Case 12-2005 — A 30-Year-Old Woman with a Mediastinal Mass
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《新英格兰医药杂志》
Presentation of Case
Dr. Rameen Beroukhim (Medical Oncology): A 30-year-old woman was admitted to the hospital because of a fever and a mediastinal mass.
The patient had been in her usual state of health until two months before admission, when pain developed in her left shoulder, arm, and chest, without trauma. She was seen by a nurse practitioner at another facility. On examination, there was tightness of the left trapezius muscle and tenderness to palpation along the costochondral junction. She was treated with ibuprofen, heat, and massage and asked to return if the symptoms worsened.
One month before admission, the patient came to the emergency department of this hospital with persistent left-sided pleuritic chest pain, which radiated from her chest to her shoulder; increased with cough, inspiration, and palpation; and was associated with a cough that was occasionally productive of blood. The vital signs were normal. Breath sounds were decreased on the left side, with splinting and tenderness to palpation. The results of a complete blood count, the levels of serum electrolytes, and results of tests of renal function were normal. A chest radiograph showed consolidation in the lingula of the left lung. The left hilum appeared enlarged, suggesting adjacent air-space disease or lymphadenopathy. She was treated with ibuprofen, levofloxacin (daily for one week), and oxycodone as needed for pain, with follow-up planned for one week, or sooner if symptoms worsened. One week later, she was seen at a follow-up appointment by her primary care physician. Her condition was only slightly improved, and she continued to cough, but no hemoptysis was present. A tuberculin skin test was administered, and two days later the result was negative.
Nineteen days before admission, computed tomographic (CT) scanning of the chest was performed after the intravenous administration of contrast material.
Dr. Suzanne L. Aquino: The initial chest radiograph shows an air-space opacity in the left midlung area that overlies the left hilar region (Figure 1). There is soft-tissue fullness in the left side of the mediastinum overlying the hilum on this single frontal view, suggesting lymphadenopathy or a mass in the area.
Figure 1. Chest Radiograph.
The initial chest radiograph shows soft-tissue fullness (arrow) along the left hilum and mediastinum that obscures the hilar anatomy. There is an air-space opacity in the middle left lung.
A CT scan of the thorax shows a mass, 7.9 cm by 10.4 cm, in the anterior mediastinum (Figure 2A). This soft-tissue mass has areas of low attenuation, suggesting necrosis, and it abuts the right ventricle. There is a small nodule, 1.4 cm in diameter, in the adjacent lingula (Figure 2B). On the lung windows, there is a mixture of both consolidation and ground-glass opacities in the left lung, especially the left upper lobe, with associated thickened interlobular septa. None of the airways or vascular structures were obstructed.
Figure 2. CT Scans of the Thorax.
The initial CT scan (Panel A) of the thorax shows a large mass with low attenuation foci (arrow) that suggests central necrosis. The mass extends anterior to the right ventricle (Panel B). A lingular nodule (arrow) abuts the mediastinal mass. Another CT scan obtained 17 days later (Panel C) shows an increase in the size of the anterior mediastinal mass. There is increased mass effect (Panel D) on the right ventricle (arrow). The adjacent lingular nodule has also increased in size (arrowhead).
Dr. Beroukhim: The next day, the patient embarked on a long-planned two-week vacation, against the advice of her physician. Upon her return, four days before admission, bronchoscopy with bronchoalveolar lavage and transbronchial needle biopsies was performed, on an outpatient basis. The left upper lobe and lingular carinal junction was splayed, and small amounts of blood were present in the left upper and left lower lobe orifices. Histologic examination of multiple biopsy specimens showed necrotic tissue. The fluid obtained was orange and moderately turbid. Cytologic examination revealed bronchial cells and foamy histiocytes, some with intracytoplasmic hemosiderin; no malignant cells were seen. A Gram's stain of the lavage fluid showed no organisms or leukocytes, and the results of an acid-fast smear and fungal wet preparation were negative. Fluid was sent for cultures for respiratory organisms, mycobacteria, and fungi.
Two days before admission, the patient returned to the emergency department with increased pain in the left side of the chest and shortness of breath. Additional imaging studies were obtained.
Dr. Aquino: A chest radiograph shows an increase in air-space opacity in the left lung, with soft-tissue fullness overlying the left hilum and mediastinum. A follow-up CT scan obtained at this time shows that both the mediastinal mass (Figure 2C) and the lingular nodule (Figure 2D) have also increased in size. There is an increase in the mass effect on the right ventricle outflow tract by this enlarging tumor. The air-space disease in the left lung has increased.
Dr. Beroukhim: The hematocrit was 31.8 percent and the hemoglobin level 10.9 g per deciliter; the remainder of the results of the complete blood count, the levels of electrolytes, and the results of renal-function tests were normal.
The next day, the patient returned to the pulmonary clinic. The pain was somewhat improved. There was tenderness to palpation over the left side, from the fifth to the eighth ribs. There were diminished breath sounds in the left lung; the right lung was clear. She had pain when lying down; possibly because of this discomfort, she had an awkward gait. The rest of the examination showed no abnormalities. A Gram's stain of a sputum specimen showed abundant leukocytes and mixed gram-positive and gram-negative organisms, with no predominant organism.
On the day of admission, when the patient was seen for a scheduled appointment in the thoracic surgery clinic, she said that she had had fevers and chills since the previous night. She had had hemoptysis every six hours, pain in the left side of the chest wall and left arm, and poor appetite and fluid intake. The temperature was 38.9°C, and she was admitted to this hospital from the emergency department for further evaluation and treatment.
The patient had been well until this illness. She had immigrated to the United States from Puerto Rico 19 years before admission. She was a homemaker and lived with her husband and children. She did not smoke, consume alcohol, or use drugs intravenously. A sister had received a liver transplant at seven years of age because of hepatitis; her mother had diabetes mellitus; and her maternal grandmother had had cervical cancer. Her medications were oxycodone, for pain, and levofloxacin.
On physical examination, she appeared ill, with sunken eyes and cheeks. The temperature was 36.8°C, the blood pressure 98/61 mm Hg, the pulse 99 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 97 percent while the patient was breathing ambient air. There was no peripheral lymphadenopathy. There were decreased breath sounds in the upper lobe of the left lung, and there was diffuse chest-wall and back pain to palpation. There was a pulsus paradoxus of 4 mm Hg; a jugular venous pressure of 7 cm, with Kussmaul's sign; and a positive pulmonary-artery tap and right ventricular heave, which were thought to be due to her thin body build. The remainder of the examination showed no abnormalities. The temperature increased to 38.5°C and the pulse to 113 beats per minute, and the blood pressure dropped to 84/48 mm Hg. The serum lactate dehydrogenase level was 457 U per liter; the levels of electrolytes, the results of tests of renal and liver function, and the results of other routine laboratory tests and urinalysis were normal. The hematocrit was 32.3 percent, the level of hemoglobin 10.9 g per deciliter, and the mean corpuscular volume 90 fl.
Ceftriaxone (1 g) and fluids were given intravenously, and metronidazole (500 mg), azithromycin (500 mg), and acetaminophen were given orally. On the second and third hospital days, the patient had fatigue, fever as high as 38.8°C, and intermittent hypotension to 78/50 mm Hg. The hematocrit fell to 25.3 percent and then to 24.6 percent. One unit of packed red cells was transfused, and boluses of fluid were administered intravenously. The antibiotic agents were changed to ceftriaxone and clindamycin, and multiple specimens of blood and sputum were sent for culture.
On the fourth hospital day, a diagnostic procedure was performed.
Differential Diagnosis
Dr. Margaret A. Shipp: In summary, this 30-year-old woman had increasingly severe symptoms of cough, hemoptysis, and chest pain, with fever, hypotension, and an elevated serum lactate dehydrogenase level. The most pertinent radiographic finding is a large anterior mediastinal mass encasing the left pulmonary vein. Although I am aware of the diagnosis in this case, it presents an opportunity to discuss the differential diagnosis of a mediastinal mass in a young woman.
The anterior mediastinal compartment, which is located anterior to the pericardium, contains the thymus, lymphatic tissue, great veins, and the extrapericardial aorta and its branches.1 Anterior mediastinal masses are often malignant; the most common tumors are thymomas, germ-cell tumors, and lymphomas (Table 1).1
Table 1. Differential Diagnosis of an Anterior Mediastinal Mass.
Thymomas occur with equal frequency in men and women, most often in adults from 30 to 50 years of age. More than half of thymomas are asymptomatic and are identified incidentally on imaging studies obtained for other reasons. Thymomas may also be found in patients with myasthenia gravis; invasive thymomas may be associated with cough or local discomfort. This patient is at the young end of the age spectrum for thymoma, and such rapid growth would be unusual.
Germ-cell tumors that present as anterior mediastinal masses fall into two categories: benign teratomas and malignant germ-cell tumors. Benign teratomas occur with equal frequency in males and females from infancy through young adulthood. In contrast, malignant germ-cell tumors are most common in young men and are usually symptomatic. Malignant germ-cell tumors that are found as anterior mediastinal masses include both seminomas and nonseminomatous germ-cell tumors. Nonseminomatous germ-cell tumors are frequently associated with elevations in the levels of serum tumor markers, including the beta subunit of human chorionic gonadotropin, alpha-fetoprotein, or both. In this adult woman, primary mediastinal germ-cell tumor would be an unlikely diagnosis.
Lymphomas that predominantly involve the anterior mediastinal masses include classic Hodgkin's lymphoma, precursor T-cell lymphoblastic lymphoma, and a recently identified subtype of large-B-cell lymphoma. Mediastinal Hodgkin's lymphoma is most frequently of the nodular-sclerosis type, which principally affects young adults, with a slight predominance in women. Precursor T-cell lymphoblastic lymphoma arises in the thymus, and is most common in adolescent and young adult men, although women and girls may be affected. The onset is usually acute, with symptoms resulting from compression of the airway and vessels by the mass; pleural and pericardial effusions are common; involvement of extrathoracic lymph nodes, peripheral blood, and bone marrow is common.
During the past 20 years, a subtype of diffuse large-B-cell lymphoma has been identified, termed primary mediastinal large-B-cell lymphoma.2 It occurs in adolescents and young adults, with a median age in the fourth decade; women are affected twice as often as men, and they usually have no disease outside the mediastinum. Patients typically present with a bulky mediastinal mass with intrathoracic extension. Although they are unlikely to have additional systemic involvement at diagnosis, relapsed mediastinal large-B-cell lymphoma often involves unusual extranodal sites, such as the central nervous system, liver, adrenal glands, and kidneys (Table 2).2 Patients with mediastinal large-B-cell lymphoma, similar to those with diffuse large-B-cell lymphomas at other sites, often have an elevated level of serum lactate dehydrogenase.
Table 2. Clinical and Genetic Features of Mediastinal Large-B-Cell Lymphoma.
This patient's age and sex, the pace of progression of her symptoms, the presence of disease confined to the anterior mediastinum, and the elevated level of serum lactate dehydrogenase all argue in favor of a diagnosis of primary mediastinal large-B-cell lymphoma.
Dr. Nancy Lee Harris: Dr. Hales, would you comment on your thoughts before the diagnostic procedure?
Dr. Charles A. Hales (Pulmonary Medicine): The presence of cavitation within the lesion, as Dr. Aquino pointed out while discussing the CT scan, led us to consider tuberculosis, but there was no evidence of it. We ultimately also favored a diagnosis of lymphoma.
Clinical Diagnosis
Lymphoma.
Dr. Margaret A. Shipp's Diagnosis
Primary mediastinal large-B-cell lymphoma.
Pathological Discussion
Dr. Harris: The diagnostic procedure was a Chamberlain minithoracotomy, performed by Dr. Douglas Mathisen. The permanent sections show fine, compartmentalizing sclerosis with a dense cellular infiltrate (Figure 3A). At higher magnification, the cells have large, round, or irregular nuclei with dispersed chromatin, multiple nucleoli, and brisk mitotic activity (Figure 3B). These histologic features are typical of large-cell, non-Hodgkin's lymphoma, but the differential diagnosis includes nonlymphoid neoplasms. Immunoperoxidase staining showed that the neoplastic cells expressed the leukocyte common antigen (CD45) and the B-cell-associated marker (CD20) but did not express immunoglobulin light chains. A stain for Ki-67 showed a high proliferation fraction (>90 percent), and the cells were positive for the germinal-center marker Bcl-6, negative for CD10 and Bcl-2, and positive for the activation antigen CD30. These results confirm the diagnosis of diffuse large-B-cell lymphoma. The combination of clinical and pathologic features is diagnostic of primary mediastinal diffuse large-B-cell lymphoma.
Figure 3. Biopsy Specimen of Mediastinal Mass (Hematoxylin and Eosin).
A medium-power view (Panel A) shows fine, compartmentalizing sclerosis that causes a resemblance to an epithelial neoplasm. A high-magnification photomicrograph (Panel B) shows large, neoplastic cells, most with multiple nucleoli and some with pale-to-clear cytoplasm.
Primary mediastinal diffuse large B-cell lymphoma was first described as an entity in the early 1980s.3,4 Before then — and even since then — it has often been misdiagnosed as a thymoma or a germ-cell tumor. With the advent of immunophenotyping studies, the tumor was identified as a large-B-cell lymphoma. Such tumors typically are composed of cells that resemble centroblasts (large germinal-center cells); rare cases may have larger cells with abundant cytoplasm and prominent nucleoli, resembling Reed–Sternberg cells and giving rise to a differential diagnosis with Hodgkin's lymphoma.5 The cytoplasm is often described as pale or clear and there is typically fine compartmentalizing sclerosis, as in this case, which may cause a resemblance to an epithelial malignancy.6,7 The tumor cells express B-cell-associated antigens, but 70 percent of the cases are negative for immunoglobulin, as this case was, although immunoglobulin genes are rearranged.8 Most cases express the antigen Bcl-6, associated with the germinal center; 25 to 30 percent are positive for CD10, another antigen associated with the germinal center; and a variable proportion express Bcl-2, the antiapoptosis protein, and CD30, a marker associated with Reed–Sternberg cells.9
Recently, expression of the MAL gene, which is associated with T-cell development, and the interleukin-4-induced gene 110 have been shown to be characteristic of primary mediastinal large-B-cell lymphoma. These markers are not available for clinical use, but they suggest that these tumors do have unique biologic features.
The tumor cells have characteristic genetic features, including mutated class-switched immunoglobulin genes without evidence of ongoing somatic hypermutation11 (Table 2). The most frequent genetic abnormalities are gains in chromosomes 2p and 9p, including gains at the JAK2 9p24 and REL 2p16 loci.12,13 In contrast to diffuse large-B-cell lymphomas, primary mediastinal large-B-cell lymphomas rarely have either BCL2 rearrangements or translocations involving BCL6.14
Primary mediastinal large-B-cell lymphoma, despite the fact that it is a B-cell neoplasm, appears to arise in the thymus, a site of T-cell differentiation. At least two cases reported in the literature have been completely confined to the thymus without evidence of lymph-node involvement.7 Although the thymus is the site of antigen-independent T-cell differentiation, a few B cells are found in the normal thymic medulla; these cells are described as asteroid cells, which have an immunophenotype similar to that of those found in mediastinal diffuse large-B-cell lymphoma.15,16
There are two important points to make with regard to this entity. First, the morphologic and immunophenotypic features are not specific and can be found in diffuse large-B-cell lymphomas of other sites. Therefore, the pathologist needs to know the key clinical feature — that is, that the mass is located in the mediastinum — in order to make the correct diagnosis. Since diagnostic biopsy specimens may come from pulmonary extensions or supraclavicular extensions of the tumor, the primary site may not always be obvious from the pathology requisition.
Second, there is morphologic and immunophenotypic overlap with Hodgkin's lymphoma of the nodular sclerosis type.5 Some cases have anaplastic or bizarre morphologic features with abundant cytoplasm and prominent nucleoli, and together with the CD30 expression this can give rise to a differential diagnosis of a lymphocyte-depleted variant of Hodgkin's lymphoma. Cases may also express CD15, a marker associated with Hodgkin's lymphoma, and such cases have been considered to represent a gray zone between diffuse large-B-cell lymphoma and classic Hodgkin's lymphoma.5
Discussion of Management
Dr. Aquino: A gallium scan performed for staging showed intense uptake in the mediastinum that corresponds to the mass. There was no increased uptake in the pulmonary parenchyma and the remaining body uptake was normal.
Dr. Shipp: Patients with mediastinal large-B-cell lymphoma are currently treated with a regimen that is similar to that used for patients with diffuse large B-cell lymphoma of other sites, with a doxorubicin-containing combination chemotherapy regimen. On the basis of findings in randomized cooperative group trials that indicated that more complicated chemotherapy regimens are no more effective than the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) combination, patients with mediastinal large-B-cell lymphoma and diffuse large-B-cell lymphoma usually receive CHOP therapy or similar treatment.17 Studies suggest that adding the B-cell-specific CD20 monoclonal antibody (rituximab) to CHOP induction therapy improves both event-free and overall survival in patients with large-B-cell lymphomas.18 Patients with mediastinal large-B-cell lymphoma with bulky mediastinal disease often receive additional directed radiotherapy after they complete their induction chemotherapy.17 For these reasons, my recommendation for the patient under discussion would be six cycles of CHOP with rituximab followed by radiotherapy to the mediastinal mass.
Analyses of patients with primary mediastinal large-B-cell lymphoma treated before the advent of rituximab use suggest that the treatment has an overall failure rate of approximately 40 percent.17 Clinical prognostic factor classification systems, such as the International Prognostic Index (IPI), are often used to predict the response of diffuse large-B-cell lymphoma to standard combination chemotherapy.19 The clinical features used to define a patient's IPI risk group (low, low-intermediate, high-intermediate, or high risk) include age at diagnosis, stage of disease, level of serum lactate dehydrogenase, performance status, and numbers of extranodal disease sites. The patient under discussion has an elevated level of lactate dehydrogenase and a nonambulatory performance status, which would place her in the low-intermediate risk group or higher.
However, even patients who are successfully treated for primary mediastinal large-B-cell lymphoma remain at risk for long-term side effects. These side effects include an increased risk of breast cancer in the radiation field, cardiac dysfunction, and coronary artery disease, as well as therapy-related acute myeloid leukemias. For these reasons, additional information regarding the genetic features of primary mediastinal large-B-cell lymphoma that might help in the development of rational therapeutic targets would be extremely useful.
To this end, we and others have compared the gene-expression profiles of primary mediastinal large-B-cell lymphoma with those of diffuse large-B-cell lymphoma of other sites.20,21 We found more than 2000 genes that were differentially expressed.20 The mediastinal large-B-cell lymphoma transcriptional signature included several genes previously reported to be expressed at high levels in this disease: the cell-surface protein and lipid-raft component, MAL; and the recently described interleukin-4-induced gene. There were also striking similarities to the expression profile of classic Hodgkin's lymphoma. Like Reed–Sternberg cells, cells in mediastinal large-B-cell lymphoma had low levels of expression of multiple B-cell signaling components and coreceptors and high levels of expression of cytokine pathway components, tumor necrosis factor (TNF) family members, and extracellular matrix elements (Table 3).5,20
Table 3. Genes with Increased Expression in Mediastinal Large-B-Cell Lymphoma.
These observations are of particular interest because mediastinal large-B-cell lymphoma and the most common subtype of classic Hodgkin's lymphoma, nodular sclerosis, have similar clinical presentations: young patients, often women, with localized mediastinal tumors (Table 4). In both mediastinal large-B-cell lymphoma and classic Hodgkin's lymphoma, there is a prominent fibrotic component, and the malignant B cells have decreased expression of immunoglobulin and major-histocompatibility-complex molecules. Both tumors have amplifications of chromosomes 2p and 9p.13,22,23,24 Finally, these two entities may coexist in some patients.5
Table 4. Similarities between Mediastinal Large-B-Cell Lymphoma and Nodular Sclerosis Hodgkin's Lymphoma.
Because the pathological distinction of primary mediastinal large-B-cell lymphoma from other diffuse large-B-cell lymphomas is difficult, we also assessed the possibility that components of the mediastinal large-B-cell lymphoma transcriptional signature might be useful immunohistochemical markers. We looked at TNF-receptor–associated factor 1 (TRAF-1) because of its roles in interleukin-13 signaling and TNF-mediated nuclear factor-B activation and the known expression of TRAF-1 in classic Hodgkin's lymphoma.25,26,27 In immunohistochemical staining, tumor cells of mediastinal large-B-cell lymphoma expressed TRAF-1, whereas cells from diffuse large-B-cell lymphomas lacked this marker.20
In classic Hodgkin's lymphoma, activation of the nuclear factor-B pathway is known to enhance the survival of Reed–Sternberg cells.28 Most cases of primary mediastinal large-B-cell lymphoma exhibit nuclear localization of the nuclear factor-B heterodimer, a feature consistent with activation of the nuclear factor-B pathway.20 These observations taken together suggest that there may be a shared survival pathway in mediastinal large-B-cell lymphoma and classic Hodgkin's lymphoma.
The shared features of mediastinal large-B-cell lymphoma and classic Hodgkin's lymphoma have several therapeutic implications. In both bulky, localized classic Hodgkin's lymphoma and primary mediastinal large-B-cell lymphoma, we irradiate the primary disease site after induction chemotherapy. In the future, we may want to revisit the ideal chemotherapy regimen for primary mediastinal large-B-cell lymphoma and consider agents with proven efficacy in classic Hodgkin's lymphoma. Furthermore, the molecular signature of mediastinal large-B-cell lymphoma suggests additional possible rational therapeutic targets, including the nuclear factor-B pathway and other signaling pathways shared by classic Hodgkin's lymphoma and mediastinal large-B-cell lymphoma.20
Dr. Harris: Dr. Beroukhim, can you tell us about the treatment of this patient and her current status?
Dr. Beroukhim: The patient received six cycles of CHOP chemotherapy with rituximab, which was complicated only by an episode of aseptic meningitis. She then received involved-field radiotherapy to the mediastinum, and is currently in complete remission, 2 years and 5 months after the diagnosis and 18 months after the completion of therapy.
Anatomical Diagnosis
Primary mediastinal diffuse large-B-cell lymphoma.
Dr. Shipp reports receiving consulting fees or lecture fees from Corixa, Millenium Pharmaceuticals, and Eli Lilly.
Source Information
From the Division of Medical Oncology, Dana–Farber Cancer Institute (M.A.S.); the Departments of Radiology (S.L.A.) and Pathology (N.L.H.), Massachusetts General Hospital; and the Departments of Medicine (M.A.S.), Radiology (S.L.A.), and Pathology (N.L.H.), Harvard Medical School.
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Dr. Rameen Beroukhim (Medical Oncology): A 30-year-old woman was admitted to the hospital because of a fever and a mediastinal mass.
The patient had been in her usual state of health until two months before admission, when pain developed in her left shoulder, arm, and chest, without trauma. She was seen by a nurse practitioner at another facility. On examination, there was tightness of the left trapezius muscle and tenderness to palpation along the costochondral junction. She was treated with ibuprofen, heat, and massage and asked to return if the symptoms worsened.
One month before admission, the patient came to the emergency department of this hospital with persistent left-sided pleuritic chest pain, which radiated from her chest to her shoulder; increased with cough, inspiration, and palpation; and was associated with a cough that was occasionally productive of blood. The vital signs were normal. Breath sounds were decreased on the left side, with splinting and tenderness to palpation. The results of a complete blood count, the levels of serum electrolytes, and results of tests of renal function were normal. A chest radiograph showed consolidation in the lingula of the left lung. The left hilum appeared enlarged, suggesting adjacent air-space disease or lymphadenopathy. She was treated with ibuprofen, levofloxacin (daily for one week), and oxycodone as needed for pain, with follow-up planned for one week, or sooner if symptoms worsened. One week later, she was seen at a follow-up appointment by her primary care physician. Her condition was only slightly improved, and she continued to cough, but no hemoptysis was present. A tuberculin skin test was administered, and two days later the result was negative.
Nineteen days before admission, computed tomographic (CT) scanning of the chest was performed after the intravenous administration of contrast material.
Dr. Suzanne L. Aquino: The initial chest radiograph shows an air-space opacity in the left midlung area that overlies the left hilar region (Figure 1). There is soft-tissue fullness in the left side of the mediastinum overlying the hilum on this single frontal view, suggesting lymphadenopathy or a mass in the area.
Figure 1. Chest Radiograph.
The initial chest radiograph shows soft-tissue fullness (arrow) along the left hilum and mediastinum that obscures the hilar anatomy. There is an air-space opacity in the middle left lung.
A CT scan of the thorax shows a mass, 7.9 cm by 10.4 cm, in the anterior mediastinum (Figure 2A). This soft-tissue mass has areas of low attenuation, suggesting necrosis, and it abuts the right ventricle. There is a small nodule, 1.4 cm in diameter, in the adjacent lingula (Figure 2B). On the lung windows, there is a mixture of both consolidation and ground-glass opacities in the left lung, especially the left upper lobe, with associated thickened interlobular septa. None of the airways or vascular structures were obstructed.
Figure 2. CT Scans of the Thorax.
The initial CT scan (Panel A) of the thorax shows a large mass with low attenuation foci (arrow) that suggests central necrosis. The mass extends anterior to the right ventricle (Panel B). A lingular nodule (arrow) abuts the mediastinal mass. Another CT scan obtained 17 days later (Panel C) shows an increase in the size of the anterior mediastinal mass. There is increased mass effect (Panel D) on the right ventricle (arrow). The adjacent lingular nodule has also increased in size (arrowhead).
Dr. Beroukhim: The next day, the patient embarked on a long-planned two-week vacation, against the advice of her physician. Upon her return, four days before admission, bronchoscopy with bronchoalveolar lavage and transbronchial needle biopsies was performed, on an outpatient basis. The left upper lobe and lingular carinal junction was splayed, and small amounts of blood were present in the left upper and left lower lobe orifices. Histologic examination of multiple biopsy specimens showed necrotic tissue. The fluid obtained was orange and moderately turbid. Cytologic examination revealed bronchial cells and foamy histiocytes, some with intracytoplasmic hemosiderin; no malignant cells were seen. A Gram's stain of the lavage fluid showed no organisms or leukocytes, and the results of an acid-fast smear and fungal wet preparation were negative. Fluid was sent for cultures for respiratory organisms, mycobacteria, and fungi.
Two days before admission, the patient returned to the emergency department with increased pain in the left side of the chest and shortness of breath. Additional imaging studies were obtained.
Dr. Aquino: A chest radiograph shows an increase in air-space opacity in the left lung, with soft-tissue fullness overlying the left hilum and mediastinum. A follow-up CT scan obtained at this time shows that both the mediastinal mass (Figure 2C) and the lingular nodule (Figure 2D) have also increased in size. There is an increase in the mass effect on the right ventricle outflow tract by this enlarging tumor. The air-space disease in the left lung has increased.
Dr. Beroukhim: The hematocrit was 31.8 percent and the hemoglobin level 10.9 g per deciliter; the remainder of the results of the complete blood count, the levels of electrolytes, and the results of renal-function tests were normal.
The next day, the patient returned to the pulmonary clinic. The pain was somewhat improved. There was tenderness to palpation over the left side, from the fifth to the eighth ribs. There were diminished breath sounds in the left lung; the right lung was clear. She had pain when lying down; possibly because of this discomfort, she had an awkward gait. The rest of the examination showed no abnormalities. A Gram's stain of a sputum specimen showed abundant leukocytes and mixed gram-positive and gram-negative organisms, with no predominant organism.
On the day of admission, when the patient was seen for a scheduled appointment in the thoracic surgery clinic, she said that she had had fevers and chills since the previous night. She had had hemoptysis every six hours, pain in the left side of the chest wall and left arm, and poor appetite and fluid intake. The temperature was 38.9°C, and she was admitted to this hospital from the emergency department for further evaluation and treatment.
The patient had been well until this illness. She had immigrated to the United States from Puerto Rico 19 years before admission. She was a homemaker and lived with her husband and children. She did not smoke, consume alcohol, or use drugs intravenously. A sister had received a liver transplant at seven years of age because of hepatitis; her mother had diabetes mellitus; and her maternal grandmother had had cervical cancer. Her medications were oxycodone, for pain, and levofloxacin.
On physical examination, she appeared ill, with sunken eyes and cheeks. The temperature was 36.8°C, the blood pressure 98/61 mm Hg, the pulse 99 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 97 percent while the patient was breathing ambient air. There was no peripheral lymphadenopathy. There were decreased breath sounds in the upper lobe of the left lung, and there was diffuse chest-wall and back pain to palpation. There was a pulsus paradoxus of 4 mm Hg; a jugular venous pressure of 7 cm, with Kussmaul's sign; and a positive pulmonary-artery tap and right ventricular heave, which were thought to be due to her thin body build. The remainder of the examination showed no abnormalities. The temperature increased to 38.5°C and the pulse to 113 beats per minute, and the blood pressure dropped to 84/48 mm Hg. The serum lactate dehydrogenase level was 457 U per liter; the levels of electrolytes, the results of tests of renal and liver function, and the results of other routine laboratory tests and urinalysis were normal. The hematocrit was 32.3 percent, the level of hemoglobin 10.9 g per deciliter, and the mean corpuscular volume 90 fl.
Ceftriaxone (1 g) and fluids were given intravenously, and metronidazole (500 mg), azithromycin (500 mg), and acetaminophen were given orally. On the second and third hospital days, the patient had fatigue, fever as high as 38.8°C, and intermittent hypotension to 78/50 mm Hg. The hematocrit fell to 25.3 percent and then to 24.6 percent. One unit of packed red cells was transfused, and boluses of fluid were administered intravenously. The antibiotic agents were changed to ceftriaxone and clindamycin, and multiple specimens of blood and sputum were sent for culture.
On the fourth hospital day, a diagnostic procedure was performed.
Differential Diagnosis
Dr. Margaret A. Shipp: In summary, this 30-year-old woman had increasingly severe symptoms of cough, hemoptysis, and chest pain, with fever, hypotension, and an elevated serum lactate dehydrogenase level. The most pertinent radiographic finding is a large anterior mediastinal mass encasing the left pulmonary vein. Although I am aware of the diagnosis in this case, it presents an opportunity to discuss the differential diagnosis of a mediastinal mass in a young woman.
The anterior mediastinal compartment, which is located anterior to the pericardium, contains the thymus, lymphatic tissue, great veins, and the extrapericardial aorta and its branches.1 Anterior mediastinal masses are often malignant; the most common tumors are thymomas, germ-cell tumors, and lymphomas (Table 1).1
Table 1. Differential Diagnosis of an Anterior Mediastinal Mass.
Thymomas occur with equal frequency in men and women, most often in adults from 30 to 50 years of age. More than half of thymomas are asymptomatic and are identified incidentally on imaging studies obtained for other reasons. Thymomas may also be found in patients with myasthenia gravis; invasive thymomas may be associated with cough or local discomfort. This patient is at the young end of the age spectrum for thymoma, and such rapid growth would be unusual.
Germ-cell tumors that present as anterior mediastinal masses fall into two categories: benign teratomas and malignant germ-cell tumors. Benign teratomas occur with equal frequency in males and females from infancy through young adulthood. In contrast, malignant germ-cell tumors are most common in young men and are usually symptomatic. Malignant germ-cell tumors that are found as anterior mediastinal masses include both seminomas and nonseminomatous germ-cell tumors. Nonseminomatous germ-cell tumors are frequently associated with elevations in the levels of serum tumor markers, including the beta subunit of human chorionic gonadotropin, alpha-fetoprotein, or both. In this adult woman, primary mediastinal germ-cell tumor would be an unlikely diagnosis.
Lymphomas that predominantly involve the anterior mediastinal masses include classic Hodgkin's lymphoma, precursor T-cell lymphoblastic lymphoma, and a recently identified subtype of large-B-cell lymphoma. Mediastinal Hodgkin's lymphoma is most frequently of the nodular-sclerosis type, which principally affects young adults, with a slight predominance in women. Precursor T-cell lymphoblastic lymphoma arises in the thymus, and is most common in adolescent and young adult men, although women and girls may be affected. The onset is usually acute, with symptoms resulting from compression of the airway and vessels by the mass; pleural and pericardial effusions are common; involvement of extrathoracic lymph nodes, peripheral blood, and bone marrow is common.
During the past 20 years, a subtype of diffuse large-B-cell lymphoma has been identified, termed primary mediastinal large-B-cell lymphoma.2 It occurs in adolescents and young adults, with a median age in the fourth decade; women are affected twice as often as men, and they usually have no disease outside the mediastinum. Patients typically present with a bulky mediastinal mass with intrathoracic extension. Although they are unlikely to have additional systemic involvement at diagnosis, relapsed mediastinal large-B-cell lymphoma often involves unusual extranodal sites, such as the central nervous system, liver, adrenal glands, and kidneys (Table 2).2 Patients with mediastinal large-B-cell lymphoma, similar to those with diffuse large-B-cell lymphomas at other sites, often have an elevated level of serum lactate dehydrogenase.
Table 2. Clinical and Genetic Features of Mediastinal Large-B-Cell Lymphoma.
This patient's age and sex, the pace of progression of her symptoms, the presence of disease confined to the anterior mediastinum, and the elevated level of serum lactate dehydrogenase all argue in favor of a diagnosis of primary mediastinal large-B-cell lymphoma.
Dr. Nancy Lee Harris: Dr. Hales, would you comment on your thoughts before the diagnostic procedure?
Dr. Charles A. Hales (Pulmonary Medicine): The presence of cavitation within the lesion, as Dr. Aquino pointed out while discussing the CT scan, led us to consider tuberculosis, but there was no evidence of it. We ultimately also favored a diagnosis of lymphoma.
Clinical Diagnosis
Lymphoma.
Dr. Margaret A. Shipp's Diagnosis
Primary mediastinal large-B-cell lymphoma.
Pathological Discussion
Dr. Harris: The diagnostic procedure was a Chamberlain minithoracotomy, performed by Dr. Douglas Mathisen. The permanent sections show fine, compartmentalizing sclerosis with a dense cellular infiltrate (Figure 3A). At higher magnification, the cells have large, round, or irregular nuclei with dispersed chromatin, multiple nucleoli, and brisk mitotic activity (Figure 3B). These histologic features are typical of large-cell, non-Hodgkin's lymphoma, but the differential diagnosis includes nonlymphoid neoplasms. Immunoperoxidase staining showed that the neoplastic cells expressed the leukocyte common antigen (CD45) and the B-cell-associated marker (CD20) but did not express immunoglobulin light chains. A stain for Ki-67 showed a high proliferation fraction (>90 percent), and the cells were positive for the germinal-center marker Bcl-6, negative for CD10 and Bcl-2, and positive for the activation antigen CD30. These results confirm the diagnosis of diffuse large-B-cell lymphoma. The combination of clinical and pathologic features is diagnostic of primary mediastinal diffuse large-B-cell lymphoma.
Figure 3. Biopsy Specimen of Mediastinal Mass (Hematoxylin and Eosin).
A medium-power view (Panel A) shows fine, compartmentalizing sclerosis that causes a resemblance to an epithelial neoplasm. A high-magnification photomicrograph (Panel B) shows large, neoplastic cells, most with multiple nucleoli and some with pale-to-clear cytoplasm.
Primary mediastinal diffuse large B-cell lymphoma was first described as an entity in the early 1980s.3,4 Before then — and even since then — it has often been misdiagnosed as a thymoma or a germ-cell tumor. With the advent of immunophenotyping studies, the tumor was identified as a large-B-cell lymphoma. Such tumors typically are composed of cells that resemble centroblasts (large germinal-center cells); rare cases may have larger cells with abundant cytoplasm and prominent nucleoli, resembling Reed–Sternberg cells and giving rise to a differential diagnosis with Hodgkin's lymphoma.5 The cytoplasm is often described as pale or clear and there is typically fine compartmentalizing sclerosis, as in this case, which may cause a resemblance to an epithelial malignancy.6,7 The tumor cells express B-cell-associated antigens, but 70 percent of the cases are negative for immunoglobulin, as this case was, although immunoglobulin genes are rearranged.8 Most cases express the antigen Bcl-6, associated with the germinal center; 25 to 30 percent are positive for CD10, another antigen associated with the germinal center; and a variable proportion express Bcl-2, the antiapoptosis protein, and CD30, a marker associated with Reed–Sternberg cells.9
Recently, expression of the MAL gene, which is associated with T-cell development, and the interleukin-4-induced gene 110 have been shown to be characteristic of primary mediastinal large-B-cell lymphoma. These markers are not available for clinical use, but they suggest that these tumors do have unique biologic features.
The tumor cells have characteristic genetic features, including mutated class-switched immunoglobulin genes without evidence of ongoing somatic hypermutation11 (Table 2). The most frequent genetic abnormalities are gains in chromosomes 2p and 9p, including gains at the JAK2 9p24 and REL 2p16 loci.12,13 In contrast to diffuse large-B-cell lymphomas, primary mediastinal large-B-cell lymphomas rarely have either BCL2 rearrangements or translocations involving BCL6.14
Primary mediastinal large-B-cell lymphoma, despite the fact that it is a B-cell neoplasm, appears to arise in the thymus, a site of T-cell differentiation. At least two cases reported in the literature have been completely confined to the thymus without evidence of lymph-node involvement.7 Although the thymus is the site of antigen-independent T-cell differentiation, a few B cells are found in the normal thymic medulla; these cells are described as asteroid cells, which have an immunophenotype similar to that of those found in mediastinal diffuse large-B-cell lymphoma.15,16
There are two important points to make with regard to this entity. First, the morphologic and immunophenotypic features are not specific and can be found in diffuse large-B-cell lymphomas of other sites. Therefore, the pathologist needs to know the key clinical feature — that is, that the mass is located in the mediastinum — in order to make the correct diagnosis. Since diagnostic biopsy specimens may come from pulmonary extensions or supraclavicular extensions of the tumor, the primary site may not always be obvious from the pathology requisition.
Second, there is morphologic and immunophenotypic overlap with Hodgkin's lymphoma of the nodular sclerosis type.5 Some cases have anaplastic or bizarre morphologic features with abundant cytoplasm and prominent nucleoli, and together with the CD30 expression this can give rise to a differential diagnosis of a lymphocyte-depleted variant of Hodgkin's lymphoma. Cases may also express CD15, a marker associated with Hodgkin's lymphoma, and such cases have been considered to represent a gray zone between diffuse large-B-cell lymphoma and classic Hodgkin's lymphoma.5
Discussion of Management
Dr. Aquino: A gallium scan performed for staging showed intense uptake in the mediastinum that corresponds to the mass. There was no increased uptake in the pulmonary parenchyma and the remaining body uptake was normal.
Dr. Shipp: Patients with mediastinal large-B-cell lymphoma are currently treated with a regimen that is similar to that used for patients with diffuse large B-cell lymphoma of other sites, with a doxorubicin-containing combination chemotherapy regimen. On the basis of findings in randomized cooperative group trials that indicated that more complicated chemotherapy regimens are no more effective than the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) combination, patients with mediastinal large-B-cell lymphoma and diffuse large-B-cell lymphoma usually receive CHOP therapy or similar treatment.17 Studies suggest that adding the B-cell-specific CD20 monoclonal antibody (rituximab) to CHOP induction therapy improves both event-free and overall survival in patients with large-B-cell lymphomas.18 Patients with mediastinal large-B-cell lymphoma with bulky mediastinal disease often receive additional directed radiotherapy after they complete their induction chemotherapy.17 For these reasons, my recommendation for the patient under discussion would be six cycles of CHOP with rituximab followed by radiotherapy to the mediastinal mass.
Analyses of patients with primary mediastinal large-B-cell lymphoma treated before the advent of rituximab use suggest that the treatment has an overall failure rate of approximately 40 percent.17 Clinical prognostic factor classification systems, such as the International Prognostic Index (IPI), are often used to predict the response of diffuse large-B-cell lymphoma to standard combination chemotherapy.19 The clinical features used to define a patient's IPI risk group (low, low-intermediate, high-intermediate, or high risk) include age at diagnosis, stage of disease, level of serum lactate dehydrogenase, performance status, and numbers of extranodal disease sites. The patient under discussion has an elevated level of lactate dehydrogenase and a nonambulatory performance status, which would place her in the low-intermediate risk group or higher.
However, even patients who are successfully treated for primary mediastinal large-B-cell lymphoma remain at risk for long-term side effects. These side effects include an increased risk of breast cancer in the radiation field, cardiac dysfunction, and coronary artery disease, as well as therapy-related acute myeloid leukemias. For these reasons, additional information regarding the genetic features of primary mediastinal large-B-cell lymphoma that might help in the development of rational therapeutic targets would be extremely useful.
To this end, we and others have compared the gene-expression profiles of primary mediastinal large-B-cell lymphoma with those of diffuse large-B-cell lymphoma of other sites.20,21 We found more than 2000 genes that were differentially expressed.20 The mediastinal large-B-cell lymphoma transcriptional signature included several genes previously reported to be expressed at high levels in this disease: the cell-surface protein and lipid-raft component, MAL; and the recently described interleukin-4-induced gene. There were also striking similarities to the expression profile of classic Hodgkin's lymphoma. Like Reed–Sternberg cells, cells in mediastinal large-B-cell lymphoma had low levels of expression of multiple B-cell signaling components and coreceptors and high levels of expression of cytokine pathway components, tumor necrosis factor (TNF) family members, and extracellular matrix elements (Table 3).5,20
Table 3. Genes with Increased Expression in Mediastinal Large-B-Cell Lymphoma.
These observations are of particular interest because mediastinal large-B-cell lymphoma and the most common subtype of classic Hodgkin's lymphoma, nodular sclerosis, have similar clinical presentations: young patients, often women, with localized mediastinal tumors (Table 4). In both mediastinal large-B-cell lymphoma and classic Hodgkin's lymphoma, there is a prominent fibrotic component, and the malignant B cells have decreased expression of immunoglobulin and major-histocompatibility-complex molecules. Both tumors have amplifications of chromosomes 2p and 9p.13,22,23,24 Finally, these two entities may coexist in some patients.5
Table 4. Similarities between Mediastinal Large-B-Cell Lymphoma and Nodular Sclerosis Hodgkin's Lymphoma.
Because the pathological distinction of primary mediastinal large-B-cell lymphoma from other diffuse large-B-cell lymphomas is difficult, we also assessed the possibility that components of the mediastinal large-B-cell lymphoma transcriptional signature might be useful immunohistochemical markers. We looked at TNF-receptor–associated factor 1 (TRAF-1) because of its roles in interleukin-13 signaling and TNF-mediated nuclear factor-B activation and the known expression of TRAF-1 in classic Hodgkin's lymphoma.25,26,27 In immunohistochemical staining, tumor cells of mediastinal large-B-cell lymphoma expressed TRAF-1, whereas cells from diffuse large-B-cell lymphomas lacked this marker.20
In classic Hodgkin's lymphoma, activation of the nuclear factor-B pathway is known to enhance the survival of Reed–Sternberg cells.28 Most cases of primary mediastinal large-B-cell lymphoma exhibit nuclear localization of the nuclear factor-B heterodimer, a feature consistent with activation of the nuclear factor-B pathway.20 These observations taken together suggest that there may be a shared survival pathway in mediastinal large-B-cell lymphoma and classic Hodgkin's lymphoma.
The shared features of mediastinal large-B-cell lymphoma and classic Hodgkin's lymphoma have several therapeutic implications. In both bulky, localized classic Hodgkin's lymphoma and primary mediastinal large-B-cell lymphoma, we irradiate the primary disease site after induction chemotherapy. In the future, we may want to revisit the ideal chemotherapy regimen for primary mediastinal large-B-cell lymphoma and consider agents with proven efficacy in classic Hodgkin's lymphoma. Furthermore, the molecular signature of mediastinal large-B-cell lymphoma suggests additional possible rational therapeutic targets, including the nuclear factor-B pathway and other signaling pathways shared by classic Hodgkin's lymphoma and mediastinal large-B-cell lymphoma.20
Dr. Harris: Dr. Beroukhim, can you tell us about the treatment of this patient and her current status?
Dr. Beroukhim: The patient received six cycles of CHOP chemotherapy with rituximab, which was complicated only by an episode of aseptic meningitis. She then received involved-field radiotherapy to the mediastinum, and is currently in complete remission, 2 years and 5 months after the diagnosis and 18 months after the completion of therapy.
Anatomical Diagnosis
Primary mediastinal diffuse large-B-cell lymphoma.
Dr. Shipp reports receiving consulting fees or lecture fees from Corixa, Millenium Pharmaceuticals, and Eli Lilly.
Source Information
From the Division of Medical Oncology, Dana–Farber Cancer Institute (M.A.S.); the Departments of Radiology (S.L.A.) and Pathology (N.L.H.), Massachusetts General Hospital; and the Departments of Medicine (M.A.S.), Radiology (S.L.A.), and Pathology (N.L.H.), Harvard Medical School.
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