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Background
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
Sacrococcygeal TeratomaOUTLINE
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE MEDIASTINAL TUMORS Germ-cell tumors of the mediastinum.
Weidner N.
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.
Lokich J.
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.
Lee KC.
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
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION 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.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION 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.
MEDIASTINUM PROSTATE
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.
RETROPERITONEUM
- 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.
SACROCOCCYGEAL THYROID
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.URACHUS
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.
UTERUS
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.
VARIANTS CHORIOCARCINOMA 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.
SEMINOMA
*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.
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.
SPECIAL STAINS/
IMMUNO-
PEROXIDASE/
OTHERCHARACTERIZATION 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.
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