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Neuroendocrine neoplasms of the mediastinum form part of a family of tumors characterized by genotypic, immunophenotypic, and functional properties of neuroendocrine differentiation. Although rare, these tumors have been the source of much attention and controversy in the literature. Their nomenclature and classification, in particular, have continued to evolve over the years. Such tumors comprise lesions derived from neuroendocrine elements within the thymus, from paraganglionic rests, or from misplaced embryonal structures within the mediastinum. The most common neuroendocrine neoplasms of this anatomic region, however, correspond to neuroendocrine carcinomas of the thymus. The light microscopic, immunohistochemical, and ultrastructural features of these tumors are reviewed along with the advances in our understanding of these lesions and current trends in nomenclature and terminology.

Primary mediastinal ependymomas are unusual tumors, with only two case reports previously reported in the literature. In this study, we review our experience with three cases of primary mediastinal ependymomas, including the clinical, histopathologic, immunohistochemical, and ultrastructural features. The three patients in this study were white women with a mean age of 50 years (age range, 36 to 71 years). Presenting symptoms were nonspecific; radiographically, all lesions were circumscribed posterior mediastinal masses without evidence of bone involvement. There was no evidence of central nervous system, sacral, or pelvic ependymoma. All tumors were completely resected, ranged in size from 5 to 7 cm (mean, 6 cm), and exhibited glistening pseudocapsules. Two tumors had a solid, tan-gray cut surface and one lesion was cystic with a mural tumor nodule. All neoplasms showed histologic features of conventional cellular ependymomas with perivascular pseudorosettes and occasional true ependymal rosettes. Germ cell components were not present in any case and immunohistochemical analysis showed glial fibrillary acidic protein, S-100, and patchy cytokeratin immunoreactivity in all three cases as well as absence of reactivity for HMB 45, chromogranin, and synaptophysin. Ultrastructural features included multipart "zipper-like" junctions, intracytoplasmic lumina containing microvilli, occasional cytoplasmic basal bodies, and apical cilia. A microscopic metastasis was present in a regional lymph node in one case at the time of resection; however, there is no evidence of recurrence or distant metastasis in any of the cases during the postoperative period (mean length of follow-up, 64 months). Ependymomas rarely occur in the mediastinum and have a predilection for the posterior mediastinum. The paravertebral location, microscopic identification of adjacent sympathetic ganglia, and lack of teratomatous or other germ cell components suggest that mediastinal ependymomas are likely derived from paravertebral ependymal rests. Primary mediastinal ependymomas are characterized by a prolonged and indolent clinical course. Metastasis to regional lymph nodes may occur, but distant metastases are unusual in our experience. Complete surgical excision seems to offer the best chance for long-term survival.

An immunohistochemical study was performed in 120 cases of mediastinal and testicular germ cell tumors from archival, paraffin-embedded material to compare the patterns of expression between the two groups with a panel of markers, including broad-spectrum keratin, CAM 5.2 low-molecular-weight cytokeratin, placental-like alkaline phosphatase (PLAP), alpha-fetoprotein (AFP), human beta-chorionic gonadotropin (hCG), vimentin, and CD30 (Ki-1 antigen). Significant differences were observed between mediastinal and testicular seminomas: mediastinal seminomas showed strong dot-like paranuclear positivity of the tumor cells with antibodies to CAM 5.2 low-molecular-weight keratin in 80% of cases (32 of 40), as compared with only 20% positivity (5 of 24) in testicular seminomas; placental alkaline phosphatase (PLAP) was also found to be less commonly expressed in testicular seminomas (12 of 24) than in mediastinal seminomas (37 of 40); a similar pattern of expression was also observed for vimentin, which was present in scattered tumor cells in a higher proportion of mediastinal seminomas (28 of 40) than in testicular seminomas (11 of 24). The staining pattern and distribution of these markers did not show significant differences between the two groups for the various other tumor categories studied, including yolk sac tumor, embryonal carcinoma, and choriocarcinoma. The tumor cells in both testicular and mediastinal embryonal carcinoma showed strong positivity for the CD30 antigen; however, strong positivity for this marker was also observed in 6 of 25 yolk sac tumors and in scattered individual tumor cells in 4 of 63 seminomas. The results of this study show that significant differences exist between the immunostaining patterns of mediastinal and testicular seminomas, suggesting that the former may be characterized by a more mature phenotype than their testicular counterparts. Also, CD30 expression may not be necessarily restricted to embryonal carcinomas and occasionally may be observed in yolk sac tumors and seminoma cells, supporting the close histogenetic relationship that exists among these tumor types.

Germ-cell tumors occurring primarily in the mediastinum have been well recognized in the literature for many years. Unfortunately, most of what has been written on these tumors has been in the form of case reports and small series of cases, thus precluding a better understanding of their clinical and demographic features, as well as of their biologic behavior in this particular location. In addition, mediastinal germ-cell tumors not only have never had a standardized nomenclature, but they also have lacked the benefit of a clinical staging scheme for assessment of prognosis. Another important aspect of these tumors that has required attention is the frequency with which teratomatous lesions are associated with malignant components in the mediastinum. Comprehensive studies of mediastinal germ-cell tumors to determine whether these lesions recapitulate the distribution, histopathologic features, and biologic behavior of their counterparts in other areas, such as the gonads, have been lacking for many years. In this article, we review our experience with a large series of cases of primary mediastinal germ cell tumors and examine recent concepts and advances in our understanding of these unusual and diagnostically challenging neoplasms.

Aims: Primary alveolar soft part sarcomas originating within the thoracic cavity are rare. The cases herein described highlight the ubiquitous distribution of this neoplasm and the importance of considering this tumour in the differential diagnosis of mediastinal tumours., Methods and Results: Two cases of alveolar soft-part sarcoma of the mediastinum are presented. The patients are two men of 22 and 23 years of age. Clinically, the patients presented with symptoms of chest pain. One tumour was in the anterior mediastinum while the second tumour was in the posterior mediastinum. Even though the bulk of the tumours were in mediastinal locations, both patients had pulmonary metastases at the time of diagnosis. Histologically, both tumours showed the classic morphology of alveolar soft part sarcoma, i.e. a proliferation of large polygonal cells with round to oval nuclei, prominent nucleoli and moderate amounts of eosinophilic cytoplasm arranged in a prominent alveolar pattern. Periodic acid-Schiff stains showed the characteristic diastase-resistant intracytoplasmic crystals. Immunohistochemical studies showed focal myoglobin reactivity in one case, while cytokeratin, vimentin, S100 protein, chromogranin, synaptophysin, neurofilaments, leu-enkephalin, desmin, smooth muscle actin and muscle-specific actin were negative in both cases. The patient with the anterior mediastinal tumour died of disease 14 months after diagnosis, and the patient with the posterior mediastinal mass remained well for at least 15 years and was later lost to follow-up., Conclusions: As has been observed in other anatomic areas, namely soft tissues, alveolar soft part sarcomas may follow an uncertain natural history. Interestingly, in our cases, the tumour in the anterior mediastinum followed a fatal course raising the possibility that the anatomic location of the tumour may have play a role in the behaviour of the tumour.

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.

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.

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.

Background: Primary seminomas of the mediastinum are unusual neoplasms that are morphologically indistinguishable from their gonadal counterparts but may have different biologic behavior because they arise at this particular location., Methods: The clinical and pathologic features in 120 cases of primary mediastinal seminoma were reviewed, and the immunohistochemical staining patterns in 50 of these tumors were also analyzed., Results: The patients were all men between the ages of 14 and 79 years (mean age, 46.5 years). Their clinical symptoms included cough, chest pain, and dyspnea. In some patients, the lesions were asymptomatic and discovered incidentally on routine chest radiographs. None of the patients had a previous history of testicular neoplasm or tumor elsewhere. Macroscopically, the tumors were described as soft and tan, with a slightly lobulated cut surface, and measured up to 16 cm in greatest dimension. Histologically, the morphologic features were similar to those of tumors occurring in the gonads, namely, a neoplastic proliferation of round-to-polygonal cells with indistinct cell borders, clear-to-lightly-eosinophilic cytoplasm with round-to-oval nuclei and prominent nucleoli, associated with a prominent inflammatory background composed mainly of mature lymphocytes. Necrosis, hemorrhage, multinucleated giant cells, granulomatous reaction, and remnants of thymic tissue were observed in a variable number of cases; mitoses were rare. Immunohistochemical studies in 50 cases showed cytoplasmic staining with placental alkaline phosphatase in 80% of the tumors, focal dotlike positivity for CAM 5.2 low-molecular-weight keratins in 75%, focal cytoplasmic staining for wide-spectrum keratin in 70%, focal positive reaction with vimentin in 70%, and focal positivity with HCG in singly scattered cells in 5%. Immunostains for carcinoembryonic antigen, epithelial membrane antigen, and alpha-fetoprotein were negative in all the cases studied. Fifty patients were Stage I, 3 patients were Stage II, and 12 patients were Stage III. Clinical follow-up information was obtained for 65 cases (54%). Forty-nine patients were alive and disease free after a period ranging from 1 to 19 years (mean follow-up, 10 years). Sixteen patients died within the same period and were found to have metastases to distant organs. Of the 16 patients who died, 6 showed extension of the tumor outside of the mediastinal compartment at the time of initial diagnosis (Stage III lesions). Aside from clinical staging, the authors' findings also suggest that patients >37 years have worse outcomes than younger individuals. The authors were unable to find any correlation between histopathologic features and clinical behavior in any of these cases., Conclusions: Clinical and pathologic staging of mediastinal seminomas are important parameters that can be useful in determining the clinical outcomes of patients with these tumors. Tumor invasion into adjacent organs represents a marker of increased morbidity and mortality. The authors' findings suggest that patients with mediastinal seminomas may have a very good prognosis when the diagnosis is made early; patients with more advanced lesions may require more aggressive therapy for improved local control and prevention of distant metastases.

Background: Yolk sac tumor (YST), embryonal carcinoma (EC), choriocarcinoma (CC), and combined germ cell tumors (CGCTs) of the mediastinum are uncommon neoplasms. Only sporadic cases have been documented in the literature; therefore, the clinical behavior of these tumors when located in the mediastinum remains relatively unknown., Methods: The clinical and pathologic features of 64 cases of primary YST, EC, CC, and CGCTs without teratomatous components were reviewed. The immunohistochemical findings in 29 cases were also analyzed using a panel of monoclonal and polyclonal antibodies in formalin fixed, paraffin embedded tissues., Results: The patients were all men between the ages of 14 and 63 years (mean, 38.5 years). Their clinical symptoms included chest pain, shortness of breath, chills, fever, and superior vena cava syndrome. None of the patients had a previous history of testicular neoplasm or tumor elsewhere. Macroscopically, the lesions in 27 patients were described as large, soft, hemorrhagic, and in some cases necrotic, and varied in greatest dimension from 6 to 20 cm. Histologically, the tumors displayed morphologic features similar to those of their gonadal counterparts. Pure YSTs accounted for the majority of cases in this series (38 of 64, 60%), followed by pure CCs (8 of 64, 12%) and pure ECs (6 of 64, 9%). CGCTs accounted for only 18% of the total cases (12 of 64). YSTs showed a variety of growth patterns; however, the reticular pattern was the most commonly observed. ECs showed a more solid growth pattern with marked pleomorphism of the tumor cells and abundant areas of necrosis. CCs were characterized by the presence of cytotrophoblastic and syncytiotrophoblastic elements with frequent areas of necrosis and hemorrhage. The cases of nonteratomatous CGCT consisted of 5 cases of EC + YST, 2 cases of EC + seminoma, 4 cases of YST + seminoma, and 1 case of EC + CC. In clinical staging, 14 patients were Stage I, 6 were Stage II, and 19 were Stage III. Information on follow-up ranging from 1 month to 13 years was available for 40 patients. Seventeen patients with YST died of their tumors. Of these, 10 who presented with Stage III disease died within the first 2 years. Unfortunately, no clinical staging was obtained for the other 7 patients in this group, and they died within 6-36 months. It is noteworthy that 4 patients with YST have survived for more than 2 years; these patients presented in Stages I and II, and 2 of them received aggressive therapy with chemotherapeutic agents and radiation. Two patients with Stage III EC died within 2 years. The remaining 4 patients with EC were lost to follow-up. Eight patients with CC died within 6 months after initial diagnosis; 7 of them presented Stage III disease and only 1 presented with Stage I. In the nonteratomatous CGCT category, 2 patients with EC + YST died within 2 years after initial diagnosis, whereas 3 patients with YST + seminoma were alive after 4-9 years., Conclusions: The results of this study confirm the aggressive nature of primary nonseminomatous germ cell tumor of the mediastinum; 72% of the patients with adequate follow-up died of their tumors within 6-36 months after diagnosis, despite aggressive therapy. Clinical and pathologic staging of mediastinal YST, EC, and CGCT are important parameters that may be helpful in predicting the clinical outcomes of patients with these tumors. The authors' findings suggest that the majority of tumors that are not limited to the mediastinum at the time of diagnosis have more aggressive behavior. On the other hand, mediastinal choriocarcinomas appeared to follow a very aggressive clinical course, regardless of treatment modality or clinical tumor stage.

Background: Primary germ cell tumors of the mediastinum are unusual neoplasms with histopathologic features that are similar to those of germ cell tumors in the gonads. However, their clinical features, behavior, and spectrum of pathologic features in the mediastinum have not yet been fully defined., Methods: The clinical and pathologic features of 322 cases of primary mediastinal germ cell tumors were reviewed, with special emphasis on teratomatous lesions. The tumors were divided into groups according to their histologic features and correlated with their order of frequency, patient gender and age distribution, and morphologic features. A clinical staging scheme based on the extent and location of the lesions was devised., Results: The overwhelming majority of patients were men (320); only 2 were women (both had teratomatous lesions with additional malignant components). The patients' ages ranged from 1 to 79 years (mean, 40 years). Histologically, all types of germ cell tumors were represented, including 138 teratomas (87 mature teratomas, 6 immature teratomas, and 45 teratomas with additional malignant components); 120 seminomas; 52 nonseminomatous, nonteratomatous germ cell tumors (38 yolk sac tumors, 6 embryonal carcinomas, and 8 choriocarcinomas); and 12 combined germ cell tumors without teratomatous components. The teratomatous lesions with additional malignant components were further separated into subtypes based on the histologic types of their malignant components, i.e., epithelial, mesenchymal, etc. Clinical staging was possible in 242 cases, with 191 cases (79%) in Stage I, 4 cases (1.6%) in Stage II, and 47 cases (19.4%) in Stage III. In each group, the clinical staging correlated well with the clinical outcome for the majority of patients., Conclusions: The results of this study showed that mediastinal germ cell tumors have demographic and histopathologic distributions similar to those of tumors occurring in the male gonads, with teratomatous and seminomatous lesions being the most common. Among the nonseminomatous germ cell tumors in this study, the yolk sac tumors appeared to occur the most frequently (the ratio of yolk sac tumor occurrence to embryonal carcinoma occurrence was 6.1:1). In addition, the subclassification of teratomas with additional malignant components based on the histologic types of malignancies may lead to more therapy choices for patients. At the same time, the use of a clinical staging scheme may be of value in predicting clinical outcome and planning therapy.

Five cases of yolk sac tumor of the anterior mediastinum associated with prominent thymic cystic changes are presented. The patients were five men between the ages of 17 and 22 years (mean, 19.5 yr). Clinically, four patients presented with symptoms of chest pain and shortness of breath, whereas the fifth was asymptomatic: his tumor was discovered during a routine physical examination. None of the patients had a history of previous tumor elsewhere. Grossly, the tumors were described as cystic lesions measuring between 8 and 12 cm in greatest dimension. Histologically, the tumors showed prominent cystic changes reminiscent of those observed in acquired multilocular thymic cysts, i.e., the presence of cystic cavities lined by squamous epithelium with prominent inflammatory changes, lymphoid hyperplasia, cholesterol cleft granulomas, and remnants of thymic tissue in the walls of the cysts. In addition, there was a neoplastic cellular proliferation composed of small cells with scant cytoplasm, round nuclei, and inconspicuous nucleoli adopting a reticular pattern of growth and, in some areas, embedded in abundant myxoid stroma. Numerous intra- and extracellular hyaline globules, as well as Schiller-Duval bodies, could also be identified. Immunohistochemical studies showed positive reaction with alpha-fetoprotein antibodies in the tumor cells. Follow-up information obtained in these patients showed that all had died of tumor 1 to 3 years after initial diagnosis. The present cases document another unusual but distinctive growth pattern of yolk sac tumor in the mediastinum and highlight the importance of proper sampling of cystic lesions in this location.

Cartilage and bone-forming tumors of the mediastinum are extremely rare neoplasms with very few cases having been reported in the literature. We studied six cases of primary malignant cartilaginous tumors presenting as extraskeletal soft tissue masses in the posterior mediastinum. The patients were five women and one man aged 11 to 63 years (median, 31 years). Histologically, the lesions showed a spectrum of features that ranged from mesenchymal chondrosarcoma, to extraskeletal myxoid chondrosarcoma, to moderately well to poorly differentiated chondrosarcoma. In all cases, the lesions presented as well-circumscribed tumor masses centered in the soft tissues in the posterior mediastinum without radiographic evidence of origin from bone. Because of their relatively small size, good circumscription, focal areas of calcification, and posterior mediastinal location, the preoperative clinical diagnoses included benign neurogenic tumor and neuroblastoma. All of the lesions were treated by complete surgical excision, followed in two cases by postoperative radiation therapy. Clinical follow-up was available in five cases: two patients with mesenchymal chondrosarcoma presented with local recurrence after 3 and 7 years, one developed metastases to the sacrum 8 years after initial diagnosis and died, and one was alive and well without evidence of disease after 6 years. The patient with myxoid chondrosarcoma of the posterior mediastinum developed bilateral pulmonary metastases 10 months after surgery and has been lost to follow-up since. Our findings reinforce previous observations on the occurrence of extraskeletal cartilaginous tumors in the mediastinum and indicate that these tumors can show a propensity for local aggressive behavior with high recurrence rate and a definite potential for distant metastases. Such tumors should be considered in the differential diagnosis of malignant neoplasms presenting as a soft tissue mass in the posterior mediastinum.

Primary mediastinal seminomas (MS) are rare tumors. Histologically, they are similar to their counterpart in the gonads. The survival rate has varied from 50% to 85% in different series. However, large series of these tumors primarily in the mediastinum are lacking. At the molecular level, a few reports document K-ras mutations in up to 40% of testicular seminomas (TS), localized predominantly to codon 12. Reports on TS p53 immunohistochemistry (IHC) range from negative to overexpression approaching 90% of cases, and by sequence analysis one small series showed a 23% mutation rate. To date, no analyses have been performed for either K-ras mutations or p53 immunohistochemical expression in primary MS. The authors studied 13 cases each of primary MS and TS from archival formalin-fixed, paraffin-embedded sections in which adequate tumor sampling and clinical history, including serological studies, and histological, histochemical, and IHC staining, were performed to confirm the diagnosis. p53 immunoperoxidase staining using citrate buffer/microwave antigen retrieval was performed. Topographic genotyping was performed on 5-microns-thick tissue sections up to 17 years old, in which the neoplastic cell population was sampled. Additionally, multiple sites within a given cases were sampled to determine clonality of the tumor cell population. Polymerase chain reaction and subsequent sequence analysis of the K-ras-2 exon-1 gene was used for mutation analysis. Focal weak staining with p53 IHC was observed in 4 of 13 (31%) MS and 10 of 13 (77%) TS cases, with all remaining cases being negative (P < .05). Only one MS case (8%) showed K-ras mutation (codon 13 GGC > GAC; glycine > aspartate), which is in contrast to 2 of the TS cases (15%), showing codon 12 mutations. All the remaining cases were wild type. Therefore, primary mediastinal seminomas appear to be different in their K-ras sequence and p53 immunostain profile from TS. Codon mutation type may be useful in determining primary versus metastatic origin of a mediastinal seminoma.

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.

Six cases of chordomas presenting as primary posterior mediastinal tumors are described. Three patients were female, and three were male between the ages of 8 and 65 years (mean, 40.6 years). In all cases, the tumors presented radiographically as relatively well-circumscribed, encapsulated soft tissue masses that did not seem to be related to the thoracic or dorsal spine. Only in one case, focal infiltration of bone at the level of T6-T7 was observed at the time of surgery. Histologically, the lesions showed a spectrum of features that ranged from sheets and cords of large cells with abundant vacuolated cytoplasm to small, stellate cells embedded within an abundant mucoid matrix. In one case, the cell population showed more pronounced nuclear atypia with loss of cytoplasmic vacuolization, frequent mitotic figures, necrosis, and solid areas characterized by a perivascular distribution of atypical spindle cells set against a myxoid stroma. Another case showed features of chondroid chordoma, with an immature chondroid-appearing matrix surrounding the atypical tumor cells. Immunohistochemical studies in all cases showed positive staining of the tumor cells with CAM 5.2 and broad-spectrum keratin, epithelial membrane antigen (EMA) and vimentin, and, to a lesser extent, with S-100 protein. Stains for muscle actin, carcinoembryonic antigen (CEA), and desmin were negative. Ultrastructural examination in two cases showed a spectrum of features that varied from large cells with abundant cytoplasm containing scattered ribosomes, glycogen granules, Golgi apparatti, abundant intermediate filaments, and small lumen formation with immature microvilli to smaller cells with elongated cytoplasmic processes, fewer intermediate filaments, rare desmosome type intercellular junctions, and complexes of mitochondria/rough endoplasmic reticulum. On clinical follow-up, two patients died with metastases to the lungs, chest wall, and liver from 1 to 3 years after diagnosis, and two patients are alive and well without evidence of disease after 3 and 16 years. Chordoma should be entertained in the differential diagnosis of posterior mediastinal tumors. Application of immunohistochemical stains or electron microscopy will be of aid in separating them from other conditions that may histologically closely resemble these lesions.

The clinical, radiologic, and pathologic features of 33 cases of mediastinal thymolipoma are presented. The patients' ages ranged from 2 to 64 (mean, 33) years; 18 were male and 15 were female. Clinically, the majority of patients (18 cases) were asymptomatic. Five patients presented with upper respiratory symptoms, two patients presented with chest pain, two patients with myasthenia gravis, and one patient with a neck mass; no clinical information was available in four patients. All the tumors were located in the anterior mediastinum and in all cases complete surgical resection of the mass was accomplished. Radiographically, 20 cases showed an anterior mediastinal tumor; when available, computed tomography and/or magnetic resonance imaging demonstrated a mixture of fat and soft tissue elements in these tumors. Grossly, the tumors were described as fairly well-circumscribed, soft, yellowish, fatty tumors with focal solid areas. The tumors varied in size from 4.5 to 36 cm in greatest dimension. Histologically, they were characterized by the presence of abundant mature adipose tissue admixed with areas containing remnants of thymic tissue. The fatty tissue consisted of mature adipocytes devoid of atypia, and the thymic tissue component varied from strands of atrophic thymic epithelium to large areas containing thymic parenchyma showing the typical mixed epithelial/lymphocytic architecture with numerous Hassall's corpuscles. Areas of calcification and cystic degeneration of Hassall's corpuscles were quite prominent in a large number of cases. Our study shows that thymolipomas span the age ranges from the very young to adult individuals with a slight prevalence for patients under the age of 40.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

We studied 28 cases of anterior mediastinal liposarcoma occurring in 16 males and 12 females with a mean age of 43 years (range, 14-72). Presenting symptoms included dyspnea (four cases) and chest pain (four cases), although 11 tumors were detected incidentally by routine chest radiography. Seven cases were believed to be located within the thymus. Most (i.e., 25) of the cases were of low grade, with the well-differentiated lipoma-like or sclerosing subtypes constituting 60% and the myxoid subtype constituting 28%; the remaining 12% exhibited mixed features. Three cases were pleomorphic type. Several low-grade tumors exhibited widespread, dense aggregates of mature-appearing lymphocytes and plasma cells, which occasionally obscured the mesenchymal nature of the neoplasm, suggesting instead a lymphoid neoplasm or a reactive fibroinflammatory condition. The three high-grade tumors showed combinations of pleomorphic and round cell patterns, with focal myxoid areas. Of the cases grossly arising within the thymus, only one showed extensive thymic tissue within the lesion ("thymoliposarcoma"); six others exhibited residual thymus peripheral to the tumor. Clinical follow-up in 23 cases revealed recurrence in seven patients (31.8%), with a mean interval to recurrence of 3 years. Eight patients died (mean survival, 2.6 years), one postoperatively and three following a recurrence. Fifteen patients were alive (mean survival, 2 years), four with recurrent tumor. The myxoid tumors had a somewhat more aggressive course than the well-differentiated tumors. Metastases were not observed in any of the patients.

A study of 18 cases of mediastinal hemangiomas is presented. The patients were eight women and 10 men between the ages of newborn to 74 years. Clinically, the most common symptoms included dyspnea, cough, and chest pain. In one patient the mediastinal hemangioma was associated with another hemangioma in the gastrointestinal tract and presented initially with gastrointestinal bleeding. Four patients were asymptomatic. Anatomically, 14 tumors were located in the anterior mediastinum and four in the posterior mediastinum. Surgical resection was the treatment of choice for all patients. Grossly, the lesions were described as well circumscribed, cystic, hemorrhagic tumors that ranged in size from 2 cm to 20 cm in diameter. Histologically, the tumors were divided into two groups, one showing the features of capillary hemangioma characterized by a lobular and solid growth pattern featuring dilated small vessels and a solid proliferation of endothelial cells and another group showing the features of cavernous hemangioma characterized by large dilated vascular spaces with areas showing interstitial inflammatory changes, fibrosis, and smooth muscle proliferation. A few tumors were characterized by prominent regressive changes, including stromal hyalinization, dystrophic ossification, cystic and perivascular myxoid changes, and extensive fatty overgrowth. Some of the tumors showed extreme cellularity with virtual obliteration of vascular lumina due to compression by tumor cells and focal mitotic activity similar to that observed in cutaneous juvenile hemangiomas. Despite their large size, often infiltrating appearance, and sporadic mitotic activity, follow-up ranging from 1 month to 4 years in 11 patients showed all to be alive and well, thus demonstrating the benign nature of these neoplasms. A discussion of the differential diagnosis and a review of the literature on these rare tumors are presented.

We present two cases of extramedullary plasmacytoma presenting as a mediastinal mass and preceding the onset of full-blown multiple myeloma. The patients are a 62-year-old woman who presented with progressive dyspnea and left-sided chest pain and a 59-year-old asymptomatic man. In both patients, radiographic studies revealed a posterior and anterior mediastinal mass, respectively. Surgical resection of the tumor was performed in the two cases. The tumors were characterized by a well-circumscribed proliferation of plasma cells surrounded by residual lymph nodal tissue. Immunohistochemical studies on paraffin sections demonstrated lambda light chain restriction. Follow-up in our patients revealed that both of them developed multiple myeloma after 6 months and 2 years, respectively. One patient received treatment with melphalan and prednisone and is currently alive and well without evidence of disease, 2 years after diagnosis. The second patient died 4 years after resection of his tumor with evidence of disease in lumbar spine, skull, and lungs. Extramedullary plasmacytoma presenting as a mediastinal mass may precede the onset of full-blown multiple myeloma; therefore, institution of early systemic therapy in these patients may be of value in preventing further progression of the disease.

Purpose: To characterize the imaging features of mediastinal hemangioma., Materials and Methods: The authors retrospectively reviewed chest radiographs and computed tomographic (CT) scans from 14 patients with mediastinal hemangioma., Results: Most mediastinal hemangiomas manifested as well-marginated masses at CT. Three masses had punctate calcifications, and one had phleboliths. Five masses were of heterogeneous attenuation at unenhanced CT. Ten of 11 (91%) hemangiomas were of heterogeneous attenuation at contrast material-enhanced CT, and the following four patterns were observed: central (n = 6, 60%), mixed central and peripheral (n = 2, 20%), peripheral (n = 1, 10%), and nonspecific (n = 1, 10%) increased attenuation. Central increased attenuation was observed more frequently after administration of a bolus of contrast material than after slow infusion., Conclusion: Hemangiomas should be considered in the differential diagnosis of well-marginated mediastinal masses that have heterogeneous attenuation on CT scans, show central enhancement after administration of contrast material or contain punctate calcification.

Background: Smooth muscle tumors presenting as mediastinal soft tissue masses are extremely rare and often are mistaken for other neoplastic conditions., Methods: Ten cases of patients with malignant smooth muscle tumors presenting as mediastinal soft tissue masses were studied and correlated with their clinical behavior. Tissues were examined histologically and with immunohistochemical stains in all cases, and by electron microscopy in two cases., Results: The patients' ages ranged from 26 to 71 years (mean, 56 years); three were women, and seven were men. Three cases were located in the anterior mediastinum and seven in the posterior mediastinum. The patients with anterosuperior mediastinal tumors all presented with signs and symptoms referable to their lesions; the patients with posterior mediastinal masses (with the exception of one) were all asymptomatic. Grossly, the lesions were well circumscribed and unencapsulated, ranging from 6 to 18 cm in greatest dimension and showed a homogeneous, rubbery cut surface with prominent cystic and myxoid areas. The tumors in all patients appeared to arise from the soft tissues within the mediastinum and were unrelated to adjacent structures. In three patients, the tumors compressed and displaced the esophagus without infiltrating its wall, and in one patient, the tumor was found in close proximity, although unattached, to a large vessel. Histologically, the lesions exhibited a spectrum of morphologic appearances that ranged from low grade leiomyosarcoma with mild-to-moderate nuclear atypia and low mitotic activity (< 3/10 high power fields [HPFs]), to high grade tumors with marked nuclear pleomorphism, extensive areas of necrosis, and high mitotic activity (> 10 mitoses/10 HPFs). One case was characterized by a striking epithelioid morphology with large, round cells arranged in small clusters; another was associated with an incidental microscopic focus of thymic seminoma in the adjacent thymus. Immunohistochemical stains in all cases showed positive labeling of the tumor cells with smooth muscle actin, desmin, and vimentin antibodies. Electron microscopy in two cases showed features of smooth muscle differentiation, i.e., spindle cells surrounded by basal lamina material, immature cell junctions, and abundant intracytoplasmic filaments with focal condensations. All patients were treated with surgical excision. On follow-up, three patients with Stage IIIb and IVa tumors died 2-7 years after surgery, and two patients with Stage Ib and IIb were alive and well 4 and 6 years after surgery, respectively., Conclusion: Leiomyosarcomas may arise as primary tumors originating from mediastinal soft tissues in both anterior and posterior compartments. Because of their large size and frequent areas of cystic and myxoid degeneration, they may be confused histologically with neural or other neoplasms. As with their counterparts in other soft tissue locations, histologic grade and clinical stage are the most useful parameters for assessing prognosis.

Twelve cases are reported of primary epithelioid hemangioendothelioma of the anterior mediastinum. Patient ages ranged from 19 to 62 years (mean, 49.4); three were women and nine were men. Seven patients presented with symptoms due to compression of surrounding structures; the remainder were asymptomatic and the lesions were discovered on routine chest x-ray films. The tumors measured from 4.5 to 13.5 cm in greatest diameter; they were encapsulated and well-circumscribed in seven cases and locally infiltrative in five. Histologically, a spectrum of features was observed ranging from those classically described for low-grade epithelioid hemangioendothelioma at other locations--including cells with abundant eosinophilic cytoplasm showing prominent vacuolization and intracellular lumen formation, few mitotic figures, and myxoid changes in the stroma--to more pronounced cytologic atypia, increased mitotic activity, and areas of necrosis. Metaplastic bone formation and osteoclast-type giant cells were observed in five cases, and four tumors displayed focally a prominent intravascular papillary endothelial component. Immunohistochemical studies showed positive staining of the neoplastic cells with factor VIII-related antigen and vimentin and focal staining in most cases with Ulex europaeus lectin. Stains for broad-spectrum keratin, CAM-5.2, S-100 protein, CD34, actin, and desmin were negative. Electron microscopic examination in three cases showed features distinctive for epithelioid vascular endothelial cells, including abundant cytoplasmic intermediate filaments, basal lamina material, marked pinocytotic activity, and primitive intracytoplasmic lumen formation. All cases were treated by surgical excision. Follow-up information was available in nine patients; seven patients were alive and well without evidence of disease 2-21 years after diagnosis (mean follow-up, 8 years); one patient had a recurrence after 1 year and died due to complications of surgery, and another patient died after 1 year of undetermined causes. Despite their often ominous clinical, radiological, and pathological features, epithelioid hemangioendotheliomas arising in the anterior mediastinum appear to behave as low-grade malignant neoplasms that may be adequately controlled in most instances by surgery alone.

A thymoma in the anterior mediastinum of a 49-year-old woman was histologically remarkable for the presence of a prominent plasma cell stromal component surrounding the neoplastic epithelial elements. Polyclonal immunoreactivity for kappa and lambda light chains was obtained by immunocytochemical staining of the plasma cells in the stroma. Although no evidence of myasthenia gravis or other type of autoimmune process could be demonstrated at the time of initial diagnosis, a polyclonal hypergammaglobulinemia of unknown cause subsequently developed in the patient. This case may represent an extreme example of aberrant immunologic modulation of the thymus to an autoimmune process with massive hyperplasia of the B-cell compartment of the gland.

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.

Background: Paragangliomas of the mediastinum are rare neoplasms. Because of their rarity, the spectrum of morphologic and immunohistochemical features and biologic behavior of these tumors in this location has not been delineated., Methods: A retrospective study of 16 cases of mediastinal paragangliomas was undertaken to evaluate their clinicopathologic and immunohistochemical features., Results: The patients were 10 men and 6 women whose ages ranged from 16-69 years of age (mean, 42.5 years). Twelve tumors were located in the posterior mediastinum, and three tumors were located in the anterior mediastinum. In one case, the exact location of the tumor within the mediastinum was not available. Microscopically, the nesting pattern (zellballen) was the most commonly encountered. Areas of stromal hyalinization were also frequent and were marked in two tumors. In two cases there was a prominent spindle cell component, and two cases showed granular cell changes in the cytoplasm of the tumor cells. Cellular pleomorphism was observed in the majority of cases. Occasional mitoses were seen in a few cases. Immunohistochemical studies in 10 cases showed chromogranin reactivity in 10 of 10 cases, S-100 protein in 9 of 10 cases, leu-enkephalin in 6 of 10 cases, and neurofilament protein in 5 of 10 cases. Keratin was negative in all cases studied. All patients underwent surgical resection of their tumors, and one patient underwent adjuvant radiation therapy. Follow-up information ranging from 1-168 months (mean, 84.5 months) was obtained in 12 patients. Nine patients (75%) were alive and well at last follow-up. In one patient the tumor metastasized to spinal space and bone marrow, and another patient died with metastases to lymph node, lung, and pelvis 14 years after initial diagnosis., Conclusions: The only parameter found to correlate with aggressive behavior was the extent of circumscription and/or local infiltration of the tumor at initial resection. No clinical, histologic, or immunohistochemical features were otherwise found to separate aggressive from indolent clinical behavior. Regular follow-up is recommended in these patients due to the potential for these tumors to metastasize.

Germ cell tumors occur most frequently in the gonad but can rarely occur in extragonadal locations, usually in or near the midline. The most common extragonadal site of primary germ cell tumors is the anterior mediastinum. The most common histologic type of mediastinal germ cell tumor is mature teratoma, which is typically asymptomatic and incidentally discovered. Radiographically, these tumors appear as rounded, often lobulated masses; calcification may be seen. Imaging studies of mature teratoma frequently demonstrate cystic components and may demonstrate fat or calcium. Malignant germ cell tumors usually occur as large masses in symptomatic young male patients. Seminomas are typically of homogeneous soft-tissue attenuation, and nonseminomatous malignant germ cell tumors are typically of heterogeneous attenuation on computed tomographic scans. Therapy varies according to cell type and may include surgery, radiation therapy, or chemotherapy. Prognosis is excellent for patients with mature teratoma, good for patients with pure seminoma, and poor for patients with nonseminomatous malignant germ cell tumors and mixed germ cell tumors.