Extrathymic Malignancies Research Articles

Deciphering the biology of thymic epithelial tumors.

Thymic cancers arise from epithelial cells of the thymus and have a predilection for intrathoracic spread. Clinical behavior varies from relatively indolent to highly aggressive with a capacity to metastasize widely and adversely affect survival. Paraneoplastic autoimmune disorders are frequently observed in association with thymoma and have a significant impact on quality of life. Underlying immune deficits associated with thymic epithelial tumors (TETs) increase the risk for development of opportunistic infections and emergence of extrathymic malignancies. Advances in the molecular characterization of thymic tumors have revealed the lowest tumor mutation burden among all adult cancers and the occurrence of distinct molecular subtypes of these diseases. Mutations in general transcription factor IIi (GTF2I) are unique to TETs and are rarely observed in other malignancies. The infrequency of actionable mutations has created obstacles for the development of biologic therapies and has spurred research to uncover druggable genomic targets. Persistence of autoreactive T cells due to altered thymic function increases the risk for development of severe immune-related toxicity and limits opportunities for use of immune-based therapies, especially in patients with thymoma. In this paper we review emerging data on the molecular characterization and immunobiology of thymic tumors and highlight clinical implications of these discoveries.

Mortality from extrathymic malignancy after thymic tumour resections: incidences and risk factors.

To identify risk factors associated with extrathymic malignancy-related mortality after thymic epithelial tumour resection. The Japanese Association for Research on the Thymus database registered the records of 2835 patients collected from 32 Japanese institutions from 1991 to 2010. The cumulative incidence function of death due to extrathymic malignancies or recurrence was calculated, with other causes of death as competing risks. Relevant risk factors associated with extrathymic malignancy-related deaths in patients with thymoma were evaluated using the Fine and Gray model. In total, 2701 patients were eligible for the analysis (thymoma, 2374; thymic carcinoma, 273; thymic neuroendocrine tumour, 54). The median follow-up period was 4.6 years. The cumulative incidence function of death due to extrathymic malignancies at 10 years was 2.2% (3.2% due to recurrence) in patients with thymoma, 1.6% (38.6% due to recurrence) in patients with thymic carcinoma and 0% (36.6% due to recurrence) in patients with thymic neuroendocrine tumour. In the multivariable analysis, age (every 10 years) at thymectomy [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.53-3.14; P < 0.001], male gender (HR 2.62, 95% CI 1.19-5.77; P = 0.017) and previous malignancies (HR 3.09, 95% CI 1.18-8.11; P = 0.022) were significant factors for death due to extrathymic malignancies after thymectomy. Continued management and early detection of extrathymic malignancies may improve survival of patients with thymoma who are male, of advanced age, or have previous malignancies. Prospective studies are required to further investigate the management of extrathymic malignancies.

Influence of Smoking and Histologic Subtype on Developing Extrathymic Malignancy in Thymoma Patients

Patients with thymomas are at high risk of developing extrathymic malignancies. We investigated the impact of extrathymic malignancies on the prognosis of patients with thymoma who underwent surgery and the risk factors for postoperative extrathymic malignancies. A multicenter retrospective review of 252 patients who underwent surgical resection of thymomas from January 1977 to March 2016 was conducted. The exclusion criteria were recurrent thymoma, rare types of thymoma, and missing data. The overall number and incidence of extrathymic malignancies were calculated. Potential predictors of extrathymic malignancies were also evaluated. Two hundred twenty-eight patients were analyzed. Fifty-five extrathymic malignancies were observed (23 postoperative, 8 synchronous, and 24 preoperative). Among the overall cohort, the incidence of extrathymic malignancies significantly increased the patients' risk of death (hazard ratio [HR], 4.02; 95% confidence interval [CI], 1.72 to 9.40; p < 0.01). Among patients aged less than 70 years, the incidence of extrathymic malignancies was an independent risk factor for death. The incidence of postoperative extrathymic malignancies was significantly higher in patients with indolent forms of thymoma (type A/AB/B1) than aggressive forms (type B2/B3) (p= 0.02). In the multivariate analysis, indolent forms of thymoma (type A/AB/B1) (HR, 4.03; 95% CI, 1.12 to 14.6, p= 0.03) and a history of ever having smoked (HR, 5.29; 95% CI, 1.30 to 21.6; p= 0.02) were significant risk factors for the cumulative incidence of postoperative extrathymic malignancies. Extrathymic malignancies increased the risk of death in patients with thymomas. Indolent forms of thymoma and a history of ever having smoked were risk factors for postoperative extrathymic malignancies.

Myasthenia Gravis as a Presenting Feature in a Patient With Hepatocellular Carcinoma: A Case Report

Myasthenia gravis (MG) as a presenting feature of extrathymic tumors are rarely reported. Here, we present a case of hepatocellular carcinoma (HCC) presented with MG. A 66-year-old Thai man presented to King Chulalongkorn Memorial hospital in September 2017 with weakness of his neck and legs. He also had trouble in swallowing and his voiced changed. The severity of those symptoms varied during a day while progressed over the past six months. Physical examination revealed weakness of neck muscle and the proximal muscle of extremities. Fatigability and enhanced ptosis were also observed. Electromyography showed a reproducible decremental response with repetitive nerve stimulation. High level of AChR-IgG (17.9 nmol/L) was compatible with a diagnosis of MG. The chest CT revealed no thymoma. However, the abdominal CT (figure 1) showed cirrhotic features with a 5.1x3.1 cm arterial enhancing and rapid venous washout mass in hepatic segment VIII invading segmental branches of right portal vein, representing the typical radiologic characteristics of HCC. The alpha-fetoprotein was 455 IU/mL. Serum immunologic test were negative for hepatitis B and C. The controlled attenuation parameter measured by transient elastography was 271 dB/m. The final diagnosis was fatty liver with cirrhosis grading Child-Pugh class A with HCC Barcelona Clinic Liver Cancer (BCLC) stage C and MG. The weakness improved after a treatment with intravenous immunoglobulin. Other medications were oral prednisolone 30 mg/d and pyridostigmine 240 mg/d which could be gradually tapered over time. Meanwhile, HCC was treated with two sessions of transarterial radioembolization (TARE) with Yttrium-90. The follow-up abdominal MRI (figure 2), 6 weeks after the 2nd TARE, demonstrated a decrease in size of both the HCC and the tumor thrombus in right portal vein. Several studies have been reported a high incidence of extrathymic malignancies with or without thymoma in MG patients, especially in the older age group. The pathophysiologic mechanism, even inconclusive, is suggested to be a paraneoplastic syndrome. However, there is no association between MG and any specific cancers. Approximately ten percent of these malignancies, with a rare report of HCC, present simultaneously with the MG. This case could be considered as the paraneoplastic MG, as an initial presentation, in a patient with advanced stage HCC. However, their associations require further investigations.2405_A Figure 1. The axial view of abdominal CT showed a 5.1x3.1 cm hypodensity mass in hepatic segment VIII (figure 1A; white arrow) with arterial enhancement in the arterial phase (figure1B) and rapid washout in the portovenous and delay phase (figure 1C and 1D, respectively) representing a typical radiologic features of HCC according to AASLD criteria.2405_B Figure 2. The axial view of the follow-up abdominal MRI (T1 dynamic phase) showed a decrease in size of HCC, 1.4x2.2 cm, in hepatic segment VIII (figure 2A; white arrow) without arterial enhancement in the arterial phase (figure 2B), representing responsiveness after TARE. Ring enhancement was observed in the portovenous and delay phase (figure 2C and 2D, respectively) representing fibrous tissue following TARE.

Extrathymic malignancies in patients with myasthenia gravis

Extrathymic malignancies in patients with myasthenia gravis

AB039. PS02.03: The risk of developing extrathymic malignancies in patients with thymoma after surgery

AB039. PS02.03: The risk of developing extrathymic malignancies in patients with thymoma after surgery

Extrathymic malignancies associated with thymoma: a forty-year experience at a single institution.

Patients with thymoma are reported to have an increased risk for developing second malignancies. The aim of this study was to assess the incidence of second malignancies among patients with thymoma. We focused especially on the impact that lung cancer has on survival in these patients. Three hundred and thirty-five patients who underwent surgery for thymoma in Chiba University Hospital from January 1971 to November 2012 were included in this study. Patient records were reviewed retrospectively for data on background, treatment, second malignancies and clinical outcome. Fourteen patients had a history of malignancy until the time of operation, with an additional 20 diagnosed simultaneously with the thymoma. Forty-three malignant lesions in 33 patients were found post-thymectomy. Lung cancer was diagnosed in 17 patients, far exceeding the expected number in the cohort, which was calculated according to Japanese national data. The median survival time of the thymoma patients who had lung cancer at the time of surgery was 5.8years. The survival of patients with thymoma and lung cancer was poor in comparison with that of others. Secondary lung cancer is frequently found in thymoma patients and could be one of the factors limiting survival. We recommend an annual computed tomographic scan of the thorax to detect not only recurrent thymoma but also lung cancer at an early stage in order to improve the survival of these patients.

Thymoma: Two hard masses of large diameter

We report a case of thymoma simultaneously associated with two hard masses of large diameter measuring about 9 cm. A 66-year-old male presented with a cough. Radiographic studies showed a mediastinal mass. Fine needle aspiration cytology and histopathological examination confirmed a diagnosis of thymoma with a coexisting undifferentiated pleomorphic sarcoma. Thymomas are associated with many extrathymic malignancies. Two hard masses were found on either side of the midline; the greatest diameter of the right mass measured 9cm and the left 8.5 cm. The mass on the right of the midline had loosely adhered to the anterior pericardium, the right subclavian vein, the cava vena superior and the anonymous vein.

Extrathymic malignancies in a defined cohort of patients with myasthenia gravis

IntroductionMyasthenia gravis (MG) may be associated with extrathymic malignancies, especially in patients with thymoma. AimTo determine the frequency and type of extrathymic malignancies in MG patients from the Belgrade area, and to identify potential risk factors associated with tumors. Patients and methodThe study comprised 390 patients with MG. Different sociodemographic and clinical variables potentially associated with extrathymic neoplasms were analyzed. ResultsExtrathymic malignancies were present in 42 (10.8%) MG patients — 22 (52.4%) males and 20 (47.6%) females. The most frequently detected were breast (40%) and lung (40%) neoplasms. The tumors appeared with similar frequency before (45.2%) and after the onset of MG (42.9%). Significant predictors for the development of extrathymic malignancies were current age (p=0.001) and immunoglobulin (IVIg) therapy (p=0.021). On the other hand, current age (p=0.001), longer MG duration (p=0.001) and generalized form of MG (p=0.002) were significant predictors of malignancy occurring after the MG onset. ConclusionOur study revealed that older MG patients, as well as those with longer duration of the disease, and those who received IVIg therapy had a higher oncogenic risk for the development of extrathymic malignancies.

Excessive risk of cancer and in particular lymphoid malignancy in myasthenia gravis patients: A population-based cohort study

The exact relationship between myasthenia gravis (MG) and extrathymic malignancies has not been established thus far. Occasional cases of MG have been reported in association with lymphoma or other lymphoproliferative disorders. To determine the risk of extrathymic malignancy with particular attention on lymphoid malignancy for MG patients in a large cohort representing 99% of the Taiwan population, claims data from the Taiwan National Health Insurance Database were used to conduct retrospective cohort analyses. The study cohort comprised 3671 MG patients who were 10-fold frequency matched by age and sex, and assigned the same index year without MG. Cox proportional hazard regression analysis was conducted to estimate the risk of cancer. The MG cohort had a 1.74-fold increased risk of developing cancer compared to the comparison cohort (HR=1.74, 95% CI=1.47–2.05). After adjusting for confounders and relative to the cohort, patients with MG had a 2.27-fold increased risk of developing lymphoid malignancies (HR=2.27, 95% CI=1.06–4.88) and a 118.47-fold increased risk of thymus cancer (HR=118.47, 95%=42.57–329.71). This population based retrospective case-control study confirms and extends previous observations on the association between MG and lymphoid malignancies.

Thymoma and the increased risk of developing extrathymic malignancies: a multicentre study†

Although thymoma is considered a relatively indolent neoplasia, patients affected by this disease are at high risk of developing second tumours (STs). The aim of this study is to assess the risk of developing STs after surgical thymoma resection. A multicentre retrospective study of patients operated on for thymoma within five Italian Thoracic Surgery Institutions, between 2000 and 2011, was conducted. The overall STs number and incidence were calculated. The number of metachronous STs was compared with the expected cancer number (ECN) in an Italian population, and the standardized incidence ratio (SIR) and 95% confidence intervals were calculated. Potential variables of STs predictors were also evaluated. There were 302 patients; myasthenia gravis (MG) was observed in 166 (55%) and other autoimmune syndromes in 49 of them. In 118 patients (39.1%), the Masaoka thymoma stage was greater than II and in 194, the WHO histological type ranged from B1 to C. Fifty STs were observed (28 metachronous, 4 synchronous and 18 detected before thymoma). The observed metachronous STs number was significantly higher than ECN. An increased risk of STs development was observed in advanced stage thymomas and in those with histological high grade. On the contrary, MG seems to be a protective factor in STs development. Our study confirms the high risk of developing STs in patients with thymoma. Aggressive forms of thymoma are those in which this risk appears to be more evident. The central role of an intrinsic immune system alteration might be the key to interpret this phenomenon.

Concurrent thymic squamous cell carcinoma and disseminated intravascular large B-cell lymphoma. A previously unreported association

Abstract The incidence of extrathymic malignancies in patients with thymoma is significantly higher than in the general population. Non-Hodgkin lymphoma represents the most commonly associated tumor type. We report the concurrence of primary thymic squamous cell carcinoma and disseminated intravascular large B-cell lymphoma (IVL) in a 78-year-old man characterized by a rapidly fatal clinical course. To our knowledge, this is the first time that such an association is reported. Due to its rarity and the multiplicity of presentations, it is very difficult to diagnose this type of extranodal lymphoma antemortem. The intravascular lymphoma should be included in the differential diagnosis when a patient presents signs of a systemic disease and marked elevation of serum LDH. In this case the lymphoma may have been developed as a result of defective immunologic surveillance or impaired immunoregulation caused by the thymic carcinoma. In our case as in some other cases of IVL, diagnosis could only be conclusively confirmed on autopsy.

Risk of extrathymic cancer in patients with myasthenia gravis in Taiwan: a nationwide population‐based study

The relationship between myasthenia gravis (MG) and extrathymic malignancies has not been determined. This study aimed to explore the risk of extrathymic malignancy in patients with MG based on a nationwide population-based dataset. We identified 2614 patients with MG from the Taiwan National Health Insurance database between 1997 and 2005 and compared the incidence rates of extrathymic malignancies with 15, 684 randomly selected age-, sex-, and comorbidity-matched subjects without MG. Both cohorts were followed until the end of 2009. Cox proportional hazard model was used to evaluate the predictors of extrathymic malignancy in the MG cohort, including age, sex, comorbidities, and prescription drugs. After an average follow-up of 8 years, the MG cohort had a higher risk of extrathymic cancers with an incidence rate ratio (IRR) of 1.38 (95% CI 1.12-1.68, P = 0.002) than the control cohort. Although breast cancer was the most common cancer found, no statistically significant relationship between MG and any specific malignancy was observed. Cox multivariate proportional hazards analysis showed that only age (HR = 1.05, 95% CI 1.04-1.06, P < 0.001) and liver cirrhosis (IRR = 3.85, 95% CI 1.22-12.14, P = 0.021) were predictors of extrathymic cancers in the MG cohort. Our study showed that patients with MG had an increased risk of extrathymic malignancy in a follow-up of 8 years, but no specific susceptibility to certain malignancies was found.

Unusual Paraneoplastic Syndrome Accompanies Neuroendocrine Tumours of the Pancreas

Neuroendocrine tumours comprise a small percentage of pancreatic neoplasia (10%) (1). Diagnosis of neuroendocrine tumours is difficult, especially if the tumours are small and nonfunctional. CT scans, MRI, and nuclear scans are sufficiently sensitive assessment tools for tumours with diameters of at least 2 cm; otherwise, the sensitivity and specificity of these techniques is less than 50% (2). Myasthenia gravis (MG) is a heterogeneous neuromuscular junction disorder that is primarily caused when antibodies form against the acetylcholine receptors (Ab-AchR). MG can develop in conjunction with neoplasia, making MG a paraneoplastic disease. In those cases, MG is most commonly associated with thymomas and less frequently associated with extrathymic malignancies. The mechanism underlying this paraneoplastic syndrome has been hypothesized to involve an autoimmune response against the tumour cells (3). No published reports have linked malignant pancreatic diseases with MG. Here, we report the case of a young woman, negative for Ab-AchR, with a neuroendocrine tumour in the pancreatic head, who experienced a complete resolution of her MG-like syndrome after surgical enucleation of the tumour.

Thymoma with Coexisting Undifferentiated Pleomorphic Sarcoma: A Case Report

We report here a case of thymoma simultaneously associated with undifferentiated pleomorphic sarcoma. A 45-year-old male presented with axillary lump. Radiographic studies showed a mediastinal mass. On fine needle aspiration cytology and histopathological examination, a diagnosis of thymoma with coexisting undifferentiated pleomorphic sarcoma was made. Although thymomas are associated with many extrathymic malignancies, it's association with undifferentiated pleomorphic sarcoma is rare. This case is being reported on to reinforce that clinicians should bear in mind the possibility of extrathymic malignancies in patients with thymomas.

Thymic Neuroendocrine Carcinoma and Thymoma Are Both Associated With Increased Risk of Extrathymic Malignancy: A 20-Year Review of a Single Institution

Thymoma has been reported to have increased risk of extrathymic malignancy; thymic carcinoma, however, has not been validated of this association. We retrospectively assessed the incidence of additional malignancy among patients with thymoma and thymic carcinoma, and compared it with that of other solid organ cancers. We reviewed the medical records between the years of 1988 and 2008 of 213 patients, including 131 with thymoma and 82 with thymic carcinoma. The overall incidence of additional malignancy in patients with thymic epithelial tumors, lung cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, and cervical cancer between 2003 and 2008 in our institution was also computed. The incidence of extrathymic malignancy in patients with thymic epithelial tumors was 12.2% (16 of 131) for thymoma and 12.2% (10 of 82) for thymic carcinoma. The overall incidence of additional malignancy between 2003 and 2008 was significantly higher among patients with thymoma than among patients with hepatocellular carcinoma, colorectal cancer, breast cancer, and cervical cancer (p=0.017, 0.022, 0.009, and 0.018, respectively). In thymic carcinoma, the likelihood of developing extrathymic malignancy was significantly higher among patients with neuroendocrine carcinoma than among patients with other thymic carcinomas (p=0.000). Extrathymic neoplasm did not pose a significant influence on the overall survival of patients with thymoma (p=0.085) and thymic carcinoma (p=0.814). Our data demonstrated the increased risk of extrathymic malignancies among patient with thymoma. In thymic carcinoma, this association mainly occurred in patients with neuroendocrine carcinoma. Actions for early detection of extrathymic malignancy should be considered for patients with these thymic epithelial tumors.

Extrathymic malignancies in thymoma patients with and without myasthenia gravis

Objective The influence of myasthenia gravis (MG) on risk of cancer is uncertain. Using nationwide, comprehensive data, we investigated the association between MG and occurrence of extrathymic malignancies in thymoma patients, and also assessed the risk of consecutive extrathymic malignancies after thymoma diagnosis. Methods Two hundred twelve thymoma patients were identified at the Cancer Registry of Norway between 1969 and 2005. Records on all extrathymic malignancies for these patients were supplied from the Registry's database. Comparisons were made between MG and non-MG patients and between thymoma patients and the general population. Results The frequency of extrathymic malignancies was similar in MG and non-MG thymoma patients, and so was the survival after thymoma diagnosis. Extrathymic malignancies occurred in 10% of thymoma patients within 10 years following the thymoma diagnosis. Thymoma patients had a significantly increased risk of developing an extrathymic malignancy compared to the general population. This was not linked to any specific kind of cancer. Thymoma morphology was not a significant predictor for an increased risk of consecutive cancer. Conclusions The immunological process underlying MG does not influence the risk of cancer in thymoma patients. Thymoma patients have a significantly increased risk of extrathymic malignancies. This is an intrinsic effect, being unaffected by a coexisting autoimmune disease such as MG and not specific for any type of cancer. Screening for extrathymic malignancies in thymoma patients is probably not recommendable, but clinicians should be aware of the high rate of extrathymic malignancies occurring in thymoma patients.

Hepatocellular carcinoma presenting as paraneoplastic myasthenia gravis

Myasthenia (Myasthenia gravis MG) is an auto-immune disease of the neuromuscular junction. Autoantibodies (IgG) link to acetylcholine receptors, making them non-functional by internalisation and deterioration processes, and blocking the acetylcholine linkage. There is a well known correlation between MG and thymoma [1]. MG is less frequently associated with extrathymic malignancies [2]. During a paraneoplastic syndrome, it is hypothesized that autoantibody production is associated with an immune response against tumor cells. Paraneoplastic myasthenia gravis related to hepatocellular carcinoma (HCC) is very rare.

F-18 FDG PET/CT Demonstration of Thymoma Followed by Development of Lung Cancer

It is well-known that thymoma can be associated with diverse extrathymic malignancies. The authors present a case of a 72-year-old man with myasthenia gravis in which F-18 FDG PET/CT demonstrated high FDG uptake in both an anterior mediastinal mass and a lung nodule. The FDG uptake in the lung nodule was significantly higher than that of the thymic lesion, which might suggest the possibility of a second development of lung cancer in this thymoma patient. Surgical resection was done for the 2 tumors, and histologic examination revealed anterior mediastinal thymoma and primary adenocarcinoma of the lung. This case demonstrates the potential usefulness of PET/CT in detecting and assessing the second extrathymic malignancy in a patient with thymoma.

Non-small-cell lung cancer associated with non-thymomatous myasthenia gravis

A non-small-cell lung cancer without distant metastases was incidentally found in a 77-year-old man who had suffered from myasthenia gravis (MG) without thymoma. The patient's condition was stabilized by oral pyridostigmine bromide which he had taken during the past 6 years. He simultaneously underwent thymectomy and left lower lobectomy with regional lymph node dissection. Although postoperative myasthenic crisis occurred, mechanical ventilation and intravenous steroid pulse relieved the patient and the symptoms improved thereafter. Cases of operable lung cancer with non-thymomatous MG have rarely been reported and the appropriate therapeutic strategy for such cases remains to be debated. Their causal association remains to be identified, whereas some studies have implied that immune disorder due to the abnormal thymus might possibly enhance the oncogenesis of extrathymic malignancies. Myasthenic crisis should also be taken into account in postoperative management of MG patients who simultaneously undergo thymectomy and lobectomy for synchronous lung cancer.