Findings in lymph nodes of patients with germ cell tumours after chemotherapy and their relation to prognosis.

One hundred and forty six patients with advanced germ cell testicular tumours (38 seminomas and 108 malignant teratomas) treated by combination chemotherapy were studied over 10 years. Most of the improvement seen was in patients with malignant teratoma undifferentiated. In the most recently treated patients (1984-1987) 75% of drug resistant cases were malignant teratoma intermediate compared with 26% in the series treated between 1978-1983. The microscopic features of 52 primary testicular tumours were compared with features seen in excised retroperitoneal lymph nodes after completion of chemotherapy. Primary malignant teratoma intermediate had a higher incidence of viable malignancy in the excised tissue than malignant teratoma undifferentiated. Mature teratoma or fibronecrotic tissue within resected tissue was associated with a good prognosis. If resection was complete patients with drug resistant malignant teratoma intermediate had a more favourable prognosis than drug resistant malignant teratoma undifferentiated. It is advised that retroperitoneal node dissection should be considered in the management of patients with advanced germ cell testicular tumours, and that as complete a resection as possible be attempted to avoid the danger of missing residual disease.     

Central nervous system as sanctuary site of relapse in patients treated with chemotherapy for metastatic testicular cancer

Isolated central nervous system relapse in patients treated successfully with cisplatin-based chemotherapy for testicular cancer has been described infrequently. In a retrospective analysis we identified this complication in six of 417 patients. Five of the six patients had advanced pulmonary dissemination at onset of chemotherapy, and post-chemotherapy surgery did not reveal viable tumour tissue in any of these cases. All six patients developed a single cerebral metastasis during complete remission a median four months after discontinuation of chemotherapy. Five patients were treated with surgery and subsequent radio-therapy, one patient with irradiation alone. Three patients are alive relapse-free 19, 62 and 86 months after diagnosis of cerebral relapse. One patient was alive with cerebral disease for 12 months without evidence of systemic recurrence. Our data demonstrate that the brain may act as a sanctuary site in chemotherapy-treated testicular cancer. A review of the literature shows that an isolated cerebral relapse is an extremely rare complication, but carries a relatively favourable prognosis.     

Management consideration in nonpulmonary visceral metastatic seminoma of testis.

To develop a more appropriate therapeutic strategy for treatment of nonpulmonary visceral metastatic testicular seminoma based on the International Germ Cell Consensus Classification, we reviewed the medical records of patients with nonpulmonary visceral metastatic testicular seminoma who were treated over a 20-year period. Only 15 (2.2%) of the 686 cases of testicular seminoma were nonpulmonary visceral metastatic seminoma. The median age of patients was 38 years (range, 22-53 years). Ten (67%) of the patients had an initial diagnosis of supradiaphragmatic or visceral metastatic disease. In addition to nonpulmonary visceral metastasis, all patients had lymph node metastasis as well, the majority of which involved the retroperitoneal lymph nodes. The median and mean progression-free survival durations after chemotherapy for advanced disease were 19 months and 63.7 months, respectively. Six patients (40%) survived, five relapsed after radiation therapy and four died of chemorefractory disease not dependent on the specific regimen. Although the number of cases reviewed in this study was small, we conclude that the choice of chemotherapeutic regimen among the current treatments for nonpulmonary visceral metastatic seminoma of testis primary does not present a different outcome. Therefore, multimodality therapies using new strategies or new agents are well indicated.     

Molecular genetic evidence supporting the neoplastic nature of stromal cells in 'fibrosis' after chemotherapy for testicular germ cell tumours

A residual retroperitoneal mass containing only fibrosis and necrosis is present in 40-52% of patients with advanced testicular germ cell tumours after chemotherapy. The biological nature and genetic characteristics of the stromal cells in these residual masses have not been adequately investigated. Laser-microdissected stromal cells from 27 patients who underwent retroperitoneal lymph node dissection after chemotherapy for metastatic testicular germ cell tumour were analysed. Allelic loss in the stromal cells of fibrosis was present at one or more of the ten microsatellite DNA loci examined in 23 (85%) of the cases. Chromosome arm 12p anomalies, the hallmark of germ cell neoplasia, were present in nine (33%) cases. The high frequency of allelic losses and chromosome arm 12p anomalies in the stromal cells from residual retroperitoneal fibrous masses after chemotherapy for testicular germ cell tumours suggests that the stromal cells are derived from the same tumour progenitor cells as the pre-existing metastatic germ cell tumour.     

Lymph node metastasis in a gynecologic malignancy

A radical hysterectomy was performed on patients with stage IA2 to IIB cervical cancer. For these patients, many histopathological parameters have been reported to be prognostic factors of cervical cancer, such as a pelvic lymph node (PLN) metastasis, the histological subtype, the tumor diameter, the depth of the stromal invasion, a lymph-vascular space invasion (LVSI), a parametrial invasion, a corpus invasion and a vaginal invasion. Ovarian cancer is normally treated with cytoreductive surgery followed by chemotherapy. Although physicians have paid a great deal of attention to intraperitoneal disease, a substantial number of ovarian cancers have reported to involve the retroperitoneal lymph nodes. Therefore, a lymph node metastasis has been introduced into FIGO staging. However, the prognostic significance of a lymph node metastasis is controversial. In order to determine the possibility of individualizing a pelvic lymph node (PLN) dissection in patients with endometrial cancer, the relationship between PLN metastasis and the various prognostic factors was investigated. In this paper, various prognostic variables including a lymph node metastasis were analyzed in cervical cancer, endometrial cancer, and ovarian cancer.     

Histopathological features in stage I non-seminomatous testicular germ cell tumours correlated to relapse. Danish Testicular Cancer Study Group

156 patients with stage I non-seminomatous testicular germ cell tumour entered a countrywide randomized study comparing the effect of postoperative irradiation of retroperitoneal lymph nodes with surveillance only. A total of 150 patients were included in this investigation of factors associated with increased risk of relapse. Thirty-four patients (23 per cent) had a relapse, i.e. 11/67 (16 per cent) in the former and 23/83 (28 per cent) in the latter group. Histopathological studies of the orchidectomy specimens were performed in order to identify features associated with relapse. Pure embryonal carcinoma and vascular involvement were significantly associated with increased risk of relapse. Thus, the relapse rate in the observation group in patients with pure embryonal carcinomas was 50 per cent (5/10) and 36 per cent (19/53) in all patients with tumours with vascular involvement.     

Challenging the conventional treatment of colon cancer by sentinel lymph node mapping and its role of detecting micrometastases for adjuvant chemotherapy

All colon cancer patients with lymph node (LN) positive disease are treated with chemotherapy. Patients with node negative disease are usually cured by surgery alone. Yet about 20% of patients develop recurrence within 5 years despite node negative status. This may often be the result of missed micrometastases by conventional examination. Sentinel lymph node (SLN) mapping was developed to find those nodes detected by blue dye which was ultrastaged to detect micrometastases. Consecutive patients, underwent SLN mapping with the blue dye with success rate of 99.2%. Average number of LN was 18.3, average number of SLN was 3/patient and overall nodal positivity was 45%. Ten patients had skip metastases. Overall survival of 235 patients was 84 months with survival of node negative patients 97 months versus 68 months for node positive patients. For stage I–IV patients, overall survival was as follows: stage I—115 months, stage II—90 months, stage III—84 months and stage IV—24 months respectively. Patients with micrometastases after chemotherapy had average survival of 108 months versus those without chemotherapy was 50 months. Thus, SLN mapping techniques is highly successful, easily reproducible and finds micrmoetastases in over 15% of patients which could have been missed by conventional pathological examination. These patients when treated with adjuvant chemotherapy have similar survival as those of node negative disease. Similarly, patients without any nodal metastases after SLN mapping and ultrastaging, may be considered as true node negative disease and may avoid further adjuvant chemotherapy.     

Cytologic diagnosis of metastatic seminoma to the prostate and urinary bladder: a case report

A 42-year-old man presented with severe abdominal pain, constipation, and hematuria. The patient had a history of seminoma treated by chemotherapy followed by bilateral orchiectomy and retroperitoneal lymph node dissection 16 years earlier. A computed tomography (CT) scan showed a 8.0 x 6.0 x 5.0 cm mass in the retrovesical space, encompassing the left side of his proximal bladder, the prostate, and the rectum. A urine cytologic specimen showed loosely cohesive cell clusters composed of highly atypical large cells and occasional large, single cells with macronucleoli present in a background of mainly lymphocytes and histiocytes was diagnosed as recurrent seminoma. Prostate biopsies showed extensively necrotic seminoma with accompanying granulomatous reaction. The tumor cells were immunoreactive for c-kit (CD117), placental-like alkaline phosphatase (PLAP), D2-40, and OCT4. To our knowledge, this is the second report on urine cytology of metastatic seminoma.     

Triple negative breast cancer: adjuvant chemotherapy effect on survival

PurposeThe purpose of this study was to evaluate the overall survival of patients with triple negative breast cancer and the impact of different adjuvant chemotherapy regimens on survival.Material/MethodsThe study group consisted of 99 breast cancer patients with immunohistochemically confirmed triple negative breast cancer. The impact of various factors as well as the impact of different chemotherapy regimens on survival was evaluated.ResultsThe overall survival of breast cancer patients was 97.0% (95% CI 90.9–99.0), 84.9% (95% CI 76.1–90.6) and 66.5% (95% CI 55.5–75.3) 10, 30 and 60 months after diagnosis, respectively. Univariate analysis demonstrated that the following were significant risk factors for breast cancer patients survival: patient's age, stage of disease, tumour size, lymph node status, type of surgery and chemotherapy. Better survival was related to younger patients’ age, smaller tumour size, lower stage of disease, no lymph nodes involvement. Survival rates were higher among patients who received adjuvant chemotherapy and underwent quadrantectomy. In the multivariate statistical analysis the significant independent prognostic variables influencing survival were lymph node status and adjuvant chemotherapy. Survival rates of the patients, who received adjuvant anthracycline containing chemotherapy were higher, than those in non-anthracycline containing treatment group, but the difference was not statistically significant.ConclusionPatients who had lymph node status N2–3 and those who did not receive adjuvant chemotherapy showed worse prognosis and survival than other patients. The impact of chemotherapy type (anthracycline containing or non-anthracycline containing) on patients survival was not statistically significant.     

Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials

About a third of patients with ovarian cancer present with localized disease; despite surgical resection, up to half the tumors recur. Since it has not been established whether adjuvant treatment can benefit such patients, we conducted two prospective, randomized national cooperative trials of adjuvant therapy in patients with localized ovarian carcinoma (International Federation of Gynecology and Obstetrics Stages Ia to IIc). All patients underwent surgical resection plus comprehensive staging and, 18 months later, surgical re-exploration. In the first trial, 81 patients with well-differentiated or moderately well differentiated cancers confined to the ovaries (Stages Iai and Ibi) were assigned to receive either no chemotherapy or melphalan (0.2 mg per kilogram of body weight per day for five days, repeated every four to six weeks for up to 12 cycles). After a median follow-up of more than six years, there were no significant differences between the patients given no chemotherapy and those treated with melphalan with respect to either five-year disease-free survival (91 vs. 98 percent; P = 0.41) or overall survival (94 vs. 98 percent; P = 0.43). In the second trial, 141 patients with poorly differentiated Stage I tumors or with cancer outside the ovaries but limited to the pelvis (Stage II) were randomly assigned to treatment with either melphalan (in the same regimen as above) or a single intraperitoneal dose of 32P (15 mCi) at the time of surgery. In this trial (median follow-up, greater than 6 years) the outcomes for the two treatment groups were similar with respect to five-year disease-free survival (80 percent in both groups) and overall survival (81 percent with melphalan vs. 78 percent with 32P; P = 0.48). We conclude that in patients with localized ovarian cancer, comprehensive staging at the time of surgical resection can serve to identify those patients (as defined by the first trial) who can be followed without adjuvant chemotherapy. The remaining patients with localized ovarian cancer should receive adjuvant therapy, and with adjuvant melphalan or intraperitoneal 32P should have a five-year disease-free survival of about 80 percent.     

High-dose chemotherapy and hematopoietic support for patients with high-risk primary breast cancer and involvement of 4 to 9 lymph nodes.

Despite modern chemotherapy, advanced breast cancer remains a significant cause of cancer morbidity and mortality in women. Patients with disease involvement of multiple lymph nodes represent a subgroup with a high risk of relapse. In particular, 50% of patients with 4 to 9 axillary lymph nodes involved will relapse after standard chemotherapy. In an effort to improve the survival of patients with 4 to 9 involved nodes, we performed a phase II study in which 61 patients with surgically diagnosed stage II or III breast cancer and 4 to 9 positive lymph nodes received 3 cycles of doxorubicin and 5-fluorouracil followed by high-dose chemotherapy consisting of cisplatin, cyclophosphamide, and carmustine and infusion of autologous hematopoietic progenitor cells. All patients received posttransplantation localized radiotherapy unless contraindicated, and all patients with hormone receptor-positive disease received tamoxifen. After a median patient follow-up of 6.7 years (range, 4.6-8.6 years), the 5-year overall survival rate was 79% (95% CI, 69%-90%), with relapse-free survival of 73% (95% CI, 62%-85%). Treatment-related mortality was 3%. Interstitial pneumonitis occurred in 69% of patients but did not contribute to mortality. Our study presents long-term favorable results regarding the use of consolidative HDC with autologous hematopoietic support in previously untreated patients with high-risk primary breast cancer.     

Clinical Significance of Lymph Node Dissection in Patients with Muscle-Invasive Upper Urinary Tract Transitional Cell Carcinoma Treated with Nephroureterectomy

We investigated the value of lymph node dissection in patients with cN0 muscle-invasive transitional cell carcinoma of the upper urinary tract (UUT-TCC). Medical records of 152 patients with cN0 muscle-invasive UUT-TCC, who underwent nephroureterectomy between 1986 and 2005, were reviewed. Sixty-three patients (41.4%) underwent lymph node dissection. The median number of lymph nodes harvested was 6 (range, 1 to 35), and from these, lymph node involvement was confirmed in 9 patients (14.3%). Locoregional recurrence (LR) and disease-recurrence (DR) occurred in 29 patients and 63 patients, respectively. Fifty-five patients (36.2%) had died of cancer at the last follow-up. The number of lymph nodes harvested was associated with the reduction of LR (χ²_trend=6.755, P=0.009), but was not associated with DR (χ²_trend=1.558, P=0.212). In the survival analysis, N stage (P=0.0251) and lymph node dissection (P=0.0073) had significant influence on LR, but not on DR or disease-specific survival. However, the number of lymph nodes harvested did not affect LR-free, DR-free, or disease-specific survival. We conclude that lymph node dissection may improve the control of locoregional cancer, as well as staging accuracy, in cN0 muscle-invasive UUT-TCC, but that it does not clearly influence survival.     

Loss of CD30 expression in metastatic embryonal carcinoma: the effects of chemotherapy?

AIMS: CD30 has been shown to be consistently strongly expressed in embryonal carcinomas. Our aim was to examine changes in CD30 expression in embryonal carcinomas before and after treatment with chemotherapy. METHODS AND RESULTS: One hundred and eighteen retroperitoneal lymph node dissections from patients with metastatic germ cell tumours were reviewed. Seventeen contained embryonal carcinoma deposits. In nine cases, the matching pre-chemotherapy orchidectomy specimens were available. The cases were immunohistochemically stained for CD30. All nine pre- chemotherapy orchidectomy specimens showed embryonal carcinoma and stained strongly positively for CD30. However, only four out of nine of the matched post-chemotherapy retroperitoneal lymph node dissection specimens and a total of six out of 17 (35%) with embryonal carcinoma deposits stained for CD30. Ten seminomas were negative for CD30. Loss of CD30 did not appear to influence the relapse rate of the patients. CONCLUSIONS: Loss of CD30 expression occurs frequently in metastatic embryonal carcinomas after chemotherapy. This finding has implications in the use of CD30 in the diagnosis of metastatic non-seminomatous germ cell tumours and suggests that chemotherapy may alter the immunophenotype of embryonal carcinoma while retaining its characteristic histological appearances.     

Pregnancy-associated breast cancer

Twelve premenopausal women diagnosed with pregnancy-associated breast cancer between May 1985 and October 1999 were reviewed. Three patients were diagnosed in the first trimester of pregnancy, five in the second trimester, and three during the third trimester. There was one patient who was five weeks postpartum. At the time of diagnosis nine patients had lymph node involvement and two of these had metastatic disease. Four patients received primary chemotherapy. The remainder had surgery. Five patients died, two had metastatic disease at time of diagnosis, median survival was 31 months. There were three fetal deaths, one termination and two during primary chemotherapy. The diagnosis of breast cancer during pregnancy is difficult. Presentation is usually at an advanced stage. Surgery can be safely performed during pregnancy and adjuvant chemotherapy should not be postponed until after delivery.     

Prevalence of occult metastases in axillary sentinel lymph nodes of breast carcinoma

Recently, sentinel lymph node biopsy (SLNB) has been accepted as a standard method of assessment of axillary lymph nodes in breast cancer patients with no clinical lymphadenopathy. There is no standard pathologic method to evaluate sentinel lymph nodes. The purpose of this study is to evaluate the frequency of occult lymph node metastasis in sentinel lymph nodes via serial sectioning and immunohistochemical study with cytokeratin and its relationship with other clinicopathologic factors. Paraffin-embedded blocks of axillary sentinel lymph nodes of breast cancer patients, biopsied in 2005-2009 and reported as negative, were reviewed with 3 μm sections, H and E staining and immunohistochemical study with an epithelial cytokeratin marker. Clinicopathologic data and relapse, if occurred was recorded and its relationship with occult metastasis was statistically analyzed. Sixty-eight sentinel pathology blocks of 66 patients (65 women and one man, median age 49 years) were investigated. Four cases (5.8%) of occult metastases were found, one by HE staining, and three cases with IHC (1 micrometastasis, 2 isolated tumor cells). Accuracy of reported cases was 94.1% upon re-examination. Sixty-four patients were followed after surgery and adjuvant therapy (range: 6-38 months, median: 21 months). No relapse was reported. There was no significant statistical relationship between occult metastasis and disease-free survival. Although 4 cases (5.8%) of sentinel lymph nodes were positive in the complementary study, with a median follow-up of 21 months, we found no difference in disease-free survival between these patients and others. To show a significant, however small, difference, one needs further research with a greater number of patients and longer follow-up.     

Spermatocytic seminoma associated with rhabdomyosarcoma

A case of spermatocytic seminoma intimately associated with rhabdomyosarcoma is reported. The patient, a 51-year-old man, presented with a two-year history of right-sided testicular enlargement. Orchiectomy was performed, and a large testicular tumor was excised. Further investigations during hospitalization revealed lung, liver, and retroperitoneal lymph node metastases. Further therapy was refused, and the patient died at home two months after orchiectomy. Autopsy was not permitted. Although the great majority of spermatocytic seminomas occur in pure form, do not metastasize, and have very good prognosis, in addition to the present case, seven cases of spermatocytic seminoma associated either with rhabdomyosarcoma or undifferentiated sarcoma have been reported. Presence of the sarcomatous element is associated with aggressive behavior, metastatic disease, and very poor prognosis. It is considered that the sarcomatous element develops from the spermatocytic seminoma by anaplastic transformation.     

Skin manifestation of extramedullary relapse in adult with acute lymphoblastic leukaemia.

In the group of 75 ALL patients treated between 1980 and 1989, two women (ages 25 and 17, both FAB-L2 and CALLA +, after 56 and 34 months of continuous CR, respectively) were found to have a relapse manifested as a local infiltration of skin, with involvement of the adjacent lymph nodes in one patient. The leukaemic character of the skin infiltration was confirmed by skin needle aspiration and tissue biopsy expressing CD10 and CD24. Both patients were given intensified systemic chemotherapy and local X-ray irradiation. Complete remission was obtained with the disappearance of the skin infiltrations followed after 13 and 8 months, respectively, followed by a marrow relapse with symptoms of CNS involvement in one case. Both patients died because of treatment resistance (the overall survival time equalled 70 and 44 months, respectively).     

DNA methylation of hMLH1 correlates with the clinical response to cisplatin after a surgical resection in Non-small cell lung cancer

Our previous study demonstrated that promoter methylation of human mutL homolog 1 (hMLH1) is involved in determining sensitivity to cisplatin in NSCLC A549/DDP cell line, The present study was designed to determine whether DNA methylation of hMLH1 affects the prognosis of non-small cell lung cancer patients who received cisplatin-based adjuvant chemotherapy. Methylation status of hMLH1 was examined by nested methylation-specific PCR (nested MSP) in 84 archived NSCLC surgically resected tissue specimens from patients receiving cisplatin-based adjuvant chemotherapy. Univariate and multivariate analysis were used to investigate the relationship between hMLH1 methylation status and the clinical prognosis of the patients mentioned above. In the cohort of 84 NSCLC cases, 80 tissue samples were successfully amplified by nested MSP. Among them, 36 samples (45%) were identified to be methylated. Moreover, hMLH1 methylation was not associated with age, gender, smoking status, T stage, histology and differentiation, but correlated with lymphatic metastasis (P=0.021). Multivariate logistic regression analysis showed that hMLH1 methylation may function as a significant independent prognostic factor for tumor recurrence in NSCLC patients treated with adjuvant cisplatin (HR 3.114, 95% CI 1.032-9.399; P=0.044). However, Kaplan-Meier method (P=0.093) and multivariate Cox regression analysis (P=0.598) revealed that hMLH1 methylation was not associated with the survival of these patients. To conclude, the cisplatin-based adjuvant chemotherapy is more beneficial for NSCLC patients without hMLH1 methylation. hMLH1 methylation may have a potential to become a biomarker of individualized therapy for NSCLC patients.     

Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer

In 1985 we presented results of a randomized trial involving 1843 women followed for five years that indicated that segmental breast resection (lumpectomy) followed by breast irradiation is appropriate therapy for patients with Stage I or II breast cancer (tumor size, less than or equal to 4 cm), provided that the margins of the resected specimens are free of tumor. Women with positive axillary nodes received adjuvant chemotherapy. Lumpectomy followed by irradiation resulted in a five-year survival rate of 85 percent, as compared with 76 percent for total mastectomy, a rate of survival free of distant disease of 76 percent, as compared with 72 percent, and a disease-free survival rate of 72 percent, as compared with 66 percent. In the current study, we have extended our observations through eight years of follow-up. Ninety percent of the women treated with breast irradiation after lumpectomy remained free of ipsilateral breast tumor, as compared with 61 percent of those not treated with irradiation after lumpectomy (P less than 0.001). Among patients with positive axillary nodes, only 6 percent of those treated with radiation and adjuvant chemotherapy had a recurrence of tumor in the ipsilateral breast. Lumpectomy with or without irradiation of the breast resulted in rates of disease-free survival (58 +/- 2.6 percent), distant-disease-free survival (65 +/- 2.6 percent), and overall survival (71 +/- 2.6 percent) that were not significantly different from those observed after total mastectomy (54 +/- 2.4 percent, 62 +/- 2.3 percent, and 71 +/- 2.4 percent, respectively). There was no significant difference in the rates of distant-disease-free survival (P = 0.2) or survival (P = 0.3) among the women who underwent lumpectomy (with or without irradiation), despite the greater incidence of recurrence of tumor in the ipsilateral breast in those who received no radiation. We conclude that our observations through eight years are consistent with the findings at five years and that these new findings continue to support the use of lumpectomy in patients with Stage I or II breast cancer. We also conclude that irradiation reduces the probability of local recurrence of tumor in patients treated with lumpectomy.     

Paraneoplastic hypoglycemia due to malignant histiocytoma (Doege-Potter syndrome) (author's transl)]

A case report is given on a male patient who was 52 years old when he died. 9 years ago a nephrectomy was performed because of a densely-packed mesenchymal tumor of the adipose tissue of the pelvis renalis. 7 years after the surgical intervention he suffered from several hypoglycemic crises. An operation was performed, and 2 large tumor nodes were removed from the greater omentum. A retroperitoneal relapse was inoperable. Nevertheless, the disorder of the carbohydrate metabolism disappeared after the operation. At the autopsy, one year later, a large retroperitoneal tumor with metastases in the lymph nodes was found. The neoplastic growth was classified as a malignant histiocytoma, and the hyperglycemia was taken as a paraneoplastic syndrome (Doege-Potter).