DOI: 10.1148/rg.262055183
RadioGraphics 2006;26:607-620
© RSNA, 2006
Oncodiagnosis Panel: 2004
Lymphoma1
Chul S. Ha, MD,
L. Jeffrey Medeiros, MD,
Chusilp Charnsangavej, MD,
Michael Crump, MD and
Mary K. Gospodarowicz, MD
1 From the Departments of Radiation Oncology (C.S.H.), Hematopathology (L.J.M.), and Diagnostic Radiology (C.C.), University of Texas M. D. Anderson Cancer Center, Unit 97, 1515 Holcombe Blvd, Houston, TX 77030; and the Departments of Medicine (M.C.) and Radiation Oncology (M.K.G.), University of Toronto Princess Margaret Hospital, Toronto, Ontario, Canada. From the Oncodiagnosis Panel at the 2004 RSNA Annual Meeting. Received September 29, 2005; revision requested November 21 and received December 21; accepted December 22. All authors have no financial relationships to disclose.
Address correspondence to C.S.H. (e-mail: chulha{at}mdanderson.org).
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Introduction
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The diagnosis and management of lymphoma have undergone significant changes in the past two decades. With the advent of routinely available immunophenotypic and molecular methods of assessing lymphomas, it became clear that traditional histology-based classification schemes for lymphoma (eg, the 1982 Working Formulation [1]) were inadequate. Pathologists then began modifying these traditional classification schemes with additional data in an attempt to further define disease entities. In 1994, a group of hematopathologists independently collated all available information into a formal system that they termed the Revised European American Lymphoma (REAL) classification scheme (2). This proposed scheme was later modified and expanded and was published in 2001 under the aegis of the World Health Organization (WHO) (3). The WHO classification scheme, although still reliant on histologic findings, also attempts to incorporate all pertinent data, such as clinical presentation, immunophenotype, and cytogenetic and molecular data. As a result, many diseases are now better defined, ultimately helping clinicians better understand and treat disease. A combined REAL-WHO classification scheme for lymphoma is summarized in the Table.
There have also been many significant advances in the staging and treatment of lymphoma. Fluorine 18 deoxyglucose positron emission tomography (PET) has evolved into an important staging tool and prognostic indicator in many different kinds of lymphoma. The role of radiation therapy in the management of lymphoma, especially in patients with early-stage Hodgkin lymphoma, has also undergone a significant change. The introduction of anti-CD20 antibody therapy has probably been one of the most significant advances in many decades in the treatment of patients with B-cell lymphoma. This year’s Oncodiagnosis Panel was opportunely dedicated to lymphoma. Leading experts in hematopathology (L.J.M.), diagnostic radiology (C.C.), radiation oncology (M.K.G.), and medical oncology (M.C.) formed a multidisciplinary team to discuss different aspects of the six cases presented in this article, call attention to pertinent literature, and make treatment recommendations. The cases presented herein include classical Hodgkin lymphoma, high-grade B-cell lymphoma with Burkitt-type morphologic features, extranodal marginal zone B-cell lymphoma of MALT, diffuse large B-cell lymphoma, synchronous manifestation of sarcoma and lymphoma, and primary central nervous system (CNS) lymphoma.
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Case 1
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A 21-year-old man presented with a 3-month history of an enlarging lymph node in the right side of the neck. Results of laboratory studies, including a complete blood cell count and serum chemistry analyses, were within normal limits.
Diagnostic Radiologist’s View
Computed tomographic (CT) scans of the neck revealed a group of enlarged lymph nodes in the right side of the neck extending from the angle of the mandible down to the lower neck. Most of these lymph nodes were 1–2 cm in size. PET revealed hypermetabolic nodes along the right side of the neck that corresponded to the lymphadenopathy identified at neck CT (Fig 1). CT scans of the chest, abdomen, and pelvis showed no evidence of the disease.
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Figure 1a. Stage I Hodgkin disease. (a) CT scan obtained at the level of the submandibular region shows enlarged nodes (arrows) at the right submandibular region along the right internal jugular vein (arrowhead). P = parotid gland, SM = sternocleidomastoid muscle. (b) CT scan obtained at the level of the thyroid cartilage (TC) shows the enlarged nodes (arrows) along the right internal jugular vein (arrowhead). SM = sternocleidomastoid muscle. (c, d) CT scans obtained at the levels of the larynx (c) and lower neck (d) show the enlarged nodes (arrows) in the right side of the neck compressing the right internal jugular vein (arrowhead). T = thyroid gland. (e) PET scan shows increased glucose uptake (arrow) in the area of the nodes.
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Figure 1b. Stage I Hodgkin disease. (a) CT scan obtained at the level of the submandibular region shows enlarged nodes (arrows) at the right submandibular region along the right internal jugular vein (arrowhead). P = parotid gland, SM = sternocleidomastoid muscle. (b) CT scan obtained at the level of the thyroid cartilage (TC) shows the enlarged nodes (arrows) along the right internal jugular vein (arrowhead). SM = sternocleidomastoid muscle. (c, d) CT scans obtained at the levels of the larynx (c) and lower neck (d) show the enlarged nodes (arrows) in the right side of the neck compressing the right internal jugular vein (arrowhead). T = thyroid gland. (e) PET scan shows increased glucose uptake (arrow) in the area of the nodes.
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Figure 1c. Stage I Hodgkin disease. (a) CT scan obtained at the level of the submandibular region shows enlarged nodes (arrows) at the right submandibular region along the right internal jugular vein (arrowhead). P = parotid gland, SM = sternocleidomastoid muscle. (b) CT scan obtained at the level of the thyroid cartilage (TC) shows the enlarged nodes (arrows) along the right internal jugular vein (arrowhead). SM = sternocleidomastoid muscle. (c, d) CT scans obtained at the levels of the larynx (c) and lower neck (d) show the enlarged nodes (arrows) in the right side of the neck compressing the right internal jugular vein (arrowhead). T = thyroid gland. (e) PET scan shows increased glucose uptake (arrow) in the area of the nodes.
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Figure 1d. Stage I Hodgkin disease. (a) CT scan obtained at the level of the submandibular region shows enlarged nodes (arrows) at the right submandibular region along the right internal jugular vein (arrowhead). P = parotid gland, SM = sternocleidomastoid muscle. (b) CT scan obtained at the level of the thyroid cartilage (TC) shows the enlarged nodes (arrows) along the right internal jugular vein (arrowhead). SM = sternocleidomastoid muscle. (c, d) CT scans obtained at the levels of the larynx (c) and lower neck (d) show the enlarged nodes (arrows) in the right side of the neck compressing the right internal jugular vein (arrowhead). T = thyroid gland. (e) PET scan shows increased glucose uptake (arrow) in the area of the nodes.
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Figure 1e. Stage I Hodgkin disease. (a) CT scan obtained at the level of the submandibular region shows enlarged nodes (arrows) at the right submandibular region along the right internal jugular vein (arrowhead). P = parotid gland, SM = sternocleidomastoid muscle. (b) CT scan obtained at the level of the thyroid cartilage (TC) shows the enlarged nodes (arrows) along the right internal jugular vein (arrowhead). SM = sternocleidomastoid muscle. (c, d) CT scans obtained at the levels of the larynx (c) and lower neck (d) show the enlarged nodes (arrows) in the right side of the neck compressing the right internal jugular vein (arrowhead). T = thyroid gland. (e) PET scan shows increased glucose uptake (arrow) in the area of the nodes.
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Hematopathologist’s View
Histologic sections demonstrated a large lymph node in which the architecture was almost completely replaced by malignant neoplasm that was vaguely to more distinctly nodular. The nodules were composed of numerous mononuclear variant cells consistent with lacunar cells in a background of small lymphocytes, histiocytes, and eosinophils. Rare diagnostic Reed-Sternberg cells were also identified. Immunohistochemical studies showed that the neoplastic cells were positive for CD15 and CD30 and negative for CD45, findings that supported the diagnosis of classical Hodgkin lymphoma (Fig 2) (4). The presence of a nodular pattern, lacunar cells, and focal fibrosis, as well as the clinical-pathologic setting, were most suggestive of nodular sclerosis type Hodgkin lymphoma. Bone marrow biopsy showed no evidence of lymphoma. However, the final diagnosis given was stage IA nodular sclerosis type classical Hodgkin lymphoma.
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Figure 2. Nodular sclerosis type classical Hodgkin lymphoma. Large photomicrograph (original magnification, x1000; hematoxylin-eosin [H-E] stain) shows numerous neoplastic lacunar cells (arrows) in a background of small lymphocytes, histiocytes, and eosinophils. Small photomicrographs (original magnification, x400; immunohistochemical stain) show that the neoplastic cells are positive for CD15 (inset, upper left) and CD30 (inset, lower right), findings that support the diagnosis of nodular sclerosis type Hodgkin lymphoma.
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The classification of Hodgkin lymphoma has undergone little change since the introduction of the Lukes-Butler classification scheme in 1966 (5). The WHO classification scheme includes three relatively minor changes to the Lukes-Butler classification scheme (3). First, the term Hodgkin disease has been changed to Hodgkin lymphoma, since the B-cell origin of almost all cases of Hodgkin lymphoma has been established. Second, the WHO classification scheme makes a distinction between nodular lymphocyte–predominant Hodgkin lymphoma and the other types of so-called classical Hodgkin lymphoma. Third, a new type of classical Hodgkin lymphoma is now recognized—lymphocyte-rich classical Hodgkin lymphoma—of which there are nodular and diffuse variants (6). There are four main types of classical Hodgkin lymphoma: nodular sclerosis, mixed cellularity, lymphocyte-depleted, and lymphocyte-rich types.
Medical and Radiation Oncologists’ Views
What Are the Management Options?—
Subtotal nodal radiation therapy used to be the standard treatment for patients with early-stage Hodgkin lymphoma, yielding a high cure rate (7). However, there has been growing concern over the use of this modality because the treatment-related mortality rate, especially with a second malignancy, continues to rise even after apparent cure from Hodgkin lymphoma (8,9). Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, which was initially developed for treatment of advanced or recurrent disease, has been tried in patients with early-stage disease in an attempt to reduce the dose and volume of radiation. In a recently published Milan trial, patients with stage I or stage II Hodgkin lymphoma were randomly assigned to undergo either subtotal nodal radiation therapy or involved-field radiation therapy after four cycles of ABVD chemotherapy (10). With a median follow-up of 116 months, there was no difference between the two groups in terms of freedom from progression and overall survival rates. This trial helped to establish four cycles of ABVD followed by involved-field radiation therapy as the standard treatment for stage I or stage II Hodgkin lymphoma. The European Organization for Research and Treatment of Cancer H8-F trial randomly assigned 543 patients with favorable stage I or stage II Hodgkin lymphoma to undergo either subtotal nodal radiation therapy or combined-modality treatment (11). The latter consisted of three cycles of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine chemotherapy followed by involved-field radiation therapy. Interim analysis with a median follow-up of 46 months showed that combined-modality treatment had a 4-year treatment failure–free survival rate of 99%, compared with 77% for subtotal nodal radiation therapy (P = .001). The 4-year overall survival rates were 99% for combined-modality treatment and 96% for subtotal nodal radiation therapy (P = .067) (11). The same approach also appears to be effective in patients with early-stage unfavorable Hodgkin lymphoma. In the HD8 trial conducted by the German Hodgkin’s Lymphoma Study Group, 1064 patients with unfavorable stage I or stage II Hodgkin lymphoma were randomly assigned to receive two cycles of cyclophosphamide, vincristine, procarbazine, and prednisone and ABVD, followed by radiation therapy consisting of either (a) 30 Gy to the extended field with a 10-Gy boost to the bulky disease, or (b) 30 Gy to the involved field with a 10-Gy boost to the bulky disease (12). With a median follow-up of 54 months, there was no significant difference between the two groups in terms of overall survival rates and freedom from treatment failure.
The patient in this case was treated with six cycles of ABVD chemotherapy, with CT and PET showing a complete response. Involved-field radiation therapy was performed on the right side of the neck (total dose, 30.6 Gy; 17 fractions). The superior asymmetric jaw of this field was lowered by 4 cm after 30.6 Gy; for the rest of the field, total dose was taken to 36 Gy at the same fraction size.
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Case 2
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A 61-year-old woman presented with an enlarging mass in the left lower neck and epigastric discomfort. Biopsy of the mass was performed.
Diagnostic Radiologist’s View
CT scans of the chest revealed enlarged left inferior cervical and supraclavicular nodal masses displacing the trachea to the right of midline. There were also enlarged paraesophageal lymph nodes. CT scans of the abdomen and pelvis revealed a large retroperitoneal mass surrounding the abdominal aorta, displacing the pancreas anteriorly, and extending into the mesentery. This lymphadenopathy also extended to the common iliac chains. PET showed multicompartmental hypermetabolic lymphadenopathy consistent with active lymphoma on both sides of the diaphragm, including left infraclavicular and supraclavicular, right paraesophageal, and extensive abdominal lymphadenopathy (Fig 3).
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Figure 3a. Stage III Burkitt-like diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the lower neck shows enlarged supraclavicular lymph nodes (arrows) in the left lower neck. The left common carotid artery (arrowhead) is markedly displaced. (b) CT scan obtained at the level of the subcarinal region shows an enlarged node (arrow) behind the esophagus (arrowhead) and medial to the descending thoracic aorta (A). (c) CT scan obtained at the level of the lower thoracic aorta shows an enlarged node (arrow) anterior to the descending thoracic aorta (A). (d) CT scan obtained at the level of the upper abdomen shows an enlarged node (straight arrows) along the left gastric artery (arrowhead). Note the infiltrative retroperitoneal mass (curved arrows) behind the spleen (Sp). The mass extended from enlarged paraaortic nodes (not shown). (e) CT scan obtained at the level of the celiac axis (arrowhead) shows an infiltrative nodal mass (arrows) in the retroperitoneum extending into the left perirenal space. (f) CT scan obtained at the level of the left renal artery (arrowhead) shows the infiltrative mass (arrows) extending into the mesentery. (g) PET scan shows multiple lesions with increased glucose uptake (arrows) that correspond to the lesions seen in a–f.
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Figure 3b. Stage III Burkitt-like diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the lower neck shows enlarged supraclavicular lymph nodes (arrows) in the left lower neck. The left common carotid artery (arrowhead) is markedly displaced. (b) CT scan obtained at the level of the subcarinal region shows an enlarged node (arrow) behind the esophagus (arrowhead) and medial to the descending thoracic aorta (A). (c) CT scan obtained at the level of the lower thoracic aorta shows an enlarged node (arrow) anterior to the descending thoracic aorta (A). (d) CT scan obtained at the level of the upper abdomen shows an enlarged node (straight arrows) along the left gastric artery (arrowhead). Note the infiltrative retroperitoneal mass (curved arrows) behind the spleen (Sp). The mass extended from enlarged paraaortic nodes (not shown). (e) CT scan obtained at the level of the celiac axis (arrowhead) shows an infiltrative nodal mass (arrows) in the retroperitoneum extending into the left perirenal space. (f) CT scan obtained at the level of the left renal artery (arrowhead) shows the infiltrative mass (arrows) extending into the mesentery. (g) PET scan shows multiple lesions with increased glucose uptake (arrows) that correspond to the lesions seen in a–f.
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Figure 3c. Stage III Burkitt-like diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the lower neck shows enlarged supraclavicular lymph nodes (arrows) in the left lower neck. The left common carotid artery (arrowhead) is markedly displaced. (b) CT scan obtained at the level of the subcarinal region shows an enlarged node (arrow) behind the esophagus (arrowhead) and medial to the descending thoracic aorta (A). (c) CT scan obtained at the level of the lower thoracic aorta shows an enlarged node (arrow) anterior to the descending thoracic aorta (A). (d) CT scan obtained at the level of the upper abdomen shows an enlarged node (straight arrows) along the left gastric artery (arrowhead). Note the infiltrative retroperitoneal mass (curved arrows) behind the spleen (Sp). The mass extended from enlarged paraaortic nodes (not shown). (e) CT scan obtained at the level of the celiac axis (arrowhead) shows an infiltrative nodal mass (arrows) in the retroperitoneum extending into the left perirenal space. (f) CT scan obtained at the level of the left renal artery (arrowhead) shows the infiltrative mass (arrows) extending into the mesentery. (g) PET scan shows multiple lesions with increased glucose uptake (arrows) that correspond to the lesions seen in a–f.
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Figure 3d. Stage III Burkitt-like diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the lower neck shows enlarged supraclavicular lymph nodes (arrows) in the left lower neck. The left common carotid artery (arrowhead) is markedly displaced. (b) CT scan obtained at the level of the subcarinal region shows an enlarged node (arrow) behind the esophagus (arrowhead) and medial to the descending thoracic aorta (A). (c) CT scan obtained at the level of the lower thoracic aorta shows an enlarged node (arrow) anterior to the descending thoracic aorta (A). (d) CT scan obtained at the level of the upper abdomen shows an enlarged node (straight arrows) along the left gastric artery (arrowhead). Note the infiltrative retroperitoneal mass (curved arrows) behind the spleen (Sp). The mass extended from enlarged paraaortic nodes (not shown). (e) CT scan obtained at the level of the celiac axis (arrowhead) shows an infiltrative nodal mass (arrows) in the retroperitoneum extending into the left perirenal space. (f) CT scan obtained at the level of the left renal artery (arrowhead) shows the infiltrative mass (arrows) extending into the mesentery. (g) PET scan shows multiple lesions with increased glucose uptake (arrows) that correspond to the lesions seen in a–f.
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Figure 3e. Stage III Burkitt-like diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the lower neck shows enlarged supraclavicular lymph nodes (arrows) in the left lower neck. The left common carotid artery (arrowhead) is markedly displaced. (b) CT scan obtained at the level of the subcarinal region shows an enlarged node (arrow) behind the esophagus (arrowhead) and medial to the descending thoracic aorta (A). (c) CT scan obtained at the level of the lower thoracic aorta shows an enlarged node (arrow) anterior to the descending thoracic aorta (A). (d) CT scan obtained at the level of the upper abdomen shows an enlarged node (straight arrows) along the left gastric artery (arrowhead). Note the infiltrative retroperitoneal mass (curved arrows) behind the spleen (Sp). The mass extended from enlarged paraaortic nodes (not shown). (e) CT scan obtained at the level of the celiac axis (arrowhead) shows an infiltrative nodal mass (arrows) in the retroperitoneum extending into the left perirenal space. (f) CT scan obtained at the level of the left renal artery (arrowhead) shows the infiltrative mass (arrows) extending into the mesentery. (g) PET scan shows multiple lesions with increased glucose uptake (arrows) that correspond to the lesions seen in a–f.
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Figure 3f. Stage III Burkitt-like diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the lower neck shows enlarged supraclavicular lymph nodes (arrows) in the left lower neck. The left common carotid artery (arrowhead) is markedly displaced. (b) CT scan obtained at the level of the subcarinal region shows an enlarged node (arrow) behind the esophagus (arrowhead) and medial to the descending thoracic aorta (A). (c) CT scan obtained at the level of the lower thoracic aorta shows an enlarged node (arrow) anterior to the descending thoracic aorta (A). (d) CT scan obtained at the level of the upper abdomen shows an enlarged node (straight arrows) along the left gastric artery (arrowhead). Note the infiltrative retroperitoneal mass (curved arrows) behind the spleen (Sp). The mass extended from enlarged paraaortic nodes (not shown). (e) CT scan obtained at the level of the celiac axis (arrowhead) shows an infiltrative nodal mass (arrows) in the retroperitoneum extending into the left perirenal space. (f) CT scan obtained at the level of the left renal artery (arrowhead) shows the infiltrative mass (arrows) extending into the mesentery. (g) PET scan shows multiple lesions with increased glucose uptake (arrows) that correspond to the lesions seen in a–f.
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Figure 3g. Stage III Burkitt-like diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the lower neck shows enlarged supraclavicular lymph nodes (arrows) in the left lower neck. The left common carotid artery (arrowhead) is markedly displaced. (b) CT scan obtained at the level of the subcarinal region shows an enlarged node (arrow) behind the esophagus (arrowhead) and medial to the descending thoracic aorta (A). (c) CT scan obtained at the level of the lower thoracic aorta shows an enlarged node (arrow) anterior to the descending thoracic aorta (A). (d) CT scan obtained at the level of the upper abdomen shows an enlarged node (straight arrows) along the left gastric artery (arrowhead). Note the infiltrative retroperitoneal mass (curved arrows) behind the spleen (Sp). The mass extended from enlarged paraaortic nodes (not shown). (e) CT scan obtained at the level of the celiac axis (arrowhead) shows an infiltrative nodal mass (arrows) in the retroperitoneum extending into the left perirenal space. (f) CT scan obtained at the level of the left renal artery (arrowhead) shows the infiltrative mass (arrows) extending into the mesentery. (g) PET scan shows multiple lesions with increased glucose uptake (arrows) that correspond to the lesions seen in a–f.
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Hematopathologist’s View
At low-power magnification, the neoplasm had a "starry sky" pattern created by pale histiocytes scattered among darker neoplastic cells. At high-power magnification, most of the neoplastic cells were intermediate in size, with some of the cells having irregular nuclear contours or small nucleoli. Mitotic figures were easily identified. Immunohistochemical studies showed that the neoplastic cells were positive for CD20 and BCL-2 and negative for CD5, findings that demonstrated a B-cell lineage. The MIB-1 (Ki-67) antibody was positive in virtually all (>99%) of the neoplastic cells, a finding that indicated a very high proliferation rate (Fig 4).
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Figure 4. High-grade Burkitt-like B-cell lymphoma. Large photomicrograph (original magnification, x1000; H-E stain) shows a starry sky pattern. The neoplastic cells are predominantly of intermediate size, with fewer large cells. Small photomicrographs (original magnification, x400; immunohistochemical stain) show that the lymphoma cells are positive for CD20 (inset, upper left) and BCL-2 (inset, upper right) and have a high proliferation rate, the latter being assessed with Ki-67 (inset, lower right).
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These histologic and immunohistochemical findings supported the diagnosis of high-grade B-cell lymphoma, and most of the neoplastic cells resembled small noncleaved cells. Further designation of this neoplasm was problematic because conventional cytogenetic or fluorescence in situ hybridization studies to assess for c-myc gene translocations were not performed. These translocations included t(8;14)(q24;q32) and the so-called variant translocations, t(2;8)(p11;q24) and t(8;22)(q24;q11). Each translocation involves the c-myc gene at 8q24 with either the immunoglobulin (Ig) H gene at 14q32, the Ig
gene at 2p11, or the Ig
gene at 22q11. Without this information, we used the terminology of the REAL classification scheme, "high-grade B-cell lymphoma, Burkitt-like." This designation emphasizes the high-grade cytologic features of this tumor and allows for the possibility that the neoplasm may carry the t(8;14) or a variant c-myc translocation consistent with Burkitt lymphoma. The results of bone marrow biopsy were negative.
In the 1982 Working Formulation, there were three general categories of non-Hodgkin lymphoma: low-, intermediate-, and high-grade (1). These categories were based on histologic classification correlated with clinical outcome. Three lymphoma types were placed in the high-grade category: small noncleaved cell, lymphoblastic, and large cell immunoblastic. The small non-cleaved cell category included two subtypes: Burkitt and non-Burkitt. The tumor in this case fitted best within the non-Burkitt subtype. The REAL classification scheme in effect recognized these two subtypes, with the former still designated as Burkitt lymphoma and the latter designated as a provisional entity, "high-grade B-cell lymphoma, Burkitt-like." Neoplasms in the latter category include true Burkitt lymphoma with atypical histologic features, as well as tumors without the t(8;14) or other c-myc translocations that resemble, in part, true Burkitt lymphoma. In the 2001 WHO classification scheme, there has been a subtle change. The category of Burkitt lymphoma includes cases with classical and atypical (Burkitt-like) histologic features. These neoplasms all carry the t(8;14) or variant c-myc translocations and are usually BCL-2 negative, with a very high (>99%) proliferation rate as seen with Ki-67 staining.
Because we did not know the c-myc translocation status in this case, we used the terminology of the REAL classification scheme. However, this neoplasm was more than 99% Ki-67 positive and was BCL-2 negative, findings that could suggest an atypical Burkitt or Burkitt-like lymphoma. The final diagnosis given was stage IIIA high-grade B-cell lymphoma, Burkitt-like.
Medical and Radiation Oncologists’ Views
What Are the Management Options?—
A Southwest Oncology Group study retrospectively compared Burkitt-like lymphomas with diffuse large B-cell lymphomas given the new provisional status of Burkitt-like lymphomas in the REAL classification scheme (13). Burkitt-like lymphomas had a higher Ki-67 index and decreased expression of BCL-2 compared with diffuse large B-cell lymphomas. When patients who had been treated with a second- or third-generation doxorubicin-containing regimen were evaluated, the median survival time for patients with Burkitt-like lymphoma was 1.2 years, compared with 2.5 years for patients with diffuse large B-cell lymphoma. However, the 5-year survival rates for the two groups were similar.
There are no data concerning the role of radiation therapy in the treatment of Burkitt-like lymphoma specifically. Results of the Eastern Cooperative Oncology Group study of the role of radiation therapy in advanced-stage aggressive lymphoma were inconclusive (14,15). More recent randomized data from Mexico support the use of consolidation radiation therapy to the sites of nodal bulky (>10-cm) disease in patients with stage IV diffuse large cell lymphoma after complete response to chemotherapy (16).
The patient in this case was treated with six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. CT scans of the abdomen and pelvis obtained after completion of chemotherapy revealed residual retroperitoneal lymphadenopathy. CT scans of the neck and chest showed complete resolution of the lymphadenopathy. The patient was treated with involved-field consolidation radiation therapy. The gross residual disease was treated with 45 Gy at 1.8 Gy per fraction. A series of cone-down fields were used to come off the kidneys while covering as much of the involved field as possible. The patient returned and received radiation to the left neck but refused radiation to the esophagus.
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Case 3
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A 70-year-old woman presented with epigastric pain. Because the test for Helicobacter pylori antibody was positive, the patient was initially treated with a combination of amoxicillin, clarithromycin, and lansoprazole by her family physician. No endoscopy was performed at that time. The epigastric pain disappeared for awhile but returned. Subsequent esophagogastroduodenoscopy and biopsy revealed microscopic evidence of lymphoma.
Hematopathologist’s View
Histologic sections of the specimen demonstrated fragments of gastric fundus–type mucosa with an extensive lymphoid infiltrate. The infiltrate involved the lamina propria and extended into the muscularis mucosae. At high-power magnification, the infiltrate was composed predominantly of small lymphoid cells with round to slightly irregular nuclear contours and pale cytoplasm. Numerous lymphoepithelial lesions were identified (Fig 5). There was no evidence of H pylori infection.
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Figure 5. MALT lymphoma. Photomicrograph (original magnification, x400; H-E stain) of a gastric biopsy specimen obtained from fundic mucosa shows extensive infiltration by small lymphoma cells with abundant pale (monocytoid) cytoplasm. Arrow indicates a lymphoepithelial lesion (lymphoma cells infiltrating a gland). Results of immunohistochemical staining proved a B-cell lineage.
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Immunohistochemical studies showed that the neoplastic cells were strongly positive for CD20 and negative for CD5, findings that demonstrated a B-cell lineage and supported the diagnosis of MALT lymphoma. In the WHO classification scheme, the terminology for this neoplasm is "extranodal marginal zone B-cell lymphoma of MALT."
Staging evaluation studies, including colonoscopy; small bowel series; CT scans of the chest, abdomen, and pelvis; and bone marrow biopsy were negative. The stage of the lymphoma was IEA. It was decided to observe the patient and perform repeat endoscopy. Endoscopy performed 4 months later revealed persistent MALT lymphoma. The final diagnosis given was stage IEA extranodal marginal zone B-cell lymphoma of the stomach. Two options were offered to the patient: observation, since she had no symptoms, or radiation therapy. The patient opted to receive radiation therapy.
Medical and Radiation Oncologists’ Views
What Are the Management Options?—
MALT lymphoma accounts for 5%–9% of all non-Hodgkin lymphomas. Sixty-five to 70% of patients present with stage I or stage II disease (17). About 30% of patients have bone marrow involvement at diagnosis. The median age at presentation is 55–60 years (17). The most common sites of involvement are the stomach, ocular adnexae, skin, thyroid gland, salivary glands, and lung (17). However, almost any extranodal site can be involved.
For patients with gastric MALT lymphoma, antibiotic therapy for H pylori can eradicate the infection and also provide relief of symptoms. Gastric MALT lymphoma shows a 60%–90% response rate to antibiotic treatment alone (18). The median time to complete response is 6 months. However, it has been reported that the response can take more than 18 months from the institution of antibiotic treatment (18). Antibiotic treatment is generally recommended as the first line of therapy for patients with gastric MALT lymphoma associated with H pylori infection.
If the MALT lymphoma fails to respond to antibiotic therapy, involved-field radiation therapy to the stomach and perigastric lymph nodes or chemotherapy is recommended. Investigators at the Princess Margaret Hospital at the University of Toronto reported on 103 patients with stage IE and stage IIE MALT lymphoma (19). The median patient age was 60 years (range, 22–83 years). Eighty-five patients were treated with radiation therapy alone (dose, 25–35 Gy). The overall 5-year survival rate was 98%, and the disease-free survival rate was 77%. No relapses were observed in patients with stomach or thyroid lymphoma, whereas 14 of 63 patients (22%) with lymphoma at other sites experienced relapse.
Many patients with MALT lymphoma of the stomach do not have evidence of H pylori infection. The lymphomas in these patients have a high prevalence of chromosomal translocations, the most common being the t(11;18)(q21;q21) translocation involving the api2 and malt1 genes. The api2 gene belongs to the inhibitor of apoptosis gene family (20).
MALT lymphomas involving nongastric sites are less well characterized in the literature. Other infectious agents are reported to be associated with MALT lymphomas, presumably playing a role analogous to that of H pylori. These agents include Borrelia burgdorferi, Chlamydia psittaci, and Campylobacter jejuni in MALT lymphomas of the skin, ocular adnexae, and jejunum, respectively (21–23).
Other chromosomal translocations are also reported in MALT lymphomas. The t(14;18) (q32;q21) translocation has been identified in approximately 10%–20% of MALT lymphomas (24). In this translocation, malt1 on chromosome 18q21 is juxtaposed with the IgH gene at 14q32. This translocation appears to have an inverse relationship with the t(11;18) translocation, being uncommon in MALT lymphomas of the stomach but more common in MALT lymphomas of the liver, ocular adnexae, skin, and salivary glands. The t(1;14)(p22;q32) translocation that juxtaposes the bcl-10 gene at 1p22 with IgH is rare, occurring in less than 5% of cases (25). Recently, Streubel et al (26) reported another translocation, the t(3;14)(p14.1;q32) translocation, in MALT lymphomas of the skin, ocular adnexae, and thyroid gland. The t(3;14) translocation involves the foxp1 gene at 3p14.1 and IgH.
Molecular evidence suggests that API2-MALT activates NF-B. Similarly, BCL-10, by binding with MALT1, forms a complex within the cell and acts synergistically to activate NF-B. Thus, at least the t(11;18), t(14;18), and t(1;14) translocations may activate a common downstream signaling pathway (24–27).
The patient in this case was treated with 30.6 Gy of radiation in 17 fractions. She was initially treated with anteroposterior-posteroanterior technique (total dose, 18 Gy; 10 fractions), followed by 12.6 Gy of boost treatment in seven fractions using right anterior oblique–left posterior oblique technique to come off the kidneys. The patient achieved complete response.
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Case 4
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A 45-year-old man presented with shortness of breath and cough. The results of blood chemistry analyses and a complete blood cell count were within normal limits, except for a serum lactate dehydrogenase level of 1581 IU/L (normal, 313–618 IU/L).
Diagnostic Radiologist’s View
CT scans of the chest revealed a large anterior mediastinal mass measuring approximately 14 x 8 cm. The mass caused compression and displacement of the superior vena cava, aorta, and heart toward the left. The mass also encased both internal mammary vessels. In addition, there were medium-sized bilateral pleural and pericardial effusions. CT scans of the abdomen and pelvis showed no evidence of disease. PET revealed a large, hypermetabolic mediastinal mass with central hypometabolism, a finding that suggested necrosis. There was no evidence of disease below the diaphragm (Fig 6).
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Figure 6a. Mediastinal diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the midmediastinum shows a large anterior mediastinal mass (arrows) anterior to the ascending aorta (AA) and pulmonary artery (PA). (b) CT scan obtained at the level of the lower chest shows the mass (arrows) along the right pericardiac region with a small pericardial effusion (Pc) and pleural effusion (Pl). (c) PET scan shows intense glucose uptake in the mass (arrows). The increased uptake is limited to the chest.
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Figure 6b. Mediastinal diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the midmediastinum shows a large anterior mediastinal mass (arrows) anterior to the ascending aorta (AA) and pulmonary artery (PA). (b) CT scan obtained at the level of the lower chest shows the mass (arrows) along the right pericardiac region with a small pericardial effusion (Pc) and pleural effusion (Pl). (c) PET scan shows intense glucose uptake in the mass (arrows). The increased uptake is limited to the chest.
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Figure 6c. Mediastinal diffuse large B-cell lymphoma. (a) CT scan obtained at the level of the midmediastinum shows a large anterior mediastinal mass (arrows) anterior to the ascending aorta (AA) and pulmonary artery (PA). (b) CT scan obtained at the level of the lower chest shows the mass (arrows) along the right pericardiac region with a small pericardial effusion (Pc) and pleural effusion (Pl). (c) PET scan shows intense glucose uptake in the mass (arrows). The increased uptake is limited to the chest.
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Hematopathologist’s View
Histologic sections of the mediastinal mass biopsy specimen showed fibrous tissue containing a diffuse atypical lymphoid infiltrate composed of large cells with oval to irregular nuclei, vesicular chromatin, and one or more distinct nucleoli. There were scattered mitotic figures, single necrotic cells, and foci of confluent necrosis. Flow cytometry immunophenotypic studies performed on a cell suspension of the specimen showed a large-sized B-cell population that was positive for CD10, CD19, CD20, CD22, FMC-7, and Ig light chain and negative for CD5, CD11c, and CD23. Immunohistochemical studies showed that the neoplastic cells were focally positive for BCL-2, with a high to very high Ki-67 proliferation index ranging from 80% to 100%. These findings supported the diagnosis of diffuse large B-cell lymphoma, whereas the morphologic features were compatible with a diagnosis of primary mediastinal large B-cell lymphoma, in accordance with the clinical presentation (Fig 7). Cytologic studies of the pleural effusion and bone marrow biopsy were negative for lymphoma. However, the final diagnosis given was stage IIA primary mediastinal large B-cell lymphoma.
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Figure 7. Mediastinal large B-cell lymphoma. Large photomicrograph (original magnification, x 1000; H-E stain) shows large neoplastic cells with vesicular nuclei. Small photomicrographs (original magnification, x 400; immunohistochemical stain) show that the neoplastic cells are focally and weakly positive for BCL-2 (inset, upper left) (in contrast with reactive lymphocytes, which tend to be strongly positive), and that the neoplasm has a high proliferation rate, as shown by Ki-67 immunoreactivity (inset, upper right). Flow cytometry immunophenotypic studies showed that the neoplasm had a B-cell lineage.
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Medical and Radiation Oncologists’ Views
What Are the Management Options?—
Zinzani et al (28) reported on 50 patients with primary mediastinal large B-cell lymphoma who were treated with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin and radiation therapy. The radiation dose ranged from 30 to 36 Gy at 1.8 Gy per fraction over 4–5 weeks. The overall survival rate for these 50 patients was 82% at 96 months. Forty-three patients achieved complete response. The relapse-free survival rate for these 43 patients was 93% at 96 months. Findings at CT and gallium 67 (67Ga) single photon emission CT (SPECT) were correlated with clinical outcome. This correlation study was performed in only 47 of 50 patients because three patients could not be evaluated due to disease progression. Thirty-three of these 47 patients had residual disease at CT after chemotherapy alone. However, only 21 patients had residual disease at CT after completion of radiation therapy. At 67Ga-SPECT, on the other hand, 31 patients had positive findings after chemotherapy alone, with only nine patients having persistent positivity after radiation therapy. Twenty-one of 47 patients achieved both CT and 67Ga-SPECT negativity after completion of combined-modality therapy. Every patient in this group remained in continuous complete response. Both CT and 67Ga-SPECT remained positive after combined-modality therapy in four patients, all of whom had progression of disease. Overall, 38 of 47 patients achieved 67Ga-SPECT negativity at the end of treatment, with none experiencing relapse. Nine patients had persistent 67Ga-SPECT positivity at the end of treatment, with relapse or progressive disease in seven of these patients. These data strongly suggest important prognostic implications for 67Ga-SPECT negativity in the management of primary mediastinal large B-cell lymphoma.
Although CHOP chemotherapy has been the standard treatment for non-Hodgkin lymphoma for more than two decades, the recent Groupe d’Etude des Lymphomes d’Adulte trial LNH-98.5 has established the superiority of R-CHOP over standard CHOP chemotherapy in terms of event-free and overall survival rates for elderly patients (29,30). An interim analysis from the MabThera International Trial (MInT) indicated that the addition of rituximab to six cycles of CHOP-like regimens improved time to treatment failure and overall survival rates even in younger patients with low-risk diffuse large B-cell lymphoma (31). Therefore, R-CHOP chemotherapy is establishing itself as a new standard regimen for treating patients with diffuse large B-cell lymphoma.
The patient in this case was treated with eight cycles of R-CHOP chemotherapy. Chest CT performed after completion of chemotherapy revealed a residual mediastinal mass. PET scans were negative. Involved-field radiation therapy was delivered with a series of cone-down fields. The gross residual disease received a final dose of 39 Gy.
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Case 5
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A 62-year-old man presented after palpating a mass in the left axilla while in the shower.
Diagnostic Radiologist’s View
CT scans of the chest showed a very large infiltrative mass in the left axilla involving the humerus and the scapula, with a cluster of enlarged lymph nodes. CT scans of the abdomen and pelvis revealed a large, well-capsulated, fat-containing retroperitoneal mass encasing the right kidney. The appearance of the retroperitoneal mass was most consistent with a lipomatous tumor. 67Ga-SPECT showed increased uptake in the left axillary lesion, with no uptake in the retroperitoneal mass (Fig 8).
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Figure 8a. Stage IIA diffuse large B-cell lymphoma and liposarcoma. (a) CT scan obtained at the level of the axillae shows an infiltrative mass (arrows) in the left axilla. (b) CT scan obtained at the level of the midthorax shows enlarged nodes (arrows) in the left axilla. (c) CT scan obtained inferior to the lower pole of the kidneys shows a 6-cm, well-circumscribed mass (arrows) with fat attenuation, a finding that is consistent with a liposarcoma. (d) Coronal 67Ga scintigram shows increased uptake in the lymph nodes in the left axilla (arrows).
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Figure 8b. Stage IIA diffuse large B-cell lymphoma and liposarcoma. (a) CT scan obtained at the level of the axillae shows an infiltrative mass (arrows) in the left axilla. (b) CT scan obtained at the level of the midthorax shows enlarged nodes (arrows) in the left axilla. (c) CT scan obtained inferior to the lower pole of the kidneys shows a 6-cm, well-circumscribed mass (arrows) with fat attenuation, a finding that is consistent with a liposarcoma. (d) Coronal 67Ga scintigram shows increased uptake in the lymph nodes in the left axilla (arrows).
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Figure 8c. Stage IIA diffuse large B-cell lymphoma and liposarcoma. (a) CT scan obtained at the level of the axillae shows an infiltrative mass (arrows) in the left axilla. (b) CT scan obtained at the level of the midthorax shows enlarged nodes (arrows) in the left axilla. (c) CT scan obtained inferior to the lower pole of the kidneys shows a 6-cm, well-circumscribed mass (arrows) with fat attenuation, a finding that is consistent with a liposarcoma. (d) Coronal 67Ga scintigram shows increased uptake in the lymph nodes in the left axilla (arrows).
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Figure 8d. Stage IIA diffuse large B-cell lymphoma and liposarcoma. (a) CT scan obtained at the level of the axillae shows an infiltrative mass (arrows) in the left axilla. (b) CT scan obtained at the level of the midthorax shows enlarged nodes (arrows) in the left axilla. (c) CT scan obtained inferior to the lower pole of the kidneys shows a 6-cm, well-circumscribed mass (arrows) with fat attenuation, a finding that is consistent with a liposarcoma. (d) Coronal 67Ga scintigram shows increased uptake in the lymph nodes in the left axilla (arrows).
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Hematopathologist’s View
The patient underwent excisional biopsy of the left axillary mass. Histologic and immunohistochemical studies supported the diagnosis of diffuse large B-cell lymphoma (very similar to that previously described). Percutaneous needle biopsy of the retroperitoneal mass revealed low-grade liposarcoma. The final diagnosis given was stage IIA diffuse large B-cell lymphoma of the axilla and liposarcoma of the retroperitoneum.
Medical and Radiation Oncologists’ Views
What Are the Management Options?—
Resection is the primary modality of treatment for sarcoma. Data indicate that the recurrence rate after resection of retroperitoneal liposarcoma is about 20%, whereas the recurrence rate for other types of retroperitoneal sarcoma can be much higher (32). The 2-year overall and event-free survival rates for patients 60–80 years of age with diffuse large B-cell lymphoma are 70% and 57%, respectively, when eight cycles of R-CHOP chemotherapy are administered (30). Given the very aggressive nature of diffuse large cell lymphoma manifesting with bulky disease, the bone involvement, and the history of rapid growth of the lesion, the patient in this case was first treated with R-CHOP chemotherapy and involved-field radiation therapy. Surgery for sarcoma was subsequently performed.
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Case 6
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A 54-year-old man presented with short-term memory loss and left-sided hemiparesis. Brain CT scans obtained at a local hospital revealed a mass in the right frontoparietal lobe. Craniotomy with partial resection of the mass was performed, yielding the diagnosis of lymphoma. The patient had no evidence of human immunodeficiency viral infection.
Diagnostic Radiologist’s View
Brain magnetic resonance (MR) images were obtained upon transfer of the patient to a tertiary cancer center. They revealed a surgical defect from recent tumor resection with hyperintense enhancement deep in the right parietal lobe with a significant amount of edema resulting in subfalcine herniation to the left side (Fig 9).
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Figure 9a. Stage IEA diffuse large B-cell lymphoma. (a) T1-weighted MR image of the brain obtained after administration of gadolinium–diethylenetriaminepentaacetic acid shows a surgical defect (SD) and residual tumor with hyperintense contrast material enhancement in the parietal lobe (arrows), along with severe edema (arrowheads). (b) T1-weighted MR image obtained 1 cm inferior to a shows the residual tumor with hyperintense contrast enhancement (arrows). (c) T2-weighted MR image shows a high-signal-intensity postsurgical defect (SD) and edematous tissue (arrowheads). The residual tumor (arrows) is hypointense relative to the edematous tissue. (d) On a T2-weighted MR image, the residual tumor (arrows) is hypointense relative to the postsurgical defect and the edematous tissue.
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Figure 9b. Stage IEA diffuse large B-cell lymphoma. (a) T1-weighted MR image of the brain obtained after administration of gadolinium–diethylenetriaminepentaacetic acid shows a surgical defect (SD) and residual tumor with hyperintense contrast material enhancement in the parietal lobe (arrows), along with severe edema (arrowheads). (b) T1-weighted MR image obtained 1 cm inferior to a shows the residual tumor with hyperintense contrast enhancement (arrows). (c) T2-weighted MR image shows a high-signal-intensity postsurgical defect (SD) and edematous tissue (arrowheads). The residual tumor (arrows) is hypointense relative to the edematous tissue. (d) On a T2-weighted MR image, the residual tumor (arrows) is hypointense relative to the postsurgical defect and the edematous tissue.
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Figure 9c. Stage IEA diffuse large B-cell lymphoma. (a) T1-weighted MR image of the brain obtained after administration of gadolinium–diethylenetriaminepentaacetic acid shows a surgical defect (SD) and residual tumor with hyperintense contrast material enhancement in the parietal lobe (arrows), along with severe edema (arrowheads). (b) T1-weighted MR image obtained 1 cm inferior to a shows the residual tumor with hyperintense contrast enhancement (arrows). (c) T2-weighted MR image shows a high-signal-intensity postsurgical defect (SD) and edematous tissue (arrowheads). The residual tumor (arrows) is hypointense relative to the edematous tissue. (d) On a T2-weighted MR image, the residual tumor (arrows) is hypointense relative to the postsurgical defect and the edematous tissue.
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Figure 9d. Stage IEA diffuse large B-cell lymphoma. (a) T1-weighted MR image of the brain obtained after administration of gadolinium–diethylenetriaminepentaacetic acid shows a surgical defect (SD) and residual tumor with hyperintense contrast material enhancement in the parietal lobe (arrows), along with severe edema (arrowheads). (b) T1-weighted MR image obtained 1 cm inferior to a shows the residual tumor with hyperintense contrast enhancement (arrows). (c) T2-weighted MR image shows a high-signal-intensity postsurgical defect (SD) and edematous tissue (arrowheads). The residual tumor (arrows) is hypointense relative to the edematous tissue. (d) On a T2-weighted MR image, the residual tumor (arrows) is hypointense relative to the postsurgical defect and the edematous tissue.
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The rest of the staging work-up (including ophthalmologic examination and CT of the chest, abdomen, and pelvis) revealed no evidence of disease.
Hematopathologist’s View
Histologic sections of the brain biopsy specimen showed fragments of cerebral cortex partially replaced by lymphoma. In less involved areas of the brain, the neoplasm had a perivascular distribution. Areas of coagulative necrosis were present. High-power photomicrography showed large neoplastic cells with vesicular chromatin and one to three distinct nucleoli. Most of the neoplastic cells resembled centroblasts, but some immunoblasts were also present. Mitotic figures were easily identified (Fig 10).
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Figure 10. Diffuse large B-cell lymphoma of the brain. Photomicrograph (original magnification, x 200; H-E stain) shows neoplastic cells resembling centroblasts and immunoblasts. Mitotic figures are easily identified. Flow cytometry immunophenotypic studies showed a B-cell lineage.
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Flow cytometry immunophenotypic studies were performed on a cell suspension of the specimen. These studies showed that the neoplastic cells were positive for CD19, CD20, and Ig light chain and negative for CD5 and CD10.
Bone marrow biopsy and cerebrospinal fluid analysis were negative. The final diagnosis given was primary diffuse large B-cell lymphoma of the brain.
Medical and Radiation Oncologists’ Views
What Are the Management Options?—
Methotrexate-based chemotherapy followed by whole-brain radiation therapy with or without boost radiation treatment has been the mainstay of treatment for primary CNS lymphoma (33). Overall, a median survival rate of 30–40 months has been achieved with this approach, although the outcome depends heavily on prognostic factors such as patient age, serum lactate dehydrogenase level, and performance status (34). Some success with this regimen has been met with long-term CNS toxicity, especially in the older patient population (35,36). Recently, multiple trials have been conducted in which patients with primary CNS lymphoma were treated with chemotherapy alone (37,38). No firm conclusion can be drawn from the results of these trials, since no randomized trial has been performed comparing methotrexate-based chemotherapy with radiation therapy to that without radiation therapy. In general, it appears that combined-modality therapy achieves better disease-free and overall survival rates than does chemotherapy alone. However, there has been less CNS toxicity in patients treated with chemotherapy alone (37). The tradeoff between improved disease-free and overall survival rates and increased CNS toxicity needs to be fully communicated to the patient with primary CNS lymphoma.
The patient in this case was treated with five cycles of high-dose methotrexate, procarbazine, and vincristine, along with intrathecal methotrexate. MR images of the brain obtained upon completion of chemotherapy showed only a postoperative cavity. The patient was treated with whole-brain radiation therapy (total dose, 30 Gy; 15 fractions), followed by a boost of 10 Gy in five fractions.
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Footnotes
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Abbreviations: ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine, CNS = central nervous system, H-E = hematoxylin-eosin, Ig = immunoglobulin, MALT = mucosa-associated lymphoid tissue, R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, REAL = Revised European American Lymphoma, WHO = World Health Organization
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References
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- Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361–1392.[Free Full Text]
- Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC, 2001.
- Thomas RK, Re D, Wolf J, Diehl V. Part I: Hodgkin’s lymphoma—molecular biology of Hodgkin and Reed-Sternberg cells. Lancet Oncol 2004;5:11–18.[CrossRef][Medline]
- Lukes RJ, Butler JJ. The pathology and nomenclature of Hodgkin’s disease. Cancer Res 1966;26: 1063–1083.[Medline]
- Diehl V, Sextro M, Franklin J, et al. Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin’s disease and lymphocyte-rich classical Hodgkin’s disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin’s Disease. J Clin Oncol 1999;17:776–783.[Abstract/Free Full Text]
- Gospodarowicz MK, Sutcliffe SB, Clark RM, et al. Analysis of supradiaphragmatic clinical stage I and II Hodgkin’s disease treated with radiation alone. Int J Radiat Oncol Biol Phys 1992;22:859–865.[Medline]
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Introduction
Case 1
