodules. Patients with HCV or coinfection with HBV and HCV exhibited a lower incidence of vascular invasion, but worse fibrosis than patients with negative serology or HBV. The median survival rate was 47.9 months. The presence of hepatitis did not significantly affect the survival rate, but hepatic fibrosis and vascular invasion predicted a decreased survival rate. The prognosis after resection of HCC is influenced by tumor factors and liver disease, but not by HBV or HCV infection. The treatment for HCC should be dictated by the extent of underlying liver disease rather than by hepatitis serology.

Molecular analysis of an immature ovarian teratoma with gliomatosis peritonei and recurrence suggests genetic independence of multiple tumors

Immature ovarian teratoma is a common germ cell tumor of young women. Patients with immature teratoma often exhibit multiple neoplasms, including tumors outside the ovaries, and occasionally a rare benign condition termed gliomatosis peritonei (GP). These multiple neoplasms are generally believed genetically-linked progeny of the ovarian tumor resulting from local recurrence/spread. In this study, we performed a molecular analysis of a single patient clinically diagnosed with immature ovarian teratoma, GP, and recurrent pelvic mucinous teratoma. Microsatellite PCR and amplicon analysis was performed to genetically characterize tissue samples from omental glial implants and multiple peritoneal tumors. PCR-based amplification of microsatellite markers identifies unique genetic differences (allelic variation) between tumors resulting from divergent natural histories among multiple tumor nodules in a single patient. A total of 21 different microsatellite markers were employed, and seven provided informative results (D3S1744, D6S1056, D7S2846, D14S306, D16S764, D18S858, D22S420). These markers demonstrated mutually exclusive genetic differences among the tumors from this patient, establishing the neoplasms as genetically distinct from each other (non-identical), and that no lineage relationship exists among them. This observation suggests that the multiple tumors arising in this patient with immature ovarian teratoma, GP, and recurrent pelvic mucinous neoplasm represent multiple independent tumors rather than true tumor recurrence/spread. The results of this study suggest strongly that patients with recurrent teratoma may be afflicted with a tumor-prone syndrome where one or more peritoneal cell types or populations are predisposed to neoplastic conversion and formation of tumors as a result of an endogenous or exogenous neoplastic stimuli.

Patterns of methylation profiles as diagnostic markers for multiple hepatocellular carcinomas

Background: Hepatocellular carcinoma often displays multiple tumor nodules, thus posing a problem for differential diagnosis between cancers of both multifocal and metastatic origin. Conventionally, pathological criteria have been used for this purpose, but these are largely subjective. In order to facilitate a more objective differential diagnosis of multiple HCCs, we used the patterns of methylation of p16INK4a, p14ARF, and GSTP1 genes as markers for each tumor nodule. Methods: Sixty‐seven nodules from 30 cases of multiple or recurrent HCCs were examined using methylation‐specific PCR (MSP) analysis for the detection of methylation profiles. Results: Hypermethylation was detected in 56.7%, 43.3% and 17.9% of the cases for p16INK4a, p14ARF, and GSTP1 genes, respectively. At the genetic level the inter‐nodule methylation profiles were heterogeneous in 23 of the cases and homogeneous in another 7, enabling a multifocal origin to be diagnosed in the former and metastatic origin in the latter. Conclusions: Methylation profiling seems to be useful in differentiating the clonal origins of multiple cancers, as the information yielded by this method is essentially objective.

Determination of the molecular relationship between multiple tumour nodules in hepatocellular carcinoma differentiates multicentric origin from intrahepatic metastasis.

The purpose of this study was to determine the molecular relationship between multiple tumour nodules in hepatocellular carcinoma (HCC) within individual patients and to evaluate their clonality, which may bear prognostic significance. In 25 HCC nodules from 11 patients with multiple HCCs, the clonal relationships of the nodules within individual patients were determined using DNA fingerprinting with loss of heterozygosity (LOH) assay, comparative genomic hybridization (CGH), and hepatitis B virus (HBV) integration pattern. Both LOH assay and CGH indicated that in four (36%) of the 11 patients, the multiple HCCs had different clonalities and hence were of multicentric origin, whereas in the remaining seven (64%) patients, the multiple HCCs had similar clonal relationships and were intrahepatic metastases. In selected cases, the HBV integration pattern helped to confirm the clonality results. Gross appearance, size, location, and histology of the tumours could not accurately predict their clonal origin in every case. Assessment of DNA alterations allows precise determination of the clonality of multiple HCCs within one patient. Of these molecular methods, LOH analysis can be used to evaluate tumour clonality in most patients even before surgical resection, since this assay can be readily applied routinely to either liver biopsies or fine needle aspirates.

Iatrogenic pheochromocytomatosis: A previously unreported result of laparoscopic adrenalectomy

Background. Laparoscopic adrenalectomy is now regarded as the procedure of choice for treatment of small or benign adrenal tumors, including pheochromocytoma. However, long-term outcomes have not been critically assessed. We report here 3 cases of pheochromocytomatosis recurring 3 to 4 years after laparoscopic adrenalectomy. We postulate laparoscopic-induced seeding of tumor as the mechanism of recurrence. Methods. We retrospectively reviewed the cases of 3 patients with documented biochemical and radiolabeled metaiodobenzylguanidine evidence of recurrent pheochromocytoma after prior presumed curative laparoscopic adrenalectomy. Results. Original pheochromocytomas were 5.5 to 6.5 cm in diameter. At the time of laparoscopic adrenalectomy, tumors were not believed to be malignant, based on clinical or histopathologic data. However, on 3- to 4-year follow-up, each patient developed symptoms, elevated urinary catecholamine levels, and metaiodobenzylguanidine imaging consistent with recurrence. At reoperation, multiple small tumor nodules were found in the adrenal bed near the site of the initial laparoscopic resection. The original operative notes suggested some possible method of local seeding: tumor fragmentation and spillage or excessive tumor manipulation. Conclusions. Pheochromocytoma recurrence may occur as a result of local spillage of tumor during laparoscopic adrenalectomy. The relative risk of recurrence between open and laparoscopic resection needs to be assessed. Long-term follow-up will continue to be important, regardless of operative approach. (Surgery 2001;130:1072-7.)

Expression of p27KIP1 and p21WAF1/CIP1 in primary hepatocellular carcinoma: Clinicopathologic correlation and survival analysis

To investigate the possible roles of p27KIP1 and p21WAF1/CIP1, inhibitors of cyclin-dependent kinases, in hepatocellular carcinoma (HCC), we examined p27KIP1 and p21WAF1/CIP1 expression in primary HCC with immunohistochemistry and Northern blot hybridization and correlated the results with clinicopathologic features and survival. With immunohistochemistry, positive staining for p27KIP1 and p21WAF1/CIP1 protein was found in 54.3% and 63.8% of HCCs, respectively. Both p27KIP1 and p21WAF1/CIP1 scores of the tumors were significantly higher than those of the corresponding nontumorous livers (P < .0001 and .009, respectively). Higher levels of p27KIP1 were associated with a lower incidence of direct liver invasion (P = .021) and, less significantly, with a low incidence of multiple tumor nodules (P = .056). Patients whose tumors had higher p27KIP1 protein scores had longer disease-free survival (P = .011). For p21WAF1/CIP1, in contrast to the overexpression of the p21WAF1/CIP1 protein in HCC, the relative amounts of p21WAF1/CIP1 messenger RNA (mRNA) in the tumors were found to be reduced compared with those of the nontumorous livers (P = .039). In conclusion, p27KIP1 and p21WAF1/CIP1 proteins were frequently overexpressed in HCC. Longer disease-free survival rates were seen in patients whose tumors had higher p27KIP1 expression. The accumulation of p21WAF1/CIP protein in the presence of a reduced mRNA level suggests probable posttranslational protein stabilization, and the reduced transcription of p21WAF1/CIP may represent a form of dysfunction of cyclin-dependent kinase inhibitor involved in hepatocarcinogenesis. HUM PATHOL 32:778-784. Copyright © 2001 by W.B. Saunders Company

Influence factors to recurrence of hepatocellular carcinoma after surgical resection

Objective: To analyze the influence factors to recurrence of hepatocellular carcinoma (HHC) after its resection according to pathologic findings of the resected primary tumor and angiographic features of the recurrence tumor. Methods: In this series, 142 cases with recurrence HCC were analyzed with respect to (1) size, number, gross and histologic findings of the primary tumor; (2) time when recurrence occurred; (3) size, number, blood supply, staining property, and accumulation of lipiodol oil in the recurrence tumor. Following angiography, arterial chemoembolization was performed. Results: In 101 of the 142 (71.1%) cases, the primary tumor was>5 cm in diameter, and in 41 cases (28.9%) it was <5 cm. In 67.7% of the cases, the capsule of the primary tumor was incomplete or absent. In 67.7% of the cases, the capsule of the primary tumor was incomplete or absent. In 47 cases (33.1%), satellite tumor nodules were seen during operation but they were seen on pathologic sections in 94 cases (66.2%). Tumor thrombus was present in the portal vein in 26 cases (18.3%) during operation and 121 cases (85.2%) on pathologic examination, respectively. In the majority of the cases (99/142), recurrence had occurred within 6 months after operation. The recurrence foci consisted of multiple tumor nodules of <5 cm in 68.3% of the cases. On angiography, the recurrence tumors were rich in blood supply and with good accumulation of lipiodol after embolization. Conclusion: Recurrence is apt to occur in HCC patients with large (>5 cm) primary tumor which has incomplete or no capsule, with satellite tumor nodules and protal vein tumor thrombus. It is suggested to perform angiography 1–2 months after surgery to detect early recurrrence and, if confirmed, the patients may be treated by trans-catheter arterial chemoembolization.

Decreased expression of p27 protein is associated with advanced tumor stage in hepatocellular carcinoma.

Reduced expression of the cyclin-dependent kinase inhibitor p27 has previously been correlated with fatal clinical outcome in some tumors, including gastric, breast, and prostate cancers. For hepatocellular carcinoma, the findings are equivocal. In situ hybridization and immunohistochemistry were performed on a series of 203 curatively (R0) resected hepatocellular carcinomas and in corresponding non-cancerous liver tissue to detect p27. Patients receiving liver transplantation were excluded. The results were correlated with histopathological stage according to the UICC system, Edmondson grade, several other histopathological factors of possible prognostic significance, and finally patient survival. Whereas p27 mRNA was expressed homogeneously in all carcinomas examined, the p27 protein was found in various amounts. The labeling index of p27 protein was significantly lower in advanced stages of the disease (P < 0.001, chi(2) = 28.1). We observed decreased p27 protein in higher pT categories (P < 0.001, chi(2) = 24.7) and in multiple tumor nodules (P < 0.001, chi(2) = 9.3). Multivariate Cox survival analysis identified age, co-existing cirrhosis, and Edmondson grade as independent prognostic factors. We conclude that evaluation of p27 in hepatocellular carcinoma is useful to predict stage of disease and may have clinical significance, e.g., in predicting optimal therapeutic regimes.

Diffuse peritoneale Leiomyomatose - Eine klinische Fallstudie - Diffuse Peritoneal Leiomyomatosis: A Case Report -

Die disseminierte peritoneale Leiomyomatose (Leiomyomatosis peritonealis disseminata, LPD) ist eine seltene Veränderung, bei der multiple, histologisch gutartige weiche Muskeltumorknötchen diffus die peritonealen und die Netzoberflächen der Frau, vorwiegend im geburtsfähigen Alter, übersäen. Obwohl die Verteilung dieser Veränderungen einen metastatischen Prozess nahelegt, nimmt die LPD in der Regel einen gutartigen klinischen Verlauf und wird als metaplastischer Prozess aufgefasst. Die Ätiologie dieser Veränderung ist kausal noch ungeklärt, wahrscheinlich aber hormonell bedingt und ist häufig mit einer Frühschwangerschaft verbunden.

Genomic heterogeneity in synchronous hepatocellular carcinomas

BACKGROUNDHepatocellular carcinoma (HCC) arising in cirrhosis is frequently multifocal. Whether HCC develops monoclonally or multiclonally is an unresolved question. Of the multiple tumour nodules present in many patients, it has...

Molecular and cellular pathology of hepatocellular carcinoma.

Mutations of the p53 gene are common in hepatocellular carcinoma (HCC) and have been found in 13-33% of HCC in Asia and 23% of HCC in Hong Kong. In addition, p53 overexpression has been found to be associated with poorer cellular differentiation and larger tumour size and may be a late event in hepatocarcinogenesis. The p53 gene is important in controlling cell cycle, apoptosis and DNA repair. The cyclin-dependent kinase inhibitor p21WAF1/CIP1 , which is downstream of p53, is regulated by both p53-dependent and p53-independent pathways. We found that HCC with p53 mutations had lower levels of p21 expression than those without p53 mutations. Moreover, p21 protein expression of the tumours was significantly higher in the tumours than in the corresponding non-tumorous livers. When the tumours were stratified into two groups, those with higher expression were found to have a significantly lower incidence of multiple tumour nodules and lower incidence of tumour microsatellite formation. p21 Expression was, however, not associated with p53 expression. Higher p21 expression is associated with solitary tumour nodules and fewer tumour microsatellites, but may not be enough to suppress tumour progression. Insulin-like growth factor II (IGF-II) gene has complex regulation of transcription resulting in multiple mRNA being produced and different mRNA occur in the adult and foetus. Using northern blot analysis, repression of normal adult promoter and re-expression of foetal promoters of IGF-II are common events in HCC, with repression of the normal adult promoter in 93% of the HCC transcripts and re-expression of the foetal transcripts (6 and 5 kb, respectively) in 40% of tumours. In addition, IGF-II expression was significantly more frequent in older patients. This may suggest that spontaneous expression of IGF-II late in life may promote the growth of tumours which have already arisen through other mechanisms, but foetal re-expression, itself, may not be enough to contribute to tumour progression.

Molecular and cellular pathology of hepatocellular carcinoma

Mutations of the p53 gene are common in hepatocellular carcinoma (HCC) and have been found in 13–33% of HCC in Asia and 23% of HCC in Hong Kong. In addition, p53 overexpression has been found to be associated with poorer cellular differentiation and larger tumour size and may be a late event in hepatocarcinogenesis. The p53 gene is important in controlling cell cycle, apoptosis and DNA repair. The cyclin‐dependent kinase inhibitor p21WAF1/CIP1, which is downstream of p53, is regulated by both p53‐dependent and p53‐independent pathways. We found that HCC with p53 mutations had lower levels of p21 expression than those without p53 mutations. Moreover, p21 protein expression of the tumours was significantly higher in the tumours than in the corresponding non‐tumorous livers. When the tumours were stratified into two groups, those with higher expression were found to have a significantly lower incidence of multiple tumour nodules and lower incidence of tumour microsatellite formation. p21 Expression was, however, not associated with p53 expression. Higher p21 expression is associated with solitary tumour nodules and fewer tumour microsatellites, but may not be enough to suppress tumour progression. Insulin‐like growth factor II (IGF‐II) gene has complex regulation of transcription resulting in multiple mRNA being produced and different mRNA occur in the adult and foetus. Using northern blot analysis, repression of normal adult promoter and re‐expression of foetal promoters of IGF‐II are common events in HCC, with repression of the normal adult promoter in 93% of the HCC transcripts and re‐expression of the foetal transcripts (6 and 5 kb, respectively) in 40% of tumours. In addition, IGF‐II expression was significantly more frequent in older patients. This may suggest that spontaneous expression of IGF‐II late in life may promote the growth of tumours which have already arisen through other mechanisms, but foetal re‐expression, itself, may not be enough to contribute to tumour progression.

P21/WAF1, p53 and PCNA expression and p53 mutation status in hepatocellular carcinoma.

The cyclin-dependent kinase inhibitor p21/WAF1 is regulated by p5S3-dependent and p53-independent pathways. In addition, p21/WAF1 binds with proliferating cell nuclear antigen (PCNA) and inhibits the action of PCNA. To investigate the possible role of p21/WAF1 in human hepatocellular carcinomas (HCCs), we examined the expression of p21/WAF1 and its relation with PCNA and p53 expression in 97 surgically resected HCCs by immunohistochemistry and with the mutation status of p53 in 26 HCCs. p53 mutation status was examined by direct DNA sequencing using 3 sets of primers covering exons 5-9. Six of the 26 tumors showed p53 point mutations and only 33% of these HCCs demonstrated p21/WAF1 expression. In contrast, 75% of HCCs without p53 mutations showed p21/WAF1 expression. Of all 97 HCCs, p21/WAF1 expression was significantly higher in the tumors than in corresponding non-tumorous liver. When the tumors were stratified into 2 groups by the median tumor p21/WAF1 score, those with higher expression were found to have a lower incidence of multiple tumor nodules (p = 0.008) and tumor microsatellite formation (p = 0.050). The tumor p21/WAF1 score was positively associated with tumor PCNA expression (p = 0.036) but not with tumor p53 expression. Thus, in HCC, expression of p21/WAF1 is in part dependent on p53 status, but a p53-independent pathway also plays a significant role in the regulation of p21/WAF1 expression. High p21/WAF1 expression is significantly associated with solitary tumor nodules and, to a lesser extent, tumor microsatellites but may not be enough to suppress tumor progression.

Ovarian carcinoma producing hypoglycaemia.

Accepted 23 July 1997 A 26-year-old woman presented with six months of abdominal discomfort. At laparotomy a 40 x 40 cm omental tumour invading the stomach and involving the spleen...

Leiomyomatosis peritonealis disseminata associated with endometriosis: a case report and literature review

Leiomyomatosis peritonealis disseminata (LPD) is a rare disease characterised by the presence of multiple smooth muscle tumour nodules throughout the peritoneal cavity. Approximately 50 cases of LPD have been reported to date in the world literature. There is a very high association with excess exogenous and endogenous female gonadal steroids, specifically oestrogen and progesterone. LPD has been described almost only in premenopausal women and is mostly asymptomatic. Four cases of malignant transformation of this disease have been reported. We report a case of a patient with prolonged exposure to oral contraceptives, operated because of hypermenorrhea and `myoma in statu nascendi'. A metastasing myomatous tumour was suspected during the operation. LPD was diagnosed by intraoperative histological examination. Abdominal hysterectomy was performed. Five months later a second laparotomy had to be done because of an ovarian endometriosis tumour of about 10 cm size. A bilateral salpingo-oophorectomy and omentectomy were performed.

Enhanced Invasion and Liver Colonization by Lung Carcinoma Cells Overexpressing the Type 1 Insulin-Like Growth Factor Receptor

The receptor for the type 1 insulin-like growth factor (IGF-1R) and its ligands IGF-1 and IGF-2 play important roles in the maintenance of the malignant phenotype. In previous studies with two sublines of the Lewis lung carcinoma (H-59 and M-27, expressing high and low levels of IGF-1R, respectively) we have shown that receptor levels in these tumor cells correlated with metastasis to the liver. In the present study we asked whether the metastatic properties can be modulated by increasing receptor levels. M-27 carcinoma cells were transfected with a plasmid vector expressing a full-length human IGF-1R cDNA. Expression of the human receptor in the stable transfectants was confirmed by RT-PCR and immunoprecipitation analysis. These cells had an enhanced proliferative response to IGF-1 and hepatocyte-conditioned medium and an increased clonogenic potential in semisolid medium. Moreover, they acquired an invasive potential as measured in the reconstituted basement membrane (Matrigel) invasion assay. When inoculated via the splenic/portal routein vivo,these cells but not mock-transfected cells gave rise to multiple tumor nodules. The results suggest that IGF-1R can modulate several cellular functions which impact on the metastatic phenotype including invasion and liver colonization.

Intraperitoneal chemotherapy in disseminated abdominal sarcoma.

There is no information in the literature concerning the use of cytoreductive surgery with intraperitoneal chemotherapy for sarcomas disseminated intraabdominally. A prospective study was initiated of exploratory laparotomy, removal of all macroscopic tumor when feasible, and intraperitoneal chemotherapy with cis-DDP 100 mg/m2 every 4 weeks. Patients were to be explored in 6 months or earlier for detectable tumor recurrence. Twenty-eight consecutive patients enrolled in the study. Complete resection of all macroscopic tumor was possible in 79% of patients. Survival rates at years 1-5 were 54%, 21%, 7%, 7%, and 7%, respectively. Of the two long-term survivors, one was found to be disease free at the second-look operation with a catheter free of adhesions, whereas the other had recurrent disease and all her lesions were resected. Of 20 patients who underwent a second-look procedure, the Tenkhoff intraperitoneal catheter was found to be densely surrounded by adhesions in 19. In the 19 patients with adhesions, there was no tumor around the catheter for a radius of 15-20 cm, but the rest of the peritoneal cavity contained multiple tumor nodules. Removal of all macroscopic tumor is possible in 79% of the patients with sarcoma disseminated in the abdominal cavity. Intraperitoneal chemotherapy with cis-DDP after cytoreductive surgery resulted in a 5-year survival rate of only 7%.

Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma.

In rats with diethylnitrosamine (DENA)-induced hepatocellular carcinoma (HCC), we studied in vivo gene transfer efficiency using intraportal injections of recombinant adenovirus carrying the lacZ reporter gene (AdCMVlacZ) and the therapeutic efficacy of adenovirus-mediated transfer of the thymidine kinase gene of the herpes simplex virus (HSV-tk) followed by ganciclovir (GCV) administration. DENA was very effective in inducing HCC but also stimulated nontumor cell replication, as shown by proliferating cell nuclear antigen (PCNA) staining. The study of in vivo gene transfer efficiency in tumor-bearing rats showed that nontumor tissue and small tumor nodules were transduced effectively whereas a poor transduction rate was noted in large tumor nodules. Concerning therapeutic efficacy, three groups of rats with established HCC were studied: group A and B received intraportally recombinant adenovirus carrying HSV-tk (AdCMVtk) or AdCMVlacZ, respectively, and 2 days after GCV was given intraperitoneally for 9 days; group C received only saline. Of the rats from groups B and C, 100% and 93% respectively, exhibited multiple HCC tumor nodules at end of the study. In contrast, a complete regression of tumor was observed in 63% of animals from group A. This group showed significant elevation of serum transaminases and a diffuse hepatotoxic lesion in liver tissue; histological signs of regeneration were observed in surviving animals. Nine out of 19 rats from group A died during the treatment period. We conclude that (i) in the DENA model of HCC, tumoral cells can be destroyed in vivo by the HSV-tk/GCV system despite poor transduction of large tumor nodules, suggesting that toxic metabolites generated by nontumor cells may exert a bystander effect on tumor tissue; (ii) significant hepatoxicity and a high mortality rate occurred in HSV-tk/GCV-treated rats; these side effects appear to be due to the fact that in DENA-treated livers enhanced cell proliferation was present not only in tumor nodules but also in nontumor parenchyma, leading to GCV sensitization of both tissues; (iii) our results have implications concerning the efficacy and potential risks of the HSV-tk/GCV system in the treatment of human HCC.

“Warthin-like Tumor” of the Thyroid

We report 13 cases of a peculiar thyroid tumor of follicular epithelial differentiation with distinctly papillary architecture, oxyphilic cytology, and lymphocytic infiltrates in papillary stalks. The majority of these tumors arose in glands with chronic lymphocytic thyroiditis. The combination of oxyphilic cells and lymphocytic stroma gives these tumors a startling resemblance to papillary cystadenoma lymphomatosum, or "Warthin's tumor" of the salivary gland. Twelve tumors occurred in women (age range: 26-66 years, mean 44 years). Two tumors were in the isthmus, six in the right lobe, and four in the left lobe. The only man, 34 years old, had multiple bilateral tumor nodules. The lesions ranged from 0.3 cm to 3.5 cm in maximum dimension. The largest lesion, in a 58-year-old woman, infiltrated skeletal muscle. Three other patients had lymph node metastases, while the nine remaining tumors were confined to the thyroid. Follow-up in these cases suggests that although the histological appearance of these neoplasms is unusual, they behave as typical papillary carcinomas. The striking lymphocytic infiltration and oxyphilic metaplasia in these tumors as well as the association with chronic lymphocytic thyroiditis suggest that as yet undefined immunological mechanisms may play a role in the pathogenesis of this disorder.

Systemic treatment with interleukin-4 induces regression of pulmonary metastases in a murine renal cell carcinoma model

Advanced metastatic renal cell carcinoma has been shown to be responsive to immunotherapy but the response rate is still limited. We have investigated the therapeutic potential of systemic interleukin-4 (IL-4) administration for the treatment of pulmonary metastases in the murine Renca renal adenocarcinoma model. Renca cells were injected iv in Balb/c mice to induce multiple pulmonary tumor nodules. From Day 5, Renca-bearing mice were treated with two daily injections of recombinant murine IL-4 for 5 consecutive days. IL-4 treatment induced a significant reduction in the number of lung metastases in a dose-dependent manner and significantly augmented the survival of treated animals. Immunohistochemistry studies, performed on lung sections, showed macrophage and CD8 + T cell infiltration in the tumor nodules 1 day after the end of IL-4 treatment. The CD8 infiltration increased by Day 7 after IL-4 treatment. Granulocyte infiltration was not detectable. To clarify further the role of the immune system in IL-4 anti-tumor effect, mice were depleted of lymphocyte subpopulations by in vivo injections of specific antibodies prior to treatment with IL-4. Depletion of CD8 + T cells or AsGM1 + cells abrogated the effect of IL-4 on lung metastases, whereas depletion of CD4 + T cells had no impact. These data indicate that CD8 + T cells and AsGM1 + cells are involved in IL-4-induced regression of established renal cell carcinoma.