Case 8-2006 — A 71-Year-Old Woman with Crohn's Disease and Altered Mental Status
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《新英格兰医药杂志》
Presentation of Case
A 71-year-old woman was admitted to the hospital because of left-sided weakness and a mass in the brain. She had had Crohn's disease for many years but was in her usual state of health until three months before admission, when she became fatigued and required daily naps. Two months before admission, episodes of blurring of vision, occipital headaches, and an unsteady gait occurred. The patient's husband described her as "tilting to the left" when she walked, and she appeared to be depressed and angry.
Two weeks before admission, the patient noted an enlarging, nontender mass in her right inguinal area. A fine-needle aspiration of the mass performed 10 days before admission disclosed necrosis, heterogeneous lymphoid cells, and epithelioid histiocytes suggestive of granulomatous inflammation. Several days later nausea developed, the patient's appetite decreased, and over the course of the next week, she lost weight (2 kg). She did not vomit; she had chronic diarrhea from her Crohn's disease, which did not change in frequency or character. Six days before admission, she was too weak to get out of bed, and her husband took her to the emergency room of another hospital, where she was admitted. Her temperature was 38.8°C; other vital signs were normal. The chest was clear, and the heart sounds were normal. The abdomen was mildly tender to palpation, without rebound or guarding. There was no organomegaly. A firm, fixed, nontender mass, 3 cm by 3 cm, was present on the right side of the inguinal region. There was rectal tenderness on digital examination. The patient was alert and oriented. The results of a neurologic examination showed no abnormalities. Cultures of blood and stool were obtained, and broad-spectrum antibiotics were administered.
On the second hospital day, the temperature was 38.8°C. That evening, the patient had a sudden loss of coordination. A neurologic consultant noted a left-sided facial droop; the motor strength on the right side was normal and 4/5 on the left side. There was left pronator drift, and finger-to-nose and heel-to-shin movements were poor on the left side. On stimulation of the plantar reflexes in both feet, the toes turned down. The neck was supple, but her headache was worse on neck flexion. A Romberg test was positive, and the patient leaned toward her left side when walking.
Magnetic resonance imaging (MRI) of the brain showed a mass, 3 cm in diameter, in the right thalamus adjacent to the lateral ventricle. Computed tomography (CT) of the abdomen and pelvis revealed the right inguinal mass; there were no other abnormalities. Treatment with dexamethasone was started. On the third hospital day, the patient had less nausea and headache, and the left-sided facial droop was not seen. The temperature rose to 38.9°C. An incisional biopsy of the right-sided inguinal mass was performed. She was transferred to this hospital on the sixth hospital day.
Crohn's disease had been diagnosed when the patient was 22 years of age, by Dr. Burrill B. Crohn, the physician for whom the disease is named. An ileal resection was performed when she was 22 years of age, and a hemicolectomy at 59 years of age. Beginning when she was 52 years of age, she had been receiving treatment with prednisone, 40 to 50 mg per day; this drug had been discontinued 10 years before admission. Six years before admission, treatment with mercaptopurine was begun; infliximab infusions every eight weeks were added to her treatment regimen three years before admission. The patient continued to have intermittent diarrhea and hematochezia. The last infusion of infliximab she received was four weeks before admission.
The patient had diabetes mellitus, hypertension, and anemia, which was treated with monthly injections of vitamin B12. She lived with her husband. She had smoked cigarettes for 16 years but quit 30 years before admission. She drank alcohol infrequently. A daughter had Crohn's disease. The patient's medications included mesalamine, pantoprazole, losartan, hydrochlorothiazide, loperamide, zolpidem, insulin, cefoxitin, vancomycin, dexamethasone, and ondansetron — in addition to those already mentioned.
The temperature was 36.1°C, the pulse 69 beats per minute, the respiratory rate 18 breaths per minute, and the blood pressure 128/56 mm Hg. On physical examination, the patient appeared chronically ill. There was a small, white lesion on the inferior aspect of the tongue. There was no cervical or axillary lymphadenopathy. There were inspiratory crackles at the left lung base, and the heart sounds were normal. The abdomen was soft and nontender, and the bowel sounds were normal. There was a right-sided inguinal mass, 3 cm by 1 cm, with a recent incision over it.
The patient was awake and alert. There was a left homonymous hemianopia. The pupils were equal and minimally reactive to light. Extraocular movements were normal, but there was decreased eye closure and reduced sensation to touch on the left side of her face. She could not raise her left arm above her head. The strength in her left arm measured 3/5 proximally and 1/5 distally, as compared with 4/5 for the entire right arm. The strength in her left leg measured 2/5 proximally and 3/5 distally, as compared with 4/5 for the entire right leg. Finger-to-nose touch and heel tapping were intact on the right side and slow on the left side. The patient was too weak to walk.
The results of laboratory tests are shown in Table 1. A lumbar puncture showed 94 white cells, with 32 percent lymphocytes, 8 percent neutrophils, 40 percent monocytes, and 19 percent large cells with nucleoli and basophilic cytoplasm; the results of flow cytometry, cytologic examination, and cultures were pending.
Table 1. Laboratory-Test Results on Admission.
Early in the morning of the second hospital day, the patient had a generalized tonic–clonic seizure and became unresponsive. The trachea was intubated to maintain airway protection, and she was transferred to the intensive care unit. CT scanning of the brain showed a heterogeneous mass, 4.3 cm (from anterior to posterior) by 4.2 cm (from left to right) in greatest dimension, centered in the right side of the thalamus, with a relatively low attenuation center and a rim of high attenuation. There was an eccentric nodular component anteriorly and medially. Local mass effect was noted on the right lateral ventricle, but there was no subfalcine or transtentorial herniation. There was architectural distortion that resulted in crowding of the foramen of Monro and mild prominence of the right temporal horn, suggesting outflow obstruction.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Daniel K. Podolsky: May we review the radiologic studies?
Dr. R. Gilberto Gonzalez: The CT scanning of the head performed without the administration of contrast material on the second hospital day (Figure 1A) revealed a large mass centered within the right side of the thalamus. The mass was predominantly hyperdense, although regions of low density were observed; it exerted mass effect on adjacent structures and appeared to extend into the ventricular system. The mass extended inferiorly to involve the temporal lobe and superiorly to the centrum semiovale.
Figure 1. CT and MRI Scans of the Head.
A CT scan (Panel A), obtained without the administration of contrast material, shows a large mass, centered in the right side of the thalamus (arrows). The mass is heterogeneous, is predominantly hyperdense, and extends into the right lateral ventricle. An MRI (Panel B), obtained six days after the CT scan, shows that the mass had increased in size. It has heterogeneous signal characteristics, including areas of relatively low T2-weighted signal corresponding to the regions of hyperdensity seen on the CT scan. The mass prevents the egress of cerebrospinal fluid, resulting in hydrocephalus.
Dr. Podolsky: This 71-year-old woman with an almost 50-year history of Crohn's disease requiring long-term immunosuppressive therapy was found to have a mass involving the central nervous system after the onset of symptoms of weakness and various neurologic findings. The imaging characteristics of the central nervous system abnormality are unlikely findings for a vascular process such as stroke or hemorrhage, and the differential diagnosis is narrowed to infection and cancer.
Infection
Infectious processes, including abscess, tuberculosis, and opportunistic infections, are important considerations. Although Crohn's disease would not predispose this patient to either an abscess or an opportunistic infection, immunosuppressive treatment could. In particular, reactivation of latent tuberculosis after the administration of infliximab has been well recognized1; the majority of patients in whom this reactivation has occurred have had extrapulmonary or disseminated disease, including central nervous system infection. In this regard, it is noteworthy that fine-needle aspiration of the inguinal mass yielded granulomatous tissue. Were it not for the brain lesion, the finding from the mass might also raise concern about the possibility of Crohn's disease involving a lymph node. However, the characteristics of the brain images are not suggestive of an infectious process, and although the patient had fever, there are few other specific signs to suggest an infectious process.
Cancer
The appearance of the brain mass is highly suggestive of a neoplasm. Considered in isolation, the imaging studies would raise concern for a primary cancer of the brain. However, given the known diagnosis of Crohn's disease and the presence of a mass in the groin, there are two more likely diagnoses: metastatic carcinoma and lymphoma. Patients with Crohn's disease are at increased risk for adenocarcinoma, particularly of the small intestine, but also in the colon. These cancers are most likely to develop in areas affected by Crohn's disease; the risk of cancer in the small intestine in patients with Crohn's disease has been estimated to be 5 to 25 times higher than that of unaffected persons,2,3 and the risk of colorectal adenocarcinoma 2 to 5 times higher than that of unaffected persons.4,5,6 The risk correlates with extent of disease, duration, and independently, the age at onset. This patient's surgical history suggests that she has had Crohn's disease affecting both the small intestine and the colon, and she appears to have had active disease for almost 50 years. However, the lesion observed on brain imaging is unlikely to represent metastatic adenocarcinoma in the absence of evidence of other metastatic disease — nor would this diagnosis account for the type of atypical cells that were seen in the cerebrospinal fluid.
Lymphoma in Crohn's Disease
It has long been suspected that there is an increased frequency of lymphoma in the setting of Crohn's disease, although this premise remains controversial. Several studies1,3,7,8 have found a risk of lymphoma among patients with Crohn's disease that is two to four times the risk among those without the disease, although others have not found any significant increase.5,9 In the aggregate, these studies support the impression of an increased risk of lymphoma in patients with Crohn's disease, but it is unlikely that the magnitude of this increase is more than twice that in patients without Crohn's disease.
The risk of lymphoma may be increased by immunosuppressive agents used in the treatment of these patients.10,11 The results of studies attempting to define the risks of lymphoma conferred by immunosuppressive therapy with azathioprine or mercaptopurine have been equivocal,10,12,13 with relative risk ranging from less than or slightly greater than 19,14 to almost 60.15,16
Infliximab and Lymphoma
Understanding how to assess the risk of lymphoma in patients with Crohn's disease has taken on new urgency with the increasing use of infliximab, a chimeric anti–tumor necrosis factor (TNF) monoclonal antibody. This antibody was initially presumed to act through neutralization of the soluble form of the proinflammatory cytokine TNF, but recent studies suggest that apoptosis of cells expressing the transmembrane precursor after binding by infliximab may be necessary for therapeutic benefit. In the several years since its initial approval, infliximab has been found to have diverse adverse effects17; some of these effects may be due to the development of antiinfliximab antibodies, whereas others may reflect the biologic effects of infliximab, such as abscess formation and opportunistic infections, including reactivation of latent tuberculosis.
Several reports have suggested that infliximab may increase the risk of lymphoma.17,18 The incidence of non-Hodgkin's lymphoma in patients with Crohn's disease treated with infliximab in several large studies ranged from 0.2 percent17 to 1.4 percent.19 A summary of all the lymphomas reported in patients receiving infliximab (including patients with rheumatoid arthritis and those with Crohn's disease) yielded an overall incidence of 0.6 percent.18 As in the setting of other types of immunosuppressive therapy, large-B-cell lymphomas that are positive for Epstein–Barr virus (EBV) appear to predominate. Dr. Siegel and my other colleagues at Massachusetts General Hospital have recently completed a survey to assess the risk of lymphoma in patients with Crohn's disease treated with infliximab.
Dr. Corey A. Siegel (Gastroenterology): We performed a systematic literature search to identify all of the studies with a minimum follow-up period of 48 weeks that specifically reported adverse effects of infliximab in the treatment of Crohn's disease. There were 5 patients with lymphoma reported among approximately 1700 patients (0.3 percent). As compared with a healthy age-matched population from the Surveillance, Epidemiology and End Results database, this percentage represents an increase in the incidence of lymphoma in patients receiving infliximab that is approximately 20 times higher.
Dr. Podolsky: In summary, this patient possesses at least three possible risk factors for non-Hodgkin's lymphoma — Crohn's disease, immunosuppressive therapy with mercaptopurine, and infliximab therapy. Although the impact of each risk factor alone may be small, the overall effects may be additive, if not synergistic. Accordingly, I believe that lymphoma may have developed in this patient, probably large-B-cell lymphoma that is positive for EBV. The diagnosis was probably made by appropriate staining of the tissue obtained from the incisional biopsy of the inguinal lymph node, flow cytometry analysis of the abnormal cells seen in the cerebrospinal fluid, or both.
Clinical Diagnosis
Probable non-Hodgkin's lymphoma.
Dr. Daniel K. Podolsky's Diagnosis
B-cell lymphoma, probably large-B-cell lymphoma that is EBV-positive, associated with immunosuppression.
Pathological Discussion
Dr. Robert P. Hasserjian: The diagnostic procedures were a review of the slides of the specimen obtained from the inguinal lymph-node biopsy from the other hospital and an analysis of the cerebrospinal fluid by cytology and flow cytometry. The lymph-node architecture was effaced by sheets of large lymphoid cells, with large areas of geographic necrosis (Figure 2A). The lymphoid cells had prominent nucleoli, expressed the B-cell marker CD20, and contained encoded RNA for EBV (Figure 2B, 2C, and 2D).
Figure 2. Inguinal Lymph-Node Biopsy Specimen.
The inguinal lymph-node architecture (Panel A) is totally effaced by diffuse sheets of cells with areas of geographic necrosis (lower right; hematoxylin and eosin). The cells are large with round-to-irregular, vesicular nuclei and prominent nucleoli (Panel B; hematoxylin and eosin). The cell-surface membrane of the large cells is positive for the B-cell marker CD20 (Panel C; immunohistochemical staining for CD20). Nearly all the large cells contain Epstein–Barr virus-encoded RNA (Panel D; in situ hybridization).
Cytologic examination of the cerebrospinal fluid disclosed large, atypical lymphocytes, morphologically similar to the nodal lymphoma cells (Figure 3). Flow cytometry revealed a predominant population of CD19+ and CD20+ B cells aberrantly expressing CD43 and lacking detectable surface or cytoplasmic immunoglobulin expression. These findings confirm an EBV-positive, diffuse large-B-cell lymphoma involving the inguinal lymph node and cerebrospinal fluid.
Figure 3. Cytologic Preparation of a Sample of Cerebrospinal Fluid.
There are large cells with vesicular nuclei and moderately abundant, eccentrically placed cytoplasm (Papanicolaou stain). These cells resemble the tumor cells on an air-dried direct smear prepared from the patient's inguinal lymph node (inset, Wright–Giemsa stain).
EBV is typically absent in cases of B-cell non-Hodgkin's lymphoma that occur in immunocompetent persons,20 but it is a hallmark of lymphomas occurring in the setting of immunodeficiency. Patients who are immunodeficient are at increased risk for the development of a variety of lymphoproliferative disorders, which share a number of clinicopathological features (Table 2).21 Lower grades or early forms of these lymphoproliferative disorders resemble florid, uncontrolled EBV infection and are often polyclonal.22 In contrast, frank lymphomas contain clonal sequences of EBV and antigen-receptor gene rearrangements, indicating derivation from a single transformed EBV-infected cell.23,24 Lymphomas arising in patients who are immunodeficient are typically diffuse large-B-cell, Burkitt's, or Hodgkin's lymphomas. In addition to the strong association with EBV, these lymphomas differ from lymphomas in patients who are immunocompetent in that such cases show a more limited histologic spectrum and a predilection for extranodal site involvement.
Table 2. Common Features of Immunodeficiency-Associated Lymphoproliferative Disorders.
Lymphomas that arise in patients with inflammatory bowel disease who have been treated with the immunosuppressive agents azathioprine and mercaptopurine have features resembling immunodeficiency-associated lymphomas.25 In contrast to lymphomas that develop in patients with inflammatory bowel disease who are not receiving such therapies, these lymphomas are typically EBV-positive and are almost exclusively high-grade B-cell and Hodgkin's lymphomas. At least one of the reported cases exhibited a viral antigen expression pattern (latency pattern, type 3) that is characteristic of immunodeficiency-associated lymphomas.26 Other recent studies have documented an increased incidence of lymphoma after relatively short periods of infliximab therapy, although many of these patients had also received immunosuppressants18,19,27; at least one of the cases in these studies was EBV-positive. The EBV-positive status and extranodal involvement in the current patient, in the context of mercaptopurine and infliximab therapy, suggest that this case should be categorized as an immunodeficiency-associated lymphoma.
Dr. Nancy Lee Harris (Pathology): The interval between starting infliximab therapy and development of lymphoma was fairly long in this patient.
Dr. Podolsky: Reports suggest that lymphoma may occur within a very short time after infliximab is first started, and an average of just three infusions before diagnosis of the cancer has been described. However, the prolonged period that is described for this patient is within the range reported.
Dr. Harris: Dr. Hochberg, can you discuss the further care of this patient?
Dr. Ephraim P. Hochberg (Hematology–Oncology): The chemotherapy agents that are currently the standard of care for systemic diffuse large-B-cell lymphomas do not penetrate the central nervous system, nor does rituximab, an anti-CD20 monoclonal antibody that is an important additional agent in treating this cancer. So we were left in this case with a choice of high-dose methotrexate as a therapy that would penetrate into the central nervous system and also affect the lymph-node disease, or whole-brain radiation for palliation. Unfortunately, the patient's neurologic status did not improve, and she also had biochemical evidence of myocardial infarction after admission to the intensive care unit. Serial CT scans and MRI (Figure 1B) showed rapid growth of the tumor. In the setting of her other medical problems and advanced age it was thought that systemic chemotherapy was not an option. The family declined radiation therapy and ultimately decided to withdraw care. She died on the eighth hospital day.
Anatomical Diagnosis
Diffuse large-B-cell lymphoma, EBV-positive, associated with iatrogenic immunosuppression.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Gastrointestinal Unit (D.K.P.) and the Departments of Radiology (R.G.G.) and Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of Medicine (D.K.P.), Radiology (R.G.G.), and Pathology (R.P.H.), Harvard Medical School.
References
Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor -neutralizing agent. N Engl J Med 2001;345:1098-1104.
Persson PG, Karlen P, Bernell O, et al. Crohn's disease and cancer: a population-based cohort study. Gastroenterology 1994;107:1675-1679.
Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91:854-862.
Choi PM, Zelig MP. Similarity of colorectal cancer in Crohn's disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut 1994;35:950-954.
Ekbom A, Helmick C, Zack M, Adami HO. Increased risk of large-bowel cancer in Crohn's disease with colonic involvement. Lancet 1990;336:357-359.
Gillen CD, Andrews HA, Prior P, Allan RN. Crohn's disease and colorectal cancer. Gut 1994;35:651-655.
Greenstein AJ, Mullin GE, Strauchen JA, et al. Lymphoma in inflammatory bowel disease. Cancer 1992;69:1119-1123.
Arseneau KO, Stukenborg GJ, Connors AF Jr, Cominelli F. The incidence of lymphoid and myeloid malignancies among hospitalized Crohn's disease patients. Inflamm Bowel Dis 2001;7:106-112.
Lewis JD, Bilker WB, Brensinger C, Deren JJ, Vaughn DJ, Strom BL. Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology 2001;121:1080-1087.
Bouhnik Y, Lemann M, Mary JY, et al. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet 1996;347:215-219.
Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999;340:1398-1405.
Fraser AG, Orchard TR, Robinson EM, Jewell DP. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther 2002;16:1225-1232.
Aithal GP, Mansfield JC. The risk of lymphoma associated with inflammatory bowel disease and immunosuppressive treatment. Aliment Pharmacol Ther 2001;15:1101-1108.
Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994;343:1249-1252.
Kinlen LJ. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 1985;78:44-49.
Farrell RJ, Ang Y, Kileen P, et al. Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low. Gut 2000;47:514-519.
Colombel JF, Loftus EV Jr, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn's disease: the Mayo Clinic experience in 500 patients. Gastroenterology 2004;126:19-31.
Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002;46:3151-3158.
Ljung T, Karlen P, Schmidt D, et al. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut 2004;53:849-853.
d'Amore F, Johansen P, Houmand A, Weisenburger DD, Mortensen LS. Epstein-Barr virus genome in non-Hodgkin's lymphomas occurring in immunocompetent patients: highest prevalence in nonlymphoblastic T-cell lymphoma and correlation with a poor prognosis. Blood 1996;87:1045-1055.
Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2001.
Knowles DM, Cesarman E, Chadburn A, et al. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 1995;85:552-565.
Cleary ML, Nalesnik MA, Shearer WT, Sklar J. Clonal analysis of transplant-associated lymphoproliferations based on the structure of the genomic termini of the Epstein-Barr virus. Blood 1988;72:349-352.
Cleary ML, Warnke R, Sklar J. Monoclonality of lymphoproliferative lesions in cardiac-transplant recipients: clonal analysis based on immunoglobulin-gene rearrangements. N Engl J Med 1984;310:477-482.
Dayharsh GA, Loftus EV Jr, Sandborn WJ, et al. Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology 2002;122:72-77.
Wong NA, Herbst H, Herrmann K, et al. Epstein-Barr virus infection in colorectal neoplasms associated with inflammatory bowel disease: detection of the virus in lymphomas but not in adenocarcinomas. J Pathol 2003;201:312-318.
Losco A, Gianelli U, Cassani B, Baldini L, Conte D, Basilisco G. Epstein-Barr virus-associated lymphoma in Crohn's disease. Inflamm Bowel Dis 2004;10:425-429.(Daniel K. Podolsky, M.D.,)
A 71-year-old woman was admitted to the hospital because of left-sided weakness and a mass in the brain. She had had Crohn's disease for many years but was in her usual state of health until three months before admission, when she became fatigued and required daily naps. Two months before admission, episodes of blurring of vision, occipital headaches, and an unsteady gait occurred. The patient's husband described her as "tilting to the left" when she walked, and she appeared to be depressed and angry.
Two weeks before admission, the patient noted an enlarging, nontender mass in her right inguinal area. A fine-needle aspiration of the mass performed 10 days before admission disclosed necrosis, heterogeneous lymphoid cells, and epithelioid histiocytes suggestive of granulomatous inflammation. Several days later nausea developed, the patient's appetite decreased, and over the course of the next week, she lost weight (2 kg). She did not vomit; she had chronic diarrhea from her Crohn's disease, which did not change in frequency or character. Six days before admission, she was too weak to get out of bed, and her husband took her to the emergency room of another hospital, where she was admitted. Her temperature was 38.8°C; other vital signs were normal. The chest was clear, and the heart sounds were normal. The abdomen was mildly tender to palpation, without rebound or guarding. There was no organomegaly. A firm, fixed, nontender mass, 3 cm by 3 cm, was present on the right side of the inguinal region. There was rectal tenderness on digital examination. The patient was alert and oriented. The results of a neurologic examination showed no abnormalities. Cultures of blood and stool were obtained, and broad-spectrum antibiotics were administered.
On the second hospital day, the temperature was 38.8°C. That evening, the patient had a sudden loss of coordination. A neurologic consultant noted a left-sided facial droop; the motor strength on the right side was normal and 4/5 on the left side. There was left pronator drift, and finger-to-nose and heel-to-shin movements were poor on the left side. On stimulation of the plantar reflexes in both feet, the toes turned down. The neck was supple, but her headache was worse on neck flexion. A Romberg test was positive, and the patient leaned toward her left side when walking.
Magnetic resonance imaging (MRI) of the brain showed a mass, 3 cm in diameter, in the right thalamus adjacent to the lateral ventricle. Computed tomography (CT) of the abdomen and pelvis revealed the right inguinal mass; there were no other abnormalities. Treatment with dexamethasone was started. On the third hospital day, the patient had less nausea and headache, and the left-sided facial droop was not seen. The temperature rose to 38.9°C. An incisional biopsy of the right-sided inguinal mass was performed. She was transferred to this hospital on the sixth hospital day.
Crohn's disease had been diagnosed when the patient was 22 years of age, by Dr. Burrill B. Crohn, the physician for whom the disease is named. An ileal resection was performed when she was 22 years of age, and a hemicolectomy at 59 years of age. Beginning when she was 52 years of age, she had been receiving treatment with prednisone, 40 to 50 mg per day; this drug had been discontinued 10 years before admission. Six years before admission, treatment with mercaptopurine was begun; infliximab infusions every eight weeks were added to her treatment regimen three years before admission. The patient continued to have intermittent diarrhea and hematochezia. The last infusion of infliximab she received was four weeks before admission.
The patient had diabetes mellitus, hypertension, and anemia, which was treated with monthly injections of vitamin B12. She lived with her husband. She had smoked cigarettes for 16 years but quit 30 years before admission. She drank alcohol infrequently. A daughter had Crohn's disease. The patient's medications included mesalamine, pantoprazole, losartan, hydrochlorothiazide, loperamide, zolpidem, insulin, cefoxitin, vancomycin, dexamethasone, and ondansetron — in addition to those already mentioned.
The temperature was 36.1°C, the pulse 69 beats per minute, the respiratory rate 18 breaths per minute, and the blood pressure 128/56 mm Hg. On physical examination, the patient appeared chronically ill. There was a small, white lesion on the inferior aspect of the tongue. There was no cervical or axillary lymphadenopathy. There were inspiratory crackles at the left lung base, and the heart sounds were normal. The abdomen was soft and nontender, and the bowel sounds were normal. There was a right-sided inguinal mass, 3 cm by 1 cm, with a recent incision over it.
The patient was awake and alert. There was a left homonymous hemianopia. The pupils were equal and minimally reactive to light. Extraocular movements were normal, but there was decreased eye closure and reduced sensation to touch on the left side of her face. She could not raise her left arm above her head. The strength in her left arm measured 3/5 proximally and 1/5 distally, as compared with 4/5 for the entire right arm. The strength in her left leg measured 2/5 proximally and 3/5 distally, as compared with 4/5 for the entire right leg. Finger-to-nose touch and heel tapping were intact on the right side and slow on the left side. The patient was too weak to walk.
The results of laboratory tests are shown in Table 1. A lumbar puncture showed 94 white cells, with 32 percent lymphocytes, 8 percent neutrophils, 40 percent monocytes, and 19 percent large cells with nucleoli and basophilic cytoplasm; the results of flow cytometry, cytologic examination, and cultures were pending.
Table 1. Laboratory-Test Results on Admission.
Early in the morning of the second hospital day, the patient had a generalized tonic–clonic seizure and became unresponsive. The trachea was intubated to maintain airway protection, and she was transferred to the intensive care unit. CT scanning of the brain showed a heterogeneous mass, 4.3 cm (from anterior to posterior) by 4.2 cm (from left to right) in greatest dimension, centered in the right side of the thalamus, with a relatively low attenuation center and a rim of high attenuation. There was an eccentric nodular component anteriorly and medially. Local mass effect was noted on the right lateral ventricle, but there was no subfalcine or transtentorial herniation. There was architectural distortion that resulted in crowding of the foramen of Monro and mild prominence of the right temporal horn, suggesting outflow obstruction.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Daniel K. Podolsky: May we review the radiologic studies?
Dr. R. Gilberto Gonzalez: The CT scanning of the head performed without the administration of contrast material on the second hospital day (Figure 1A) revealed a large mass centered within the right side of the thalamus. The mass was predominantly hyperdense, although regions of low density were observed; it exerted mass effect on adjacent structures and appeared to extend into the ventricular system. The mass extended inferiorly to involve the temporal lobe and superiorly to the centrum semiovale.
Figure 1. CT and MRI Scans of the Head.
A CT scan (Panel A), obtained without the administration of contrast material, shows a large mass, centered in the right side of the thalamus (arrows). The mass is heterogeneous, is predominantly hyperdense, and extends into the right lateral ventricle. An MRI (Panel B), obtained six days after the CT scan, shows that the mass had increased in size. It has heterogeneous signal characteristics, including areas of relatively low T2-weighted signal corresponding to the regions of hyperdensity seen on the CT scan. The mass prevents the egress of cerebrospinal fluid, resulting in hydrocephalus.
Dr. Podolsky: This 71-year-old woman with an almost 50-year history of Crohn's disease requiring long-term immunosuppressive therapy was found to have a mass involving the central nervous system after the onset of symptoms of weakness and various neurologic findings. The imaging characteristics of the central nervous system abnormality are unlikely findings for a vascular process such as stroke or hemorrhage, and the differential diagnosis is narrowed to infection and cancer.
Infection
Infectious processes, including abscess, tuberculosis, and opportunistic infections, are important considerations. Although Crohn's disease would not predispose this patient to either an abscess or an opportunistic infection, immunosuppressive treatment could. In particular, reactivation of latent tuberculosis after the administration of infliximab has been well recognized1; the majority of patients in whom this reactivation has occurred have had extrapulmonary or disseminated disease, including central nervous system infection. In this regard, it is noteworthy that fine-needle aspiration of the inguinal mass yielded granulomatous tissue. Were it not for the brain lesion, the finding from the mass might also raise concern about the possibility of Crohn's disease involving a lymph node. However, the characteristics of the brain images are not suggestive of an infectious process, and although the patient had fever, there are few other specific signs to suggest an infectious process.
Cancer
The appearance of the brain mass is highly suggestive of a neoplasm. Considered in isolation, the imaging studies would raise concern for a primary cancer of the brain. However, given the known diagnosis of Crohn's disease and the presence of a mass in the groin, there are two more likely diagnoses: metastatic carcinoma and lymphoma. Patients with Crohn's disease are at increased risk for adenocarcinoma, particularly of the small intestine, but also in the colon. These cancers are most likely to develop in areas affected by Crohn's disease; the risk of cancer in the small intestine in patients with Crohn's disease has been estimated to be 5 to 25 times higher than that of unaffected persons,2,3 and the risk of colorectal adenocarcinoma 2 to 5 times higher than that of unaffected persons.4,5,6 The risk correlates with extent of disease, duration, and independently, the age at onset. This patient's surgical history suggests that she has had Crohn's disease affecting both the small intestine and the colon, and she appears to have had active disease for almost 50 years. However, the lesion observed on brain imaging is unlikely to represent metastatic adenocarcinoma in the absence of evidence of other metastatic disease — nor would this diagnosis account for the type of atypical cells that were seen in the cerebrospinal fluid.
Lymphoma in Crohn's Disease
It has long been suspected that there is an increased frequency of lymphoma in the setting of Crohn's disease, although this premise remains controversial. Several studies1,3,7,8 have found a risk of lymphoma among patients with Crohn's disease that is two to four times the risk among those without the disease, although others have not found any significant increase.5,9 In the aggregate, these studies support the impression of an increased risk of lymphoma in patients with Crohn's disease, but it is unlikely that the magnitude of this increase is more than twice that in patients without Crohn's disease.
The risk of lymphoma may be increased by immunosuppressive agents used in the treatment of these patients.10,11 The results of studies attempting to define the risks of lymphoma conferred by immunosuppressive therapy with azathioprine or mercaptopurine have been equivocal,10,12,13 with relative risk ranging from less than or slightly greater than 19,14 to almost 60.15,16
Infliximab and Lymphoma
Understanding how to assess the risk of lymphoma in patients with Crohn's disease has taken on new urgency with the increasing use of infliximab, a chimeric anti–tumor necrosis factor (TNF) monoclonal antibody. This antibody was initially presumed to act through neutralization of the soluble form of the proinflammatory cytokine TNF, but recent studies suggest that apoptosis of cells expressing the transmembrane precursor after binding by infliximab may be necessary for therapeutic benefit. In the several years since its initial approval, infliximab has been found to have diverse adverse effects17; some of these effects may be due to the development of antiinfliximab antibodies, whereas others may reflect the biologic effects of infliximab, such as abscess formation and opportunistic infections, including reactivation of latent tuberculosis.
Several reports have suggested that infliximab may increase the risk of lymphoma.17,18 The incidence of non-Hodgkin's lymphoma in patients with Crohn's disease treated with infliximab in several large studies ranged from 0.2 percent17 to 1.4 percent.19 A summary of all the lymphomas reported in patients receiving infliximab (including patients with rheumatoid arthritis and those with Crohn's disease) yielded an overall incidence of 0.6 percent.18 As in the setting of other types of immunosuppressive therapy, large-B-cell lymphomas that are positive for Epstein–Barr virus (EBV) appear to predominate. Dr. Siegel and my other colleagues at Massachusetts General Hospital have recently completed a survey to assess the risk of lymphoma in patients with Crohn's disease treated with infliximab.
Dr. Corey A. Siegel (Gastroenterology): We performed a systematic literature search to identify all of the studies with a minimum follow-up period of 48 weeks that specifically reported adverse effects of infliximab in the treatment of Crohn's disease. There were 5 patients with lymphoma reported among approximately 1700 patients (0.3 percent). As compared with a healthy age-matched population from the Surveillance, Epidemiology and End Results database, this percentage represents an increase in the incidence of lymphoma in patients receiving infliximab that is approximately 20 times higher.
Dr. Podolsky: In summary, this patient possesses at least three possible risk factors for non-Hodgkin's lymphoma — Crohn's disease, immunosuppressive therapy with mercaptopurine, and infliximab therapy. Although the impact of each risk factor alone may be small, the overall effects may be additive, if not synergistic. Accordingly, I believe that lymphoma may have developed in this patient, probably large-B-cell lymphoma that is positive for EBV. The diagnosis was probably made by appropriate staining of the tissue obtained from the incisional biopsy of the inguinal lymph node, flow cytometry analysis of the abnormal cells seen in the cerebrospinal fluid, or both.
Clinical Diagnosis
Probable non-Hodgkin's lymphoma.
Dr. Daniel K. Podolsky's Diagnosis
B-cell lymphoma, probably large-B-cell lymphoma that is EBV-positive, associated with immunosuppression.
Pathological Discussion
Dr. Robert P. Hasserjian: The diagnostic procedures were a review of the slides of the specimen obtained from the inguinal lymph-node biopsy from the other hospital and an analysis of the cerebrospinal fluid by cytology and flow cytometry. The lymph-node architecture was effaced by sheets of large lymphoid cells, with large areas of geographic necrosis (Figure 2A). The lymphoid cells had prominent nucleoli, expressed the B-cell marker CD20, and contained encoded RNA for EBV (Figure 2B, 2C, and 2D).
Figure 2. Inguinal Lymph-Node Biopsy Specimen.
The inguinal lymph-node architecture (Panel A) is totally effaced by diffuse sheets of cells with areas of geographic necrosis (lower right; hematoxylin and eosin). The cells are large with round-to-irregular, vesicular nuclei and prominent nucleoli (Panel B; hematoxylin and eosin). The cell-surface membrane of the large cells is positive for the B-cell marker CD20 (Panel C; immunohistochemical staining for CD20). Nearly all the large cells contain Epstein–Barr virus-encoded RNA (Panel D; in situ hybridization).
Cytologic examination of the cerebrospinal fluid disclosed large, atypical lymphocytes, morphologically similar to the nodal lymphoma cells (Figure 3). Flow cytometry revealed a predominant population of CD19+ and CD20+ B cells aberrantly expressing CD43 and lacking detectable surface or cytoplasmic immunoglobulin expression. These findings confirm an EBV-positive, diffuse large-B-cell lymphoma involving the inguinal lymph node and cerebrospinal fluid.
Figure 3. Cytologic Preparation of a Sample of Cerebrospinal Fluid.
There are large cells with vesicular nuclei and moderately abundant, eccentrically placed cytoplasm (Papanicolaou stain). These cells resemble the tumor cells on an air-dried direct smear prepared from the patient's inguinal lymph node (inset, Wright–Giemsa stain).
EBV is typically absent in cases of B-cell non-Hodgkin's lymphoma that occur in immunocompetent persons,20 but it is a hallmark of lymphomas occurring in the setting of immunodeficiency. Patients who are immunodeficient are at increased risk for the development of a variety of lymphoproliferative disorders, which share a number of clinicopathological features (Table 2).21 Lower grades or early forms of these lymphoproliferative disorders resemble florid, uncontrolled EBV infection and are often polyclonal.22 In contrast, frank lymphomas contain clonal sequences of EBV and antigen-receptor gene rearrangements, indicating derivation from a single transformed EBV-infected cell.23,24 Lymphomas arising in patients who are immunodeficient are typically diffuse large-B-cell, Burkitt's, or Hodgkin's lymphomas. In addition to the strong association with EBV, these lymphomas differ from lymphomas in patients who are immunocompetent in that such cases show a more limited histologic spectrum and a predilection for extranodal site involvement.
Table 2. Common Features of Immunodeficiency-Associated Lymphoproliferative Disorders.
Lymphomas that arise in patients with inflammatory bowel disease who have been treated with the immunosuppressive agents azathioprine and mercaptopurine have features resembling immunodeficiency-associated lymphomas.25 In contrast to lymphomas that develop in patients with inflammatory bowel disease who are not receiving such therapies, these lymphomas are typically EBV-positive and are almost exclusively high-grade B-cell and Hodgkin's lymphomas. At least one of the reported cases exhibited a viral antigen expression pattern (latency pattern, type 3) that is characteristic of immunodeficiency-associated lymphomas.26 Other recent studies have documented an increased incidence of lymphoma after relatively short periods of infliximab therapy, although many of these patients had also received immunosuppressants18,19,27; at least one of the cases in these studies was EBV-positive. The EBV-positive status and extranodal involvement in the current patient, in the context of mercaptopurine and infliximab therapy, suggest that this case should be categorized as an immunodeficiency-associated lymphoma.
Dr. Nancy Lee Harris (Pathology): The interval between starting infliximab therapy and development of lymphoma was fairly long in this patient.
Dr. Podolsky: Reports suggest that lymphoma may occur within a very short time after infliximab is first started, and an average of just three infusions before diagnosis of the cancer has been described. However, the prolonged period that is described for this patient is within the range reported.
Dr. Harris: Dr. Hochberg, can you discuss the further care of this patient?
Dr. Ephraim P. Hochberg (Hematology–Oncology): The chemotherapy agents that are currently the standard of care for systemic diffuse large-B-cell lymphomas do not penetrate the central nervous system, nor does rituximab, an anti-CD20 monoclonal antibody that is an important additional agent in treating this cancer. So we were left in this case with a choice of high-dose methotrexate as a therapy that would penetrate into the central nervous system and also affect the lymph-node disease, or whole-brain radiation for palliation. Unfortunately, the patient's neurologic status did not improve, and she also had biochemical evidence of myocardial infarction after admission to the intensive care unit. Serial CT scans and MRI (Figure 1B) showed rapid growth of the tumor. In the setting of her other medical problems and advanced age it was thought that systemic chemotherapy was not an option. The family declined radiation therapy and ultimately decided to withdraw care. She died on the eighth hospital day.
Anatomical Diagnosis
Diffuse large-B-cell lymphoma, EBV-positive, associated with iatrogenic immunosuppression.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Gastrointestinal Unit (D.K.P.) and the Departments of Radiology (R.G.G.) and Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of Medicine (D.K.P.), Radiology (R.G.G.), and Pathology (R.P.H.), Harvard Medical School.
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