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Journal of Clinical Oncology, Vol 26, No 10 (April 1), 2008: pp. 1752-1755 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.5656
Widespread Metastases After Resection of Noninvasive ThymomaDepartment of Medicine, Akron General Medical Center, Akron, OH
Department of Medicine, Akron General Medical Center, Akron; Northeastern Ohio Universities College of Medicine, Rootstown, OH
Department of Pathology, Akron General Medical Center; Northeastern Ohio Universities College of Medicine, Rootstown, OH
Section of Hematology and Medical Oncology, Department of Medicine, Akron General Medical Center; Northeastern Ohio Universities College of Medicine, Rootstown, OH A 77-year-old white female presented with new onset dyspnea on exertion. Two-dimensional echocardiogram revealed normal systolic function and a solid mass abutting the right atrium. Contrast-enhanced computed tomography (CT) scan of the chest confirmed an 11 x 9 cm anterior mediastinal mass. Due to concern for a hypervascular tumor, an open incisional biopsy of the mass was performed. Histologic sections (Fig 1) revealed a nested epithelial tumor predominantly composed of oval to spindle cells lacking atypia or mitosis that were arranged in rosettes. The tumor was positive for keratin and negative for chromogranin, S-100 protein, and synaptophysin—findings that supported a diagnosis of thymoma. The patient subsequently underwent complete resection of a 12 x 10 x 9 cm tumor with extensive removal of pleuropericardial fat pads. There was no evidence of gross invasion to contiguous structures in the chest although the surgeon noted adhesion of the tumor to the right middle lobe of the lung. Histopathological examination did not demonstrate any evidence of microscopic invasion through the capsule or into blood vessels, pleura, or any adjacent structures, including the area of tumor adhesion to pulmonary tissue. The pleuropericardial fat pads and associated lymph nodes were likewise negative for malignancy. A diagnosis of noninvasive thymoma, Masaoka stage I (Table 1) was created. No adjuvant treatment was thus indicated. The patient never developed symptoms of myasthenia gravis or any other paraneoplastic syndrome. Surveillance chest CT 8 months after resection revealed absence of tumor recurrence. Fourteen months after thymectomy, the patient presented to the emergency department with grand-mal seizures. Magnetic resonance imaging (MRI) of the brain (Fig 2) showed multiple, intra-axial, ring-enhancing lesions in the cerebral and cerebellar hemispheres, the largest of which measured 2.2 x 2.6 cm located in the left frontal-parietal region. Chest CT scan revealed superior and middle mediastinal lymphadenopathies, the largest measuring 2.2 cm, which were absent on previous imaging. Further evaluation with abdominopelvic CT and bone scan was unrevealing. The patient underwent a stereotactic, minimally invasive craniotomy for resection of the left frontal-parietal mass. Histologic sections of this lesion (Fig 3) demonstrated a well-circumscribed, cellular neoplasm with a compact arrangement of oval to spindle cells with rosette formation that was positive for keratin and negative for chromogranin, S-100 protein, and synaptophysin. Previous slides from the mediastinal thymoma were reviewed and due to the resemblance between the brain and mediastinal tumors, metastasis from thymoma was considered. The unusual occurrence of brain metastasis from a noninvasive thymoma prompted a case review by Juan Rosai, MD (Genzyme; Milan, Italy), who concurred with the diagnosis of thymoma metastatic to the brain (J Rosai, personal communication, March 2006). Additionally, Dr Rosai classified the original mediastinal tumor as WHO type A (Table 2). The patient received whole brain radiation therapy and subsequently underwent gamma-knife stereotactic radiosurgery at the Cleveland Clinic Foundation (Cleveland, OH) for the nonresected brain lesions. Surveillance CT scans of the head showed no progression of disease; however, follow-up chest CT showed interval progression of mediastinal lymphadenopathy. She continued follow-up and had an uneventful course until 11 months after discharge when she was found to have enhancing mass lesions in the liver, the largest measuring 3.3 x 2.7 cm on abdominal MRI (Fig 4). Ultrasound guided biopsy revealed epithelial cells compatible with metastatic thymoma. Chemotherapy was offered at this time, but the patient refused and opted only for palliative care. Four months later, the patient was readmitted to the hospital due to right leg weakness. There were no new lesions on brain MRI; however, MRI of the thoracic spine demonstrated spinal cord compression at the T2-T3 level by an intradural, well-circumscribed 2 cm ovoid mass (Fig 5) that was thought to be metastatic in nature due to its anatomic location. She received high-dose steroid and radiation therapy and was eventually discharged to hospice for palliative care. She eventually died two months later, 31 months after her initial diagnosis of thymoma.
The Masaoka system is the most widely accepted system for staging thymomas (Table 1).1 According to this classification, stage I tumors are well encapsulated and lack macroscopic or microscopic invasiveness and are thus considered benign. In contrast, stages II to IV, which exhibit invasiveness are considered malignant despite the absence of clear-cut cytologic atypia, a feature of thymic carcinomas.2,3 Numerous studies have shown that the Masaoka staging system is the single most important prognostic variable among patients with thymoma.4,5 Five-year survival rates after complete surgical resection have been shown to be tightly correlated with disease stage, and are 93% to 100%, 86% to 95%, 69% to 81%, and 50% to 61% for stage I, II, III, and IV, respectively.1,4,6 In 1999, a WHO committee led by Dr Juan Rosai proposed a histologic classification system for thymic epithelial tumors (TET) that stratified thymomas into five distinct entities (type A, AB, B1, B2, and B3) and differentiated them from thymic carcinomas (type C), based on the absence or presence, respectively, of overt cytological features of malignancy such as atypia, anaplasia, and increased mitoses (Table 2).2 The WHO classification correlates well with the Masaoka staging system and has been shown to be an important prognostic indicator among patients with TET, with 5- and 10-year survival rates of 100% and 95%, 93% and 90%, 89% and 85%, 82% and 71%, and 71% and 40%, for type A, AB, B1, B2, and B3, respectively.4,7 The 5-year survival rate for type C is 23%.7 Our patient's original mediastinal tumor was a noninvasive, stage I, type A thymoma that was completely resected but recurred in the mediastinal lymph nodes and metastasized to the brain, liver, and thoracic spine after 14, 25, and 29 months, respectively. Complete surgical excision is considered curative for stage I thymomas,9,11 and therefore adjuvant radiotherapy is not indicated based on studies that have shown local or intrathoracic recurrence rates after complete resection of only 0% to 4%.6,8-12 Review of literature validates that stage I tumors do not metastasize extrathoracically after complete resection.9-11,13 When studied according to the WHO classification, no recurrence was noted for type A thymomas.10-12 Thymomas in general, are known to recur locally with a few reported cases of postoperative metastasis to the liver and bone.8,13 To the best of our knowledge, this is the first reported case of a noninvasive, stage I, type A thymoma that metastasized to extrathoracic sites (brain, liver, and thoracic spine) after complete resection of the original tumor. A review of the literature revealed one case of thymoma with widespread metastases to brain and other distant organs; that case however, presented as untreated metastatic disease with the diagnosis established postmortem.14 Our patient, on the other hand, presented as stage I disease that was treated with complete surgical resection before eventual metastasis to the brain and other organs. Thus we look into other factors that might explain the unusual clinical outcome of our patient's tumor. The presence of intraoperative adhesions in our patient's original tumor deems consideration. In a study of 283 cases treated at the Mayo Clinic (Rochester, MN), it was noted that postoperative recurrences among patients who underwent complete resection of noninvasive thymomas were significantly higher among those who had intraoperative adhesions (20%) versus those who had none (7.7%).15 Another study involving 307 patients revealed that noninvasive thymomas recurred only among patients who were noted to have significant intraoperative adhesions despite the absence of gross and microscopic invasion.16 Based on these findings, a modified staging system was proposed which subclassified stage I into Ia and Ib, based on the absence and presence, respectively, of peritumoral adherences in these tumors. We, therefore, reintroduce the question of whether there is in fact a need to amend the Masaoka staging system specifically to take into account the presence or absence of adhesions in stage I patients. Several scholars have observed transformation of low-grade histologic subtypes to higher-grade histologic subtypes in recurrent thymomas.17,18 Our patient's original tumor was composed predominantly of oval to spindle cells, which falls into the category of spindle cell thymoma based on the traditional classification of thymomas proposed in 1961, which is essentially regarded as the equivalent of WHO type A.1,19 In several reports by independent investigators, spindle cell thymoma was shown to progress and transform into a higher grade of malignancy.20,21 Another consideration as to why metastasis occurred in our patient may have been the size of the original tumor. In a retrospective study of 179 patients at Massachusetts General Hospital (Boston, MA), TET of 8 cm or larger were found to have a significantly increased recurrence rate (< 8 cm, 1.8%; > 8 cm, 28%), and were more likely to be stage III or IV than to be stage I or II, and WHO type B1 or greater than A or AB.22 Thus, size was considered an independent predictor for recurrence. Other studies have also ascribed worse outcomes to larger tumors, but did not investigate the association in detail.8,15 It is possible, due to the large size of our patient's original tumor, that some areas of the tumor with more adverse histological features were missed. The clinical behavior of our patient's tumor, along with other reported cases of noninvasive thymomas that recurred despite complete removal, emphasizes the unpredictability of thymomas. Several studies have demonstrated the role of oligonucleotide microarrays and real-time quantitative reverse transcription polymerase chain reaction as potentially useful approaches in identifying molecular differences between early-stage (stage I or II) and late-stage (stage IVa) thymomas.23,24 It was found that late-stage thymomas had a higher expression of certain genes when compared to early-stage thymomas, and that these genes may be used as candidate molecular markers that correlate with tumor progression and invasiveness. Further research, particularly in the field of molecular biology, could provide better predictors of tumor recurrence and metastasis that may be of paramount importance for patients who are thought to have benign pathology by stage and histologic grade. Finally, we suggest that stage I thymomas be further subdivided according to the presence or absence of intraoperative adhesions in light of the current evidence ascribing increased recurrence rates to tumors with adhesions despite absence of invasion. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS We thank Juan Rosai, MD, whose invaluable contributions led to the precise diagnosis of this case, as well as Judy Knight, MLS, and Melissa Trace of the Akron General Medical Center Library for their assistance with the references. REFERENCES 1. Masaoka A, Monden Y, Nakahara K, et al: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48:2485-2492, 1981[CrossRef][Medline] 2. Rosai J, Sobin LH: Histological Typing of Tumours of the Thymus (ed 2). New York, NY, Springer, 1999, pp 9-15 3. Engels EA, Pfeiffer RM: Malignant thymoma in the United States: Demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 105:546-551, 2003[CrossRef][Medline] 4. Kim DJ, Yang WI, Choi SS, et al: Prognostic and clinical relevance of the World Health Organization schema for the classification of thymic epithelial tumors: A clinicopathological study of 108 patients and literature review. Chest 127:755-761, 2005[CrossRef][Medline] 5. Chen G, Marx A, Wen-Hu C, et al: New WHO histologic classification predicts prognosis of thymic epithelial tumors: A clinicopathologic study of 200 thymoma cases from China. Cancer 95:420-429, 2002[CrossRef][Medline] 6. Rena O, Papalia E, Maggi G, et al: World Health Organization histologic classification: An independent prognostic factor in resected thymomas. Lung Cancer 50:59-66, 2005[CrossRef][Medline] 7. Park MS, Chung KY, Kim KD, et al: Prognosis of thymic epithelial tumors according to the new World Health Organization histologic classification. Ann Thorac Surg 78:992-998, 2004 8. Blumberg D, Port JL, Weksler B, et al: Thymoma: A multivariate analysis of factors predicting survival. Ann Thorac Surg 60:908-914, 1995 9. Haniuda M, Miyazawa M, Yoshida K, et al: Is postoperative radiotherapy for thymoma effective? Ann Surg 224:219-224, 1996[CrossRef][Medline] 10. Lardinois D, Rechsteiner R, Lang RH, et al: Prognostic relevance of Masaoka and Muller-Hermelink classification in patients with thymic tumors. Ann Thorac Surg 69:1550-1555, 2000 11. Sonobe S, Miyamoto H, Izumi H, et al: Clinical usefulness of the WHO histological classification of thymoma. Ann Thorac Cardiovasc Surg 11:367-373, 2005[Medline] 12. Okumura M, Ohta M, Tateyama H, et al: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: A clinical study of 273 patients. Cancer 94:624-632, 2002[CrossRef][Medline] 13. Park HS, Shin DM, Lee JS, at al: Thymoma: A retrospective study of 87 cases. Cancer 73:2491-2498, 1994[CrossRef][Medline] 14. Yoshida A, Shigematsu T, Mori H, et al: Non-invasive thymoma with widespread blood-borne metastasis. Virchows Arch A Pathol Anat Histol 390:121-126, 1981[CrossRef][Medline] 15. Lewis JE, Wick MR, Scheithauer BW, et al: Thymoma. A clinicopathologic review. Cancer 60:2727-2743, 1987 16. Regnard JF, Magdeleinat P, Dromer C, et al: Prognostic factors and long-term results after thymoma resection: A series of 307 patients. J Thorac Cardiovasc Surg 112:376-384, 1996 17. Nakahara K, Ohno K Hashimoto I, et al: Thymoma: Results with complete resection and adjuvant postoperative irradiation in 141 consecutive patients. J Thorac Cardiovasc Surg 95:1041-1047, 1988[Abstract] 18. Pescarmona E, Rendina EA, Venuta F, et al: Recurrent thymoma: Evidence for histological progression. Histopathology 27:445-449, 1995[CrossRef][Medline] 19. Bernatz PE, Harrison EG, Clagett OT: Thymoma: A clinicopathological study. J Thorac Cardiovasc Surg 42:424-444, 1961[Medline] 20. Kuo TT, Chan JKC: Thymic carcinoma arising in thymoma is associated with alterations in immunohistochemical profile. Am J Surg Pathol 22:1474-1481, 1998[CrossRef][Medline] 21. Suster S, Moran CA: Spindle cell thymic carcinoma: Clinicopathologic and immunohistochemical study of a distinctive variant of primary thymic epithelial neoplasm. Am J Surg Pathol 23:691-700, 1999[CrossRef][Medline] 22. Wright CD, Wain JC, Wong DR, et al: Predictors of recurrence in thymic tumors: Importance of invasion, World Health Organization histology, and size. J Thorac Cardiovasc Surg 130:1413-1421, 2005 23. Sasaki H, Ide N, Fukai I, et al: Gene expression analysis of human thymoma correlates with tumor stage. Int J Cancer 101:342-347, 2002[CrossRef][Medline] 24. Sasaki H, Ide N, Yukiue H, et al: Arg and DAP3 expression was correlated with human thymoma stage. Clin Exp Metastasis 21:507-513, 2004[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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