Non-germ Cell Research Articles

Unusual Neoplasms Detected in Testis Cancer Patients Undergoing Post-Chemotherapy Retroperitoneal Lymphadenectomy

Approximately 30% of patients with disseminated testis cancer who receive platinum-based chemotherapy will experience normalization of tumor markers but have persistent, radiographically evident disease in the retroperitoneum. These patients usually undergo retroperitoneal lymph node dissection. Of 557 patients undergoing post-chemotherapy retroperitoneal lymph node dissection at our university medical center 45 (8.1%) had neoplastic elements distinct from the classical germ cell tumor types within the resected specimens. Examples include various sarcomas in 19 patients (3.7%), other nonsarcomatous nongerm cell cancers in 18 (3.2%) and cystic atypical choriocarcinoma in 8 (1.4%). No distinct patient characteristics or histological patterns in the primary tumor are predictive of these unusual findings in the retroperitoneal lymph node dissection specimen, although sampling error in the orchiectomy specimen could be the reason for this lack of correlation. Surgical resection of these chemoresistant tumors is potentially curative, with disease-free survival in 13 of 19 patients (68.4%) with sarcoma, 10 of 18 (55.6%) with nonsarcomatous cancer and 7 of 8 (87.5%) with cystic atypical choriocarcinoma at a mean followup of 30.6, 42.5 and 24.7 months, respectively.

The effect of testicular nongerm cell tumors on local spermatogenesis

To assess ipsilateral spermatogenesis in men with malignant and benign nongerm cell tumors of the testis. Histologic review of radical orchiectomy specimens performed for 20 men with malignant nongerm cell tumors and 15 with benign testicular lesions, including five Leydig cell tumors with benign clinical features. Degree of spermatogenesis was determined on a 1 to 10 scale, with 10 representing mature sperm within a seminiferous tubule. For each patient "near" and "far" scores were determined by obtaining the mean score of 50 tubules adjacent (< 3 mm) to the tumor and 50 tubules distant (> 3 mm) from the tumor, respectively. Total, near, and far scores were all lower for malignant tumors than for benign lesions. Scores for Leydig cell tumors were similar to benign lesions. Malignant tumors demonstrated a gradient effect, with greatest impairment of spermatogenesis occurring adjacent to tumor. In contrast, a distinction between near and far scores was not observed for benign lesions or Leydig cell tumors. Malignant nongerm cell tumors of the testis were associated with significant impairment of ipsilateral spermatogenesis, particularly in areas adjacent to tumor. These findings are similar to those observed for testicular germ cell tumors, suggesting a generalized negative influence on ipsilateral spermatogenesis by malignant tumors.

Hematopoietic precursor cells within the yolk sac tumor component are the source of secondary hematopoietic malignancies in patients with mediastinal germ cell tumors

Patients with mediastinal germ cell tumors (MGCT) have a high incidence of hematologic malignancies unrelated to cytotoxic chemotherapy. It has been suggested that these leukemic conditions originate from a MGCT progenitor cell capable of undergoing non-germ cell (hematopoietic) differentiation.To assess this hypothesis, histologic material from six patients with MGCTs associated with leukemia was examined using monoclonal and polyclonal antibodies capable of labeling cells of the different marrow cell lineages.Morphologically identifiable hematologic cells were found within the yolk sac tumor component of the MGCT in four of these patients. In three of the four cases, the cells consisted of poorly differentiated blast cells, whereas in the fourth, clusters of erythroblasts were identified. The leukemic cells within the MGCT and in the bone marrow had similar morphology, constant expression of the early progenitor cell marker CD34, and variable expression of more mature myeloid, monocytic, erythroid, and megakaryocytic markers. Three cases expressed p53, a nuclear protein associated with neoplastic transformation in a wide range of malignancies, including testicular cancers, but which rarely is reported in leukemias. Karyotype of the leukemia was assessed in five cases: two showed an i(12p), a cytogenetic marker of GCT not identified in the usual cases of leukemia.The results support the hypothesis that these leukemic conditions originate in the MGCT through a mechanism of differentiation from a yolk sac tumor-derived progenitor cell, with subsequent homing to the marrow.

Production of placental alkaline phosphatase (PLAP) and PLAP-like material by epithelial germ cell and non-germ cell tumours in vitro

Placental and placental-like alkaline phosphatase (PLAP) levels in the culture media of 87 cell lines of neoplastic and 'normal' origin were measured by a conventional immunosorbent enzymatic assay (IAEA) and by a new immunoradiometric assay (IRMA). The IRMA detected immunoreactive PLAP in 37 of 80 (46%) human epithelial and germ cell cultures, while the IAEA detected PLAP in only 25 (33%). Of the 52 non-germ cell tumour cultures, the IRMA detected expression in 24 (46%) and the IAEA in only 16 (31%). In 17 cases (21%) the IRMA recorded levels double that of the IAEA, while in five cultures (6%) the reverse was true. The IRMA was much more robust than the IAEA and had considerably lower inter- and intra-assay coefficients of variation (3.75-8.5% vs 5.2-46%). Detection of PLAP(-like) expression by IAEA is dependent on neoplastic expression of enzymatically functional molecules and quantification assumes constant enzyme kinetics. PLAP-like material has a higher catalytic rate constant than PLAP and thus will give higher values on a stoichiometric basis in an IAEA. The higher detection rate and levels of PLAP-like material in neoplastic cultures when measured by the IRMA clearly demonstrate ectopic expression of non-enzymatic PLAP and PLAP-like genes. The incidence of PLAP(-like) expression by non-germ cell and possible germ cell tumours has been underestimated and its utility as a tumour marker should be re-examined using assays which measure antigen mass rather than phosphatase activity.

Synchronous bilateral testis tumor: Mixed germ cell and theca cell tumors

Synchronous bilateral testis tumors of different histologic types are rare. All previous cases have demonstrated germ cell tumors on both sides. The simultaneous appearance of a germ cell tumor and a contralateral non-germ cell tumor has not been reported. We herein report a thirty-four-year-old man who presented with a mixed nonseminomatous germ cell tumor of the left testis and theca cell tumor of the right testis.

Surgical and Medical Management of Germ Cell Tumors of the Chest

Germ cell tumors are highly curable when treated appropriately. The majority of germ cell tumors arise in the testes, with a proportion having pulmonary parenchymal or mediastinal metastases. For patients who have such tumors, prompt diagnosis and treatment with chemotherapy are essential. A subset of these patients will have persistent radiographic abnormalities after chemotherapy and will benefit from post-chemotherapy resection of residual masses. These patients need to be distinguished from those who should be observed and those who require further chemotherapy. A small proportion of patients with germ cell tumors will present with tumors arising in the mediastinum. Prompt diagnosis, with adequate tissue for histopathologic and immunohistochemical staining, is essential. Primary therapy for such patients should be chemotherapy, except for some patients with mediastinal seminomas in whom radiotherapy is preferable. Mediastinal nonseminomatous germ cell tumors have a poor prognosis due, in part, to their bulk and relative chemosensitivity, but also due in part to their association with non-germ cell elements and acute leukemia. Proper coordination of the different modalities is essential in optimizing the cure rate of patients with these tumors.

Immunohistochemical and biochemical characterisation of the expression of a human embryonal carcinoma cell proteoglycan antigen in human germ cell tumours and other tissues

In the embryonal carcinoma (EC) cell line GCT 27, monoclonal antibody GCTM-2 recognises an epitope on a 200 kD pericellular matrix keratan sulphate proteoglycan. Immunohistochemical analyses demonstrated staining of tissue sections from 21 out of 22 human non-seminomatous germ cell tumours, and from 22 out of 28 sections of seminomas. In normal human fetal tissues gut epithelium and muscle stained strongly, and certain other epithelia stained moderately. In adult tissues, the distribution of the epitope was similar, but staining intensity was weaker. Neoplastic tissues showed reactivity with embryonal rhabdomyosarcoma and colorectal carcinoma, but no other non-germ cell tumours. Immunofluorescence microscopy showed that GCTM-2 also stained cell lines from human colorectal carcinoma, embryonal rhabdomyosarcoma and choriocarcinoma. In contrast to EC cells the epitope in these other cell types required permeabilisation of the cells to be visualised, and the protein bands in immunoblots lacked extensive modification with keratan sulphate and were smaller. Thus, GCTM-2 reacts with an epitope which has a previously unrecognised tissue distribution; its expression as a pericellular matrix proteoglycan is predominantly a characteristic of human EC cells.

A New Technique Examines the Connective Tissue Framework in Normal Testis and in Testis Cancer

A method of cellular digestion known as Etching facilitated scanning electron microscopy (SEM) of the connective tissue framework in normal testis and in cases of testis cancer. The collagen in the seminiferous tubules in normal testis has distinct lamellae and a well-defined outer border. In the germ cell tumours examined, the tubular connective tissue appeared hypertrophied, the distinct outer border was maintained in a seminoma specimen unlike in a case of non-seminoma. In a specimen of non-germ cell lymphoma there was gross distortion of the tubular connective tissue. These apparent variations in the collagen framework may have implications regarding local tumour development.

Oncogenes in human testicular cancer: DNA and RNA studies

Oncogene dosage and expression were studied in 16 testicular neoplasms, 14 of germ cell and two of non-germ cell origin. In comparison with normal DNA, tumour DNA of a total of eight patients (seven with germ cell neoplasm and one with testicular lymphoma) showed increased dosages of KRAS2, PDGFA, EGFR, MET and PDGFB. The most frequent (occurring in six tumours) and prominent (up to 3-4-fold) increases were detected in the dosages of KRAS2 (on chromosome 12p) and PDGFA (chromosome 7p), relative to a reference locus from chromosome 2. Importantly, there was a similar increase in 12p dosage in general in these tumours, suggesting the presence of the characteristic isochromosome 12p marker. On the contrary, possible 7p polysomy (assessed by molecular methods) did not explain the PDGFA (or EGFR) changes in all cases. NRAS, MYCN, CSFIR, MYB, MYC, ABL, HRASI, TP53, and ERBB2 did not reveal any consistent alterations in tumour DNA. In RNA dot blot assays the expression of KRAS2, PDGFA, EGFR, or MYC was generally not increased in the tumour samples when compared to that in normal testicular tissue of the same patients although there was interindividual variation in mRNA levels. It thus appears that while oncogene dosage changes occur in a proportion of testis cancers, they are often part of changes in large chromosomal regions or whole arms and are seldom accompanied by altered expression.

Mediastinal germ cell tumor with secondary nongerm cell malignancy, and extensive hematopoietic activity: Pathology, DNA-ploidy, and karyotyping

We report on a malignant germ cell tumor located in the anterior mediastinum. After chemotherapy the tumor was classified as residual teratoma with sarcomatous components. There was extensive hematopoiesis in the tumor tissue. The tumor cells had a modal chromosome number of 76; the only structural abnormality was a deletion of the long arm of chromosome 9. An i(12p) chromosome was lacking in this tumor. Karyotyping of peripheral blood and bone marrow occasionally showed metaphases with numerical and structural abnormalities, probably related to chemotherapy. The patient died within two years after the initial diagnosis, of a poorly differentiated hematopoietic malignancy, probably of myelomonocytic origin, based on morphology and the fact that non-specific esterase activity was demonstrated in the tumor cells. The karyotype of this malignancy was highly abnormal, but unrelated to that of the mediastinal malignant GCT. In this case there is no proof that the secondary malignancy was derived from the primary mediastinal malignant GCT. In view of the multiple aneuploid stem lines in the primary tumor, this possibility cannot be dismissed either.

Non-germ cell tumors of testis

Testicular tumors of non-germ cell origin represent from 5 percent to 10 percent of all testicular neoplasms. Included in this group are sex cord/gonadal stromal tumors, most originating from Leydig or Sertoli cells, mixed tumors, and tumors of mesenchymal or hematopoietic origin. In addition, various miscellaneous lesions, tumor-like conditions, and secondary testicular tumors may be classified as non-germ cell tumors. This review covers the presentation, diagnosis, and treatment of these rare lesions.

Testicular tumors in infancy and childhood—a review of 10 germ cell tumors and 10 non-germ cell tumors : P. Frey, C. Fliegel, and B. Herzog. Z Kinderchir 45:229–234, (August), 1990

Testicular tumors in infancy and childhood—a review of 10 germ cell tumors and 10 non-germ cell tumors : P. Frey, C. Fliegel, and B. Herzog. Z Kinderchir 45:229–234, (August), 1990

BOP/VIP - A new platinum-intensive chemotherapy regimen for poor prognosis germ cell tumours

Ninety-one patients with poor prognosis non-seminomatous germ cell tumours (NSGCT) were treated with an initial intensive chemotherapy schedule. Suitable patients fulfilled one or more of the following criteria: lymph node metastases greater than 10 cm diameter; liver, brain or bone metastases; serum HCG level greater than 50,000 IU/L; and extragonadal primary tumours. Treatment consisted of 3 cycles of bleomycin, vincristine and cisplatin (BOP) administered at 10 day intervals, followed by 3 cycles of etoposide, ifosfamide and cisplatin (VIP) at 21 day intervals. A total of 64 patients (70%) achieved a complete remission. This comprised 46 patients who received BOP/VIP only, and 18 patients who received additional chemotherapy after BOP/VIP. Of these 64 patients, 51 underwent complete surgical resection of residual masses, including 11 in whom there was evidence of teratoma with cellular atypia or non-germ cell cancer in the resected tissue. A further 9 patients had persisting unresected radiological masses in the presence of marker complete remission. The overall response rate was 80%. Currently 57 patients (63%) remain alive and free from disease progression. The median follow-up period is 90 weeks (range 24-206 weeks), with a 2 yr actuarial progression-free survival of 66% (95% c.i. 55-77%). Major toxicity was myelosuppression, occurring during the VIP arm of therapy, with a median nadir WBC of 1.1 x 10(9)/L and median platelet count of 51 x 10(9)/L. Other toxicity included peripheral neuropathy (WHO Grade 2 and 3 in 22%). We conclude that treatment results with the BOP/VIP schedule in this poor prognosis patient group are at least comparable with other schedules, and toxicity is manageable.(ABSTRACT TRUNCATED AT 250 WORDS)

Rhabdomyosarcoma of the Testicular Appendage

This is a case report of embryonal rhabdomyosarcoma of the epididymal appendage in a 15-month old infant. It is a rare tumor with a good prognosis when treated promptly. The ultrasound examination showed the testicle to be enlarged but hypo-echoic in comparison to the epididymis which was infiltrated with tumor. An inflammatory mass or enlargement of a testicle demands careful diagnosis and appropriate therapy with immediate referral to a urologist if the normal clinical course deviates. Representative images are included. Rhabdomyosarcoma of the testicle or extra testicular scrotal structures is rare. A report in 1983 by Kage et al from Japan revealed two cases of the tumor, however, both were in adult males. This case report is an embryonal rhabdomyosarcoma in a fifteen month old infant which presented with a confusing clinical picture. This case is presented in an effort to alert the clinician to the possibility of a rare, non-germ cell tumor presenting as an inflammatory lesion.

Pineal and CNS germ cell tumors: royal marsden hospital experience 1962–1987

A retrospective analysis has been made of all patients with pineal and CNS germ cell tumors who were treated at the Royal Marsden Hospital between 1962–1987. A total of 67 new cases were seen: 17 had initial histological verification of tumor type and the remainder were tested for radiosensitivity with a dose of 20 Gy following a shunting procedure. Patients with germ cell or radiosensitive tumors were treated with a uniform policy of whole neuraxis radiotherapy giving 50 Gy to the local tumor and 30 Gy to the remaining brain and spinal cord. Nonresponding lesions continued with local fields to a dose of 50 Gy. Patients were divided into three groups (a) germinoma and radiosensitive tumours, 34 cases; (b) malignant teratoma, 12 cases; (c) non-germ cell, 21 cases. Median follow-up is 83 months (range 2–246 months). Overall and cause specific actuarial 5/10 year survival were for group 1, 81.7%/69.4% and 86.5%/86.5%; group 2, 18.2%/18.2% and 18.2%/18.2%, and group 3, 64.3%/46.8% and 64.3%/52.6%, respectively. No patient in group 1 treated during the last 12 years has recurred. Univariate analysis of factors at presentation, showed that neurological performance status if(p (001) as well as tumor type if(p <001) correlated with outcome. Recurrence was confined to the primary site in only 1 of 4 patients in group 1 compared to 6 of 9 patients in group 2 and 9 of 10 patients in group 3. No isolated spinal recurrence occurred in group 1 patients. A total of eight patients have received platinum containing chemotherapy for recurrence (6 cases) or adjuvant therapy (4 cases). Germinomas appear to respond better than teratomas, all of which have recurred rapidly following initial partial response. Shunting and radiosensitivity testing remains the treatment of choice for tumors compatible with germinoma. Craniospinal irradiation is associated with low morbidity providing spinal growth is complete and is recommended in older patients as salvage following spinal recurrence is unsatisfactory. Aggressive combined modality approaches with surgery, radiotherapy and chemotherapy need to be investigated to improve results in CNS teratoma.

Second non-germ cell malignancies after radiotherapy of testicular cancer with or without chemotherapy

The incidence of a new primary non-germ cell malignancy was determined in 876 patients with testicular cancer treated at the Norwegian Radium Hospital from 1956 to 1977. Sixty-five patients developed a second cancer leading to a statistically significant increased relative risk (RR = 1.58), especially if extended radiotherapy had been given (RR = 4.13). The excess risks of developing lung cancer and malignant melanoma were 2.03 and 3.89, respectively. Increased RR for these two cancer types were seen both after extended radiotherapy and after radiotherapy combined with chemotherapy. Studies of the time between treatment and secondary lung cancer indicated that the development of the new lung cancer could be partly treatment related, whereas the raised incidence of malignant melanoma may be related to the frequent health checks performed in patients with testicular cancer. Patients who had received extended radiotherapy were also at an increased risk of developing cancer of the stomach and of the colon. Three cases of acute leukaemia were observed more than 5 years after treatment, all of them in patients who had received abdominal radiotherapy only. It is concluded that patients apparently cured of a testicular cancer have an increased risk of developing a new treatment related non-germ cell malignancy, in particular lung cancer. The application of the extended radiotherapy or the combination of radiotherapy and chemotherapy containing alkylating drugs should be avoided in order to reduce this excess risk.

Cytogenetic and Immunohistochemical Evidence for the Germ Cell Origin of a Subset of Acute Leukemias Associated With Mediastinal Germ Cell Tumors

Most acute leukemias occurring in patients with mediastinal germ cell tumors (MGCTs) appear to be primary rather than therapy-related; however, no data have been obtained to date to confirm the hypothesized germ cell origin of the leukemias in this syndrome. We identified six male patients with this syndrome treated at Memorial Sloan-Kettering Cancer Center: in all six, the leukemia was studied immunohistochemically for various hematologic and germ cell antigens; in four, the karyotype of the leukemia was available; in one, the MGCT had also been karyotyped. In three patients, we found evidence of a germ cell origin of the acute leukemias. A 19-year-old male developed an acute myeloblastic leukemia 11 months after presenting with an MGCT; karyotypes of the two tumors showed them to be clonally related, both showing an i(12p), a cytogenetic marker of germ cell tumors. A 16-year-old male with probable Klinefelter's syndrome presented simultaneously with acute monocytic leukemia and an MGCT; although the MGCT was not karyotyped, the leukemia showed an i(12p). A 23-year-old male developed concurrently an MGCT and acute myelomonocytic leukemia; the leukemia cells coexpressed myelomonocytic antigens (HAM56, My4, My9) and cytokeratin, suggesting dual differentiation, myeloid and germ cell. Evidence for a germ cell origin of the acute leukemias in the three other patients was not obtained, although in all three the MGCT and the leukemia occurred simultaneously, supporting an etiologic relationship. Hence, these leukemias may represent another form of non-germ cell malignancy developing in germ cell tumors. All patients died of the leukemia, with a median survival of less than 2 months. This syndrome may be a useful pathologic model for the study of germ cell differentiation and hematopoietic ontogeny.

Hepatoid adenocarcinoma: A distinctive histological subtype of alpha-fetoprotein-producing lung carcinoma

Seven cases of alpha-fetoprotein (AFP)-producing lung carcinoma were studied histologically to determine whether they fell into any previously described category. The patients were all males from 40 to 73 years of age and their serum AFP levels ranged from 1039 to 320,000 ng/ml. Five cases of hepatoid adenocarcinoma, one case of endodermal sinus tumour, and one case of papillary adenocarcinoma were found. The possible origins of the tumours and their differential diagnosis are discussed. Hepatoid adenocarcinoma is a major histological category among AFP-producing lung carcinoma; other types are less frequent. The occurrence of hepatoid adenocarcinoma in both the stomach and the lung suggests that this neoplasm may also be seen in other organs of endodermal origin. It may be a major histological subtype of AFP-producing endodermal neoplasms of non-germ cell origin.

Tumours in Iceland. 13. Malignant tumours of the testis

Data from 76 patients with malignant tumours of the testis registered with the Icelandic Cancer Registry during the period 1955-1984 were analyzed and classified histologically according to the WHO criteria. In 55 patients the tumours were of one histological type (72% of total). In the order of frequency, seminoma was diagnosed in 35 (46%), embryonal carcinoma in 14 (18%) and teratoma in 6 patients (8%). Twenty patients had tumours of more than one histological type (26%), i.e. a combination of embryonal carcinoma and teratoma (teratocarcinoma) in nine (12%) and combined tumours (seminoma component with other tumours) in seven (9%). Two patients had choriocarcinomas and three had yolk sac (endodermal sinus) tumours, both of them in combination with other neoplasms. Embryonal rhabdomyosarcoma was the only malignant non-germ cell tumour diagnosed. The age-adjusted incidence of malignant testis tumours increased by 48% from 1.6 per 100,000 per annum in 1955-1964 to 3.1 per 100,000 in 1975-1984. The increase affected both seminoma and non-seminomatous tumours (NSGCT). There has been an improvement in survival with time. Sixteen deaths were related to testis tumours and all occurred within four years of diagnosis. The incidence of testicular tumours in Iceland is intermediate between "high risk" and "low risk" countries.

Radiotherapy for testicular seminoma stage I: treatment results and long-term post-irradiation morbidity in 365 patients.

After infradiaphragmatic radiotherapy the cancer-related 10 year survival was 99% in 365 patients with seminoma Stage I referred to the Norwegian Radium Hospital between 1970 and 1982. Thirteen patients relapsed, 11 of them within the first 3 years after treatment. Nine of the recurrent patients were cured by radiotherapy alone (4) or in combination with chemotherapy (5). There is no need to include the inguinal lymph nodes into the irradiation field or to give scrotal irradiation, not even to patients with tumor infiltration beyond the testicular tissue, or to those with prior scrotal or inguinal surgery. At least 1 year after radiotherapy moderate or more severe dyspepsia was observed in 16 patients. Nine patients developed a peptic ulcer. In general, there was no increased risk for development of a second non-germ cell cancer after radiotherapy. However, 4 patients developed a pulmonary cancer indicating a border-line significance of increased risk for this type of malignancy. (p:0.05). In conclusion, infradiaphragmatic radiotherapy remains the optimal routine treatment in seminoma patients with Stage I.