Cortical Thymoma Research Articles

Histogenetic and disease-relevant phenotypes in thymic epithelial tumors (TETs): The potential significance for future TET classification.

Thymic epithelial tumors (TETs) encompass morphologically various subtypes. Thus, it would be meaningful to explore the expression phenotypes that delineate each TET subtype or overarching multiple subtypes. If these profiles are related to thymic physiology, they will improve our biological understanding of TETs and may contribute to the establishment of a more rational TET classification. Against this background, pathologists have attempted to identify histogenetic features in TETs for a long time. As part of this work, our group has reported several TET expression profiles that are histotype-dependent and related to the nature of thymic epithelial cells (TECs). For example, we found that beta5t, a constituent of thymoproteasome unique to cortical TECs, is expressed mainly in type B thymomas, for which the nomenclature of cortical thymoma was once considered. Another example is the discovery that most thymic carcinomas, especially thymic squamous cell carcinomas, exhibit expression profiles similar to tuft cells, a recently discovered special type of medullary TEC. This review outlines the currently reported histogenetic phenotypes of TETs, including those related to thymoma-associated myasthenia gravis, summarizes their genetic signatures, and provides a perspective for the future direction of TET classification.

RARE PRESENTATION OF A THYMOMA AT AN INFREQUENT LOCATION

RARE PRESENTATION OF A THYMOMA AT AN INFREQUENT LOCATION

Histological Classification of Thymoma

Background: Many thymoma classifications have been followed and have been updated by newer or alternative schemes. Many classifications were based on the morphology and histogenesis of normal thymus as the backbone, while other classifications have followed a more simplified scheme, whereby thymomas were grouped based on biological behavior. The WHO classification is currently the advocated one, which is based on “organotypical” features (i.e. histological characteristics mimicking those observed in the normal thymus) including cytoarchitecture (encapsulation and a “lobular architecture”) and the cellular composition, mostly the nuclear morphology is generally appreciated.
 Objectives: This study aims to re-classify thymomas by establishing certain morphometric parameters to evaluate the epithelial cells nuclei. An appraisal of thymoma classification as cortical/ lymphocytic/ type B1 and B2 or medullary/ spindle cells/ type A will be attempted as objective re-evaluation of thymoma.
 Patients: This study is a retrospective evaluation of 50 cases of thymoma, 20 cases of thymic hyperplasia and 10 cases of normal thymus (control group). Using a 5 µm formalin-fixed paraffin embeded tissue sections, stained with hematoxylin-eosin stain, these cases were previously classified histologically into lymphocytic (6 cases), lymphoepithelial (mixed) (28 cases) and epithelial (16 cases), including 2 cases of spindle cell thymoma.
 Methods: Computer-assisted morphometry was performed for 80 cases. This involves digitization of the histopathological features and application of morphometric analysis through software. The morphometric parameters used are nuclear area, maximum nuclear diameter and Form factor of epithelial cells nuclei. Ten normal thymus glands from the archived cases were also evaluated as a control groups.
 Results: The results showed that epithelial thymomas possess significantly different nuclear areas from that of a normal thymus, the maximum nuclear diameter (D-Max) follows the same pattern and adds no further outcomes. The numerical morphometric analysis showed no significant differences between lymphocytic predominant thymoma and those classified as cortical thymoma (Type B2). Thus it does not support such a re-classification. Form factor is an indication of pleomorphism, but it should be cautiously used when spindle cells are present since it may give a false indication of pleomorphism.
 Conclusion: Computer-Assisted morphometric analysis provides an objective, reproducible and comparable results for thymoma histological classification.
 Keywords: Thymoma, Histological classification, Grading, Morphometry, Computer-assistedmorphometry.

A case of co-existing paraganglioma and thymoma

BackgroundHead and neck paragangliomas are rare tumours and can arise as a part of inherited syndromes. Their association with thymic tumour is not well known.Case descriptionThis report describes a female patient who presented with right sided neck paragangliomas. The histology of the tumour was consistent with paraganlioma. Few years later her MRI scan of the chest revealed presence of an anterior mediastinal mass that corresponded to the location of the thymus. Review of her previous scans showed that the mass was present all along and had gradually increased in size. Patient developed symptoms including fatigue, dyspnoea, migratory polyarthritis, Raynaud’s phenomenon and erythema nodosum. She had sternotomy and excision of mediastinal mass. The histology was consistent with cortical thymoma (WHO type B2) and she had radiotherapy. After treatment her constitutional symptoms improved. Her paraganglioma susceptibility genes are negative.Discussion and evaluationTo our knowledge this is only the second case report in the literature of coexistence of carotid body tumour and thymoma. The first case reported was bilateral carotid body tumour, thyroid gland adenoma and thymoma. This case also highlights the importance of long term surveillance, multidisciplinary management and being aware of associated pathologies in patients with isolated paraganglioma.

Thymoma in Myasthenia Gravis: From Diagnosis to Treatment

One half of cortical thymoma patients develop myasthenia gravis (MG), while 15% of MG patients have thymomas. MG is a neuromuscular junction disease caused in 85% of the cases by acetylcholine receptor (AChR) antibodies. Titin and ryanodine receptor (RyR) antibodies are found in 95% of thymoma MG and 50% of late-onset MG (MG onset ≥50 years), are associated with severe disease, and may predict thymoma MG outcome. Nonlimb symptom profile at MG onset with bulbar, ocular, neck, and respiratory symptoms should raise the suspicion about the presence of thymoma in MG. The presence of titin and RyR antibodies in an MG patient younger than 60 years strongly suggests a thymoma, while their absence at any age strongly excludes thymoma. Thymoma should be removed surgically. Prethymectomy plasmapheresis/iv-IgG should be considered before thymectomy. The pharmacological treatment does not differ from nonthymoma MG, except for tacrolimus which is an option in difficult thymoma and nonthymoma MG cases with RyR antibodies.

Transdiaphragmatic growth of asymptomatic dumb-bell thymoma

Fig. 1. CT scan revealed a large inhomogeneous mass with focal area of calcification and diffuse infiltration of the left lung and parietal pleura. Pleural percutaneous biopsy revealed a cortical thymoma CD3+ CD99+ and CD1a+ which was classed as B1 type according to WHO classification. The mass was unchanged after six cycles of chemotherapy; at PET scan after chemotherapy, SUV was 7.1. At preoperative MRI of the chest, extrafascial plane invasion was not shown.

Novel association between thymomas and T-cell Non-Hodgkin's lymphomas: Evaluation of 5 cases

7326 Background: Thymomas are often accompanied by a variety of paraneoplastic syndromes and have been associated with abnormal intra-thymic T-cell development, as well as oligoclonal T-cell populations in the bone marrow of certain patients. Prior series have shown an increased incidence of secondary malignancies in patients with thymoma. Recently, Engels et al. (Int. J. Cancer: 105, 546–551) demonstrated an excessive occurrence of Non-Hodgkin's lymphomas (NHL) after a thymoma diagnosis, identifying 7 cases among 9 SEER registries; however, only B-cell NHL cases were found. We report the association between thymomas and T-cell NHLs and examine its possible causal relationship to abnormal T-cell maturation within the thymus, employing immunohistochemical stains and assessment of T-cell clonality. Methods: Five patients with thymoma and T-cell NHL (both biopsy-proven) were identified through the Thymoma Clinic database at Indiana University. The T-NHL diagnosis could precede, concur or be subsequent to the thymoma. Original thymic samples are being stained for CD2, CD3, CD5, CD4, CD8, CD25, CDK6, p53 and compared to NHL samples. Thymic T-lymphocytes and original T-NHL lymphocytes are being subjected to T-cell receptor gene rearrangement studies by PCR. Results: Median age at the time of thymoma diagnosis was 38 years (range, 28–56). Patient characteristics are summarized in the table. All patients had cortical thymoma. Two patients (cases 4 and 5) presented with the T-NHL in the setting of persistent thymoma. Conclusions: We describe a novel clinical association between thymomas and T-cell NHLs. Abnormal T-cell maturation induced by thymomas may play a role in T-NHL pathogenesis in these patients. Correlative studies will be available for presentation at the time of the Annual Meeting. No significant financial relationships to disclose.

Novel association between thymomas and T-cell Non-Hodgkin's lymphomas: Evaluation of 5 cases

7326 Background: Thymomas are often accompanied by a variety of paraneoplastic syndromes and have been associated with abnormal intra-thymic T-cell development, as well as oligoclonal T-cell populations in the bone marrow of certain patients. Prior series have shown an increased incidence of secondary malignancies in patients with thymoma. Recently, Engels et al. (Int. J. Cancer: 105, 546–551) demonstrated an excessive occurrence of Non-Hodgkin's lymphomas (NHL) after a thymoma diagnosis, identifying 7 cases among 9 SEER registries; however, only B-cell NHL cases were found. We report the association between thymomas and T-cell NHLs and examine its possible causal relationship to abnormal T-cell maturation within the thymus, employing immunohistochemical stains and assessment of T-cell clonality. Methods: Five patients with thymoma and T-cell NHL (both biopsy-proven) were identified through the Thymoma Clinic database at Indiana University. The T-NHL diagnosis could precede, concur or be subsequent to the thymoma. Original thymic samples are being stained for CD2, CD3, CD5, CD4, CD8, CD25, CDK6, p53 and compared to NHL samples. Thymic T-lymphocytes and original T-NHL lymphocytes are being subjected to T-cell receptor gene rearrangement studies by PCR. Results: Median age at the time of thymoma diagnosis was 38 years (range, 28–56). Patient characteristics are summarized in the table. All patients had cortical thymoma. Two patients (cases 4 and 5) presented with the T-NHL in the setting of persistent thymoma. Conclusions: We describe a novel clinical association between thymomas and T-cell NHLs. Abnormal T-cell maturation induced by thymomas may play a role in T-NHL pathogenesis in these patients. Correlative studies will be available for presentation at the time of the Annual Meeting. No significant financial relationships to disclose.

High Incidence of Thymic Epithelial Tumors in E2F2 Transgenic Mice

In virtually all human tumors, genetic and epigenetic alterations have been found which affect the INK4/-CYCLIN D/RB pathway, which regulates cell cycle entry and exit in normal cells. E2F transcription factors are important downstream components of this pathway, which act by controlling the expression of genes involved in DNA replication and cell cycle progression. To determine whether E2F2 deregulation promotes proliferation and tumorigenesis in vivo, we generated E2F2 transgenic mice, in which the Emu and murine pim1 promoter (pp) direct high expression of E2F2 in thymic epithelial cells. Emu-pp-E2F2 mice start to develop cytokeratin- and ER-TR4-positive cortical thymomas from the age of 20 weeks, and within 1 year, nearly all mice succumb to gross thymic epithelial tumors. General thymic morphology is largely maintained, but T cell development is perturbed in thymomas, with proportionately less CD4(+)CD8(+) double-positive thymocytes. In the first 3 months, E2F2 transgenic thymi exhibit only mild epithelial hyperplasia, and thereafter thymomas arise stochastically, probably following additional mutations. Interestingly, Emu-pp-E2F1 mice do not display cortical thymomas. These data argue that E2F2 promotes unscheduled cell division and oncogenic transformation of thymic epithelial cells.

Long-term outcome after multimodality treatment for stage III thymic tumors

Background Surgery remains the cornerstone of therapy for thymic tumors, but the optimal treatment for advanced, infiltrative lesions is still controversial. The introduction of multimodality protocols has substantially modified survival and recurrence rate. We reviewed our 13-year prospective experience with multimodality treatment of stage III thymoma and thymic carcinoma. Methods Since 1989 we have prospectively used a multimodality approach in 45 stage III thymic tumors. Sixteen patients (35%) had myasthenia gravis. Twenty-three patients (51%) had pure or predominantly cortical thymoma (group 1), 11 (24.5%) had well-differentiated thymic carcinoma (group 2), and 11 (24.5%) had thymic carcinoma (group 3). Tumors that were not considered radically resectable at preoperative workup underwent biopsy and induction chemotherapy (15 patients, 33%) followed by surgical resection; all patients were referred for adjuvant chemoradiotherapy. Results No operative mortality was recorded; 1 treatment-related death during adjuvant chemotherapy was observed in group 1. Complete resection was feasible in 91% of patients in groups 1 and 2 and 82% in group 3. The overall 10-year survival was 78%. Ten-year survival for groups 1 and 2 was 90% and 85%, respectively; 8-year survival for group 3 was 56%. During follow-up, tumor recurrence was noted in 3 patients (13%) from group 1, 3 (27%) from group 2, and 3 (27%) from group 3. Conclusions Multimodality treatment with induction chemotherapy (when required) and adjuvant chemoradiotherapy offers encouraging results for stage III thymic tumors; the outcome is more favorable for cortical thymoma and well-differentiated thymic carcinoma.

Titin and ryanodine receptor epitopes are expressed in cortical thymoma along with costimulatory molecules

Cortical-type thymomas are associated with myasthenia gravis (MG) in 50% of the cases. MG is caused by antibodies against the acetylcholine receptors (AChR), but additional non-AChR muscle autoantibodies such as those against titin and ryanodine receptor (RyR) are found in up to 95% of MG patients with thymoma. To elucidate the induction of non-AChR autoantibodies in thymoma-associated MG, we studied cortical-type thymomas from seven thymoma MG patients, and sera from six of them. All six had titin antibodies, and four had RyR antibodies. Titin and RyR epitopes were co-expressed along with LFA3 and B7 (BB1) costimulatory molecules on thymoma antigen-presenting cells (APC) in all thymomas. In normal thymus, the staining by anti-titin, anti-RyR, anti-LFA3, and anti-BB1 antibodies was weak and occurred exclusively in the medulla and perivascularly. Our results indicate a primary autosensitization against titin and RyR antigens inside the thymoma. In MG-associated thymoma, the mechanisms involved in the initial autosensitization against titin and RyR are probably similar to those implicated in the autosensitization against AChR. In all cases, there is an overexpression of muscle-like epitopes and costimulatory molecules indicating that the T-cell autoimmunization is actively promoted by the pathogenic microenvironment inside the thymoma.

Thymectomy in the treatment of ocular myasthenia gravis

Background: Thymectomy is an effective and accepted treatment for myasthenia gravis, but thymectomy for ocular myasthenia gravis (Osserman stage I) is controversial. Objective: To assess the efficacy and propriety of thymectomy for the treatment of ocular myasthenia gravis. Methods: We conducted a review and follow-up of all patients who had thymectomy for the treatment of ocular myasthenia gravis between 1970 and 1998 at the University of California, Davis, Medical Center, and the University of Rome, “La Sapienza,” Rome, Italy. Patient response to thymectomy was categorized as follows: cured, patients who became symptom-free and required no further medication; improved, patients who required less medication and whose symptoms were less severe; unchanged, patients whose symptoms and medications were the same; worse, patients who had more severe symptoms, needed more medication, or died. Results: Sixty-one patients (mean age 37 years; range 14–73 years) were followed up for a mean duration of 9 years (range 0.5–29 years). Ocular myasthenia gravis with mixed and cortical thymomas, stages I to IV, occurred in 12 patients, and ocular myasthenia without thymomas occurred in 49 patients. Transsternal thymectomy (n = 55) and transcervical thymectomy (n = 6) resulted in cure in 31 (51%) patients, improvement in 12 (20%) patients, no change in 16 (26%) patients, and worsening of symptoms (including 1 postoperative death) in 2 patients. Patient outcomes were statistically independent of the duration of preoperative symptoms (mean 9.5 months), patient age, or the presence or absence of thymoma. In patients with ocular myasthenia, 70% were cured or improved after thymectomy; in the subgroup of patients with ocular myasthenia and thymoma, 67% were cured or improved. Conclusion: Thymectomy is an effective and safe treatment for patients with ocular myasthenia gravis.

Histopathologic changes of thymoma preoperatively treated with corticosteroids.

Preoperative treatment of thymoma in advanced stages with corticosteroids may reduce the size of the tumor, but no precise histologic evaluation has been performed. We examined the histopathologic features of pretreatment biopsy and posttreatment surgical specimens of eleven cases of thymoma with such treatment to see the changes of the histologic subtypes based on Muller-Hermelink classification. All specimens were also assessed immunohistochemically for MIB-1 labeling and apoptotic cells to verify the effectiveness of this pretreatment. Seven tumors clinically diminished in size after the treatment with corticosteroids. Fungal infection occurred in three cases postoperatively. The histology of mixed thymomas (two cases) was converted to that of medullary thymoma. Predominantly cortical thymomas (four cases) and cortical thymomas (three cases) changed to show similar histologic features; both became epithelial-rich thymoma with large polygonal tumor cells having indistinct cell borders. In contrast, two well-differentiated thymic carcinomas showed at surgery more prominent squamoid appearance with distinct cell borders. The apoptotic indices of epithelial cells were increased (P = 0.001), and the MIB-1 indices tended to be decreased with corticosteroid treatment. These results suggest that there may be a histogenetic relationship between medullary and mixed thymomas and also between predominantly cortical and cortical thymomas. Corticosteroids may cause degenerative changes in the epithelial cells and lymphocytes and, in thymomas in advanced stages, corticosteroid pretreatment may be warranted, although attention should be paid to infection after surgery.

Evidence for distinct mechanisms in the shaping of the CD4 T cell repertoire in histologically distinct myasthenia gravis-associated thymomas.

The major histocompatibility complex (MHC) class II is involved both in thymocyte maturation and peptide presentation and might thus play a key role in the pathogenesis of paraneoplastic myasthenia gravis (MG) in thymomas. To further investigate this issue, we analyzed and scored the expression of epithelial class II expression in 35 thymomas (medullary, MDT; mixed, MXT; cortical and well differentiated thymic carcinoma, CT / WDTC) and correlated it with the histological tumor subtype, prevalence of MG and thymocyte maturation, which was analyzed by flow cytometry and RT-PCR. Our results show that both MHC class II expression and thymocyte maturation are highly dependent on the histological tumor subtype. CT / WDTC retain features of the normal outer thymic cortex, namely substantial MHC class II expression together with normal early thymocyte maturation until late phases of positive selection, but disturbed terminal thymopoiesis. By contrast, MDT and MXT retain features of the normal inner cortex and the medulla with low to absent class II expression and highly abnormal early thymocyte maturation including impaired positive selection, while terminal T cell maturation in MXT appeared undisturbed. There was no correlation between MHC class II expression and MG status for a given tumor subtype. In conclusion, our results provide evidence for a different histogenesis of cortical thymomas and well differentiated carcinomas on the one hand and mixed and medullary thymomas on the other. Decreased expression levels of MHC class II, although of crucial importance for abnormal intratumorous maturation, are not sufficient to explain the emergence of paraneoplastic MG.

Somatostatin Receptor Subtypes in Human Thymoma and Inhibition of Cell Proliferation by Octreotide in Vitro

Somatostatin (SS) and SS receptor (SSR) subtypes, code-named sst1–5, are heterogeneously expressed in the normal human thymus. This suggests their involvement in controlling the immune and/or neuroendocrine functions in this organ. Moreover, recently a high in vivo uptake of[ 111In-DTPA-d-Phe1]octreotide has been reported in patients bearing thymoma. The present study characterizes in vivo and in vitro, functional SS-binding sites in a human thymoma. A high uptake of[ 111In-DTPA-d-Phe1]octreotide was observed in the chest of a patient with myasthenia gravis due to a cortical thymoma. Specific binding of[ 125I-Tyr11]SS-14 was found on a membrane preparation of the surgically removed thymoma. Scatchard analysis showed high affinity binding sites (Kd, 47.5 ± 2.5 pmol/L) with low maximum binding capacity (23.5 ± 2.5 fmol/mg membrane protein). RT-PCR analysis showed the presence of sst1, sst2A, and a predominant sst3 messenger RNA (mRNA) expression in the tumor tissue. Primary cultured tumor cells expressed ss...

Thymoma—the usefulness of some prognostic factors for diagnosis and surgical treatment

Aims The aim of the study was to identify prognostic factors which could help evaluate both the treatment offered to patients with thymoma and late results. Methods Forty patients were treated for mediastinal thymoma. The patients were staged clinico-pathologically (according to Masaoka) on the basis of the retrospective analysis of their operation protocols as follows: seven (17.5%)—stage I, 19 (22.5%)—stage II, 17 (42.5%)—stage III, seven (17.5%)—stage IV. Analysis of DNA contents in cell nuclei of 23 thymomas was performed by the flow cytofluorometric method. Results From the whole group of patients, 65% survived for 5 years, 55% survived for 10 years and 43% survived for 15 years. We noted significant differences in survival time between stage I and stage IV (P<0.0012); stage II and stage IV (P<0.0006), as well as between stage III and stage IV (P<0.005). Significantly worse prognosis was observed in the case of cortical thymomas as compared with medullary or mixed types (P<0.0001 P<0.002). Analysis of DNA content showed signficantly higher probability of survival for the patients who had DI=1.0 (diploid), as compared with DNA >1.0 (aneuploid) (P<0.006). Of the 11 patients with diploid tumours, 91% survived for 5 years, but of the 12 aneuploid, only 23% survived.Conclusion The most important positive prognostic factors influencing survival rate in patients with thymoma are: lower stage, medullary type (according to Muller-Hermelink classification), possibility of performing complete resection, diploidal nature of the tumour. Multivariate analysis of survival revealed clinico-pathological stage (according to Masaoka) and histological type (according to Salyer) as significantly independent prognostic factors.

Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study

Purpose: With the conventional approach of surgery and postoperative radiotherapy for patients with Masaoka Stage III thymoma, progress has been slow for an improvement in the long-term survival rate over the past 20 years. The objective of this study was to evaluate the pattern of failure and survival after surgery and postoperative radiotherapy in Stage III thymoma and search for a new direction for better therapy outcome. Methods and Materials: Between 1975 and 1993, 111 patients with thymoma were treated at Massachusetts General Hospital. Of these, 32 patients were determined to have Masaoka Stage III thymoma. The initial treatment included surgery for clinically resectable disease in 25 patients and preoperative therapy for unresectable disease in 7 patients. Surgical procedure consisted of thymectomy plus resection of involved tissues. For postoperative radiotherapy ( n = 23), radiation dose consisted of 45–50 Gy for close resection margins, 54 Gy for microscopically positive resection margins, and 60 Gy for grossly positive margins administered in 1.8 to 2.0 Gy of daily dose fractions, 5 fractions a week, over a period of 5 to 6.6 weeks. In preoperative radiotherapy, a dose of 40 Gy was administered in 2.0 Gy of daily dose fractions, 5 days a week. For patients with large tumor requiring more than 30% of total lung volume included in the target volume ( n = 3), a preoperative radiation dose of 30 Gy was administered and an additional dose of 24–30 Gy was given to the tumor bed region after surgery for positive resection margins. Results: Patients with Stage III thymoma accounted for 29% (32/111 patients) of all patients. The median age was 57 years with a range from 27 to 81 years; gender ratio was 10:22 for male to female. The median follow-up time was 6 years. Histologic subtypes included well-differentiated thymic carcinoma in 19 (59%), high-grade carcinoma in 6 (19%), organoid thymoma in 4 (13%), and cortical thymoma in 3 (9%) according to the Marino and Müller-Hermelink classification. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. Ten of the 25 patients who were subjected to surgery as initial treatment were found to have incomplete resection by histopathologic evaluation. The 5- and 10-year survival rates were 86% and 69% for patients ( n = 15) with clear resection margins as compared with 28% and 14% for those ( n = 10) with incomplete resection margins even after postoperative therapy, p = 0.002. Survival rates at 5 and 10 years were 100% and 67% for those with unresectable disease treated with preoperative radiation ( n = 6) and subsequent surgery ( n = 3). Recurrence was noted in 12 of 32 patients and 11 of these died of recurrent thymoma. Recurrences at pleura and tumor bed accounted for 77% of all relapses, and all pleural recurrences were observed among the patients who were treated with surgery initially. Conclusion: Incomplete resection leads to poor results even with postoperative radiotherapy or chemoradiotherapy in Stage III thymoma. Pleural recurrence is also observed more often among patients treated with surgery first. These findings suggest that preoperative radiotherapy or chemoradiotherapy may result in an increase in survival by improving the rate of complete resection and reducing local and pleural recurrences.

PE-35-related antigen expression and CD1a-positive lymphocytes in thymoma subtypes based on Müller-Hermelink classification. An immunohistochemical study using catalyzed signal amplification.

PE-35 monoclonal antibody, detecting a cell-surface antigen of various types of carcinoma and normal epithelium, reacts exclusively with the medullary epithelium in the thymus; therefore, the antigen has been considered as a marker of medullary differentiation in thymomas. Using the catalyzed signal amplification method, which made it possible to apply PE-35 to routinely processed, archival tissues, we examined expression of this antigen, together with CD1a reactivity of lymphocytes, in 40 thymic epithelial tumors subclassified using the Mü1ler-Hermelink system. Medullary thymomas infiltrated with a small number of CD1a-negative lymphocytes were PE-35 positive, although many of the long spindle tumor cells were PE-35 negative. Mixed thymomas and predominantly cortical thymomas, both with prominent CD1a-positive lymphocytes, were also PE-35 positive, although some areas of the latter type were PE-35 negative. Cortical thymomas with decreased numbers of CD1a-positive lymphocytes were largely PE-35 negative. In well-differentiated thymic carcinomas with a few CD1a-positive lymphocytes, two cases were negative, but four cases were at least focally positive with PE-35. All high-grade thymic carcinomas infiltrated with some CD1a-negative lymphocytes were PE-35 positive. These results suggested that medullary thymoma generally possesses the medullary nature, although the latter tends to be lost in the long spindle tumor cells. Mixed and predominantly cortical thymomas may have mixed medullary phenotype and cortical function. Cortical thymoma and many well-differentiated thymic carcinomas may possess the cortical nature, while the large polygonal tumor cells tend to lose immature T-lymphocyte-retaining function.

Evaluation of the malignant grade of thymic epithelial tumors according to the epithelial subclassification.

We investigated the clinicopathological correlations among 49 surgically resected thymic epithelial tumors (TET), which were subclassified according to the six subtypes established by the Marino, Kirchner, and Müller-Hermelink system, which were renamed as follows: spindle cell type (medullary thymoma), mixed spindle and polygonal cell type (mixed medullary and cortical thymoma), small polygonal cell type (predominantly cortical thymoma), large polygonal cell type (cortical thymoma), atypical type (well differentiated thymic carcinoma), and cytologically malignant type (high-grade thymic carcinoma). The related categories were grouped for statistical analysis as follows: group 1, spindle cell type and mixed type; group 2, small polygonal cell type and large polygonal cell type; group 3, atypical type; group 4, cytologically malignant type. The association of each group with the presence of myasthenia gravis, tumor stage, and the length of survival was studied. Myasthenia gravis was significantly present in patients with small polygonal type, large polygonal type, and atypical type tumors (groups 2 and 3) (P = 0.003). The tumors in group 1 showed the lowest tumor stage while those of group 4 had the most advanced tumor stage (P = 0.002). The patients in group 4 had the worst prognosis, followed by those in group 3, 2, and 1, in that order. The differences among these groups were statistically significant (P = 0.0003). From our results, we determined that TET can be separated into an extremely low-grade malignancy group (group 1), a low-grade malignancy group (group 2), an intermediate malignancy group (group 3), and a high-grade malignancy group (group 4).

Somatostatin receptor subtypes in human thymoma and inhibition of cell proliferation by octreotide in vitro.

Somatostatin (SS) and SS receptor (SSR) subtypes, code-named sst1-5, are heterogeneously expressed in the normal human thymus. This suggests their involvement in controlling the immune and/or neuroendocrine functions in this organ. Moreover, recently a high in vivo uptake of [111In-DTPA-D-Phe1]octreotide has been reported in patients bearing thymoma. The present study characterizes in vivo and in vitro, functional SS-binding sites in a human thymoma. A high uptake of [111In-DTPA-D-Phe1]octreotide was observed in the chest of a patient with myasthenia gravis due to a cortical thymoma. Specific binding of [125I-Tyr11] SS-14 was found on a membrane preparation of the surgically removed thymoma. Scatchard analysis showed high affinity binding sites (Kd, 47.5 +/- 2.5 pmol/L) with low maximum binding capacity (23.5 +/- 2.5 fmol/mg membrane protein). RT-PCR analysis showed the presence of sst1, sst2A, and a predominant sst3 messenger RNA (mRNA) expression in the tumor tissue. Primary cultured tumor cells expressed sst3 mRNA only. In contrast to the normal thymus, SS mRNA was not expressed. By immunohistochemistry, the tumor cells highly expressed sst3 receptors, weakly expressed sst1 receptors, and showed no immunostaining for sst2A receptors. sst2A immunoreactivity was found in the stromal compartment of the tumor, particularly on the endothelium of small intratumoral blood vessels. In primary cultured tumor cells, both SS and octreotide (10 nmol/L) significantly inhibited [3H]thymidine incorporation by 40.6% and 43.2%, respectively. The following conclusions were reached. 1) As this tumor displayed a high immunoreactivity for sst3 and the cultured tumor cells expressed the sst3 mRNA only, this SSR may be the subtype involved in the inhibition of epithelial tumor cell proliferation by octreotide in vitro. 2) A loss of endogenous SS production in this thymoma might be implicated in the uncontrolled cell growth. 3) In this case, the sst3 may play a role in determining the uptake of [111In-DTPA-D-Phe1]octreotide by in vivo SS receptor scintigraphy.