Dyspnea on Exertion in a 40 year old man

A 40-year-old man presents to the emergency department with a 5-day history of progressively worsening breathlessness on exertion and mild, general flulike symptoms. He also complains about night sweats and an intermittent low-grade fever, both of which started about 2 weeks ago.  This interesting case was actually misdiagnosed as early pneumonia caused by influenza.  The patient was treated with anti-influenza medication and was discharged home.  He returned two days later in a worsened condition.  Read more about this condition and how it was diagnosed.

When he returned to the ER, on physical examination, the patient did not appear to be in any acute distress. His vitals signs were measured as a pulse of 89 bpm, blood pressure of 140/85 mm Hg, and a respiratory rate of 19 breaths/min. He was afebrile, with a temperature of 99.8°F (37.7°C). The chest examination revealed nothing out of the ordinary, and his cardiovascular and respiratory examinations, including auscultation, were unremarkable. The abdominal examination revealed no fluid thrill, shifting dullness, or bruit. The liver and the spleen were not enlarged. There were no palpable lymph nodes. Of note, there were multiple areas of hyperpigmentation, but otherwise the skin inspection was unremarkable; no hematomas, bruises, wounds, or scars were noted. ECG showed a sinus rhythm with a heart rate of 84 bpm, and the T waves were somewhat flattened in leads V1, aVL, and III, but they are otherwise unremarkable.

Significant laboratory findings include a white blood cell count of 9.1 x 103/µL (9.1 x 109/L; reference range, 3.5-8.8 x 109/L), a platelet count of 429 x 103/μL (429 x 109/L; reference range, 140-350 x 109/L), a C-reactive protein level of 91 mg/L (reference range, < 10 mg/L), a lactate dehydrogenase (LDH) level of 4.7 microkatals (µkat)/L (reference range, < 3.5 µkat/L), an erythrocyte sedimentation rate (ESR) of 30 mm/h (reference range, 1-12 mm/h), and a D-dimer of 2.2 mg/L (reference range, < 0.25 mg/L). A spiral computed tomography (CT) scan was performed, which showed no pulmonary embolism. It did, however, reveal the presence of a significant pericardial effusion (1 cm ventral x 2.5 cm dorsal) and a multilobular substernal mass occupying the anterior superior mediastinum that is about 2.5 cm in thickness and 7 cm in length, with high absorption. Additionally, the mediastinal lymph nodes were enlarged; some are as large as 2 cm in size. No other pertinent findings on spiral CT were reported. An emergent bedside echocardiogram was obtained. The echocardiographic findings confirm the presence of pericardial effusion, without signs or symptoms of a cardiac tamponade; additionally, a retrosternal mass was detected consistent with a thymoma.


The patient in this case was eventually diagnosed with thymoma. Symptoms from a thymoma or thymic carcinoma may be due to the presence of a tumor in the mediastinum, or they may be a manifestation of a paraneoplastic syndrome. Up to one half of thymomas are diagnosed incidentally on the basis of a radiographic abnormality in an asymptomatic patient. Clinical signs and symptoms are related to both the size of the tumor and its effects on adjacent organs (eg, chest pain, shortness of breath, cough, phrenic nerve palsy, and superior vena cava obstruction). Less commonly, systemic ("B") symptoms, including fever, weight loss, and/or night sweats, may be present. Pleural or pericardial effusions are the most common manifestation of metastatic involvement. Extrathoracic metastases occur in less than 7% of patients, most commonly to the kidney, extrathoracic lymph nodes, liver, brain, adrenals, thyroid, and bone. Metastases to the ipsilateral lung are unusual.

For patients presenting with mediastinal masses, an extensive differential should come to mind. Anterior mediastinal masses include germ cell tumors, lymphoma, thymic carcinoma, and masses arising from the thyroid. Tumors that can arise directly from the thymus include thymoma, lymphoma, carcinoid tumors, thymolipoma, and thymic carcinoma.  Thymomas account for about 20% of mediastinal neoplasms. Most patients are between 40 and 60 years of age, and there is a slight male predominance[1]; however, other studies have not reported a sex difference in prevalence. There are no known risk factors. Thymic carcinomas account for less than 1% of thymic malignancies.  Malignant thymoma is exceptionally rare, with an overall incidence of 0.15 per 100,000 person-years. 

The thymus is a lymphoid organ consisting of 2 pyramidal lobules situated in the anterior superior mediastinum. It is the site of production for T lymphocytes. Precursor cells migrate to the outer cortex, where they proliferate; then move through the inner cortex, wherein T-cell surface markers are acquired; and finally into the medulla, where they become mature T cells.  The thymus weighs 12-15 g at birth, reaches its maximum weight of 40 g around puberty, and then involutes into a mass of adipose tissue that persists in an atrophic state in old age.

Thymoma is an uncommon tumor, best known for its association with the neuromuscular disorder myasthenia gravis. About 15% of patients with myasthenia gravis develop thymoma, which accounts for about 30%-40% of all thymoma cases. An additional 5% of patients with thymomas have other systemic syndromes, including red cell aplasia, dermatomyositis, systemic lupus erythematosus, Cushing syndrome, and syndrome of inappropriate antidiuretic hormone secretion. 

Differentiating thymoma from the more aggressive thymic carcinoma is extremely important. Thymic carcinoma exhibits aggressive cytologic features with evidence of mediastinal invasion in the majority of patients. Histologically, thymic carcinomas exhibit cellular atypia, increased proliferative capacity, and anaplastic features.  Radiographically, thymomas are more likely to exhibit smooth contours and a round shape on CT scans than thymic carcinomas, which more commonly exhibit irregular contours.  The histologic diagnosis of thymic neoplasms can be difficult. There appears to be a continuum of differentiation from thymoma to thymic carcinoma, and primary thymic epithelial neoplasms can have features of both. Carcinoma and thymoma can occur synchronously, or carcinoma can develop within a preexisting thymoma after an interval of years. The World Health Organization (WHO) system is widely used to classify thymomas into 6 types, on the basis of histologic differences. When staging thymomas, 2 main classifications are the Masaoka staging system and the French Groupe d'Etudes des Tumeurs Thymiques (GETT) system. Staging by the Masaoka system has correlated well with overall 5-year survival rates in several large series.

Paraneoplastic autoimmune syndromes associated with thymoma include myasthenia gravis, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, thyroiditis, and Sjögren syndrome, among others.  Several case reports have described a syndrome of thymoma-associated multiorgan autoimmunity that is similar to graft-vs-host disease. Patients present with variable combinations of a morbilliform skin eruption, chronic diarrhea, and liver enzyme abnormalities. Histopathology of the skin or bowel mucosa is similar to that seen with graft-vs-host disease.   Autoimmune pure red cell aplasia and hypogammaglobulinemia affect approximately 5% and 5%-10% of patients with thymoma, respectively. Thymoma-associated autoimmune disease involves an alteration in circulating T-cell subsets. Most thymomas are diagnosed and staged at the time of surgical intervention. Surgical resection is the preferred treatment for patients who can tolerate surgery and have a mediastinal mass that is suspected of being a thymoma. A total thymectomy with complete resection of all tumor tissue can be achieved in nearly all early-stage patients. Later stages are associated with higher morbidity and mortality, and postoperative radiation therapy is generally employed in these cases. Most thymomas in the later stages can only rarely be resected completely, and patients are usually offered debulking surgery and postoperative radiation therapy as palliative measures.  The likelihood of long-term survival depends on the completeness of surgical resection. Resection of the pericardium and accompanying lung parenchyma is often required to achieve a complete resection with histologically negative margins.  Radiation therapy may be useful in the management of patients with microscopic or macroscopic residual thymoma or thymic carcinoma after an incomplete surgical resection, as an adjuvant following complete resection of an invasive tumor, and for those with locally advanced or metastatic unresectable disease. 

In patients with locally invasive tumor or large bulky masses, immediate surgical resection may not be technically feasible. Combination chemotherapy followed by radical resection with or without postoperative adjuvant therapy is considered experimental at this point. Various chemotherapy regimens have been used for neoadjuvant therapy, most of which are cisplatin based.  These neoadjuvant therapies are commonly used, but they are not a standard practice on the basis of current literature.

Patients with thymoma are also at risk for the development of other malignancies, which have been reported in 17%-28% of patients following thymectomy. In a series of 849 cases of thymoma identified through the Surveillance Epidemiology and End Results (SEER) database, the risk was significantly increased for B-cell non-Hodgkin lymphoma, gastrointestinal cancers, and soft-tissue sarcomas (standardized incidence ratios [SIR] 4.7, 1.8, and 11.1, respectively, compared with the number of cases expected in the general population). 

In the case above, there was a multilobular tumor in the anterior superior section of the mediastinum, which is usually occupied by the thymic cortex. The mass had occasional calcifications surrounded by small tumor nodules. The pericardial infiltration measured up to 3 cm from the base of the heart to the apex area. The lungs and the abdomen were free of tumor infiltrations. The patient was transferred to the nearby university hospital and was admitted to the intensive care unit of the cardiology department, wherein pericardiocentesis was performed; 500 mL of bloody pericardial effusion were drained, samples of which were sent for cytology. A subsequent CT scan of the thorax and the abdomen showed that the pericardial effusion had regressed almost completely. Serum alpha-fetoprotein and beta–human chorionic gonadotropin findings were negative. Because of the tumor's location, a fine-needle aspiration biopsy or a bronchoscopy (with transbronchial biopsy) was not feasible; therefore, a video-assisted thoracic surgical biopsy under general anesthesia was performed. Further pertinent lab results included a urine electrophoresis with no trace of Bence-Jones proteinuria and a plasma electrophoresis showing signs of an inflammatory process, with normal immunoglobulins and no M components. The cellular analysis of the pericardial effusion showed few lymphoid cells associated with an inflammatory process. The biopsy confirmed the presence of a thymoma. The patient was transferred to the pulmonary medicine department with a combined treatment plan of chemotherapy, radiation treatment, and surgery. At the time of this report, the patient had completed the third chemotherapy cycle with cisplatin, doxorubicin, and cyclophosphamide, without complications. The next planned step was surgical extraction of the tumor

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