These germ cell neoplasms share histological similarity to the tumors which occur in the ovaries and testis. The prognosis is determined by the mix of different histologic subtypes as well as the location and stage of the tumor.
Germ Cell Tumors-Ovaries
Germ Cell Tumors-Testis
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE MEDIASTINAL TUMORS
Germ-cell tumors of the mediastinum.
Department of Pathology, University of California, San Francisco 94143, USA.
Semin Diagn Pathol 1999 Feb;16(1):42-50 Abstract quote
Mediastinal germ-cell tumors (GCTs) usually occur within the anterior mediastinum, accounting for about 15% of all mediastinal cysts and tumors. They are associated with the thymus, presumably arising from extragonadal germ cells or thymic cells with germ-cell potential.
Mediastinal seminoma develops primarily in young males with rare cases reported in females; likewise, embryonal carcinoma, endodermal sinus tumor or yolk-sac tumor, choriocarcinoma, and malignant mixed or combined GCTs also overwhelmingly affect males. Mature cystic teratoma affects males and females equally. The prognosis for mediastinal mature cystic teratoma and seminoma is very good.
Nonseminomatous malignant GCTs of the mediastinum often present with advanced disease and do not respond as well to chemotherapy as their gonadal counterparts. Nonetheless, it is important to separate mediastinal GCTs from other undifferentiated malignant tumors, especially thymic carcinoma, which has a poor prognosis. Clearly, some patients with mediastinal GCTs respond very well to modern therapies.
DISEASE ASSOCIATIONS CHARACTERIZATION HEMATOLOGIC DISORDERS
Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors.
Hartmann JT, Nichols CR, Droz JP, Horwich A, Gerl A, Fossa SD, Beyer J, Pont J, Fizazi K, Einhorn L, Kanz L, Bokemeyer C.
Tuebingen University Medical Center II, Germany
J Natl Cancer Inst 2000 Jan 5;92(1):54-61 Abstract quote
BACKGROUND. The association between primary germ cell tumors of the mediastinum (the space between the lung pleura that contains the heart and other chest viscera) and hematologic malignancies has been described by retrospective analysis of patients treated at individual clinical centers. To better characterize the risk of hematologic disorders in patients with extragonadal germ cell tumors and to describe the clinical and biologic features of the disorders, we studied an unselected population in a large, international, multicenter database.
METHODS. Six hundred thirty-five patients treated at 11 centers in the United States and Europe from 1975 through 1996 were evaluated retrospectively.
RESULTS. A hematologic disorder was observed in 17 patients with germ cell tumors. All cases developed among the 287 patients with primary mediastinal nonseminomatous germ cell tumors, giving an incidence rate in this group of 2.0% (95% confidence interval [CI] = 1.1%-3.1%) per year over a median follow-up time of 3 years. The risk of developing hematologic disorders was statistically significantly increased in patients with primary mediastinal nonseminomatous germ cell tumors in comparison with the age-matched general population (standardized incidence ratio = 250; 95% CI = 140-405). The median time to onset of hematologic neoplasia was 6 months (range, 0-47 months), and the median survival after diagnosis of the hematologic disorder was 5 months (range, 0-16 months) (two-sided P<.0001, comparing survival from the time of diagnosis of the germ cell tumor of patients with and without hematologic disorders).
CONCLUSION. In our study, approximately one in 17 patients with primary mediastinal nonseminomatous germ cell tumors was affected by a hematologic disorder, whereas no cases were seen among 334 patients with other extragonadal germ cell tumors. The hematologic disorder had a statistically significant impact on prognosis, with none of the 17 reported patients surviving for more than 2 years.
GONADAL GERM CELL TUMOR
Metachronous gonadal and extragonadal primary germ cell tumors: two case reports.
Cancer Center of Boston, Massachusetts 02120.
Cancer Invest 1994;12(4):406-8 Abstract quote
Bilateral synchronous or metachronous germ cell tumors (GCT) of the testis are recognized in 2-3% of patients.
Extragonadal GCT in the mediastinum or the retroperitoneum have been rarely reported in patients with primary GCT of the testes. Two patients were observed with two separate primary GCT; in 1 a retroperitoneal embryonal carcinoma was successfully treated with chemotherapy and surgery and a new primary developed 14 years later in the testicle as a seminoma. A second patient had a primary teratocarcinoma of the testes treated with surgery only; 4 years later he developed a mediastinal endodermal sinus tumor, which was fatal.
These cases suggest that not only is the remaining testicle at risk for a second primary GCT, but also that extragonadal sites impose a similar risk and monitoring of patients should consider all potential sites for the development of GCT.
INTRATUBULAR GERM CELL NEOPLASIA OF THE TESTIS
Primary mediastinal germ cell tumor with intratubular germ cell neoplasia of the testis--further support for germ cell origin of these tumors: a case report.
Cancer 1997 Sep 1;80(5):1007-8 THYMIC CYST
Multilocular thymic cyst associated with mature mediastinal teratoma: a report of 2 cases.
Rakheja D, Weinberg AG.
Department of Pathology, The University of Texas Southwestern Medical Center, DallasTex 75235, USA.
Arch Pathol Lab Med. 2004 Feb;128(2):227-8. Abstract quote
Acquired thymic cysts are multilocular and show florid xanthomatous and myofibroblastic inflammation. They usually occur in association with mediastinal neoplasms, systemic autoimmune diseases, or trauma.
We describe 2 cases (in a 12-year-old girl and an 11-year-old boy) of acquired thymic cysts occurring in association with cystic teratomas, an association that to our knowledge has not been described previously in the literature.
PATHOGENESIS CHARACTERIZATION Primitive rests of germ cells These germ cells may be distibuted through the midline and may give rise to these tumors
CHARACTERIZATION RADIOLOGIC LABORATORY MARKERS
Tumour antigens associated with primary mediastinal choriocarcinoma.
Forest JC, Talbot J, Page M, Loiselle JM.
Can Med Assoc J 1977 Dec 17;117(12):1386-8 Abstract quote
Various biochemical markers of cancer were investigated in two men aged 26 and 45 years with primary mediastinal choriocarcinoma.
The daily excretion of urinary human chorionic gonadotropin (HCG) and the serum concentration of the beta-subunit of HCG were elevated in both patients, but carcinoembryonic antigen, Regan isoenzyme, alpha1-fetoprotein, serum pregnancy-associated globulin and human chorionic somatomammotropin were not detectable.
Comparison of the results of the investigation of biochemical markers of this rare neoplasm in these two men with those published previously illustrates the discordance in the expression of biochemical markers of primary mediastinal choriocarcinoma.
Primary mediastinal malignant germ cell tumour. Single institution experience in Chinese patients and correlation with specific alpha-fetoprotein bends.
Chan AT, Ho S, Yim AP, Chang AR, Cheng P, Yuen J, Leung TW, Johnson PJ.
Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Acta Oncol 1996;35(2):221-7 Abstract quote
Ten Chinese patients were reviewed, all with mediastinal germ cell tumours and treated in our centre during the past 8 years.
Three patients with pure seminomas were given chemotherapy with or without radiotherapy. AB achieved complete remission with no relapse. Seven patients with non-seminomatous germ cell tumours (NSGCT) were given chemotherapy, with or without surgery. Two patients with rapid decay of alpha-fetoprotein (AFP) levels (half-life less than or equal to 7.2 days) during chemotherapy achieved complete remission with no relapse. Five patients with prolonged decay of AFP levels (half-life > 7.2 days) failed to achieve complete remission with initial chemotherapy and all but one patient died between 5 and 9 months later. One patient developed acute megakaryocytic leukaemia. Using isoelectric focusing, AFP bands specific to NSGCT were quantified, and comparison was made with the total AFP in five cases.
In each case the change in NSGCT-specific AFP concentration in response to therapy closely paralleled that of total AFP. Estimation of NSGCT-specific AFP offers no apparent advantage in monitoring disease response or progression.
CHARACTERIZATION GENERAL VARIANTS INTRACRANIAL
Intracranial germ cell tumors in children with and without Down syndrome.
Chik K, Li C, Shing MM, Leung T, Yuen PM.
Department of Pediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin NT.
J Pediatr Hematol Oncol 1999 Mar-Apr;21(2):149-51 Abstract quote
PURPOSE: Two Chinese children with Down syndrome affected by intracranial germ cell tumors are described. Because they represent two of eight affected patients in the current series from 1990 to 1996, it is postulated that such occurrence may be more than a coincidental event.
PATIENTS AND METHODS: Two children with Down syndrome developed germ cell tumors in atypical intracranial sites that affected basal ganglion and cerebellum. The pathology showed germinoma and yolk sac tumor, respectively. These were treated by radical surgical resection and chemotherapy with cisplatin, etoposide, and bleomycin, but without radiotherapy.
RESULTS: One patient survived 3 years without radiologic evidence of tumor. The other died from infective complications caused by severe myelosuppression after chemotherapy.
CONCLUSIONS: Subtle neurologic manifestations in developmentally handicapped patients with intracranial space-occupying lesions could result in delayed diagnosis. Children with Down syndrome suffering from brain tumors may have a higher chance for germ cell tumors. Assay for alpha-fetoprotein and beta-human chorionic gonadotrophin could hasten diagnosis in some cases. This observation and review of literature suggest an increased risk of developing intracranial germ cell tumors in subjects with Down syndrome.
Primary prostatic endodermal sinus tumor (yolk sac tumor) combined with a small focal seminoma.
Han G, Miura K, Takayama T, Tsutsui Y.
Am J Surg Pathol 2003 Apr;27(4):554-9 Abstract quote
We report on a primary endodermal sinus tumor (EST) (yolk sac tumor) combined with a focal seminoma of the prostate occurring in a 24-year-old man.
The prostate was widely infiltrated with neoplasms that penetrated the capsule and invaded into the bladder wall and urethra. Most areas of the tumor were composed of papillary and glandular epithelium in the fibrous or myxoid stroma. Schiller-Duval bodies and periodic acid-Schiff-positive hyaline bodies were focally present. In addition to yolk sac tumor, solid nests of seminoma were found in some areas.
Immunohistochemistry using specific antibodies for alpha-fetoprotein and cytokeratin showed positive reaction on the EST portion, and placental alkaline phosphatase revealed positive staining in the seminoma portion and a part of EST. Tumor cells exhibited negative staining for prostate-specific antigen, prostatic acid phosphatase, carcinoembryonic antigen, vimentin, chromogranin A, and human chorionic gonadotropin. Despite radical surgery and ordinary cisplatin-based chemotherapy, the patient died 8 months after operation. At autopsy, only EST elements had metastasized to the lungs, liver, and brain, and no tumors were found in either testis.
To our knowledge, this is the first reported case of a primary EST combined with a focal seminoma in the prostate.
- Retroperitoneal Seminoma in Limited Biopsies: Morphologic Criteria and Immunohistochemical Findings in 30 Cases.
Sung MT, Maclennan GT, Cheng L.
*Departments of *Pathology and Laboratory Medicine section signUrology, Indiana University School of Medicine, Indianapolis, IN daggerDepartment of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan double daggerDepartment of Pathology, Case Western Reserve University, Cleveland, OH.
Am J Surg Pathol. 2006 Jun;30(6):766-773. Abstract quote
The incidence of retroperitoneal seminoma is much less than that of its gonadal counterpart. Accurate diagnosis of retroperitoneal seminoma is critical, because it carries an excellent prognosis due to its favorable response to radiation therapy and/or cisplatin-based chemotherapy. However, correctly diagnosing a retroperitoneal seminoma may be challenging, especially when the biopsy material is limited.
The present study was conducted to evaluate histologic findings and immunohistochemical staining patterns in biopsy specimens of retroperitoneal seminoma and to compare their utility as diagnostic tools. Thirty biopsy specimens of retroperitoneal seminoma were assessed for histologic characteristics and immunohistochemical expression of OCT4, c-kit, placental-like alkaline phosphatase, and cytokeratin AE1/AE3. The clinical information, morphologic features, and staining intensities and the percentages of positively staining tumor cells were analyzed. The mean age of patients was 38 years. Lymphocytic infiltration and nucleolar prominence in tumor cells were found in all 30 cases (100%). The incidence of other histologic characteristics were as follows: fibrous septa/stroma in 80% (24 cases), clear tumor cell cytoplasm in 70% (21 cases), tumor necrosis in 60% (18 cases), cellular pleomorphism in 53% (16 cases), granulomatous inflammation in 50% (15 cases), distinct cell borders in 46% (14 cases), intercellular edema in 23% (7 cases), and syncytiotrophoblasts in 3% (1 case). The mean mitotic count was 3 (range 0 to 15) per 10 high-power fields. All 30 cases (100%) of retroperitoneal seminoma revealed moderate to strong nuclear OCT4 staining in more than 50% of tumor cells. Twenty-one cases (70%) showed membranous expression of c-kit by tumor cells, with moderate to strong staining intensity in most cases.
Variable degrees of staining for placental-like alkaline phosphatase were identified in 23 cases (77%) with occasional background staining artifact. Six cases (20%) displayed a positive cytokeratin AE1/AE3 staining pattern with weak to moderate intensity.
In conclusion, the most common histologic findings in limited biopsy specimens of retroperitoneal seminoma were lymphocytic infiltration and nucleolar prominence in tumor cell nuclei. OCT4 immunostaining, with its superior sensitivity and easy interpretation compared with other markers, is a powerful tool for confirming the diagnosis of retroperitoneal seminoma.
Primary Thyroid Teratomas in Children: A Report of 11 Cases With a Proposal of Criteria for Their Diagnosis.
Riedlinger WF, Lack EE, Robson CD, Rahbar R, Nose V.
From the Departments of *Pathology, double daggerRadiology, and section signOtolaryngology, Children's Hospital Boston, Harvard Medical School, Boston, MA; daggerDepartment of Pathology, Washington Hospital Center, Washington, DC; and parallelDepartment of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2005 May;29(5):700-706. Abstract quote
Cervical teratomas are uncommon neoplasms, although the commonest neck tumors in newborns and infants. Presence of associated thyroid tissue often causes speculation as to the site of origin, ie, arising from within thyroid, adjacent soft tissue with secondary involvement of thyroid, or as innate part of a cervical teratoma.
Twenty-eight cases of cervical teratomas were identified over 75 years, including 11 cases containing associated thyroid tissue. Clinical history, treatment, and follow-up were reviewed and the neoplasms analyzed regarding location, size, degree of maturity, and relative arrangement of thyroid and other tissues. All thyroid teratomas were congenital, measured 3.5 to 13.5 cm in diameter (median size, 6.9 cm), and were resected.
Follow-up ranged from 1 to 45 years (median, 17 years) without recurrent disease in any patient. Neuroglial tissue predominated in 10 of 11 tumors. Intimate admixture of thyroid and other tissues with or without surrounding fibrous pseudocapsule was present in 8 cases, suggesting thyroid as origin.
Histologic immaturity in congenital thyroid teratomas is not the harbinger of adverse behavior as seen in adolescents and adults. Intimate intermingling of thyroid tissue with teratoma and presence of a pseudocapsule seem to be the most significant criteria for establishing thyroid as origin.
Primary yolk sac tumor of the urachus.
Huang HY, Ko SF, Chuang JH, Jeng YM, Sung MT, Chen WJ.
Department of Pathology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University, Kaohsiung, Taiwan.
Arch Pathol Lab Med 2002 Sep;126(9):1106-9 Abstract quote
Pure yolk sac tumor is the most common malignant gonadal tumor of infants and toddlers. However, the majority of extragonadal germ cell tumors in the midline are either seminomas (germinomas) or teratomas, and pure yolk sac tumors account for only a small fraction of these lesions. To date, only 1 primary urachal pure yolk sac tumor has been reported in the literature.
We describe another case, occurring in a 7-month-old male infant who presented with a rapidly enlarging intra-abdominal tumor with marked engorgement of the superficial venous plexus around the umbilicus. With periodic follow-up for 3 years following surgical extirpation of the tumor and adjuvant chemotherapy, this patient is still alive without evidence of disease. Notably, the glandular elements predominating in the frozen sections resulted in the initial misdiagnosis of the tumor as a urachal adenocarcinoma, although the entirely resected specimen revealed typical histologic patterns and Schiller-Duval bodies. Immunohistochemistry showed that the tumor cells were diffusely reactive to alpha-fetoprotein, alpha(1)-antitrypsin, and cytokeratin. Tumor cells were negative for p53 protein, but revealed overexpression for MDM2 protein. Flow cytometry demonstrated a diploid DNA content with S-phase being as high as 55.36%.
This case emphasizes that pure yolk sac tumor can occur primarily in the remnant of the urachus in young children.
Primary endodermal sinus tumor of the endometrium. A clinicopathologic, immunocytochemical, and ultrastructural study.
Joseph MG, Fellows FG, Hearn SA.
Department of Pathology, St. Joseph's Health Centre, London, Ontario, Canada.
Cancer 1990 Jan 15;65(2):297-302 Abstract quote
We report a case of primary endodermal sinus tumor (EST) of the endometrium in a 42-year-old female. Although numerous extragonadal EST have been reported, primary EST of the endometrium is exceedingly rare.
To our knowledge this is the fourth documented case of this nature. The tumor had the typical microscopic features of EST, with papillary, tubular, reticular, and solid growth patterns; occasional Schiller-Duval bodies and many intracellular and extracellular periodic-acid Schiff positive hyaline globules were seen. The neoplastic cells stained positively for alpha-fetoprotein (AFP), alpha-1-antitrypsin (A1AT), cytokeratin, and placental alkaline phosphatase. The globules were positive for AFP, A1AT, albumin, transferrin, and fibronectin. The tumor cells were negative for type IV collagen and the beta subunit of human chorionic gonadotropin (B hcG). Electron microscopic examination showed intracellular and extracellular basement membrane-like material, intracytoplasmic lumina with microvilli, and glycogen.
The patient was treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by four cycles of adjunct chemotherapy (vinblastine, bleomycin, and cisplatinum) repeated every 3 weeks. The serum AFP level was elevated significantly before the surgery and the tumor response was monitored by serial determination of serum AFP level. There was no evidence of recurrence 24 months after surgery.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Fine-needle aspiration biopsy of nonteratomatous germ cell tumors of the mediastinum.
Chhieng DC, Lin O, Moran CA, Eltoum IA, Jhala NC, Jhala DN, Simsir A.
Department of Pathology, University of Alabama at Birmingham, USA.
Am J Clin Pathol 2002 Sep;118(3):418-24 Abstract quote
We assessed the usefulness of fine-needle aspiration biopsy (FNAB) in the diagnosis of mediastinal germ cell tumors (GCTs). In the archives of 3 pathology departments, we found records of 7 patients with mediastinal GCTs who underwent mediastinal FNAB as part of the diagnostic workup.
The FNAB smears, results of the immunocytochemical analysis, the corresponding histologic findings, and the clinical charts were reviewed. All patients were men (age range, 24-44 years; mean, 32 years). One patient had a history of testicular mixed GCT 10 years earlier. The 6 primary mediastinal GCTs consisted of 3 seminomas and 3 yolk sac tumors. Based on the cytologic features and immunocytochemicalfindings, a cytologic diagnosis of GCT was made in 5 cases, including the case of metastatic GCT In 2 cases, the differential diagnosis was between poorly differentiated carcinoma and GCT Results of ancillary studies were noncontributory in 1 case, and the aspirate of the second case demonstrated extensive necrosis.
Our findings demonstrate that a diagnosis of mediastinal GCT, primary or secondary, can be established with a high degree of accuracy on the basis of FNAB. Immunocytochemical analysis helps confirm the diagnosis.
Primary mediastinal choriocarcinomas: a clinicopathologic and immunohistochemical study of eight cases.
Moran CA, Suster S.
Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA
Am J Surg Pathol 1997 Sep;21(9):1007-12 Abstract quote
Primary choriocarcinoma of the anterior mediastinum is by far the rarest and most controversial form of extragonadal germ cell tumor. A clinicopathologic study of eight primary mediastinal neoplasms bearing the histopathologic and immunohistochemical features of choriocarcinoma is presented.
The patients were all men between the ages of 21 and 63 years (mean, 42 years). Clinical symptoms included shortness of breath, chest pain, cough, and superior vena cava syndrome; one patient also had gynecomastia. All patients presented with large anterior mediastinal masses on chest radiographs that measured an average of 10 cm in greatest diameter. Grossly, the tumors were described as large, soft, extensively hemorrhagic, and with foci of necrosis.
Histologically, they were characterized by a dual cell population composed of cytotrophoblastic cells with uniform, round nuclei, clear cytoplasm, and prominent nucleoli admixed with large, multinucleated syncytiotrophoblastic cells with bizarre nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. Immunohistochemically, the tumors were notable for strong keratin and beta-human chorionic gonadotropin (HCG) positivity. Seven patients presented at the time of diagnosis with thoracic and extrathoracic (liver, adrenal, kidney, and spleen) metastases. In one case, the tumor was entirely confined to the mediastinum. All patients died over a period of 1 to 2 months. Complete autopsies were performed in all cases; none of the patients showed evidence of a testicular tumor or scar after thorough examination of the testes on serial sectioning.
The present cases demonstrate the widespread distribution of germ cells in the human body and lend further support to the existence of primary extragonadal choriocarcinoma arising in the thymic region.
ENDODERMAL SINUS TUMOR
Endodermal sinus tumor of the mediastinum.
Kuzur ME, Cobleigh MA, Greco FA, Einhorn LH, Oldham RK.
Cancer 1982 Aug 15;50(4):766-74 Abstract quote
Endodermal sinus tumor (EST) of the mediastinum is a rare germ-cell neoplasm affecting mainly young adult males. Ten patients with EST were treated with a multimodality approach that included surgery, chemotherapy, and radiotherapy. All patients had relapses after achieving a transient response except one who is still in complete remission more than five years following the diagnosis of the disease. Optimal therapy for this neoplasm has yet to be discovered.
The disease is a subset of extragonadal germ cell tumors which appears to be lethal in most cases, particularly when the primary tumor is unresectable. The first case of five-year disease-free survival is described
MALIGNANT NON-GERM CELL ELEMENTS
Occurrence of malignant non-germ cell components in primary mediastinal germ cell tumours.
Kolodziejski L, Duda K, Niezabitowski A, Dyczek S, Staniec B.
Centre of Oncology, Cracow, Poland.
Eur J Surg Oncol 1999 Feb;25(1):54-60 Abstract quote
METHODS: Thirty-five patients with primary mediastinal germ cell tumours (PMGCT) underwent primary thoracotomy in a 30-year period (1965-1994). Of the 35 patients, 12 had benign teratomas, five pure seminomas and 18 non-seminomatous germ cell tumours.
RESULTS: Out of 18 non-seminomatous germ cell tumours, 14 comprised more than one malignant component. In two cases malignant teratomas had an additional malignant non-germ cell component: one a mixed sarcomatous component and the other a neuroendocrinal component. There were different methods of treatment between 1965 and 1994. All but one of patients with seminomas survived for 5 years. Among 18 patients with malignant PMGCT, all but two died within 5 years (mean survival rate was 15 months).
CONCLUSIONS: When planning treatment of patients with malignant PMGCT we have to take into account the fact that malignant non-germ-cell components may occur. In this circumstances, surgical resection after initial chemotherapy is recommended.
- Primary Mediastinal Seminoma: A Comprehensive Assessment Integrated With Histology, Immunohistochemistry, and Fluorescence In Situ Hybridization for Chromosome 12p Abnormalities in 23 Cases.
*Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan †Department of Pathology, Case Western Reserve University, Cleveland, OH ‡Department of Pathology, Cordoba University, Cordoba, Spain Departments of §Pathology and Laboratory Medicine ¶Urology, Indiana University School of Medicine, Indianapolis, IN ∥Institute of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy.
- Am J Surg Pathol. 2008 Jan;32(1):146-155. Abstract quote
Accurate diagnosis of mediastinal seminoma is critical because of its favorable response to radiation therapy and/or cisplatin-based chemotherapy. Immunohistochemical staining for OCT4 has recently been validated as a powerful tool for detecting gonadal seminoma. However, discrepancies between the genetic alterations and immunoprofiles of mediastinal and testicular seminomas have been reported, raising the question of whether techniques that are useful in the diagnosis of gonadal seminoma are applicable to its mediastinal counterpart.
The present study was conducted to evaluate the morphologic and immunohistochemical characteristics and chromosomal abnormalities of 12p in 23 primary mediastinal seminomas and to compare their applicability as diagnostic tools. Dual-color fluorescence in situ hybridization (FISH) analyses for chromosome 12p and immunostains for OCT4, c-kit, placental-like alkaline phosphatase, CD30, and a panel of cytokeratins, including cytokeratin AE1/AE3 (AE1/3), high molecular weight cytokeratin (34betaE12, HMWCK), CAM5.2, cytokeratin 7 (CK7), cytokeratin 20 (CK20), and epithelial membrane antigen were performed. Lymphocytic infiltration was found in all 23 cases (100%). The incidence of other histologic characteristics were as follows: fibrous septa/stroma (21 cases, 91%), prominent tumor cell nucleoli (21 cases, 91%), clear tumor cell cytoplasm (20 cases, 87%), distinct tumor cell borders (20 cases, 87%), granulomatous inflammation (17 cases, 74%), cellular pleomorphism (10 cases, 43%), necrosis (8 cases, 35%), prominent cystic change (2 cases, 8%), intercellular edema (1 case, 4%), and syncytiotrophoblasts (1 case, 4%). The mean mitotic count was 4.4 (range 0 to 16) per 10 high-power fields. Moderate to strong nuclear OCT4 staining was identified in all 23 cases (100%). Seventeen tumors (74%) showed membranous expression of c-kit, with variable staining intensity and percentages. Weakly to moderately intense immunostaining for placental-like alkaline phosphatase was identified in 10 cases (43%) with occasional background staining artifact. The incidences of positive staining were 43% for AE1/3, 39% for HMWCK, 48% for CAM5.2, 39% for CK7, and 9% for epithelial membrane antigen, respectively. In most cases, these epithelial markers highlighted only a small proportion of tumor cells with variable intensities.
Immunostaining for CD30 and CK20 was completely negative in all seminomas. Twenty-two seminomas (96%) revealed chromosome 12p abnormalities, including 12p amplification in 20 cases (87%) or i(12p) in 15 cases (65%). Lymphocytic infiltration is the most common histologic feature observed in primary mediastinal seminoma and both OCT4 immunostain and FISH for 12p abnormalities can be very helpful in diagnosing mediastinal seminoma.
The intense staining pattern of OCT4 and the high sensitivity of FISH make them superior to other auxiliary diagnostic utilities for detecting seminoma. In addition, the incidences of cytokeratin expression of primary mediastinal seminoma are similar to those of its gonadal counterpart and pathologists must exercise caution in the interpretation of epithelial markers in mediastinal neoplasms.
Mediastinal seminomas with prominent cystic changes. A clinicopathologic study of 10 cases.
Moran CA, Suster S.
Department of Pulmonary & Mediastinal Pathology Armed Forces Institute of Pathology, Washington, D.C. 20306-6000, USA.
Am J Surg Pathol 1995 Sep;19(9):1047-53 Abstract quote
We present 10 cases of thymic seminomas associated with prominent cystic changes. All patients were males, aged 16 to 79 years (median, 23.5). Clinically, two patients presented with chest pain/four were asymptomatic and the tumors were discovered on routine chest radiographs; one tumor was discovered incidentally at autopsy; and in three patients no clinical information was obtained.
Grossly, the tumors were described as multilocular cystic lesions that ranged in size from 7 to 19 cm in greatest dimension, showing small focal areas of induration within the cyst walls. Histologically, the lesions were characterized by cystic spaces lined by squamous or cuboidal epithelium showing severe chronic inflammatory changes with areas of cholesterol cleft granulomas, lymphoid follicular hyperplasia, and scattered foci of residual thymic parenchyma within the walls of the cysts, resulting in a picture indistinguishable from acquired multilocular thymic cysts. Careful examination, however, revealed microscopic foci composed of a neoplastic proliferation of large polygonal cells with slightly eosinophilic to clear cytoplasm and large nuclei with prominent nucleoli. The atypical cells were admixed with an inflammatory background and were often accompanied by a florid granulomatous reaction. Periodic acid-Schiff histochemical reaction with diastase revealed moderate amounts of glycogen within the cytoplasm of the tumor cells.
Immunohistochemical studies in five cases showed positive labeling of the tumor cells with placental alkaline phosphatase. Nine patients were treated by complete surgical excision of the mass, and additional postoperative radiation therapy was given to two patients. Follow-up information available for five patients showed all to be alive and well from 2 to 19 years after diagnosis (mean follow-up, 9 years). Four of the patients were lost to follow-up. The pathogenesis of the cystic process in these cases remained unsettled but may represent a reactive change secondary to epithelial hyperplasia of thymic epithelium.
Thymic seminoma should be considered in the differential diagnosis of cystic lesions of the anterior mediastinum; extensive sampling of such lesions is therefore recommended for proper evaluation.
YOLK SAC TUMOR
Yolk sac tumors of the mediastinum with prominent spindle cell features: a clinicopathologic study of three cases.
Moran CA, Suster S.
Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Am J Surg Pathol 1997 Oct;21(10):1173-7 Abstract quote
Three cases of primary mediastinal yolk sac tumors with prominent spindle cell features are presented.
The patients were three men 24-34 years of age (mean 29). Clinically, two patients presented with symptoms of chest pain and cough; no clinical information was provided for the third patient.
Grossly, the tumors were described as large mediastinal masses, with a hemorrhagic and necrotic cut surface. Histologically, the tumors were characterized by a predominantly atypical spindle cell proliferation admixed with areas that showed focally the characteristic reticular growth pattern of yolk sac tumors, with the presence of Schiller-Duval bodies and intra- and extracellular hyaline globules.
Immunohistochemical studies performed in one case showed positive staining for keratin and alpha-fetoprotein in both the spindle cell and reticular components of the tumor.
Follow-up information was obtained in two patients; they both died of tumor with metastases to the lungs 1 year after initial diagnosis.
The present cases expand the spectrum of histopathologic growth patterns that may be observed in yolk sac tumors of the mediastinum and stress the issue of careful sampling and evaluation of mediastinal neoplasms for arriving at the correct diagnosis.
Hepatoid yolk sac tumors of the mediastinum: a clinicopathologic and immunohistochemical study of four cases.
Moran CA, Suster S.
Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Am J Surg Pathol 1997 Oct;21(10):1210-4 Abstract quote
Four cases of primary hepatoid yolk sac tumors of the anterior mediastinum are described. The patients were all men between the ages of 26 and 40 years (median 33). Clinically, they all presented with a history of shortness of breath and chest pain of several weeks' duration. None of the patients had a history of germ cell tumor elsewhere or evidence of any hepatic abnormality.
Grossly, all the tumors were described as large mediastinal masses that impinged on adjacent structures. Histologically, they were characterized by sheets of medium-sized, round to polygonal neoplastic cells with moderate amounts of eosinophilic cytoplasm and round to oval nuclei with prominent nucleoli. The cellular proliferation was homogeneous and displayed moderate cellular atypia and scattered mitotic activity. All the tumors showed focally the presence of more conventional areas of yolk sac tumor, with islands of tumor cells showing a reticular pattern of growth admixed with scattered intra- and extracellular hyaline globules and occasional Schiller-Duval bodies.
Immunohistochemical studies showed strong positivity of the tumor cells for alpha-fetoprotein in both components of the lesions. Follow-up information was available in three patients, all of whom developed lung metastases within a year after initial diagnosis. Two of these patients died of tumor within the same period, whereas a third patient has been lost to follow-up.
The present cases illustrate an unusual histologic pattern of yolk sac tumor in the mediastinum and highlight the importance of considering this tumor in the differential diagnosis of lesions showing a hepatoid pattern of growth in the mediastinal area.
CHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE Similar to gonadal germ cell tumors OCT4
- OCT4 Immunohistochemistry Is Superior to Placental Alkaline Phosphatase (PLAP) in the Diagnosis of Central Nervous System Germinoma.
Hattab EM, Tu PH, Wilson JD, Cheng L.
From the *Department of Pathology and Laboratory Medicine, Indiana University Medical Center, Indianapolis, IN; daggerDepartment of Pathology, Washington University Medical Center, St. Louis, MO; and double daggerDepartment of Pathology, William Beaumont Hospital, Royal Oak, MI.
Am J Surg Pathol. 2005 Mar;29(3):368-371. Abstract quote
OCT4 is an 18-kDa POU-domain transcription factor encoded by the POU5F1 gene. Also known as OCT3, OTF3, and POU5F1, OCT4 is involved in the initiation, maintenance, and differentiation of pluripotent and germline cells during normal development. It is expressed in mouse and human embryonic stem and germ cells but absent from all differentiated somatic cell types in vitro and in vivo. OCT4 has been detected in primary testicular germ cell tumors with pluripotent potential: seminoma and embryonal carcinoma.
We investigated: 1) whether a similar pattern of expression is present in primary intracranial germinomas; and 2) how OCT4 compares with placental alkaline phosphatase (PLAP) in terms of specificity and sensitivity as a potential diagnostic tool. We examined histologic sections from 25 cases of germinoma in which paraffin blocks with sufficient material were available. All cases were reviewed and sections from 32 different blocks were obtained and immunostained for OCT4 and PLAP. Additionally, 49 primary and metastatic brain tumors that may be potentially confused with germinoma, either clinically or histologically, were investigated for OCT4 expression.
All but one germinoma were pure (ie, lacking other germ cell components). Intense and often diffuse nuclear staining was detected in 100% of germinomas. PLAP immunoreactivity was detected in 23 of 25 cases and was absent in the remaining 2 cases. The intensity of OCT4 immunostaining was significantly better than that of PLAP. None of the 49 control cases, which included glioblastoma multiforme, pineoblastoma, pituitary adenoma, malignant lymphoma, metastatic melanoma, capillary hemangioblastoma, meningioma, schwannoma, and a variety of metastatic carcinomas showed immunoreactivity for OCT4.
Our study demonstrates that OCT4 is a highly specific and sensitive immunohistochemical marker for primary intracranial germinomas. OCT4 should be part of immunoperoxidase staining panels in which germinoma enters the differential diagnosis.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES LYMPHOMA OF THE MEDIASTINUM
Pleomorphic large cell lymphomas of the mediastinum.
Suster S, Moran CA. Arkadi M. Rywlin
Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA.
Am J Surg Pathol 1996 Feb;20(2):224-32 Abstract quote
Nine cases of primary non-lymphoblastic, non-Hodgkin's large cell lymphomas of the mediastinum characterized by a highly pleomorphic histologic appearance are described.
The patients, four women and five men, were aged 30 to 65 years. All patients presented with symptoms referable to their tumors, including cough, chest pain, dyspnea, pleural effusion, and superior vena cava syndrome. Clinical and pathologic staging in all patients showed that the bulk of the tumor was confined to the chest cavity at the time of initial diagnosis, with local infiltration into the neck, lung hilum, and surrounding mediastinal structures.
Three different histological growth patterns were observed: one composed of a diffuse proliferation of pleomorphic, highly atypical cells with bizarre nuclear features that closely resembled a high grade sarcoma; another one composed of sheets of large, epithelial-appearing atypical cells suggestive of anaplastic carcinoma; and another pattern characterized by a pleomorphic proliferation of large lymphoid cells admixed with numerous scattered Reed-Sternberg-like cells reminiscent of the lymphocyte-depleted variant of Hodgkin's disease.
Immunohistochemical studies on paraffin-embedded tissue sections in all cases showed positive staining of the tumor cells with CD20 and CD45 antibodies and negative staining with a large panel of markers, including broad-spectrum keratin, CAM 5.2, carcinoembryonic antigen, epithelial membrane antigen, vimentin, actin, desmin, HMB 45, S-100 protein, CD3, CD15, CD30, and CD45RO. Because of their location restricted to the anterior mediastinum, frequent lack of recognizable lymph node architecture, and bizarre cytologic features, the present group of lesions posed difficulties for diagnosis, their correct identification was achieved through the application of a panel of immunohistochemical markers.
An awareness of these unusual histologic appearances of primary large cell lymphoma in the mediastinum and inclusion of a broad panel of lymphoid markers are therefore recommended for the evaluation of pleomorphic, undifferentiated malignant neoplasms of this anatomic region.
METASTATIC GERM CELL TUMOR
Anterior mediastinal metastasis of testicular germ cell tumor: relation to benign thymic hyperplasia.
Suzuki K, Kurokawa K, Suzuki T, Yoshida I, Otaki A, Imai K, Yamanaka H.
Department of Urology, Gunma University School of Medicine, Maebashi, Japan.
Eur Urol 1997;32(3):371-4 Abstract quote
OBJECTIVE: To assess the anterior mediastinal mass in recurrent testicular cancer, with relation to thymic hyperplasia after treatment.
METHODS: The anterior mediastinal regions were fully evaluated by chest computed tomography (CT) at the initial staging and after treatment in 24 of 44 patients with testicular cancer.
RESULTS: One patient with stage IIB tumor had thymic hyperplasia before treatment, and one with stage III had benign thymic hyperplasia after chemotherapy with salvage surgery. Three of 4 patients who had recurrence had an anterior mediastinal mass. One had benign thymic hyperplasia confirmed by histology and 2 had metastatic tumor confirmed by histology and clinical course, in which the mass became so enlarged that it obstructed major vessels.
CONCLUSION: Although the relationship of the CT finding to the response to treatment in the anterior mediastinal mass and other metastatic lesions provide some clues helpful in differentiating benign from malignant masses, surgical exploration is recommended for the patient with an indication for salvage surgery.
NEUROENDOCRINE CARCINOMA OF THE MEDIASTINUM
Neuroendocrine carcinoma of the posterior mediastinum: a possible primary lesion.
Horie Y, Kato M.
Department of Pathology, Tottori University Hospital, Tottori, Japan.
Arch Pathol Lab Med 1999 Oct;123(10):933-6 Abstract quote
A paravertebral mass was noted in the posterior mediastinum in a 47-year-old man.
Microscopically, the tumor showed solid and trabecular patterns and consisted of poorly differentiated atypical cells that often formed Flexner-Wintersteiner rosettelike glands. Immunohistochemically, the tumor cells expressed both epithelial and neuroendocrine markers, including cytokeratin (AE1/3), carcinoembryonic antigen, epithelial membrane antigen, neuron-specific enolase, chromogranin A, and synaptophysin, but were negative for CD99 (MIC2).
Ultrastructurally, numerous desmosomes and neurosecretory granules were identified in the tumor cells. The present lesion was a primary neuroendocrine carcinoma of the posterior mediastinum-an unusual site for such a lesion.
RHABDOMYOSARCOMAS OF THE MEDIASTINUM
Rhabdomyosarcomas of the anterior mediastinum: report of four cases unassociated with germ cell, teratomatous, or thymic carcinomatous components.
Suster S, Moran CA, Koss MN.
Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL 33140.
Hum Pathol 1994 Apr;25(4):349-56 Abstract quote
Four cases are presented of primary anterior mediastinal tumors in young adults that were characterized by solid, infiltrative lesions showing histologic and immunohistochemical features of rhabdomyoblastic differentiation.
The patients were three men and one woman between 19 and 27 years of age (mean age, 23 years). All patients presented with symptoms referable to their tumors, including cough, chest pain, dyspnea, and left-sided pleural effusion. Grossly and radiographically, the lesions were characterized by their solid, infiltrative appearance.
Histologically, two cases corresponded to the solid variant of alveolar rhabdomyosarcoma, one case was an embryonal rhabdomyosarcoma with a predominant spindle cell component, and the remaining case showed the features of a pleomorphic rhabdomyosarcoma. No glandular, epithelial, or other component could be identified in any of the tumors on extensive sampling.
Immunohistochemical studies showed positive staining of the tumor cells with actin, desmin, and vimentin antibodies, with focal positivity for myoglobin in three cases and focal positive staining with S-100 protein in one case. Stains for low and high molecular weight keratin, carcinoembryonic antigen, alpha-fetoprotein, human chorionic gonadotropin, placental alkaline phosphatase, leukocyte-common antigen, and neuron-specific enolase were negative. All patients experienced rapid recurrence and metastases within the first 6 months after diagnosis. Three patients died within this period due to their tumors; the fourth patient has been lost to follow-up.
Pure primary rhabdomyosarcomas of the anterior mediastinum are highly aggressive neoplasms that should be distinguished from germ cell, teratomatous, or carcinosarcomatous tumors with a focal rhabdomyoblastic component.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS GENERAL
Long term results of treatment in patients with extragonadal germ cell tumours.
Gutierrez Delgado F, Tjulandin SA, Garin AM.
Department of Clinical Pharmacology and Chemotherapy, Cancer Research Center, Russian Academy of Medical Sciences, Moscow.
Eur J Cancer 1993;29A(7):1002-5 Abstract quote
From 1979 to 1991 56 patients with extragonadal germ cell tumours (EGCT) received cisplatin based chemotherapy.
From 16 patients with seminomatous EGCT 13 achieved complete remission (CR) with chemotherapy alone, 2 with additional radiotherapy with final CR rate of 94%. 5 (31%) patients developed relapses and at a median follow-up of 38 (5-103) months 11 (69%) are alive and 10 (62%) have no evidence of disease (NED). Only 7 patients with non-seminomatous EGCT reached CR with chemotherapy alone and 8 more with additional chemotherapy or surgery.
Overall CR was 37% and 3 (20%) relapses have been observed. At a median follow-up of 26 (3-114) months 14 (35%) are alive and remain free of disease, 26 (65%) have died. By univariate analysis seminomatous EGCT patients had a significantly greater likelihood of achieving a CR, for non-seminomatous EGCT BEP induction chemotherapy was superior to VAB-6, and NSEGCT patients with serum levels > 2000 ng/ml had worse prognosis.
Current staging systems are insufficient to predict the treatment outcome in EGCT.
Extragonadal germ cell tumors: prognostic factors and long-term follow-up.
Aparicio J, Montalar J, Munarriz EB, Reynes G, Gomez-Codina J, Pastor M, Herranz C.
Department of Medical Oncology, Hospital La Fe, Valencia, Spain.
Eur Urol 1995;28(1):19-24 Abstract quote
The records of 23 patients (22 male and 1 female, median age 28 years) with extragonadal germ cell tumors (EGCT) treated between 1974 and 1993 were reviewed retrospectively to investigate long-term survival and prognostic factors.
Treatment consisted of cisplatin-based chemotherapy plus local irradiation or surgery. There were 7 seminomas, 5 poorly differentiated carcinomas (PDC) with elevated biomarkers, and 11 nonseminomatous germ cell tumors (NSGCT). The primary sites were retroperitoneum (10 cases), mediastinum (5 cases), pineal gland (4 cases) and other (4 cases). Two partial and 14 complete responses (69.6% overall) were achieved with primary therapy. After a median follow-up of 63 months, 10 (43.5%) patients live disease-free and 5-year survival is 55%.
Seminomas showed an excellent outcome. Retroperitoneal NSGCT behaved like testicular neoplasms. Between nonseminoma patients, PDC histology and mediastinal primary were associated with the worst prognoses. EGCT patients should be treated and reported separately according to histology and primary site.
Extragonadal germ cell tumor: a clinical study.
Bassetto MA, Pasini F, Franceschi T, Mustacchi G, Cetto GL.
Cattedra di Oncologia Medica, Universita di Verona, Italy.
Anticancer Res 1995 Nov-Dec;15(6B):2751-4 Abstract quote
Among 18 patients with primary extragonadal germ cell tumors (8 seminoma and 10 non- seminoma), the disease involved the mediastinum (7), the retroperitoneum (8), multiple lymph nodal sites (2) and the pinealis gland (1). Seventeen patients received cisplatin-based chemotherapy as part of the initial treatment. Fifteen patients (83%) achieved complete remission (6 seminoma and 9 non-seminoma): 12 of them are relapse-free after a median follow-up of 82 months (range 13-138).
Five-year overall survival was 65%. No statistically significant survival difference was found between mediastinal and retroperitoneal tumors or patients with seminoma and nonseminoma.
Extragonadal germ-cell tumors: a ten-year experience.
Jacob R, Ramadas K, Jyothirmayi R, Kusumakumary P, Nair MK.
Department of Radiotherapy, Regional Cancer Centre, Trivandrum, India.
Am J Clin Oncol 1998 Apr;21(2):198-202 Abstract quote
Extragonadal germ-cell tumors (EGCT) are uncommon and biologically distinct from their gonadal counterparts.
Thirty-seven patients who had EGCT were treated over a ten-year period at the Regional Cancer Centre, Trivandrum, India. There were 26 men and boys and 11 women and girls. The sites of primary tumor were mediastinum (n=18), central nervous system (n=5), sacrococcygeal region (n=4), retroperitoneum (n=2), and other sites (n=8). After combined modality therapy, 13 of 18 patients who had mediastinal EGCT--1 of 2 with retroperitoneal, 1 of 4 with sacrococcygeal, 0 of 5 with central nervous system, and 2 of 8 patients with tumor in other sites-were alive with no evidence of disease at a median follow-up of 16 months.
The overall 5-year survival rate was 40%. Histologic subtype and elevated marker levels were the significant prognostic factors on univariate analysis.
Primary mediastinal germ cell tumors in children and adolescents: results of the German cooperative protocols MAKEI 83/86, 89, and 96.
Schneider DT, Calaminus G, Reinhard H, Gutjahr P, Kremens B, Harms D, Gobel U.
Department of Pediatric Hematology and Oncology, Heinrich-Heine-University, D]usseldorf, Germany.
J Clin Oncol 2000 Feb;18(4):832-9 Abstract quote
PURPOSE: To evaluate children and adolescents with primary mediastinal teratoma and malignant germ cell tumors (GCTs).
PATIENTS AND METHODS: Forty-seven patients from the German nontesticular GCT studies were analyzed (median age, 2.5 years; range, neonate to 17 years). Teratoma (n = 21) were resected, and no adjuvant treatment was given. Malignant GCTs (n = 26) were treated with cisplatin-based chemotherapy and resection. Three of 26 patients underwent radiotherapy.
RESULTS: In all patients with teratoma, tumor markers were normal. Surgery of teratoma was complete in 17 of 21 patients and microscopically incomplete in four of 21 patients, and we observed no relapse after a median follow-up of 29 months. In 23 of 26 patients with malignant GCTs, alpha-fetoprotein and/or beta-human chorionic gonadotropin were elevated. Twelve of 26 patients received adjuvant chemotherapy after initial resection, which was complete in six of 12 patients, whereas delayed resection after preoperative chemotherapy was complete in 10 of 11 patients (P =.03). Four of six patients underwent second-look thoracotomy after incomplete primary surgery. Three of 26 patients did not undergo tumor resection. The final completeness of resection was the strongest prognostic indicator (event-free survival [inverted question mark]EFS, 0.94 +/- 0.06 v 0.42 +/- 0.33; P <.002). Local stage and distant metastases were not prognostically significant at the.05 level. For all malignant GCTs, the 5-year survival rate was 0.87 +/- 0.05 (median follow-up, 51 months), with an EFS of 0.83 +/- 0.05.
CONCLUSION: The prognosis of mediastinal teratoma is excellent after complete or microscopically incomplete resection. In children with malignant GCT, the prognosis is favorable with a therapeutic strategy of delayed resection after preoperative chemotherapy. In most children, the diagnosis can be based on elevated tumor markers and imaging. Biopsy is indicated in nonsecreting GCT.
Results of modern therapy for patients with mediastinal nonseminomatous germ cell tumors.
Ganjoo KN, Rieger KM, Kesler KA, Sharma M, Heilman DK, Einhorn LH.
Division of Hematology/Oncology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA.
Cancer 2000 Mar 1;88(5):1051-6 Abstract quote
BACKGROUND: The aim of this study was to determine the effects of independent prognostic variables, such as prechemotherapy tumor markers, the extent of disease at diagnosis, the tumor markers postchemotherapy (PC), and the pathology of the PC residual mass on the overall survival of patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCT).
METHODS: The authors undertook a retrospective review of 39 patients with PMNSGCT between 1983 and 1997 who received their initial chemotherapy at Indiana University and 36 additional patients referred for PC resection. All patients received chemotherapy based on the combination of cisplatin and etoposide. The median follow-up was 22 months (range, 12-144 months).
RESULTS: The prechemotherapy tumor markers did not affect overall survival. Extent of disease (mediastinal only vs. visceral metastases) was an important prognostic factor for survival in univariate analysis (P = 0.042). Sixty-two of 75 patients underwent PC resection of residual disease. Fifteen of the 62 patients achieved a CR with chemotherapy alone, as the PC resection revealed only necrosis. Fourteen of these 15 patients continuously had no evidence of disease (NED). Forty-seven of the 62 patients had NED with chemotherapy and PC resection, including 31 with teratoma and 16 with carcinoma. However, 11 of 31 with teratoma and 11 of 16 with carcinoma subsequently relapsed. Although 18 patients had elevated tumor markers at the time of PC resection, 6 of 18 had only necrosis and 4 had teratoma. The PC tumor markers did not affect survival. The pathology of the resected specimen was the most significant predictor of survival in multivariate analysis (P < 0.001).
CONCLUSIONS: Twenty-eight of 39 patients (71.8%) with PMNSGCT treated at Indiana University achieved NED status, but only 16 (41%) continuously had NED. Twenty of 36 (55.5%) referred for resection continuously had NED. Disease confined to the mediastinum and necrosis in the PC specimen were important prognostic factors for survival.
Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis.
Bokemeyer C, Nichols CR, Droz JP, Schmoll HJ, Horwich A, Gerl A, Fossa SD, Beyer J, Pont J, Kanz L, Einhorn L, Hartmann JT.
Tuebingen University Medical Center II, Tuebingen, Germany.
J Clin Oncol 2002 Apr 1;20(7):1864-73 Abstract quote
PURPOSE: To characterize the clinical and biologic features of extragonadal germ cell tumor (EGCT) and to determine the overall outcome with currently available treatment strategies.
PATIENTS AND METHODS: Of an unselected population of 635 consecutive patients treated from 1975 through 1996 at 11 cancer centers, 341 patients (54%) had primary mediastinal EGCT, and 283 patients (45%) had retroperitoneal EGCT. Five hundred twenty-four patients (83%) had a nonseminomatous germ cell tumor (GCT), and 104 patients (16%) had a seminomatous histology.
RESULTS: After platinum-based induction chemotherapy with or without secondary surgery, 141 patients (49%) with mediastinal nonseminomas (median follow-up, 19 months; range, 1 to 178 months) and 144 patients (63%) with retroperitoneal nonseminoma (median follow-up, 29 months; range, 1 to 203 months) are alive (P =.0006). In contrast, the overall survival rate for patients with a seminomatous EGCT is 88%, with no difference between patients with mediastinal or retroperitoneal tumor location (median follow-up, 49 months; range, 4 to 193 months; respective 70 months; range, 1 to 211 months). A significantly lower progression-free survival rate was found in seminoma patients treated with initial radiotherapy alone compared with chemotherapy. Nonseminomatous histology, presence of nonpulmonary visceral metastases, primary mediastinal GCT location, and elevated beta-human chorionic gonadotropin were independent prognostic factors for shorter survival. Hematologic malignancies (n = 17) occurred without exception in patients with primary mediastinal nonseminoma. Sixteen patients developed a metachronous testicular cancer despite the use of platinum-based chemotherapy.
CONCLUSION: Whereas patients with pure seminomatous EGCT histology have a long-term chance of cure of almost 90% irrespective of the primary tumor site, 45% of patients with mediastinal nonseminomas are alive at 5 years. This outcome is clearly inferior compared with patients with nonseminomatous retroperitoneal primary tumors.
Primary mediastinal malignancies in children: report of 22 patients and comparison to 197 adults.
Temes R, Allen N, Chavez T, Crowell R, Key C, Wernly J.
The Cleveland Clinic Foundation, Department of Cardiothoracic Surgery, Cleveland, Ohio, USA.
Oncologist 2000;5(3):179-84 Abstract quote
PURPOSE: Examine a contemporary series of patients with primary pediatric malignant mediastinal tumors and determine epidemiology, histology, treatment, and survival. Patients and Methods. All malignancies diagnosed between January 1, 1973 and December 31, 1995 were analyzed.
RESULTS: Twenty-two patients, age 18 years or less, with pediatric primary mediastinal malignancies were identified from a database of 110,284 patients with primary malignancies. During the same period, 197 adult patients with primary mediastinal malignancies were identified. Fifty-nine percent of the pediatric patients were male. Median age was 11 years. Lymphoma was present in 55%, neurogenic malignancies in 23%, malignant germ cell tumors in 18%, and sarcoma in 5%. Neurogenic tumors presented in infants and lymphomas and germ cell tumors presented in teens (p = 0.005). In treated children, surgery was used more often in neurogenic tumors and germ cell tumors than in lymphomas (p = 0.002). Five-year survival was 74% for lymphomas, 67% for neurogenic tumors, 25% for germ cell tumors, and 61% overall (p = 0.23). Compared to adults, children had more neurogenic tumors (p < 0.001) and fewer thymomas (p = 0.0499). There were no significant differences in staging or survival between children and adults.
CONCLUSIONS: Pediatric mediastinal malignancies occurred with a frequency of 1/5,013 patients with malignant tumors. Lymphoma, neurogenic tumors, and germ cell tumors predominated. Compared to adults, children had more neurogenic tumors and fewer thymomas. Within the pediatric group, differences were found in age of presentation between histologic groups. These differences between adults and children, and between infants and teens, should be considered when evaluating a patient suspected of having mediastinal malignancy.
Extragonadal seminoma: an international multicenter analysis of prognostic factors and long term treatment outcome.
Bokemeyer C, Droz JP, Horwich A, Gerl A, Fossa SD, Beyer J, Pont J, Schmoll HJ, Kanz L, Einhorn L, Nichols CR, Hartmann JT.
Tuebingen University Medical Center II, Tuebingen, Germany
Cancer 2001 Apr 1;91(7):1394-401 Abstract quote
BACKGROUND: The objectives of this study were to evaluate the long term outcome of patients with extragonadal seminomatous germ cell tumors (GCT) so that prognostic variables for disease recurrence and patient survival could be identified and to access the efficacy of different treatment modalities.
METHODS: Six hundred thirty-five patients with extragonadal GCT who were treated consecutively at 11 centers in the United States and Europe during the cisplatin-based chemotherapy era between 1975 and 1996 were evaluated retrospectively.
RESULTS: Fifty-two patients with primary retroperitoneal GCT (50%) and 51 patients with primary mediastinal GCT (49%) of pure seminomatous histology were identified (n = 1 patient with a primary cervical lymph node) representing 16.4% of 635 patients with extragonadal GCT who were included in the data base. The median age was 37 years (range, 18-70 years). Treatment consisted of platin-based chemotherapy in 77 patients (74%), radiotherapy in 9 patients (9%), and combined modality in 18 patients (17%). Ninety-two percent of patients (95% confidence interval, 87-97%) achieved a favorable response to primary therapy. After a median follow-up of 61 months (range, 1-211 months), 18 patients (17%) have had recurrent disease: 14% of those who received chemotherapy and 67% of those who received radiation therapy. The 5-year progression free survival rate favored the chemotherapy group, with 87% compared with 33% for irradiated patients (P = 0.006), whereas the overall survival rates were equal (90% vs. 67%; P = 0.13). No differences in overall survival or progression free survival were observed among patients with primary retroperitoneal and mediastinal seminoma. Prognostic factors that were identified to influence survival negatively were liver metastases (P = 0.01) and two or more metastatic sites (P = 0.04).
CONCLUSIONS: In patients with extragonadal seminoma, a survival rate of > 90% at 5 years is achieved with adequate cisplatin-based chemotherapy. Compared with patients with nonseminomatous extragonadal GCT, no difference in long term survival exists between patients with primary retroperitoneal or mediastinal seminoma location. Primary radiotherapy seems to be associated with a significantly higher rate of disease recurrence, although most patients will be salvaged by subsequent chemotherapy.
Extragonadal germ cell tumors. Clinicopathologic findings and treatment experience in 12 patients.
McLeod DG, Taylor HG, Skoog SJ, Knight RD, Dawson NA, Waxman JA.
Department of Surgery, Walter Reed Army Medical Center, Washington, DC 20307-5001.
Cancer 1988 Mar 15;61(6):1187-91 Abstract quote
In patients with primary germ cell tumors, treatment with combination chemotherapy followed by surgical debulking of residual tissue usually produces favorable results. The best treatment for patients with extragonadal germ cell tumors (EGCT) remains a problem.
In our series of 12 patients, important clinical features were related to the site of bulky tumor, and all patients exhibited sharply elevated levels of lactate dehydrogenase (LDH), beta subunit human chorionic gonadotropin (beta-HCG), and/or alpha-fetoprotein (AFP). Each patient was treated with systemic chemotherapy, and ten were treated with the same combination chemotherapy--cyclophosphamide, actinomycin, vinblastine, bleomycin, and cisplatin (VAB) alternating with VP-16 and vincristine (VV). Of these ten patients, five died of progressive disease, three of whom had brain metastases. The other five are alive and clinically free of disease. The addition of VP-16 and vincristine did not improve responses.
Advanced disease at presentation contributes to the poorer prognosis for these patients. Earlier diagnosis and surgical debulking may improve the long-term survival of patients with this disease.
Primary mediastinal nonseminomatous germ cell tumors: results of modern therapy including cisplatin-based chemotherapy.
Fizazi K, Culine S, Droz JP, Kramar A, Theodore C, Ruffie P, Le Chevalier T.
Institut Gustave-Roussy, Villejuif, France.
J Clin Oncol 1998 Feb;16(2):725-32 Abstract quote
PURPOSE: Primary mediastinal nonseminomatous germ cell tumors (NSGCT) are uncommon neoplasms and clinically and biologically distinct from other germ cell tumors (GCT). We describe the clinical and biologic features of these patients and evaluate the results of treatment during the cisplatin era.
PATIENTS AND METHODS: Between 1976 and 1993, 38 patients with mediastinal NSGCT received cisplatin-based chemotherapy as part of their primary treatment. Twenty-nine of them were initially treated at the Institut Gustave-Roussy (IGR), VillejuiF, France, and nine were referred for salvage treatment.
RESULTS: Of the 29 patients initially treated at IGR, 11 (39%) had metastasis. A complete response (CR) to therapy was obtained in 19 of 29 patients (66%) after chemotherapy and surgery. Ten patients (34.5%) have remained free of disease with a median follow-up of 89 months. All patients who did not achieve a CR died of disease. The 2-year overall survival rate for the IGR patients is 45% and the 2-year disease-free survival is 37%. Only the presence of extrapulmonary metastasis was of prognostic significance in the univariate analysis (P = .0095). None of the 20 patients who required salvage therapy is currently disease-free. Five patients developed and subsequently died of a hematologic malignancy at an interval range of 1 to 47 months from treatment of mediastinal NSGCT. Cytogenetic analysis of leukemic cells found an isochromosome of the short arm of chromosome 12 (12p) in two cases. The incidence of leukemia was 21% in patients who attained a CR.
CONCLUSION: Primary mediastinal NSGCT is a clinical and biologic entity that should be distinguished from other GCT. About 40% of these patients can envisage long-term survival with modern therapy that includes cisplatin-based chemotherapy followed by surgical resection of residual masses. New strategies are required for patients who do not attain a CR. Predictive factors and improvement in therapy are required for mediastinal NSGCT-associated leukemia.
Extragonadal germ cell tumors: clinicopathologic findings, staging and treatment experience in 14 patients.
Berkmen F, Peker AF, Ayyildiz A, Basay S, Arik AI, Ugur I.
Dept. of Urologic Oncology and Radiotherapy, Ankara Oncology Education and Research Hospital, Turkey.
J Exp Clin Cancer Res 2000 Sep;19(3):281-5 Abstract quote
Extragonadal germ cell tumors (EGCT) are a rare group of neoplasms histologically identical to testicular counterparts.
Fourteen cases of primary mediastinal and retroperitoneal germ cell tumors were treated with chemotherapy and radiotherapy between 1987 and 1999 in Ankara Oncology Hospital. There were 9 (64%) complete remissions (CR),one (7%) partial remission (PR) and 2 (14%) stable diseases (SD). The remaining 2 patients were lost due to dissemination of disease. The median duration of response was 19 months.
Our modified chemotherapeutic results were similar to original doses of PVB and BEP but toxicity was less. The neccesity of a uniform staging system and treatment programs are discussed.
Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum.
Vuky J, Bains M, Bacik J, Higgins G, Bajorin DF, Mazumdar M, Bosl GJ, Motzer RJ.
Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
J Clin Oncol 2001 Feb 1;19(3):682-8 Abstract quote
PURPOSE: To evaluate the role of postchemotherapy surgery in patients with nonseminomatous germ cell tumors arising from the anterior mediastinum.
PATIENTS AND METHODS: Thirty-two patients with nonseminoma arising from a mediastinal primary site were treated on a clinical trial at our center, and they underwent postchemotherapy surgery. The results of postchemotherapy surgical resection, frequency of viable tumor found during postchemotherapy surgery, and prognostic factors for survival were assessed.
RESULTS: Complete resection of all gross residual disease was achieved in 27 patients (84%). Histologic analysis of resected residua postchemotherapy revealed viable tumor in 66%, teratoma in 22%, and necrosis in 12% of the specimens. Viable tumor included embryonal carcinoma, choriocarcinoma, yolk sac carcinoma, seminoma, and teratoma with malignant transformation to nongerm cell histology (eg, sarcoma). Clinical characteristics associated with a shorter survival after surgery included the presence of viable tumor in a resected specimen (P =.003) and more than one site resected during surgery (P =.06). There were no statistically significant differences in survival for patients who underwent surgical resection with normal markers compared with patients with elevated serum tumor markers (P =.33). A trend toward shorter survival was found in patients with increasing tumor markers before surgery compared with patients with normal and declining serum tumor markers (P =.09).
CONCLUSION: Surgical resection of residual mass after chemotherapy plays an integral role in the management of patients with primary mediastinal nonseminoma. Teratoma and viable tumor were found in the majority of resected residua after chemotherapy. Because patients who undergo conventional salvage chemotherapy programs rarely achieve long-term disease-free status, selected patients with elevated markers after chemotherapy are considered candidates for surgical resection.
Preliminary observations for a new treatment in children with primary intracranial yolk sac tumor or embryonal carcinoma. Report of five cases.
Ushio Y, Kochi M, Kuratsu J, Itoyama Y, Marubayashi T.
Department of Neurosurgery, Kumamoto University Medical School, Kumamoto, Japan.
J Neurosurg 1999 Jan;90(1):133-7 Abstract quote
The authors evaluated the effect of adjuvant therapy (preoperative chemotherapy combined with radiotherapy) followed by radical tumor removal in the treatment of children with primary intracranial yolk sac tumor, embryonal carcinoma, or mixed germ cell tumors containing yolk sac tumor components.
Between 1988 and 1995, five consecutive patients were treated with adjuvant therapy followed by total tumor removal. The diagnosis was based on markedly elevated concentrations of serum alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (beta-HCG) in four children and the results of biopsy sampling in one child.
The chemotherapy regimen consisted of cisplatin (20 mg/m2) and etoposide (60 mg/m2) daily for 5 days (one course) given three times at 4-weeks intervals. Radiotherapy consisted of 30 to 40 Gy to the whole brain or an area including all ventricles and a 15- to 20-Gy boost to the tumor site. Spinal radiation of 25 Gy was added in one patient. In all patients the serum level of AFP and beta-HCG gradually decreased during the adjuvant therapy and disappeared completely on its completion. In two of the five patients the tumor disappeared as well. In the other three patients the tumor size was moderately or markedly reduced and the remaining tumor was totally removed; there were no neurological deficits. Chemotherapy was maintained after the initial treatment and was repeated every 2 to 4 months for less than 2 years. All children are alive and well without recurrence at 33 to 118 months (average 88 months) after the start of adjuvant therapy.
Our preliminary results indicate that adjuvant therapy consisting of combination chemotherapy with cisplatin and etoposide and concomitant radiotherapy, followed by removal of the tumor, is highly effective in the treatment of pediatric patients with primary intracranial yolk sac tumor, embryonal carcinoma, or mixed germ cell tumors containing yolk sac tumor components.
Primary intracranial germ cell tumors in children: a report of eight cases and review of the literature.
Akyuz C, Koseoglu V, Bertan V, Soylemezoglu F, Kutluk MT, Buyukpamukcu M.
Department of Pediatric Oncology, Hacettepe University Institute of Oncology, Ankara
Turk J Pediatr 1999 Apr-Jun;41(2):161-72 Abstract quote
This study was conducted to evaluate the signs and symptoms on admission, diagnosis, localization, therapy, and survival of patients with primary intracranial germ cell tumors (PICGCT).
Eight patients with surgically confirmed PICGCTs were treated and followed up at Hacettepe University's Department of Pediatric Oncology between 1974 and 1995. While one patient was admitted with a second recurrence of her disease, the others were admitted or referred primarily to our institution.
In this period, 357 germ cell tumor and 684 primary intracranial malignant tumors were diagnosed and treated at our institution. Thus, PICGCTs comprised 1.1 percent of the primary intracranial malignant tumors and 2.2 percent of the germ cell tumors. There were four females and four males and the median age was eight years (13 months to 12 years). On admission, the most common symptoms were diabetes insipidus (3/8) and vomiting (3/8). One patient also and Down's syndrome. Locations of the tumors were suprasellar in three, in the third ventricle in two, and in the cerebral parenchyma, and pineal and hypothalamic regions in the remainder. There were germinomas, three malignant teratomas, and two mixed germ cell tumors. Only two patients could be treated with appropriate and adequate chemotherapy and radiotherapy. Three patients died: one in the postsurgical period, one after the third surgical approach and one 11 months after the diagnosis of progressive disease; three were lost to follow-up. The remaining two patients (with second recurrence and disseminated disease) are alive and without disease.
Our experience with these patients demonstrated that appropriate and adequate chemotherapy is as effective a treatment as radiotherapy, even with recurrence of the disease.
Primary retroperitoneal germ cell tumours: excision via a thoracoabdominal extraperitoneal approach.
Christmas TJ, Doherty AP, Rustin GJ, Seckl MJ, Newlands ES.
Department of Urology, Charing Cross Hospital, London, UK.
Br J Surg 1997 Jul;84(7):1022-5 Abstract quote
BACKGROUND: Primary retroperitoneal germ cell tumours usually present as a large abdominal mass in young men. The testes are normal on examination and ultrasonography but there are usually raised serum levels of human chorionic gonadotrophin and/or alpha-fetoprotein.
METHODS: Fourteen men (median age 33 years) with primary retroperitoneal germ cell tumours were treated by chemotherapy followed by surgical resection of the primary tumour and metastases via a thoracoabdominal extraperitoneal approach.
RESULTS: There was minimal morbidity. The survival rate was 13 of 14 and the disease-free survival rate was 11 of 14 after a median follow-up of 15 months.
CONCLUSION: The thoracoabdominal extraperitoneal approach for the removal of retroperitoneal germ cell tumours and their metastases after chemotherapy improves tumour clearance, morbidity and recovery time compared with the transperitoneal anterior approach.
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.
Learn how a pathologist makes a diagnosis using a microscope
Surgical Pathology Report
Examine an actual biopsy report to understand what each section means
Understand the tools the pathologist utilizes to aid in the diagnosis
How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate
Recent teaching cases and lectures presented in conferences
Last Updated January 9, 2008
Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.
Copyright © The Doctor's Doctor