Case 2-2005 — A 39-Year-Old Woman with Headache, Stiff Neck, and Photophobia
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《新英格兰医药杂志》
Presentation of Case
A 39-year-old woman was admitted to the hospital because of a recurring headache, photophobia, and a stiff neck.
The woman had been well until three months earlier, when a headache developed that was worse when she was lying down. It became more severe over the next few days, and photophobia and neck stiffness developed. Ibuprofen and acetaminophen gave minimal relief. Ten days after the onset of symptoms, she came to the emergency department of this hospital. The temperature was 38.8°C. A lumbar puncture was performed (Table 1). She was admitted to the hospital because meningitis was suspected. The results of computed tomography (CT) of the head and sinus area and magnetic resonance imaging (MRI) of the spine were normal. A presumptive diagnosis of meningitis was made, and she was initially treated with ceftriaxone and ampicillin. The levels of electrolytes, the results of kidney- and liver-function tests, and the levels of total protein and albumin were normal. The results of complete blood counts are shown in Table 2. The headache gradually resolved; blood cultures and cultures of cerebrospinal fluid, serologic analysis, and polymerase-chain-reaction (PCR) testing for viruses and other agents (Table 3) were negative, and the antibiotic treatment was discontinued. The patient was discharged after eight days.
Table 1. Results of Cerebrospinal Fluid Analysis.
Table 2. Results of Hematologic Testing.
Table 3. Results of Microbiologic and Serologic Testing.
Two weeks later, the headache and low-grade fever recurred, and the patient was readmitted to the hospital. The results of chest radiography, CT scanning of the abdomen, and MRI of the head were normal. Two lumbar punctures were performed (Table 1). The results of routine chemistry studies were normal. The results of other tests are shown in Table 2 and Table 3. A tuberculin skin test was positive. The symptoms again improved, and the patient was discharged on the 11th hospital day.
Two weeks later, six weeks before the current admission, the woman was readmitted to the hospital with recurrent headache that had worsened over time, was associated with photophobia and neck and back pain, and became worse when she was lying down. The temperature was 37.6°C, the heart rate 98 beats per minute, and the blood pressure 104/56 mm Hg; the findings on physical examination were unchanged from those of the previous admissions. The results of laboratory tests performed during this admission are shown in Table 1, Table 2, and Table 3. Flow cytometry and cytopathological examination of the cerebrospinal fluid did not reveal a malignant cell population. Rifampin and doxycycline were given because of a positive serologic test for brucellosis, and isoniazid, ethambutol, and pyrimethamine were given because of the positive tuberculin skin test. The patient was given morphine for pain control and seen in consultation by a psychiatrist; she was discharged after two weeks.
The patient's headaches persisted after she was discharged. She described a constant, knife-like bifrontal pain, originating behind the eyes. She began to note blurred vision, generalized weakness, and diffuse bone pain, particularly in her arms. On the day before the fourth and current admission, the temperature rose to 37.9°C, and nausea developed, with one episode of vomiting. She was readmitted to the hospital.
The patient did not have confusion, bleeding, shortness of breath, or abdominal pain. She had been born in Albania and had lived in Greece for many years before immigrating to the United States five months before this admission. She had at first worked in the kitchen of a local hospital but had been unable to work since the onset of her illness. She was married and lived with her husband and 10-year-old son, who were well. She had not traveled outside of Boston recently. Her mother was alive with coronary artery disease and hypertension. Her father was alive with obesity and blindness in one eye. A 29-year-old sister was healthy.
The patient had drunk unpasteurized milk for much of her life. There was no history of transfusions, alcohol consumption, smoking, or intravenous drug use. Her medications included esomeprazole, rifampin, doxycycline, pyrazinamide, ethambutol, isoniazid, gabapentin, acetaminophen, oxycodone, levothyroxine, escitalopram, and clonazepam.
On physical examination, the patient was awake and alert and appeared uncomfortable. The temperature was 37.5°C, the pulse 88 beats per minute, the blood pressure 116/68 mm Hg, and the respiratory rate 18 breaths per minute. She had pain in the neck on touching her chin to her chest and on extension of the legs at the knees. The remainder of the physical and neurologic examination was normal. The results of the complete blood count are shown in Table 2. The results of kidney- and liver-functions tests were normal. Lumbar puncture produced clear and colorless cerebrospinal fluid; the results of the analysis are shown in Table 1.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Karen K. Ballen: This young woman had recurrent symptoms of meningitis over a three-month period, with negative cultures and serologic tests and a slowly progressive monocytosis of the blood and cerebrospinal fluid. Although I am aware of the diagnosis in this case, the patient's clinical presentation provides an opportunity to discuss the differential diagnosis of meningitis. Meningitis in a young woman may be infectious or neoplastic.
Meningitis is far more often infectious than malignant. Causative agents include bacteria, fungi, viruses, and parasites. Bacterial meningitis is usually of sudden onset and characterized by an appearance of being ill, high fevers, headaches, and photophobia. The cerebrospinal fluid has a predominance of neutrophils; the protein level is often elevated and the glucose level decreased. The predominance of lymphocytes in the cerebrospinal fluid and the negative cultures make a diagnosis of bacterial meningitis unlikely in this case. Viral meningitis is typically diagnosed in young patients during the summer months (this woman's symptoms started in June). Early in the course of viral meningitis, there may be a predominance of neutrophils in the cerebrospinal fluid, with a subsequent shift to lymphocytosis.1 Enterovirus may be isolated from the central nervous system by culture or by PCR techniques. This patient first presented in the summer, and viral meningitis was the initial diagnosis. The repetitive episodes without improvement prompted further evaluation. Mollaret's meningitis — recurrent aseptic meningitis with the presence of large monocytes in the cerebrospinal fluid — is a syndrome in which the DNA of the herpes simplex virus has been detected in the cerebrospinal fluid; no viral DNA was detected in this patient.2
Tuberculous meningitis may present with a predominance of either neutrophils or lymphocytes in the cerebrospinal fluid. It may occur in patients with a history of tuberculosis, in those with exposure to active disease, or in the presence of immunosuppression, such as occurs in a patient infected with the human immunodeficiency virus. Acid-fast bacilli are rarely revealed on staining of a specimen of cerebrospinal fluid, but they may be cultured or detected by PCR. The patient's positive reaction to the purified-protein derivative skin test and the presence of monocytosis may have suggested a tuberculous process, but no mycobacteria were detected in the cerebrospinal fluid by a variety of techniques. The weakly positive serologic test for brucellosis in a patient with a history of consuming unpasteurized milk raised the possibility of neurobrucellosis.3 Treatment with antibiotics was undertaken to cover both of these possibilities, but the patient did not improve.
Some medications may cause headache and lymphocytosis in the cerebrospinal fluid.4 Sulfonamides and nonsteroidal antiinflammatory drugs are common offending agents. Medication-induced meningitis was suspected in this patient, but her symptoms persisted when medications were withdrawn.
Carcinomatous meningitis occurs in a variety of cancers, especially breast cancer in women. Cranial-nerve findings are often present, and cancer cells are typically found in the cerebrospinal fluid on cytologic examination. Carcinomatous meningitis would be most unusual as the primary presentation of a solid tumor. The lack of localized neurologic abnormalities on physical examination and the normal-appearing CT scans of the head, chest, and abdomen, as well as the negative results of cytologic examination of the cerebrospinal fluid, make carcinomatous meningitis unlikely in this case.
Meningitis due to leukemia is usually associated with headache; photophobia may occasionally be present. Leukemic meningitis is more common in acute lymphoblastic leukemia than in acute myelogenous leukemia (AML), and it is especially common in childhood acute lymphoblastic leukemia. Meningitis is a feature of only about 1 to 2 percent of cases of AML in adults at presentation.5 The diagnosis is usually made concurrently with a bone marrow diagnosis of acute leukemia.
Although we think of a patient with acute leukemia as typically presenting with a rapid onset of symptoms reflecting replacement of the bone marrow, such as fatigue, bleeding, or infection, the onset may be subtle, as in this case. In particular, adults often do not have peripheral-blood leukocytosis and may have a normal complete blood count. The presence of persistent and increasing monocytosis in both the peripheral blood and the cerebrospinal fluid in this patient, without evidence of infection, raises the possibility of a leukemia with monocytic features. Another worrisome finding is the gradually worsening anemia. During the patient's current admission, blasts were observed on the peripheral-blood smear, heightening the suspicion that the underlying process was a leukemia.
A bone marrow aspiration and biopsy were performed, with portions of the aspirate sent for flow cytometric and cytogenetic analysis.
Dr. Karen K. Ballen's Diagnosis
AML with central nervous system involvement.
Pathological Discussion
Dr. Robert P. Hasserjian: The biopsy specimen of the bone marrow was hypercellular and contained sheets of immature cells with folded nuclei, indistinct nucleoli, and relatively abundant nongranular eosinophilic cytoplasm (Figure 1A). These cells had morphologic features of promonocytes and made up 70 percent of the cells on the bone marrow–aspirate smear (Figure 1B). On cytochemical staining, the cells were positive for alpha-naphthyl butyrate (nonspecific) esterase and negative for myeloperoxidase, consistent with monocytic differentiation. Only a few maturing erythroid, myeloid, and megakaryocytic elements were present; they did not show evidence of morphologic dysplasia. Flow cytometry of the bone marrow aspirate revealed a predominant population of cells expressing the myeloid marker CD33 and the monocytic marker CD14. Cytogenetic analysis of the bone marrow revealed a normal (46,XX) karyotype. The constellation of findings confirmed the diagnosis of AML with monocytic differentiation. A cryptic genetic abnormality that is not detected by routine cytogenetic analysis is present in 5 to 10 percent of cases of AML with apparently normal karyotypes.6,7,8 Since cases of AML bearing translocations involving the MLL (mixed-lineage leukemia) gene often display monocytic differentiation, we performed fluorescence in situ hybridization analysis to detect a cryptic MLL translocation; this study was negative.
Figure 1. Bone Marrow–Biopsy Specimen and Aspirate, Peripheral-Blood Smear, and Cerebrospinal Fluid Sample.
The biopsy specimen showed a hypercellular marrow containing sheets of immature cells with folded nuclei, representing neoplastic promonocytes and monoblasts (Panel A, Giemsa stain). The bone marrow aspirate contained a preponderance of blasts and promonocytes with folded nuclei and moderately abundant cytoplasm (Panel B, Wright–Giemsa stain). The monocytic cells from the patient's blood (Panel C) and from the cerebrospinal fluid (Panel D) at diagnosis consisted mainly of monocytes and promonocytes, with more abundant cytoplasm than the more immature cells in the bone marrow (Wright–Giemsa stain). A subgroup of the leukemic cells in the biopsy specimen showed aberrant localization of nuclear protein nucleophosmin (NPM) in the cytoplasm as well as in the nucleus (Panel E; immunohistochemical evaluation with anti-NPM antibody, alkaline phosphatase anti–alkaline phosphatase technique). Normal cells showed nuclear staining only, as seen in the megakaryocyte (arrow). Positive staining is indicated by the red chromogen. Panel E courtesy of Dr. B. Falini.
In contrast to the immature appearance of the bone marrow monocytic cells, the cells in the patient's peripheral blood were mainly mature monocytes, with only a few promonocytes and monoblasts. A sample of cerebrospinal fluid taken at the time of the bone marrow biopsy also revealed mature monocytes and promonocytes, indicating cerebrospinal fluid involvement by the patient's leukemia (Figure 1C and Figure 1D).
Increasingly, specific cytogenetic abnormalities are proving to be the best predictors of clinical behavior in AML. Thus, the current World Health Organization classification stratifies cases primarily according to cytogenetic features, using additional morphologic, clinical, and immunophenotypic features9 to identify distinct categories of disease and to help predict the outcome and direct therapy10 (Table 4). More than half of cases of AML in adults fall into one of the categories with recurrent cytogenetic abnormalities or into one of the two poor-prognosis categories defined by morphologic or clinical features.10 The remaining cases are termed "AML, not otherwise categorized" and may be subclassified by the French–American–British (FAB) system.11 Some of these cases have cytogenetic abnormalities; as outcome data accumulate, additional clinically relevant categories may emerge.12,13 However, 40 to 50 percent of patients with AML have a normal karyotype; for these cases the outcome is highly variable and clinical management is controversial.14,15
Table 4. Classification of AML (World Health Organization).
This cytogenetically normal case falls into the broad category of AML, not otherwise categorized. The FAB system classifies acute myelogenous leukemia with monocytic differentiation into monoblastic (M5a) and monocytic (M5b) subtypes on the basis of the degree of maturation of the neoplastic cells. This case was therefore classified as acute monocytic leukemia because of the preponderance of promonocytes, rather than monoblasts, in the bone marrow. More mature cells (promonocytes and monocytes) may be present in the peripheral blood and cerebrospinal fluid than in the bone marrow, as in this case, in both acute monocytic and acute monoblastic leukemias. Thus, examination of bone marrow is warranted in cases of unexplained, persistent monocytosis.16
Since the category of AML, not otherwise categorized, is thought to be heterogeneous, numerous studies have attempted to define biologically or clinically distinct subgroups within this category. Activating mutations in the gene for FMS-like tyrosine kinase-3 (FLT3) are found in about 45 percent of patients with AML who have a normal karyotype.17 FLT3 is a cytokine receptor expressed on normal hematopoietic progenitors as well as AML blasts, and signaling through FLT3 enhances proliferation of leukemic blasts in vitro.18,19 Sequencing of the FLT3 gene in this patient identified a point mutation at the Asp835 locus, which has been shown to cause constitutive activation of the FLT3 receptor.
Recent studies have used the new technology of gene-expression profiling by DNA microarrays to define subtypes of AML, particularly within the group of patients with a normal karyotype. Although multiple categories with different expression signatures could be identified and some expression patterns predicted the clinical outcome, no homogeneous subgroups have yet emerged.20,21
A report in this issue of the Journal22 describes the finding of abnormal cytoplasmic localization of the nuclear protein nucleophosmin (NPM) in 60 percent of cases of AML with a normal karyotype. This finding is associated with a mutation in the c-terminal region of the NPM gene that alters its DNA-binding site. This localization pattern was not found in cases with major cytogenetic abnormalities or in secondary AML. Cases with this abnormality had an increased frequency of FLT3 mutations; data on the clinical outcome are not yet available. Immunohistochemical staining for NPM in the case under discussion (Figure 1E) showed localization in the cytoplasm of the neoplastic cells. Thus, this case is an example of AML with abnormal cytoplasmic localization of NPM.
Discussion of Management
Dr. Ballen: Acute myelogenous leukemia is the most common acute leukemia in adults, but it is nonetheless a rare disease, with 12,000 new cases each year in the United States. The incidence increases with age, with a median age at onset of 63 years.23 The disease can either be a primary condition, as in this patient, or a secondary condition, as a complication of chemotherapy or radiotherapy or arising from a preexisting myelodysplastic syndrome.
The selection of treatment for acute leukemias depends on stratification according to lineage (myeloid vs. lymphoid) and the correct classification according to cytogenetic evaluation and other criteria. Immunophenotyping of the cells from either the peripheral blood or bone marrow is used to distinguish whether the lineage in the particular case is myeloid or lymphoid.24 Cytogenetic studies are performed at the time of diagnosis to provide prognostic information and to guide postremission therapy. Echocardiography or radionuclide ventriculography is used to determine the cardiac ejection fraction before the administration of anthracycline-based chemotherapy; this patient's ejection fraction was normal. Since involvement of the central nervous system is rare in patients with AML, they do not routinely undergo lumbar puncture at diagnosis and do not receive central nervous system prophylaxis, in contrast to patients with acute lymphoblastic leukemia.
Molecular Targets for Therapy
There has been recent progress in the development of molecular targets associated with AML. The best example is the use of tretinoin for patients with acute promyelocytic leukemia. Tretinoin targets the chimeric protein encoded by the t(15;17) translocation associated with acute promyelocytic leukemia. Recently the internal-tandem-duplication mutations of the FLT3 gene that are found in about 30 percent of cases of AML have been shown to be associated with a poor prognosis.25,26 Mutations in the activation loop of the second tyrosine kinase domain, as seen in the patient under discussion, are not associated with a difference in overall survival from that among patients who are negative for FLT3 mutations.17
Currently, several oral FLT3 inhibitor compounds are in phase 1 and phase 2 clinical trials involving patients with AML.27 In one study of 43 patients with refractory AML or elderly patients with AML who were not candidates for chemotherapy, 1 patient had a complete remission and 7 had a partial response.28 Currently, the choice of initial treatment of AML is not influenced by the presence or absence of FLT3 mutations.
The recent identification of NPM mutations in 60 percent of patients with AML who have a normal karyotype22 suggests that this gene may play a role in tumorigenesis in some cases of AML. In the future, inhibitors of this molecule may offer additional treatment options for patients such as the one under discussion here.
Chemotherapy
Treatment for patients with AML, such as the woman in this case, is divided into induction chemotherapy, designed to reduce the leukemic burden,29 and consolidation chemotherapy, designed to maintain a complete remission. Approximately 80 percent of patients under the age of 60 years will have complete remission, but the remission rate falls rapidly for patients 60 years of age or older. The treatment is aggressive, with a usual hospital stay of three to four weeks and a rate of death from complications of therapy (usually infection or bleeding) of between 5 and 10 percent. After the patient has a complete remission, consolidation therapy, consisting of two to four months of additional chemotherapy, is administered. The success of this treatment varies considerably depending on the karyotype.30 Survival in patients with findings on cytogenetic analysis that suggest they are good candidates for the treatment is 60 percent, whereas in those who are considered to have a poor prognosis, five-year survival is 10 percent. The majority of patients, including this one, fall into the intermediate-risk group (normal results on cytogenetic evaluation), and they have a five-year survival rate of 40 percent. An algorithm for the treatment of patients under the age of 60 years with AML is provided in Figure 2.
Figure 2. Treatment Algorithm for Patients Younger Than 60 Years with New Diagnosis of AML.
Issues related to the management of disease in this patient focused on the choice of initial induction therapy, the intensity of postremission therapy, and the selection of treatment of the central nervous system to clear the leukemia and prevent recurrence. The patient was enrolled in a Cancer and Leukemia Group B study of induction therapy, which was followed by risk-adapted consolidation therapy and a random assignment to either treatment with interleukin-2 or observation after the chemotherapy.
All patients in this study receive the same induction therapy of daunorubicin, etoposide, and cytarabine (the study was initially designed to test an inhibitor of multidrug resistance that is no longer available). Patients with a favorable cytogenetic evaluation receive consolidation therapy with high-dose cytarabine. All other patients receive one cycle of consolidation chemotherapy followed by autologous stem-cell transplantation. Allogeneic transplantation is not included in this protocol, although patients may be withdrawn from the study in order to undergo allogeneic transplantation. After the transplantation, patients are randomly assigned either to treatment with interleukin-2, which increases natural-killer-cell activity, or to observation. The patient in this case completed induction chemotherapy according to the protocol, and entered into complete remission. Her pain improved dramatically after only two days of treatment.
The use of autologous transplantation for patients in first remission is controversial. Five-year survival rates range from 35 to 55 percent, with transplantation-related mortality rates of 5 to 10 percent. The Medical Research Council AML trial showed that there was a survival advantage to autologous stem-cell transplantation, as compared with standard chemotherapy for patients with AML in first remission; however, other studies have not confirmed these results.31 Since the normal cytogenetic evaluation of the patient under discussion placed her in the intermediate-risk category, she underwent autologous transplantation according to the protocol. Allogeneic transplantation was considered, but her sister was not HLA-identical. The patient received chemotherapy with high-dose cytarabine and etoposide to mobilize stem cells into the peripheral blood; autologous stem cells were collected. She then received a myeloablative conditioning regimen of busulfan and etoposide, followed by the infusion of stem cells. Her course of treatment was complicated by nausea and vomiting, fever, neutropenia, and mucositis.
Appropriate therapy for the patient's disease in the central nervous system, which was intended to clear the leukemia and to prevent recurrent disease in the cerebrospinal fluid, also proved controversial. The patient received intrathecal therapy with methotrexate and cytarabine. She required three intrathecal treatments to clear the leukemia cells from cerebrospinal fluid and received two additional treatments. A sixth intrathecal treatment was given just before the transplantation. Since total-body irradiation was not part of the conditioning regimen for transplantation, consideration was given to cranial radiotherapy to prevent recurrence in the central nervous system. There is very little information about the benefit of cranial radiotherapy in the central nervous system in patients with acute myelogenous leukemia. One small, nonrandomized study has suggested an improvement in survival with combined intrathecal therapy and cranial radiotherapy.5 Given the paucity of data, after discussion with a consultant from the Department of Radiation Oncology, we decided not to proceed with radiotherapy in the central nervous system.
The patient elected not to participate in the interleukin-2 portion of the protocol. She is still in remission one year after the diagnosis and six months after the autologous transplantation. She continues to have a mild headache of unclear cause.
In summary, this patient had an unusual manifestation of an uncommon neoplasm: acute myelogenous leukemia with involvement of the central nervous system. Because initially the complete blood counts did not reveal any abnormalities, leukemia was not suspected for several months. Since leukemia is a rare disease, enrolling patients in national protocols designed to test new treatments is important if progress is to be made. This patient was treated according to a national leukemia protocol that offers a good possibility of long-term survival.
Anatomical Diagnosis
AML, not otherwise categorized, with normal karyotype, mutation of the FLT3 tyrosine kinase domain, and cytoplasmic localization of NPM.
Source Information
From the Division of Hematology and Oncology, Department of Medicine (K.K.B.), and the Department of Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of Medicine (K.K.B.) and Pathology (R.P.H.), Harvard Medical School.
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A 39-year-old woman was admitted to the hospital because of a recurring headache, photophobia, and a stiff neck.
The woman had been well until three months earlier, when a headache developed that was worse when she was lying down. It became more severe over the next few days, and photophobia and neck stiffness developed. Ibuprofen and acetaminophen gave minimal relief. Ten days after the onset of symptoms, she came to the emergency department of this hospital. The temperature was 38.8°C. A lumbar puncture was performed (Table 1). She was admitted to the hospital because meningitis was suspected. The results of computed tomography (CT) of the head and sinus area and magnetic resonance imaging (MRI) of the spine were normal. A presumptive diagnosis of meningitis was made, and she was initially treated with ceftriaxone and ampicillin. The levels of electrolytes, the results of kidney- and liver-function tests, and the levels of total protein and albumin were normal. The results of complete blood counts are shown in Table 2. The headache gradually resolved; blood cultures and cultures of cerebrospinal fluid, serologic analysis, and polymerase-chain-reaction (PCR) testing for viruses and other agents (Table 3) were negative, and the antibiotic treatment was discontinued. The patient was discharged after eight days.
Table 1. Results of Cerebrospinal Fluid Analysis.
Table 2. Results of Hematologic Testing.
Table 3. Results of Microbiologic and Serologic Testing.
Two weeks later, the headache and low-grade fever recurred, and the patient was readmitted to the hospital. The results of chest radiography, CT scanning of the abdomen, and MRI of the head were normal. Two lumbar punctures were performed (Table 1). The results of routine chemistry studies were normal. The results of other tests are shown in Table 2 and Table 3. A tuberculin skin test was positive. The symptoms again improved, and the patient was discharged on the 11th hospital day.
Two weeks later, six weeks before the current admission, the woman was readmitted to the hospital with recurrent headache that had worsened over time, was associated with photophobia and neck and back pain, and became worse when she was lying down. The temperature was 37.6°C, the heart rate 98 beats per minute, and the blood pressure 104/56 mm Hg; the findings on physical examination were unchanged from those of the previous admissions. The results of laboratory tests performed during this admission are shown in Table 1, Table 2, and Table 3. Flow cytometry and cytopathological examination of the cerebrospinal fluid did not reveal a malignant cell population. Rifampin and doxycycline were given because of a positive serologic test for brucellosis, and isoniazid, ethambutol, and pyrimethamine were given because of the positive tuberculin skin test. The patient was given morphine for pain control and seen in consultation by a psychiatrist; she was discharged after two weeks.
The patient's headaches persisted after she was discharged. She described a constant, knife-like bifrontal pain, originating behind the eyes. She began to note blurred vision, generalized weakness, and diffuse bone pain, particularly in her arms. On the day before the fourth and current admission, the temperature rose to 37.9°C, and nausea developed, with one episode of vomiting. She was readmitted to the hospital.
The patient did not have confusion, bleeding, shortness of breath, or abdominal pain. She had been born in Albania and had lived in Greece for many years before immigrating to the United States five months before this admission. She had at first worked in the kitchen of a local hospital but had been unable to work since the onset of her illness. She was married and lived with her husband and 10-year-old son, who were well. She had not traveled outside of Boston recently. Her mother was alive with coronary artery disease and hypertension. Her father was alive with obesity and blindness in one eye. A 29-year-old sister was healthy.
The patient had drunk unpasteurized milk for much of her life. There was no history of transfusions, alcohol consumption, smoking, or intravenous drug use. Her medications included esomeprazole, rifampin, doxycycline, pyrazinamide, ethambutol, isoniazid, gabapentin, acetaminophen, oxycodone, levothyroxine, escitalopram, and clonazepam.
On physical examination, the patient was awake and alert and appeared uncomfortable. The temperature was 37.5°C, the pulse 88 beats per minute, the blood pressure 116/68 mm Hg, and the respiratory rate 18 breaths per minute. She had pain in the neck on touching her chin to her chest and on extension of the legs at the knees. The remainder of the physical and neurologic examination was normal. The results of the complete blood count are shown in Table 2. The results of kidney- and liver-functions tests were normal. Lumbar puncture produced clear and colorless cerebrospinal fluid; the results of the analysis are shown in Table 1.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Karen K. Ballen: This young woman had recurrent symptoms of meningitis over a three-month period, with negative cultures and serologic tests and a slowly progressive monocytosis of the blood and cerebrospinal fluid. Although I am aware of the diagnosis in this case, the patient's clinical presentation provides an opportunity to discuss the differential diagnosis of meningitis. Meningitis in a young woman may be infectious or neoplastic.
Meningitis is far more often infectious than malignant. Causative agents include bacteria, fungi, viruses, and parasites. Bacterial meningitis is usually of sudden onset and characterized by an appearance of being ill, high fevers, headaches, and photophobia. The cerebrospinal fluid has a predominance of neutrophils; the protein level is often elevated and the glucose level decreased. The predominance of lymphocytes in the cerebrospinal fluid and the negative cultures make a diagnosis of bacterial meningitis unlikely in this case. Viral meningitis is typically diagnosed in young patients during the summer months (this woman's symptoms started in June). Early in the course of viral meningitis, there may be a predominance of neutrophils in the cerebrospinal fluid, with a subsequent shift to lymphocytosis.1 Enterovirus may be isolated from the central nervous system by culture or by PCR techniques. This patient first presented in the summer, and viral meningitis was the initial diagnosis. The repetitive episodes without improvement prompted further evaluation. Mollaret's meningitis — recurrent aseptic meningitis with the presence of large monocytes in the cerebrospinal fluid — is a syndrome in which the DNA of the herpes simplex virus has been detected in the cerebrospinal fluid; no viral DNA was detected in this patient.2
Tuberculous meningitis may present with a predominance of either neutrophils or lymphocytes in the cerebrospinal fluid. It may occur in patients with a history of tuberculosis, in those with exposure to active disease, or in the presence of immunosuppression, such as occurs in a patient infected with the human immunodeficiency virus. Acid-fast bacilli are rarely revealed on staining of a specimen of cerebrospinal fluid, but they may be cultured or detected by PCR. The patient's positive reaction to the purified-protein derivative skin test and the presence of monocytosis may have suggested a tuberculous process, but no mycobacteria were detected in the cerebrospinal fluid by a variety of techniques. The weakly positive serologic test for brucellosis in a patient with a history of consuming unpasteurized milk raised the possibility of neurobrucellosis.3 Treatment with antibiotics was undertaken to cover both of these possibilities, but the patient did not improve.
Some medications may cause headache and lymphocytosis in the cerebrospinal fluid.4 Sulfonamides and nonsteroidal antiinflammatory drugs are common offending agents. Medication-induced meningitis was suspected in this patient, but her symptoms persisted when medications were withdrawn.
Carcinomatous meningitis occurs in a variety of cancers, especially breast cancer in women. Cranial-nerve findings are often present, and cancer cells are typically found in the cerebrospinal fluid on cytologic examination. Carcinomatous meningitis would be most unusual as the primary presentation of a solid tumor. The lack of localized neurologic abnormalities on physical examination and the normal-appearing CT scans of the head, chest, and abdomen, as well as the negative results of cytologic examination of the cerebrospinal fluid, make carcinomatous meningitis unlikely in this case.
Meningitis due to leukemia is usually associated with headache; photophobia may occasionally be present. Leukemic meningitis is more common in acute lymphoblastic leukemia than in acute myelogenous leukemia (AML), and it is especially common in childhood acute lymphoblastic leukemia. Meningitis is a feature of only about 1 to 2 percent of cases of AML in adults at presentation.5 The diagnosis is usually made concurrently with a bone marrow diagnosis of acute leukemia.
Although we think of a patient with acute leukemia as typically presenting with a rapid onset of symptoms reflecting replacement of the bone marrow, such as fatigue, bleeding, or infection, the onset may be subtle, as in this case. In particular, adults often do not have peripheral-blood leukocytosis and may have a normal complete blood count. The presence of persistent and increasing monocytosis in both the peripheral blood and the cerebrospinal fluid in this patient, without evidence of infection, raises the possibility of a leukemia with monocytic features. Another worrisome finding is the gradually worsening anemia. During the patient's current admission, blasts were observed on the peripheral-blood smear, heightening the suspicion that the underlying process was a leukemia.
A bone marrow aspiration and biopsy were performed, with portions of the aspirate sent for flow cytometric and cytogenetic analysis.
Dr. Karen K. Ballen's Diagnosis
AML with central nervous system involvement.
Pathological Discussion
Dr. Robert P. Hasserjian: The biopsy specimen of the bone marrow was hypercellular and contained sheets of immature cells with folded nuclei, indistinct nucleoli, and relatively abundant nongranular eosinophilic cytoplasm (Figure 1A). These cells had morphologic features of promonocytes and made up 70 percent of the cells on the bone marrow–aspirate smear (Figure 1B). On cytochemical staining, the cells were positive for alpha-naphthyl butyrate (nonspecific) esterase and negative for myeloperoxidase, consistent with monocytic differentiation. Only a few maturing erythroid, myeloid, and megakaryocytic elements were present; they did not show evidence of morphologic dysplasia. Flow cytometry of the bone marrow aspirate revealed a predominant population of cells expressing the myeloid marker CD33 and the monocytic marker CD14. Cytogenetic analysis of the bone marrow revealed a normal (46,XX) karyotype. The constellation of findings confirmed the diagnosis of AML with monocytic differentiation. A cryptic genetic abnormality that is not detected by routine cytogenetic analysis is present in 5 to 10 percent of cases of AML with apparently normal karyotypes.6,7,8 Since cases of AML bearing translocations involving the MLL (mixed-lineage leukemia) gene often display monocytic differentiation, we performed fluorescence in situ hybridization analysis to detect a cryptic MLL translocation; this study was negative.
Figure 1. Bone Marrow–Biopsy Specimen and Aspirate, Peripheral-Blood Smear, and Cerebrospinal Fluid Sample.
The biopsy specimen showed a hypercellular marrow containing sheets of immature cells with folded nuclei, representing neoplastic promonocytes and monoblasts (Panel A, Giemsa stain). The bone marrow aspirate contained a preponderance of blasts and promonocytes with folded nuclei and moderately abundant cytoplasm (Panel B, Wright–Giemsa stain). The monocytic cells from the patient's blood (Panel C) and from the cerebrospinal fluid (Panel D) at diagnosis consisted mainly of monocytes and promonocytes, with more abundant cytoplasm than the more immature cells in the bone marrow (Wright–Giemsa stain). A subgroup of the leukemic cells in the biopsy specimen showed aberrant localization of nuclear protein nucleophosmin (NPM) in the cytoplasm as well as in the nucleus (Panel E; immunohistochemical evaluation with anti-NPM antibody, alkaline phosphatase anti–alkaline phosphatase technique). Normal cells showed nuclear staining only, as seen in the megakaryocyte (arrow). Positive staining is indicated by the red chromogen. Panel E courtesy of Dr. B. Falini.
In contrast to the immature appearance of the bone marrow monocytic cells, the cells in the patient's peripheral blood were mainly mature monocytes, with only a few promonocytes and monoblasts. A sample of cerebrospinal fluid taken at the time of the bone marrow biopsy also revealed mature monocytes and promonocytes, indicating cerebrospinal fluid involvement by the patient's leukemia (Figure 1C and Figure 1D).
Increasingly, specific cytogenetic abnormalities are proving to be the best predictors of clinical behavior in AML. Thus, the current World Health Organization classification stratifies cases primarily according to cytogenetic features, using additional morphologic, clinical, and immunophenotypic features9 to identify distinct categories of disease and to help predict the outcome and direct therapy10 (Table 4). More than half of cases of AML in adults fall into one of the categories with recurrent cytogenetic abnormalities or into one of the two poor-prognosis categories defined by morphologic or clinical features.10 The remaining cases are termed "AML, not otherwise categorized" and may be subclassified by the French–American–British (FAB) system.11 Some of these cases have cytogenetic abnormalities; as outcome data accumulate, additional clinically relevant categories may emerge.12,13 However, 40 to 50 percent of patients with AML have a normal karyotype; for these cases the outcome is highly variable and clinical management is controversial.14,15
Table 4. Classification of AML (World Health Organization).
This cytogenetically normal case falls into the broad category of AML, not otherwise categorized. The FAB system classifies acute myelogenous leukemia with monocytic differentiation into monoblastic (M5a) and monocytic (M5b) subtypes on the basis of the degree of maturation of the neoplastic cells. This case was therefore classified as acute monocytic leukemia because of the preponderance of promonocytes, rather than monoblasts, in the bone marrow. More mature cells (promonocytes and monocytes) may be present in the peripheral blood and cerebrospinal fluid than in the bone marrow, as in this case, in both acute monocytic and acute monoblastic leukemias. Thus, examination of bone marrow is warranted in cases of unexplained, persistent monocytosis.16
Since the category of AML, not otherwise categorized, is thought to be heterogeneous, numerous studies have attempted to define biologically or clinically distinct subgroups within this category. Activating mutations in the gene for FMS-like tyrosine kinase-3 (FLT3) are found in about 45 percent of patients with AML who have a normal karyotype.17 FLT3 is a cytokine receptor expressed on normal hematopoietic progenitors as well as AML blasts, and signaling through FLT3 enhances proliferation of leukemic blasts in vitro.18,19 Sequencing of the FLT3 gene in this patient identified a point mutation at the Asp835 locus, which has been shown to cause constitutive activation of the FLT3 receptor.
Recent studies have used the new technology of gene-expression profiling by DNA microarrays to define subtypes of AML, particularly within the group of patients with a normal karyotype. Although multiple categories with different expression signatures could be identified and some expression patterns predicted the clinical outcome, no homogeneous subgroups have yet emerged.20,21
A report in this issue of the Journal22 describes the finding of abnormal cytoplasmic localization of the nuclear protein nucleophosmin (NPM) in 60 percent of cases of AML with a normal karyotype. This finding is associated with a mutation in the c-terminal region of the NPM gene that alters its DNA-binding site. This localization pattern was not found in cases with major cytogenetic abnormalities or in secondary AML. Cases with this abnormality had an increased frequency of FLT3 mutations; data on the clinical outcome are not yet available. Immunohistochemical staining for NPM in the case under discussion (Figure 1E) showed localization in the cytoplasm of the neoplastic cells. Thus, this case is an example of AML with abnormal cytoplasmic localization of NPM.
Discussion of Management
Dr. Ballen: Acute myelogenous leukemia is the most common acute leukemia in adults, but it is nonetheless a rare disease, with 12,000 new cases each year in the United States. The incidence increases with age, with a median age at onset of 63 years.23 The disease can either be a primary condition, as in this patient, or a secondary condition, as a complication of chemotherapy or radiotherapy or arising from a preexisting myelodysplastic syndrome.
The selection of treatment for acute leukemias depends on stratification according to lineage (myeloid vs. lymphoid) and the correct classification according to cytogenetic evaluation and other criteria. Immunophenotyping of the cells from either the peripheral blood or bone marrow is used to distinguish whether the lineage in the particular case is myeloid or lymphoid.24 Cytogenetic studies are performed at the time of diagnosis to provide prognostic information and to guide postremission therapy. Echocardiography or radionuclide ventriculography is used to determine the cardiac ejection fraction before the administration of anthracycline-based chemotherapy; this patient's ejection fraction was normal. Since involvement of the central nervous system is rare in patients with AML, they do not routinely undergo lumbar puncture at diagnosis and do not receive central nervous system prophylaxis, in contrast to patients with acute lymphoblastic leukemia.
Molecular Targets for Therapy
There has been recent progress in the development of molecular targets associated with AML. The best example is the use of tretinoin for patients with acute promyelocytic leukemia. Tretinoin targets the chimeric protein encoded by the t(15;17) translocation associated with acute promyelocytic leukemia. Recently the internal-tandem-duplication mutations of the FLT3 gene that are found in about 30 percent of cases of AML have been shown to be associated with a poor prognosis.25,26 Mutations in the activation loop of the second tyrosine kinase domain, as seen in the patient under discussion, are not associated with a difference in overall survival from that among patients who are negative for FLT3 mutations.17
Currently, several oral FLT3 inhibitor compounds are in phase 1 and phase 2 clinical trials involving patients with AML.27 In one study of 43 patients with refractory AML or elderly patients with AML who were not candidates for chemotherapy, 1 patient had a complete remission and 7 had a partial response.28 Currently, the choice of initial treatment of AML is not influenced by the presence or absence of FLT3 mutations.
The recent identification of NPM mutations in 60 percent of patients with AML who have a normal karyotype22 suggests that this gene may play a role in tumorigenesis in some cases of AML. In the future, inhibitors of this molecule may offer additional treatment options for patients such as the one under discussion here.
Chemotherapy
Treatment for patients with AML, such as the woman in this case, is divided into induction chemotherapy, designed to reduce the leukemic burden,29 and consolidation chemotherapy, designed to maintain a complete remission. Approximately 80 percent of patients under the age of 60 years will have complete remission, but the remission rate falls rapidly for patients 60 years of age or older. The treatment is aggressive, with a usual hospital stay of three to four weeks and a rate of death from complications of therapy (usually infection or bleeding) of between 5 and 10 percent. After the patient has a complete remission, consolidation therapy, consisting of two to four months of additional chemotherapy, is administered. The success of this treatment varies considerably depending on the karyotype.30 Survival in patients with findings on cytogenetic analysis that suggest they are good candidates for the treatment is 60 percent, whereas in those who are considered to have a poor prognosis, five-year survival is 10 percent. The majority of patients, including this one, fall into the intermediate-risk group (normal results on cytogenetic evaluation), and they have a five-year survival rate of 40 percent. An algorithm for the treatment of patients under the age of 60 years with AML is provided in Figure 2.
Figure 2. Treatment Algorithm for Patients Younger Than 60 Years with New Diagnosis of AML.
Issues related to the management of disease in this patient focused on the choice of initial induction therapy, the intensity of postremission therapy, and the selection of treatment of the central nervous system to clear the leukemia and prevent recurrence. The patient was enrolled in a Cancer and Leukemia Group B study of induction therapy, which was followed by risk-adapted consolidation therapy and a random assignment to either treatment with interleukin-2 or observation after the chemotherapy.
All patients in this study receive the same induction therapy of daunorubicin, etoposide, and cytarabine (the study was initially designed to test an inhibitor of multidrug resistance that is no longer available). Patients with a favorable cytogenetic evaluation receive consolidation therapy with high-dose cytarabine. All other patients receive one cycle of consolidation chemotherapy followed by autologous stem-cell transplantation. Allogeneic transplantation is not included in this protocol, although patients may be withdrawn from the study in order to undergo allogeneic transplantation. After the transplantation, patients are randomly assigned either to treatment with interleukin-2, which increases natural-killer-cell activity, or to observation. The patient in this case completed induction chemotherapy according to the protocol, and entered into complete remission. Her pain improved dramatically after only two days of treatment.
The use of autologous transplantation for patients in first remission is controversial. Five-year survival rates range from 35 to 55 percent, with transplantation-related mortality rates of 5 to 10 percent. The Medical Research Council AML trial showed that there was a survival advantage to autologous stem-cell transplantation, as compared with standard chemotherapy for patients with AML in first remission; however, other studies have not confirmed these results.31 Since the normal cytogenetic evaluation of the patient under discussion placed her in the intermediate-risk category, she underwent autologous transplantation according to the protocol. Allogeneic transplantation was considered, but her sister was not HLA-identical. The patient received chemotherapy with high-dose cytarabine and etoposide to mobilize stem cells into the peripheral blood; autologous stem cells were collected. She then received a myeloablative conditioning regimen of busulfan and etoposide, followed by the infusion of stem cells. Her course of treatment was complicated by nausea and vomiting, fever, neutropenia, and mucositis.
Appropriate therapy for the patient's disease in the central nervous system, which was intended to clear the leukemia and to prevent recurrent disease in the cerebrospinal fluid, also proved controversial. The patient received intrathecal therapy with methotrexate and cytarabine. She required three intrathecal treatments to clear the leukemia cells from cerebrospinal fluid and received two additional treatments. A sixth intrathecal treatment was given just before the transplantation. Since total-body irradiation was not part of the conditioning regimen for transplantation, consideration was given to cranial radiotherapy to prevent recurrence in the central nervous system. There is very little information about the benefit of cranial radiotherapy in the central nervous system in patients with acute myelogenous leukemia. One small, nonrandomized study has suggested an improvement in survival with combined intrathecal therapy and cranial radiotherapy.5 Given the paucity of data, after discussion with a consultant from the Department of Radiation Oncology, we decided not to proceed with radiotherapy in the central nervous system.
The patient elected not to participate in the interleukin-2 portion of the protocol. She is still in remission one year after the diagnosis and six months after the autologous transplantation. She continues to have a mild headache of unclear cause.
In summary, this patient had an unusual manifestation of an uncommon neoplasm: acute myelogenous leukemia with involvement of the central nervous system. Because initially the complete blood counts did not reveal any abnormalities, leukemia was not suspected for several months. Since leukemia is a rare disease, enrolling patients in national protocols designed to test new treatments is important if progress is to be made. This patient was treated according to a national leukemia protocol that offers a good possibility of long-term survival.
Anatomical Diagnosis
AML, not otherwise categorized, with normal karyotype, mutation of the FLT3 tyrosine kinase domain, and cytoplasmic localization of NPM.
Source Information
From the Division of Hematology and Oncology, Department of Medicine (K.K.B.), and the Department of Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of Medicine (K.K.B.) and Pathology (R.P.H.), Harvard Medical School.
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