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Table. Immunohistochemical Profile of LFTP and Other Similar Neoplasms
Vimentin
Keratin
CD34
CD99
Bcl-2
LFTP
Positive
Negative
Positive
Positive
Positive
Malignant
mesothelioma
Negative
Positive
Negative
Negative
Negative
Hemangiopericytoma
Positive
Negative
Positive
Unusual
Variable
Fibrosarcoma
Positive
Negative
Negative
Negative
Variable
Fibrous histiocytoma
Positive
Negative
Negative
Variable
Variable
3.69 Answer: D
A recent review by de Perrot and colleagues summarized the results of 15 publications
pertaining to LFTP documented by adequate histologic and immunohistochemical techniques.
In this review, tumor histology (i.e., benign versus malignant) and morphology (i.e.,
pedunculated versus sessile) were used to evaluate the rates of tumor recurrence and disease-
related death. Patients with malignant sessile tumors had the highest rate of recurrence (63%),
with 23% dying of tumor within 24 months of diagnosis. Malignant pedunculated tumors had
a much lower rate of recurrence (14%), followed by benign sessile tumors (8%) and benign
pedunculated tumors (2%). Most recurrences are isolated to the ipsilateral hemithorax,
although blood-borne metastases to the liver, brain, spleen, peritoneum, adrenal gland,
gastrointestinal tract, and other organs may be seen.
References
de Perrot M, Fischer S, Bründler MA, et al. Solitary fibrous tumors of the pleura. Ann Thorac
Surg. 2002;74:285-293.
England DM, Hochholzer L, McCarthy MJ. Localized benign and malignant fibrous tumors
of the pleura. A clinicopathologic review of 223 cases. Am J Surg Pathol. 1989;13:640-
658.
3.70 Answer: C
In the BTS randomized feasibility study collaborating centres registered all new patients
with
mesothelioma. Those eligible and giving informed consent completed
EORTC QLQ-
C30+LC13 and FACT-L QL questionnaires and were randomized
between all three or any
two of (1) ASC only, (2) ASC+4 cycles
of MVP (mitomycin C, vinblastine, and cisplatin) (3)
ASC+12 weekly doses of venorelbine (N).
During 1 year, 242 patients were registered of whom
109 (45%) were randomised (55%
of the 197 eligible patients).
Fifty two patients from 20 centres were randomized to an option
including ASC only.
This randomized feasibility study has shown that, in the treatment of malignant
pleural
mesothelioma, randomization to ASC with or without chemotherapy
was sufficiently
acceptable to patients and clinicians for a
large multicentre randomized trial comparing active
symptom control (ASC) only versus
ASC+MVP versus ASC+N to be feasible. Of the patients
eligible
for randomisation, 55% were randomised between all three or
any two of the
treatment groups, half of whom accepted a randomisation
option including ASC only.
The EORTC QL questionnaire was superior to FACT-L in
terms of completeness of data
and patient preference. The study was not powered to make reliable comparisons between
the
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270
treatment groups, but an important finding is that clinically
relevant levels of palliation were
achieved with ASC only.
Reference
Muers MF, Rudd RM, O'Brien ME, et al. BTS randomised feasibility study of active
symptom control with or without chemotherapy in malignant pleural mesothelioma:
ISRCTN 54469112. Thorax. 2004;59:144-148.
3.71 Answer: C
The MED trial assessed
the use of early versus delayed cytotoxic therapy. The study
opened in 1998, and closed in view of a competing national study
(MSO 1) in 2003. Eligible
patients had a performance status 2, life
expectancy >3 months and had stable symptoms for
at least
4 weeks prior to randomisation. Patients were randomised to
receive immediate
chemotherapy or initial best supportive care with the addition
of chemotherapy at time of
symptomatic progression. All patients
received the same platinum-based chemotherapy
regimen, MVP [mitomycin
C 8 mg/m
2
cycles 1, 2, 4 and 6, vinblastine 6 mg/m
2
, maximum
10
mg, and cisplatin 50 mg/m
2
(or carboplatin AUC 5)], every
3 weeks for up to six cycles.
A total of 43 patients were recruited, of which 21
were randomised to the early treatment
group and 22 to the delayed
treatment group. The median ages were 59 years (range 50–78)
and 67 years (range 48–75), respectively (P = 0.1); other
baseline parameters were well
matched between the two groups.
All 21 patients in the early group received chemotherapy
versus
17 patients in the delayed group. Median time to symptomatic
progression was 25
weeks in the early group compared with 11
weeks for the delayed group (P = 0.1). Median
survival was 14
months (1-year survival 66%) for the early group compared with
10 months
(1-year survival 36%) for the delayed group (P = 0.1).
Quality of life was in general better
maintained for early treatment
and the health resources use was similar in both arms.
The trial
was not powered to detect a difference in overall survival,
but the patients whose
treatment was delayed had a marginally
poorer survival (median 14 versus 10 months; P =
0.1)
even after adjusting for performance status (P = 0.1).
Reference
O‘Brein ME, Watkins D, Ryan C, et al. A randomised trial in malignant mesothelioma (M) of
early (E) versus delayed (D) chemotherapy in symptomatically stable patients: the MED
trial. Ann Oncol. 2006;17:270-5.
3.72 Answer: E
Autoimmune myasthenia gravis (MG) encompasses all of the immunologically-mediated
disorders affecting the endplate region of the postsynaptic neuromuscular junction. Nearly all
of these disorders involve a loss of immunological self-tolerance, though transitory neonatal
MG is a self-limited disorder that follows passive transfer of maternal antibodies to the fetus.
Congenital myasthenic syndromes stem from genetic mutations that result in abnormal
neuromuscular transmission.
Although MG is rare, prevalence rates for MG have increased over time, likely due to
improvements in diagnosis and treatment. Recent prevalence rates approach 20/100,000. A
wide range of incidence is reported with an estimate of about 2.0 to 10.4/million/year in
Virginia to 21.27/million/year in Barcelona, Spain. The onset of MG is influenced by gender
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and age in a bimodal fashion. In patients younger than 40, women predominate with a ratio of
7:3. In the fifth decade, new cases of MG are evenly distributed between men and women.
After age 50, new cases of MG are slightly more common in men with a ratio of 3:2.
In MG, patients present with fluctuating and fatigable weakness of specific muscle
groups rather than with generalized fatigue or pain. The weakness is variable from day to day
and from hour to hour, but it is generally worse later in the day. Sustained exercise and
increased body temperature may increase the degree of weakness. Ocular weakness with
asymmetric ptosis and binocular diplopia is the most common initial presentation, while early
or isolated oropharyngeal or limb weakness is less common.
Ocular weakness presents as fluctuating, fatigable, and sometimes alternating ptosis and
binocular diplopia that resolves with closing or covering one eye. Many patients report
difficulties with driving, reading, or watching television. Bright lights may be quite
bothersome. Retrospectively, many patients report periods of intermittent blurred vision
before they were able to discern dual visual images. Examination may demonstrate
asymmetrical weakness of multiple extraocular muscles that cannot be attributed to a single
cranial neuropathy. Pupillary function is normal. Ptosis may be elicited or increased with
sustained upgaze. In MG, ptosis is generally asymmetrical, and it may be associated with
ipsilateral frontalis muscle contraction to help compensate for the weak levator palpebrae.
Excessive lid elevation or Cogan's lid twitch sign may be observed when gaze is directed
from down to upward.
References
Juel VC. Massey JM. Myasthenia gravis. Orphanet J Rare Dis. 2007;2:44.
Phillips LH 2nd. The epidemiology of myasthenia gravis. Ann NY Acad Sci. 2003;998:407–
412.
3.73 Answer: E
Autoimmune myasthenia gravis (MG) results from antibody-mediated, T cell-dependent
immunologic attack on the postsynaptic membrane of the neuromuscular junction. Abnormal
neuromuscular transmission and clinical weakness in MG result from the effects of antibodies
that bind to various epitopes of the skeletal muscle endplate region. In most cases, antibodies
bind to the main immunogenic region of the α-subunit of the acetylcholine receptor (AChR).
In seropositive MG, binding of antibody to the AChR initiates autoimmune attack on the
endplate region. Subsequent damage to the postsynaptic membrane results in simplification of
the normal, highly-infolded surface that is accompanied by reduced number and density of
AChR. The functional loss of AChRs reduces the probability of successful neuromuscular
transmission following quantal release of acetylcholine by the motor nerve terminal, resulting
in clinical weakness in striated muscles.
MG and other autoimmune disorders result from the loss of tolerance to self-antigens. T-
lymphocyte tolerance to self-antigens is established in the thymus, and thymic abnormalities
are often present in MG. Thymic hyperplasia is observed in about 65% of MG patients, and
thymomas are present in about 10% of MG patients. MG patients with thymoma have more
severe and generalized weakness, higher AChR antibody titers, and more severe
electrophysiologic abnormalities. Accordingly, patients with seronegative and ocular MG are
less likely to have thymomas.
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272
References
Juel VC. Massey JM. Myasthenia gravis. Orphanet J Rare Dis. 2007;2:44.
Santa T, Engel AG, Lambert EH. Histomeric study of neuromuscular junction ultrastructure I.
Myasthenia gravis. Neurology. 1972;22:71-82.
3.74 Answer: B
Thymomas represent the most common mediastinal neoplasm as well as the most
common anterior mediastinal compartment neoplasm, constituting about 20% and 50% of all
mediastinal and anterior compartment tumors occurring in the adult population, respectively.
However, the overall incidence of thymoma is rare, with 0.15 cases per 100,000, based on
data from the National Cancer Institute Surveillance, Epidemiology, and End Results
Program. Thymoma is an epithelial tumor generally considered to have an indolent growth
pattern but malignant nonetheless because of potential for local invasion, pleural
dissemination, and even systemic metastases. Most patients are between the age of 40 and 60
years at the time of diagnosis with an equal gender distribution. Approximately one-third of
patients with localized disease at presentation are symptomatic, most commonly reporting
cough or vague chest discomfort. Patients demonstrating either locally advanced or
disseminated thymoma at the time of presentation are usually symptomatic with significant
chest pain, shortness of breath from lung involvement, phrenic nerve paralysis, pleural
effusions, and/or SVC syndrome.
Of unique interest, several immune disorders have been associated with thymoma.
Abnormal regulation of lymphocytes within the thymus gland can result in autoimmunity
and/or immunodeficiency. Autoimmunity may also be caused by cross immunity of antigens
in other tissues with thymoma associated antigens. As a result, several end organs may be
affected and more than one immunologic disorder may be present in any given patient
diagnosed with a thymoma. Myasthenia gravis is the most common autoimmune disease
associated with thymoma. Approximately 30% to 65% of patients with thymoma have been
diagnosed with myasthenia gravis in reported series. Conversely, only 10% to 15% of patients
with myasthenia gravis will have a thymoma. Patients with thymoma associated myasthenia
gravis can produce autoantibodies to a variety of neuromuscular antigens, particularly the
acetylcholine receptor and titin, a striated muscle antigen. Up to 28% of thymoma patients
will present with an immune disorder other than myasthenia gravis. The most common
include pure red cell aplasia, lupus erythematosus, and hypogammaglobulinemia.
References
Wright CD, Kessler KA. Surgical treatment of thymic tumors. Semin Thorac Cardiovasc
Surg. 2003;17:20-26.
Engels EA, Pfeiffer RM. Malignant thymoma in the United States: Demographic patterns in
incidence and associations with subsequent malignancies. Int J Cancer. 2003;105:546-
551.
Morgenthaler TI, Brown LR, Colby TV, et al. Thymoma. Mayo Clin Proc. 1993;68:1110-
1123.
Souadjian JV, Enriquez P, Silverstein MN, Pépin JM. The spectrum of diseases associated
with thymoma: Coincidence or syndrome?. Arch Intern Med. 1974;154:374-379.
Thoracic Surgery: Answers
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Voltz RD, Albrich WC, Nägele A, et al. Paraneoplastic myasthenia gravis: Detection of anti-
MGT30 (titin) antibodies predicts thymic epithelial tumor. Neurology. 1997;49:1454-
1457.
Gautel M, Lakey A, Barlow DP, et al. Titin antibodies in myasthenia gravis: Identification of
a major immunogenic region of titin. Neurology. 1993;43:1581-1585.
3.75 Answer: A
Chest computed tomography (CT) scan with intravenous contrast is the radiologic
examination of choice for evaluation of all mediastinal masses in the anterior compartment.
Multiple different types of anterior mediastinal masses may be encountered on CT imaging,
and many of these lesions are neoplastic in etiology. These include masses arising from the
thymus, thyroid and parathyroid glands, as well as lymph nodes, pericardium, and vessels and
nerves. Often, the CT attenuation of the mass can be helpful in narrowing down the
differential diagnosis, and attenuation values suggesting fat, water or calcium may suggest
certain diagnoses; significant enhancement of the mass with intravenous contrast may also be
a helpful feature. Lesions with fatty attenuation include teratomas, thymolipomas and
Morgagni hernias. Lesions that may manifest the attenuation of water include pericardial and
thymic cysts, abscesses, and lymphangiomas, as well as neurogenic and germ cell tumors.
Multiple types of lesions may contain calcium, including thyroid goiters and cancers,
thymomas, thymic carcinomas and carcinoids, treated lymphoma, germ cell tumors,
parathyroid adenomas, and lymph nodes involved with silicosis, sarcoid, tuberculosis, fungal
diseases and pneumocystis. Contrast enhancement may be seen in lesions of vascular origin
and in vascular neoplasms, such as parathyroid adenomas and Castleman's disease. In
addition to CT attenuation values, the exact location and morphology of the mass in question,
in conjunction with clinical features such as patient age, gender, signs, symptoms, and
laboratory values, can usually lead to a short list of possible etiologies, thereby directing
appropriate additional diagnostic procedures or therapeutic approaches.
References
Takahashi K, Al-Janabi NJ. Computed tomography and magnetic resonance imaging of
mediastinal tumors. J Magn Reson Imaging. 2010;32:1325-39.
Quint LE. Imaging of anterior mediastinal masses. Cancer Imaging. 2007;7 Spec No A:S56-
62.
Rebner M, Gross BH, Robertson JM, et al. CT evaluation of mediastinal masses. Comput
Radiol. 1987;11:103-10.
3.76 Answer: A
In type A thymoma, the neoplastic epithelial cells assume an elongated or spindle cell
appearance and are arranged in fascicles or in a whorling storiform pattern, superficially
resembling a mesenchymal tumor. The spindled epithelial cells of type A thymoma may
express the B-cell marker CD20, in contrast to cortical thymomas which are CD20 negative.
Lymphocytes are typically sparse and have the phenotype of mature, medullary thymocytes
(CD4+ or CD8+, CD1a−, TdT−). This quality of the admixed lymphocytes may be helpful in
cases difficult to classify based on epithelial cell features alone. An unusual variant known as
micronodular thymoma is characterized by small nodules of spindled epithelial cells in a
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274
background of predominantly B-cells with lymphoid follicles. Type A thymomas are
significantly more likely to be lower stage than type B thymomas.
References
Hasserjian RP, Ströbel P, Marx A. Pathology of thymic tumors. Semin Thorac Cardiovasc
Surg. 2005;17:2-11.
Pan CC, Chen WY, Chiang H. Spindle cell and mixed spindle/lymphocytic thymomas: An
integrated clinicopathologic and immunohistochemical study of 81 cases. Am J Surg
Pathol. 2001;25:111-120.
3.77 Answer: E
In contrast to type A thymomas, the type B (cortical) thymomas have ovoid or polygonal
epithelial cells and immature, cortical-type (double CD4+ 8+, CD1a+, TdT+) thymocytes.
The latter cells are most abundant in type B1 thymoma and may obscure the rather
inconspicuous, scattered epithelial cells. Cytokeratin staining often highlights more epithelial
cells than is evident on routine histology. A hallmark of type B1 thymoma is the presence of
focal medullary differentiation, manifested by small pale areas of somewhat more elongated
epithelial cells within a background of mature, medullary-type thymocytes which is less
dense than the surrounding cortical areas. Because this characteristic pattern of both cortical
and medullary-like areas recapitulates normal thymic structure, this pattern is often referred to
as ‗organoid‘. Although often large, among the cortical-type thymomas, type B1 is the most
likely to be low stage.
In contrast to Type B1 thymomas, pale areas of medullary differentiation are absent or
rare in Type B2 thymomas. The epithelial cells are more numerous, larger, and have more
distinct nucleoli than those of Type B1 thymoma. Lymphocytes are still frequent and have an
immature, cortical thymocyte phenotype. The frequent epithelial cells are readily identifiable
on routine histology, and may form clusters or trabeculae. Perivascular spaces (edematous
areas surrounding tumor blood vessels) are commonly seen in this type of thymoma.
Among the cortical thymomas, Type B3 has the highest ratio of epithelial cells to
thymocytes. In contrast to Types B1 and B2 thymomas, the epithelial cells in this type are
atypical, rounded cells with small, irregular nuclei, abundant pale cytoplasm and sharply
defined cell borders. Areas of squamous differentiation and even keratinization may be
present. Some cases may have a spindled appearance which may lead to confusion with the
much more indolent Type A thymoma; however, the spindled epithelial cells will manifest
cytologic atypia, which should not be present in Type A thymoma. Type B3 thymoma almost
always has genetic abnormalities, in contrast to the typically diploid Type A and AB
thymomas.
References
Hasserjian RP, Ströbel P, Marx A. Pathology of thymic tumors. Semin Thorac Cardiovasc
Surg. 2005;17:2-11.
Zettl A, Ströbel P, Wagner K, et al. Recurrent genetic aberrations in thymoma and thymic
carcinoma. Am J Pathol. 2000;157:257-266.
Gschwendtner A, Fend F, Hoffmann Y, et al. DNA-ploidy analysis correlates with the
histogenetic classification of thymic epithelial tumours. J Pathol. 1999;189:576-580.
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3.78 Answer: D
In 1981, Masaoka initially proposed an anatomic classification based on the presence or
absence of gross or microscopic invasion of the capsule and the presence or absence of
metastases. This classification was subsequently revised in 1994. Several studies have
attempted to correlate morphologic staging systems with tumor invasion and prognosis. The
Masaoka staging system (Table) remains as the most widely accepted staging system on
which current management recommendations are based.
Table. Modified Masaoka Clinical Staging of Thymoma
Masaoka
Stage
Diagnostic Criteria
Stage I
Macroscopically and microscopically completely encapsulated
Stage II
A. Microscopic transcapsular invasion
B. Macroscopic invasion into surrounding fatty tissue or grossly adherent to but not
through mediastinal pleura or pericardium
Stage III
Macroscopic invasion into neighboring organs (i.e., pericardium, great vessels,
lung)
A. Without invasion of great vessels
B. With invasion of great vessels
Stage IV
A. Pleural or pericardial dissemination
B. Lymphogenous or hematogenous metastasis
References
Wright CD, Kessler KA. Surgical treatment of thymic tumors. Semin Thorac Cardiovasc
Surg. 2003;17:20-26.
Masaoka A, Yamakawa Y, Niwa H. Thymectomy and malignancy. Eur J Cardiothoracic
Surg. 1994;8:251-253.
3.79 Answer: C
The operative morbidity and mortality is low for otherwise healthy patients with thmoma
even following extensive resections. Premorbid conditions such as myasthenia gravis and
other autoimmune and immunodeficient states may adversely affect the outcome of surgery.
Operative morbidity, particularly respiratory morbidity, in patients with myasthenia gravis
can approach the low risk of patients without myasthenia in centers who frequently treat these
patients. Aggressive use of preoperative plasmapheresis and immunoglobulin therapy can
minimize perioperative weakness even in severe cases of myasthenia. It has previously been
reported that the presence of a thymoma is associated with poor remission of myasthenia
gravis after thymectomy. However, de Perrot and coworkers found that myasthenia gravis
patients with thymoma were significantly older and demonstrated a male predominance. After
adjusting for age and gender, these authors speculated that there was no difference in
myasthenia gravis remission rates after thymectomy. Previous reports have also cited
myasthenia gravis as a negative prognostic factor for long-term survival; however, more
recent large series have not found myasthenia gravis to negatively influence survival.
The Masaoka staging system stratifies survival fairly well. In the largest series published
to date, Kondo reported on 1,320 patients treated at 115 centers in Japan with 100% and 98%
Shahzad G. Raja
276
overall 5-year survival following complete surgical excision for Stages I and II respectively.
Stage III patients experienced an 88% 5-year survival, which included a small subset of
patients who were either deemed unresectable or underwent less than complete surgical
resection. Patients presenting in Masaoka Stages IVA and IVA demonstrated rather
remarkable 70% and 52% 5-year survival rates, respectively. The WHO histologic type of
tumor also stratifies survival well and has been found to be an independent predictor of
survival in multivariable models. The Table below lists the prognostic factors that have been
identified in multivariable analysis in recent reports.
Table. Prognostic Factors in Thymic Tumors
Masaoka stage (no difference between stage I and II, significant differences between Stage I,
II, and III and between III and IV)
WHO histology (no difference between A and AB, significant differences between A, AB,
and B1, B2, B3, and C)
Complete resection
Size
Great vessel invasion
References
Wright CD, Kessler KA. Surgical treatment of thymic tumors. Semin Thorac Cardiovasc
Surg. 2003;17:20-26.
Masaoka A, et al. Follow-up study of thymoma with special reference to their clinical stages.
Cancer. 1981;48:2485-2492.
Masaoka A, Yamakawa Y, Niwa H, et al. Thymectomy and malignancy. Eur J
Cardiothoracic Surg. 1994;8:251-253.
Kondo K, Monden Y. Therapy for thymic epithelial tumors: A clinical study of 1,320 patients
from Japan. Ann Thorac Surg. 2003;76:878-885.
Budde JM, Morris CD, Gal AA, et al. Predictors of outcome in thymectomy for myasthenia
gravis. Ann Thorac Surg. 2001;72:197-202.
de Perrot M, Liu J, Bril V, et al. Prognostic significance of thymomas in patients with
myasthenia gravis. Ann Thorac Surg. 2002;74:1658-1662.
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 1996;112:376-
384.
3.80 Answer: B
Thymic tumors, including thymomas, invasive thymomas, and thymic carcinomas, are
predominantly surgical diseases. The majority of patients with thymic tumors present with
early stage disease and are cured with surgical excision, with or without postoperative
radiation therapy. For the patient who presents with unresectable stage III or IV disease, or
for the patient who experiences recurrence of disease after an attempt at cure, chemotherapy
can play a significant role in ensuring long-term survival and offering palliation.
Thymic tumors are sensitive to chemotherapy. This was discovered through the treatment
of patients with advanced thymic tumors for whom surgery and radiation were not options.
Response rates in the metastatic setting range from 30% to 60%. These responses can often be
Thoracic Surgery: Answers
277
durable, although cures are not common. If chemotherapy can lead to responses in the
diffusely metastatic setting, it is therefore possible that chemotherapy may improve long-term
disease-free survival rates for patients who are surgical candidates. Chemotherapy may also
transform a patient with inoperable disease into a patient with operable disease. While
randomized, controlled data are lacking in part because of the rarity of thymic tumors, there is
evidence supporting the ability of chemotherapy to accomplish both of these goals.
References
Evans TL, Lynch TJ. Role of chemotherapy in the management of advanced thymic tumors.
Semin Thorac Cardiovasc Surg. 2005;17:41-50.
3.81 Answer: A
Malignant thymomas are usually slow-growing tumors with an indolent natural history.
Although histologically benign, they are capable of local and regional invasion with a marked
tendency of recurrence in the mediastinum and pleura. Intrathoracic recurrence can develop
after complete surgical resection up to 40% of those with invasive disease. Also, late relapse
is not uncommon requiring prolonged follow-up.
Although the role of adjuvant radiation for thymomas has never been tested in a
prospective randomized fashion, radiation therapy is an effective adjuvant therapy for
invasive thymomas, as these tumors are usually radioresponsive. In patients with Masaoka
stage II disease with gross fibrous adhesions of the tumor to the pleura at the time of surgery
or microscopic invasion of the pleura on histology, there is an increased risk for recurrence.
Haniuda and colleagues found that patients with fibrous adhesion to the mediastinal pleura
without microscopic invasion benefited the most from postoperative radiation therapy. The
recurrence rates, with and without adhesion to the mediastinal pleura, were 36.4% versus 0%,
respectively. In a study by Monden and colleagues, there was a 29% recurrence rate for
patients with resected stage II thymoma who did not undergo adjuvant radiation therapy, as
compared with an 8% recurrence rate with postoperative irradiation. Although postoperative
radiation therapy has been shown to be effective at decreasing local recurrence in completely
resected invasive thymoma, it does not appear to decrease the incidence of subsequent pleural
dissemination that may occur in these patients whose pleurae are usually outside of radiation
fields and not treated. In Haniuda‘s study, 12 of the 13 (92%) recurrences were pleural
dissemination. This may be a reflection of the natural pattern of spread of this disease with
pleural dissemination occurring even before, during, or after the time of surgery.
Unfortunately, extended irradiation to include the entire pleura significantly increases the
normal tissue complications, and thus is not routinely employed.
References
Eng TY, Thomas CR. Radiation therapy in the management of thymic tumors. Semin Thorac
Cardiovasc Surg. 2005;17:32-40.
Cohen DJ, Ronnigen LD, Graeber GM, et al. Management of patients with malignant
thymoma. J Thorac Cardiovasc. 1984;87:301-307.
Ohara K, Tatsuzaki H, Fuji H, et al. Radioresponse of thymomas verified with histologic
response. Acta Oncologica. 1998;37:471-474.
Haniuda M, Morimoto M, Nishimura H, et al. Adjuvant radiotherapy after complete resection
of thymoma. Ann Thorac Surg. 1992;54:311-315.
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Haniuda M, Miyazawa M, Yoshida K, et al. Is postoperative radiotherapy for thymoma
effective?. Ann Surg. 1996;224:219-224.
Monden Y, Nakahara K, Iioka S, et al. Recurrence of thymoma: Clinicopathological features,
therapy, and prognosis. Ann Thorac Surg. 1985;39:165-169.
3.82 Answer: C
For stage III/IV disease, the evidence supporting the use of postoperative radiation
therapy is more apparent. Urgesi and colleagues reported no in-field recurrences in a study of
33 patients with completely resected stage III thymoma given postoperative irradiation. All
three recurrences occurred out-of-field. Curran and associates reported a 53% 5-year actuarial
mediastinal relapse rate in those with stage II/III who did not receive post operative radiation
therapy, comparing to 0% for those receiving radiation after total resection, or 21% for those
after subtotal resection or biopsy. Similarly, in another study of 70 patients with Masaoka
stage III/IV thymoma, the relapse rate in patients receiving postoperative radiation therapy
was reduced from 50% to 20%, and most of these recurrences (80%) occurred outside of the
irradiated field.
For locally advanced, large, invasive thymomas that are unresectable or marginally
resectable, preoperative adjuvant radiation therapy has been advocated to render it resectable.
Several studies on limited numbers of patients who received preoperative radiotherapy for
extensive disease note a decrease in tumor burden at the time of surgery with response rates
as high as 80%, and describe a theoretical decrease in the potential for tumor seeding during
surgery. These series report that preoperative irradiation facilitated total or subtotal resection
of the invasive thymoma mass by reducing the tumor volume.
Combining radiotherapy with chemotherapy and/or surgery can be effective with
acceptable results, even in cases of locally advanced or metastatic thymoma. Neoadjuvant
chemotherapy followed by surgery and adjuvant radiotherapy may improve the survival of
patients with locally advanced thymoma. Induction chemotherapy may be effective at down-
staging thymoma, allowing patients initially thought not to be surgical candidates to undergo
resection. In a study reported by Shin and colleagues, induction chemotherapy consisting of
cyclophosphamide, doxorubicin, and cisplatin was given to patients with unresectable stage
III and IV thymoma. Out of eleven patients initially thought to be unresectable, nine were
able to undergo complete resection. All nine patients were given additional postoperative
adjuvant chemotherapy and radiotherapy. Out of these patients, seven were disease-free at a
median follow-up period of 43 months. Although chemo-radiation appears effective and may
be appropriate for some patients with locally advanced unresectable malignant thymoma,
higher rates of complications including hematologic toxicity are expected.
The optimal treatment of thymic carcinoma remains unclear at present, owing to the
rarity of the disease. Although surgical extirpation remains the cornerstone of treatment in
most published studies, surgery has often been followed by radiation therapy. A prescriptive
dose range has yet to be identified, with most studies using 40 to 70 Gy with standard
fractionation scheme (1.8 to 2.0 Gy/fraction). Although a survival benefit has not been seen,
there is a trend toward improved survival and local control. No dose-related advantage in
mortality has been established, though a relationship between dose and local control has been
demonstrated. In a series of 26 patients treated with surgery and postoperative radiation
without chemotherapy, Hsu and coworkers observed a 77% 5-year overall survival, with
respective 82% and 66% survival rates for completely resected and subtotally resected