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J Thorac Cardiovasc Surg 2000;119:624-629
© 2000 Mosby, Inc.
CLINICAL-PATHOLOGIC CONFERENCE |
Participants
From the Washington University School of Medicine, Barnes-Jewish Hospital, St Louis, Missouri
THORACIC SURGERY, Dr Joel Cooper, Dr G. Alexander Patterson, Dr Bryan Meyers, Dr Richard Anderson
RADIOLOGY, Dr David Gierada
PATHOLOGY, Dr Lawrence Johnson, Dr Jon Ritter
Case presentation
Dr Anderson:
The patient is a 31-year-old woman who works as a bartender. Six months before presentation she began to notice that she was dropping glasses while she was at work. She also noted occasional episodes of diplopia. At the time, the patient was recovering from a recent influenza infection and initially attributed her weakness to this illness. However, her symptoms began to progress and by the fall of 1998 had worsened to the point that she sought medical attention. On the basis of her symptoms, a presumptive diagnosis of myasthenia gravis was made. Results of an edrophonium chloride (Tensilon) test were positive, as were results of an anti-acetylcholinesterase receptor antibody test. She was placed on a regimen of pyridostigmine bromide (Mestinon) and her symptoms markedly improved. She still had ocular symptoms when she was working late at night, but otherwise her symptoms pretty much resolved. At the time of her original presentation, a computed tomographic (CT) scan showed a lobulated soft tissue mass in the anterior mediastinum contiguous with the aortic arch. A subsequent CT scan in May 1999 demonstrated no significant change. We will review her chest radiographic and CT images from May 1999.
Dr Gierada:
The chest radiograph was considered to show no abnormalities (Fig 1). The heart size and mediastinal contours were within normal limits. However, the CT scan revealed a soft tissue mass in the anterior part of the mediastinum involving the thymus (Fig 2
). On the most cephalad image in which the mass is seen (Fig 2, A ), the lesion extends anterior to the left brachiocephalic vein. At a slightly more caudal level (Fig. 2, B ), there is a small, low-density component with a thin, calcified rim that could represent either a small cyst or focal necrosis. There is also an outward bulge in the contour of the upper portion of the left thymic lobe near this level. These findings are suggestive of a thymoma. However, although the remainder of the thymus appears enlarged, it maintains a bilobed configuration (Fig 2, C and D ). Both right and left lobes look diffusely enlarged, raising the possibility of thymic hyperplasia. Thus possible explanations for these findings include a hyperplastic thymus containing a small cyst, thymoma arising in a hyperplastic thymus, or thymoma. There was no evidence of extracapsular spread within the mediastinum or evidence of pleural metastases.
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Dr Gierada:
Very little. There may be a few ill-defined small lobules or a thin linear or ovoid strip of soft tissue, but most of the thymus at this age should be composed of fat on CT. Any focal alteration in contour of the margins would be considered abnormal.
Dr Cooper:
I have been observing an asymptomatic patient in his mid-30s who has an enlarged thymus. It is homogeneous in appearance with no displacement or distortion of adjacent structures. He is a nonmyasthenic patient who was referred with a presumptive diagnosis of thymoma. However, the size and appearance has not changed over a number of years, and our chest radiologists informed me that such an enlarged thymus is not an uncommon incidental finding on chest CT imaging. The degree of thymic enlargement seen in today’s patient, who has myasthenia, is not unusual, but my other patient had more thymic hyperplasia than I have seen in an individual without myasthenia.
Dr Gierada:
Normally by the age of 31 years the thymus will be involuted and replaced by fat. A small percentage of patients will have a fair amount of thymic tissue left at that age, but most do not. If there is no evidence of myasthenia, other causes of hyperplasia should be considered, the most common of which are rebound hyperplasia after chemotherapy or steroid therapy, hyperplasia after therapy for Cushing syndrome, and Graves disease. Other reported associations include autoimmune diseases such as lupus erythematosus, Hashimoto thyroiditis, and Addison disease, as well as acromegaly. Occasionally, a prominent thymus will be observed in a healthy person, but it is not a common finding.
Dr Anderson:
In a patient such as this, is it difficult to make any comment regarding invasion on the basis of CT examination?
Dr Gierada:
Yes, without loss of fat planes or extension into the lung, it is very difficult to make any comment regarding local invasion.
Dr Anderson:
The CT scan was actually reviewed by several radiologists. We had prepared the patient for the worst case scenario. She was aware that this lesion might be a thymoma and that a median sternotomy might be required to accomplish an adequate resection. However, after discussion with the patient and review with our radiology colleagues, we decided that this procedure could commence with a transcervical approach because of the possibility that this was a hyperplastic thymus. We anticipated that if a mass was discovered consistent with a thymoma, we could convert the transcervical approach into a median sternotomy and accomplish a complete resection.
Dr Cooper:
We have encountered this situation before; in 9 of 10 cases the CT images have been "overinterpreted" and the patient is ultimately found to have thymic hyperplasia. In those circumstances, a transcervical approach is satisfactory and, in my opinion, the preferred approach. This patient fits that scenario quite well. She is young and does not have florid or rapidly progressive symptoms of myasthenia gravis. In addition, findings on the CT examination were inconclusive. On the basis of this clinical pattern, we thought a transcervical approach was appropriate. However, it is important to stress that when we are convinced preoperatively that a thymoma is present, we always select a transsternal approach. The transcervical approach is inappropriate for excision of thymoma, except under very unusual circumstances.
Dr Anderson:
The operation commenced with exposure of the thymus through a transcervical approach. On mobilization of the upper poles, the gland seemed hyperplastic. However, as the dissection proceeded into the mediastinum, anterior to the innominate vein, a hard mass was apparent and we realized that we were dealing with a thymoma and not thymic hyperplasia. At this point, we converted from a transcervical approach to a median sternotomy. On exploration of the anterior mediastinum, we discovered a mass arising from the left lower pole of the thymus. Because the mass appeared to invade the pericardium, the pericardium was resected en bloc over the area of fixation. Interestingly, we encountered a degree of adherence as we dissected the tumor from the innominate vein. A tedious dissection was required to mobilize the innominate vein through tumor-free margins. There was no invasion and the innominate vein was preserved. Although the tumor was adjacent to the left phrenic nerve, there was no invasion at that site and the left phrenic nerve was also preserved.
Dr Patterson:
The innominate vein and ipsilateral phrenic nerve should be sacrificed, if necessary, to obtain tumor-free margins.
Dr Johnson:
Fig 3 is an illustration of the cut surface of the gross specimen showing fairly normal thymic and surrounding soft tissue, measuring 8.5 cm in greatest dimension. Within this specimen is the tumor, measuring 6.0 cm in greatest dimension. The lesion has a fairly characteristic appearance, with yellow-tan solid areas admixed with some cystic areas. Quite commonly, thymomas will undergo cystic degeneration and that can complicate the differential diagnosis, requiring one to distinguish between a thymic cyst versus a thymoma that has undergone cystic degeneration. This distinction can only be made histologically. Fig 4 shows the microscopic appearance of normal thymic tissue. Normal thymic tissue in an older person shows yellow adipose tissue admixed with more cellular areas, containing Hassell’s corpuscles and other cellular elements. An even closer view shows the benign-appearing epithelioid cells making up the Hassell’s corpuscles with admixed small, benign lymphocytes (Fig 4). Adjacent to this area is the tumor, showing broad fibrous bands, a very characteristic growth pattern, that dissects through the tumor (Fig 5). Histologic examination of the tumor demonstrates a mainly epithelioid population of fairly round cells with pink cytoplasm, as well as cells that are slightly spindled, with interdigitating small, benign-appearing lymphocytes (Fig 6). These features are consistent with the definition of a thymoma as a lesion with cytologically benign-appearing epithelioid cells derived from thymic epithelial tissue. Other portions of the specimen show a predominant small lymphocytic population. This accentuates the need to extensively sample any thymic tissue. There is a risk of missing the tumor completely, because although some lesions can be multiple, most are focal. The histologic diagnosis in this case was a mixed thymoma. Four general categories are used in classifying thymomas: spindled, epithelial, mixed, and lymphocyte predominant. This raises issues on frozen section diagnosis. During surgery a specimen was submitted by the surgeon as possibly representing the superior pole of the thymus. At low power this area might easily be taken to be thymus, given the presence of fat, small, benign-appearing lymphocytes and apparently epithelioid-like cells. At a higher power, some lymphocytes can be seen, but these are mainly within sinuses, as one would expect in normal lymph nodes. In addition, the epithelioid-like cells are histiocytes. One article reported an error rate of 37% regarding the accuracy of frozen section diagnosis in determining whether a lesion is a thymoma or not. We did see that the tumor came within 1 mm of one of the inked margins, and there was microinvasion mainly with the tumor protruding into the capsule but not extending into the soft tissue (Fig 7). Therefore, according to the widely used Masaoka system, we would classify this lesion as a stage 2-A lesion.
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In any event, the patient ultimately received a median sternotomy. Therefore, in this circumstance, we have a patient who has undergone a neck dissection and subsequently had the same sternotomy that she would have been subjected to anyway. I would like your comments on that.
Dr Cooper:
This raises the question as to how we should best treat a patient with myasthenia caused by thymic hyperplasia. Jaretsky, who was the foremost proponent of radical resection, used a neck incision and a full sternotomy for every thymectomy, even in benign cases. His opinion was that the neck incision was necessary to do a complete resection of thymus and surrounding fat. In addition, sternotomy was required to accomplish radical exenteration of pleura, dissection around both phrenic nerves, excision of all pericardial fat, and pleural stripping. In a previous debate with Dr Jaretsky, I referred to his procedure as a mediastinal exenteration. I used the term in a pejorative sense, but he liked the term so much that he considered it flattery and subsequently adopted the term to describe his radial thymectomy. Then there is the larger group of surgeons who believe that sternotomy alone is the best approach, arguing that the upper poles can be adequately excised through the upper portion of the sternotomy incision. In addition, we have the thoracoscopy advocates who describe a bilateral thoracoscopic approach. The difficulty with this approach is the requirement for multiple small thoracostomy ports, each with a potential for an intercostal nerve injury, as well as the need for a double-lumen tube and arterial line. Finally, our own group believes that a transcervical approach provides the least invasive access, might be better accepted by patients, and therefore might actually encourage a neurologist to refer patients for thymectomy at an earlier stage of their disease. So, Dr Patterson is correct that the approach that is used for these patients is highly controversial. Probably 85% of thymectomies for myasthenia are performed via the sternotomy approach.
Nonetheless, the available data suggest that the transcervical approach, the radical Jaretsky maximal thymectomy approach, and the standard sternotomy used in the Duke series all yield the same 5-year results in comparable groups of patients with myasthenia gravis. One can only conclude that either none of these operations provides any benefit and that the long-term results are entirely due to natural history or that all of these procedures accomplish the same goal. Clearly I prefer to believe the latter explanation.
This particular patient underwent a transcervical approach, which in our experience has proven satisfactory in the vast majority of patients. I suppose one could argue that she paid the price for the other 9 of 10 patients with an indeterminate CT scan who are found to have hyperplasia and for whom the transcervical approach is satisfactory.
Dr Cooper:
Dr Johnson indicated that the lesion was classified as Masaoka stage 2-A. Do you have an illustration showing the infiltration of the capsule?
Dr Ritter:
The limited degree of microscopic capsular invasion can be visualized in Fig 7
.
Dr Meyers:
We believe that the extent of microscopic invasion (stage 2-A or 2-B) is an important distinction and has a significant impact on survival.
Dr Johnson:
Unfortunately, microscopic invasion in the stage 2-A lesion is controversial. No data are currently available to show that microscopic invasion in a stage 2-A lesion has any significant impact on patient prognosis. Furthermore, no studies have answered the question of whether radiation therapy is indicated in these types of lesions. Many centers advocate irradiation for these types of lesions, but no comparison has been made with those patients with the same stage not treated with radiation therapy. It is still an open question.
Dr Cooper:
For many years, we relied on the surgeon’s judgment as to whether the lesion was benign or malignant. Lesions that were believed to be locally invasive at the time of surgery were considered malignant and those that were not adherent to surrounding structures in any way would be judged benign. However, recent information suggests that patients who have microscopic capsular invasion and certainly microscopic invasion into mediastinal fat do have a worse prognosis and should undergo postoperative radiation therapy.
Dr Ritter:
I would be interested to see in large series whether there is any difference in survival between stage 2-A and 2-B disease.
Dr Cooper:
Our inclination is to recommend postoperative radiation in patients with microscopic invasion, whether 2-A or 2-B. We believe that the incidence of local recurrence justifies the risk of mediastinal radiation. I believe that this patient could undergo a course of radiation confined to the upper part of the mediastinum without serious long-term consequences. However, at the age of 31 years she is certainly at risk for having complications of radiation in later life.
Footnotes
This case, with added links and enhanced graphics, is available for further study on the World Wide Web at: http://www.ctsnet.org/doc/3196 . 
Received for publication Oct 25, 1999. Accepted for publication Nov 14, 1999.
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