Ann Thorac Surg 2004;78:411-416
© 2004 The Society of Thoracic Surgeons
Original article: general thoracic
Atypical thymoma: A report of seven patients
Johanna L. Baran, BSa,
Cynthia M. Magro, MDb,
Mark A. King, MDc,
Thomas E. Williams, Jr, MD, PhDd,
Patrick Ross, Jr, MD, PhDd*
a School of Medicine and Public Health, Columbus, OH, USA
b Department of Pathology, Ohio State University, Columbus, OH, USA
c Division of Diagnostic Radiology, Ohio State University, Columbus, OH, USA
d Division of Cardiothoracic Surgery, Ohio State University, Columbus, Ohio, USA
Accepted for publication December 29, 2003.
* Address reprint requests to Dr Ross, Division of Cardiothoracic Surgery, Ohio State University, N839 Doan Hall, 410 West 10th Ave, Columbus, OH 43210, USA
e-mail: ross-3{at}medctr.osu.edu
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Abstract
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BACKGROUND: Most thymic neoplasms fall under the designation of thymoma, consisting of well-differentiated epithelial cells, resembling normal thymus. At the opposite spectrum are thymic carcinomas; the cell of origin while similar is malignant. Recently a third category of thymic neoplasms, atypical thymomas, has been recognized representing thymic neoplasms manifesting atypia although without overt cytomorphologic criteria of malignancy.
METHODS: Seven patients with a diagnosis of atypical thymoma were encountered over a 6-year period from the patient files of the cardiothoracic division of The Ohio State Medical Center.
RESULTS: In all patients there was gross or light microscopic invasive disease with involvement of the capsule, phrenic nerve, diaphragm, chest wall, and lung. Surgical extirpation/de-bulking along with radiation therapy in six and chemotherapy in one led to complete disease regression. Intrathoracic recurrences developed in 4 involving lung, pleura, chest wall and diaphragm. All patients are well.
CONCLUSIONS: Atypical thymomas are locally aggressive tumors with a high incidence of intrathoracic recurrence; extrathoracic spread is not seen. Our study corroborates other reports that death attributable to atypical thymoma is uncommon.
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Introduction
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Most primary thymic epithelial neoplasms represent thymomas, consisting of well differentiated epithelial cells of thymic origin; they exhibit features reminiscent of the normal thymus including a lobulated architecture, the presence of perivascular spaces, Hassall's bodies, and variably intense T-cell rich lymphocytic infiltrate [1, 2]. In the classic thymoma, the neoplastic cellular element demonstrates a benign cytomorphology. At the opposite biological spectrum are thymic carcinomas whereby the cell of origin is thymic in nature, however the cells are malignant [2]. More recently a third category of thymic epithelial neoplasms has been described, representing thymomas with supervening cytologic atypia although from a cytomorphologic perspective the cells are not malignant. Such lesions fall under the designation of atypical thymoma, a term that was coined by Suster and Moran in 1996 and 1997 [2, 3]. The purpose of this study was to better categorize the clinical presentation, surgical aspects, and patient outcome in atypical thymoma.
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Material and methods
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A natural language search was conducted to obtain all pathology reports generated in the Department of Pathology at the Ohio State Medical Center in which thymic tissue was removed by member of the cardiothoracic division of the hospital between 1997 and 2003. A total of 82 patient histories were retrieved, comprising benign lymphoid hyperplasia (18 patients), involuted thymus (10 patients), thymoma (22 patients), atypical thymoma (7 patients), cysts (5 patients), metastatic tumor (4 patients), lymphoma (3 patients), lipoma (3 patients), thymic carcinoma (2 patients), germ cell tumors (2 patients), ectopic parathyroid tissue (2 patients), normal thymic tissue (2 patients), Castleman's disease (1 patient), substernal thyroid tissue (1 patient), and hematoma (1 patient). Atypical thymoma patients comprised 8% and 22% of all thymic epithelial neoplasms fell in the category of atypical thymoma. The follow-up data on these 7 patients was available from 3 months to 23 years (mean follow-up time: 6 years). The histologic diagnosis was verified by a surgical pathologist (CM) in consultation with Dr. Saul Suster (SS) to verify the diagnosis of atypical thymoma.
Specific criteria were applied to allow designation as an atypical thymoma, differentiating it from typical thymoma. The diagnosis of thymoma is based on a proliferation of round or spindled epithelial cells without significant cytologic atypia accompanied by a variable number of lymphocytes, in the context of an intrathymic mass. Mitoses are usually absent. In addition the tumor must exhibit an organotypical growth pattern, the hallmark being a lobulated growth pattern. Hassall's corpuscles are well formed.
In contrast, atypical thymomas while manifesting lobulation and perivascular spaces, exhibit supervening mild to moderate cytologic atypia. The dominant cell type is one comprising round or oval epithelial tumor cells with a sparse to absent lymphocytic component; perivascular palisading is characteristic. Mitoses are present although few in number.
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Results
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Patient demographics and presenting signs/symptoms are presented in Table 1. The patient population comprised 3 females and 4 males (mean age: 49 years old); 2 had a history of myasthenia gravis. Symptoms at initial presentation included fatigue, chest wall discomfort, and respiratory compromise. Two patients were asymptomatic; the thymoma was first detected on routine chest film. A recurrence developed in 3 patients heralded by back pain, pleuritic chest pain, pleural effusion, and a right lung mass and developing 15 years and 23 years (2 recurrences), 6 years, and more than 4 years with involvement of the lung, chest wall, pericardium, diaphragm and ribs (Fig 1).
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Fig 1. Computed tomographic image with mediastinal window reveals a homogeneously attenuating soft tissue mass in the left lower chest wall consistent with recurrence of atypical thymoma.
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Surgical procedures and findings are listed in Table 2. A complete thymectomy with en bloc resection of involved structures was performed in patients 2, 3, 5, 6, and 7 in 1980, 1997, 2001, 2001, and 2003, respectively. Patient 1 was considered unresectable. Resection of recurrent disease included a left lower lobectomy with en bloc resection of the diaphragm and in patient 2, chest wall and diaphragm resection in patient 3, and right middle and bilobectomy in patient 4. The operative records of the original thymectomy (apparently complete) in patient 4 were not available.
Regarding the surgical stage at initial presentation (Table 2), gross capsular involvement was seen in patients 1, 3, 5, and 6; pericardial involvement in patients 1, 3, 5, 6 and 7; phrenic nerve involvement in 5, 6, and 7; great vessel involvement in 1 and 5; visceral pleura in patients 1, 3, 5, 6, and 7; parietal pleural involvement in patients 1, 3, 5, and 6; lung involvement in patients 3, 5, 6, and 7; and chest wall in patient 3 (Fig 2).
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Fig 2. The gross specimen was observed adherent to the chest wall infiltration of the parietal pleura and extending into the rib.
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At the time of recurrence (Table 2), the diaphragm was involved in patients 2, 3, and 4; the lung in the patients 2 and 4; the visceral and parietal pleura in patient 2; parietal pleura only in patient 3; and rib and chest wall involvement in both recurrences in patient 2.
With respect to post surgical adjuvant therapy (Table 3), 24 to 27 treatments over 4 weeks to 4 months were given in patients 1, 2, 3, 5, 6, and 7 following the initial thymectomy. The radiation doses ranged from 4320 cGy to 4850 cGy. Chemotherapy was given in patient 1 and consisted of three courses of cisplatin, adriamycin, vincristine, and cyclophosphamide.
Patient outcome
The follow-up period ranges from 3 months to 23 years (mean 6 years). All patients are alive and well without any evidence of recurrent disease. One patient with unresectable residual disease is stable.
Pathologic findings
The initial resection specimens in 6 patients and the recurrence in 1 patient were compatible with a diagnosis of atypical thymoma (depicted in Figs 2–8). The tumor assumed an organoid lobulated architectural growth pattern separated by dense collagen and vessels with either no lymphocytic infiltrate or a sparse one (Fig 3). The tumor manifested a peripheral palisade around perivascular spaces (Fig 4) The cells were large, exhibiting a polygonal shape with variable amounts of eosinophilic cytoplasm; moderate cellular atypia was seen (Fig 5). Mitoses were rare and appeared atypical (Fig 6). There was variable infiltration of the capsule (2 patients), lung parenchyma (3 patients), rib and adjacent fatty tissue (1 patient; Figs 7 and 8).
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Fig 3. In patient 1 the tumor exhibits a lobulated growth pattern, comprising cohesive nests of large polygonal epithelial cells with only a sparse accompanying lymphocytic infiltrate amid a background of dense collagen (hematoxylin & eosin stain; original magnification x10).
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Fig 4. Characteristically these tumors are revealed palisading around perivascular spaces (hematoxylin & eosin stain; original magnification x20).
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Fig 5. The cells from patient 1 are large polygonal cells with mild to moderate atypia (hematoxylin & eosin stain; original magnification x40).
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Fig 6. In the sample from patient 3 mitoses are present, although few in number (arrow; hematoxylin & eosin stain; original magnification x40).
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Fig 7. The tumor is infiltrating the visceral pleura of the lung (hematoxylin & eosin stain; original magnification x20).
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Fig 8. The tumor is infiltrating bone. This photomicrograph reveals that the bony trabeculae (arrow) juxtaposed to sheets of tumor cells (green triangle) with admixed marrow elements (hematoxylin & eosin stain; original magnification x20).
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Comment
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Thymic epithelial tumors encompass three principle entities: thymoma, atypical thymoma, and thymic carcinoma [2, 4–6]. We have presented the clinical and pathologic features of 7 patients with atypical thymoma, representing 22% of all thymic epithelial neoplasms diagnosed at our institution. Extra-thymic extension including involvement of the great vessels, pericardium and lung parenchyma was characteristic. Recurrence following initial surgery was also very common, occurring in 2 of 3 of all patients and involved the diaphragm, lung and pleura. Paradoxically despite this apparently locally aggressive disease pattern, no patient thus far has succumbed to the disease; the patients have responded well to a combination of surgical debulking in concert with chemotherapy and radiation therapy.
It was Levine and Rosai and later Mackay who first acknowledged that there is a gray zone in which morphologic features of thymoma and thymic carcinoma may overlap [3, 7, 8]. In 1987 Lewis and his colleagues [9] recognized a form of thymoma that differed from typical thymomas by virtue of the presence of cytologic atypism; at the time the existing classification schemes precluded further categorization of such tumors. Similar tumors were later described [10] under the designation of "well-differentiated thymic carcinoma,." In 1999, Suster and Moran [11] introduced the term of atypical thymoma [2, 3, 10, 12, 13] for this distinctive thymic neoplasm.
The World health Organization (WHO) Committee of the International Histologic Classification of Tumors recognizes atypical thymoma under the designation of thymoma B3 [14]. The WHO terminology divides thymomas into type A and type B respectively based on an spindled and epithelioid morphology respectively. Type B thymomas are subdivided into three categories, based on their lymphocytic content and the amount of atypia shown by the epithelial cells. Type B1 thymomas have a prominent lymphocytic component. Type B2 thymomas are characterized by an approximately equal admixture of epithelial cells and lymphocytes. Type B3 thymomas, the atypical thymoma, are composed of epithelioid appearing cells with variable atypia and a sparse lymphocytic infiltrate [15].
All of the patients in our series would have been considered as having either stage III or stage IV disease, according to the clinical staging scheme proposed by Masoka and colleagues. The clinical staging for thymic neoplasms according to their criteria are as follows: Stage I: tumor is macroscopically encapsulated with no microscopic detectable capsular invasion; Stage II: microscopic invasion into the capsule or macroscopic invasion of mediastinal fatty tissue; Stage III, macroscopic invasion of the neighboring structures; Stage IV: pleural or pericardial dissemination, lymphogenous or hematogenous metastasis, or both dissemination and metastasis) [7, 9, 16–20]. Others have also found that atypical thymomas while invading adjacent structures and causing endothoracic metastasis, are rarely fatal [21, 22].
Although there are no specific prior articles addressing the surgical management of atypical thymomas exclusively, the same general principles as used for any thymoma should be applied.
Therefore initial management if surgically feasible is complete surgical resection [14, 22–30]. The standard approach is a median sternotomy with total thymectomy and en bloc resection of involved structures. There is an emerging role for video-assisted thorascopic surgery (VATS) approach to thymic disease, however it is largely reserved for thymic hyperplasia associated with myasthenia gravis and small thymomas [31] and for reoperation after previous transcervical or trans-sternal thymectomies for thymoma [32, 33].
Subtotal excision and/or biopsy has been used for unresectable tumors [19]. In fact biopsies are likely only warranted in those cases which are deemed unresectable, in part because of a potential for spread through biopsy tracks. This complication manifests as pleural recurrence as was first documented by Edmunds and coauthors [34] in their seminal paper on thymoma. In the authors' series, biopsies were performed on 13 of 63 patients due to extensive mediastinal invasion precluding more definitive surgical treatment. Needle tract seeding of other forms of malignancy is also described [35, 36]. We advocate as much tumor de-bulking as possible in cases deemed unresectable followed by post operative adjuvant therapy.
In regards to adjuvant therapy, radiation in completely or incompletely resected stage III or IV thymomas is the standard of care and expectedly was given in all except one of our patients. A study from the Massachusetts General Hospital indicated that up to 22% of stage II thymomas developed recurrences leading to the proposal of postoperative radiation in all stage II thymomas [37, 38, 39]. In our institution radiation therapy is given for all stages higher than I. The efficacy of adjuvant therapy for atypical thymoma is well exemplified by this patient cohort as all the patients who received chemotherapy and radiotherapy in addition to an attempt at surgical extirpation or debulking have done well with minimal morbidity. Chemotherapy is largely given to those cases deemed unresectable either at the initial presentation or in the context of a recurrence [38, 39].
In conclusion, we consider atypical thymoma a distinct clinical and pathologic entity and find the term apposite reflective of its intermediate histology and clinical course. Despite a seemingly indistinct categorization it defines a unique entity. While the enhanced cytologic atypism relative to benign thymoma is translated clinically into more aggressive disease at least locally, the failure to identify unequivocal cytomorphologic criteria of malignancy may denote a better long term clinical outcome compared to overt thymic carcinoma.
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Abstract
Introduction
