Thorough follow-up of medical history reveals unexpected diagnosis

Malignant disease processes can at times present with unusual systemic manifestations, whether it is a paraneoplastic syndrome or a direct tumor-related effect. Recently, we evaluated a patient who was initially referred for one of the most common reasons for a hematology consultation, thrombocytopenia. However, it soon became apparent that the case had a few unexpected elements.

The patient is a 41-year-old woman with a largely unremarkable past medical history. She reported that about 2 weeks prior to presentation, one of the children she was babysitting was found to have the flu. Subsequently, the patient began to develop significant sharp, strong aches and pains along her arms and legs. There was no pain elsewhere, including pleuritic pain. She did not have fevers, chills, night sweats or abnormal weight loss. The patient had not had a flu vaccine.

When these symptoms arose, she sought medical attention with her primary care physician, who performed a complete blood count. She was found to have a platelet count of 200,000 with a white blood cell of 19,400 with 87.8% neutrophils. She was prescribed oxycodone, but about 40 minutes after taking the medication, she began to develop severe, excruciating low back pain. This necessitated her going to the emergency department.

Severe pain

There, she received hydromorphone IV, but this caused a similar pain syndrome. After these events, she was considered to potentially have an allergy to oxycodone and hydromorphone. As such, she took ibuprofen and acetaminophen around the clock, but this only partially relieved the discomfort. It was severe enough to wake her from her sleep.

About 2 weeks afterward, the patient picked at a scab on the right side of her nose and began to have a significant oozing of blood. This did not abate for several minutes. She had no other significant bruising or bleeding symptoms. She then went back to her PCP, and a CBC revealed a platelet count of 3,000/mcL, WBC count of 10,900/mcL and hemoglobin level was 13.1 g/dL. For the acute severe thrombocytopenia, the patient was referred for further evaluation.

Amit Mehta

At this point, the other cell lines were preserved, and although it was not readily clear if the pain symptoms had any relation to the thrombocytopenia, she had no other alarm symptoms. The patient had provided a fairly plausible timeline of events, including the exposure to the child with the flu; the disclosure that she had not had a flu vaccine; and documented CBC 2 weeks before and again at presentation.

Physical examination was unrevealing, aside from a few petechiae seen in the oral cavity. As part of her initial workup, viral studies were negative for Epstein-Barr virus, cytomegalovirus, viral hepatitis and HIV. The peripheral blood smear showed occasional atypical lymphocytes and large platelets, without schistocytes. Coagulation parameters were within normal limits. Based on this, she was presumptively treated for idiopathic thrombocytopenic purpura and started on oral prednisone at 1 mg/kg daily.

Course of treatment

The patient had an excellent response to prednisone, with a platelet count normalizing to 246,000 by the 10th day of therapy. The patient also felt the extremity and back pain largely disappear with high-dose prednisone. A slow taper was then started, but as the prednisone dose was tapered, and particularly below a dose of about 30 mg daily, the patient had a relapse of thrombocytopenia, as well as diffuse arm, leg and back pain. The patient would be in visible discomfort at this point and required tramadol to attain temporary relief. Conversely, upon restarting a higher dose of prednisone, the platelets and the pain would both improve. This pattern repeated a second time, so higher-dose prednisone was again restarted.

Second-line treatment options for ITP were discussed with the patient, including splenectomy and rituximab (Rituxan, Genentech/Idec Pharmaceuticals). The patient elected for rituximab therapy. She began and completed four doses of weekly rituximab, but with no benefit in the platelet count; the platelet count remained at about 25,000.

Along with the difficulty of weaning off prednisone and lack of response from rituximab, the patient had a recurrence of severe pain in the same locations. She, unfortunately, also began to experience a very heavy menstrual period, requiring multiple blood transfusions, as the hemoglobin dropped to less than 7 g/dL.

With this constellation of symptoms and findings, the differential diagnosis included a possible autoimmune condition, such as an inflammatory myositis, that perhaps responded to prednisone. Evaluation for a possible myositis showed a normal creatine phosphokinase level, but an elevated aldolase at 83.8 U/L. This suggested a possible concomitant inflammatory myositis, such as inclusion body myositis, combining inflammation and pain.

Other possibilities included refractory ITP, as well as a hematologic malignancy. Further questioning of her medical history increased the probability of lymphoma. She recalled experiencing abdominal pain 4 years ago of different character and location than the current pain. As part of her evaluation at that time, a CT scan of the abdomen and pelvis demonstrated mesenteric and retroperitoneal lymphadenopathy. These findings were not pursued further at that time.

As such, a CT abdomen/pelvis was performed and showed slightly more prominent lymphadenopathy (up to 1.5 to 2 cm in greatest diameter) as well as moderate splenomegaly.

These findings were clearly of concern and a bone marrow aspiration and biopsy were obtained. This study showed that the marrow had a 100% cellularity, with lymphoma cells comprising this entire space. Ki-67 was 10%. Flow cytometry showed a large CD19 and CD10+ B-cell population that featured lambda light chain restriction. Cytogenetics revealed t(14;18) and del(6q).

The diagnosis was now established as follicular lymphoma. It was postulated that the patient had a concomitant inclusion body myositis (or other inflammatory myopathy) or lymphomatous involvement of the muscle. Although classified as a low-grade lymphoma, she was clearly symptomatic in terms of persistent severe thrombocytopenia. In addition, because the bone marrow had a 100% lymphoma cellularity, she was experiencing a myelophthisic process, resulting in a large number of peripheral blood lymphoma cells and relative neutropenia. This consequently led to a rapidly increasing WBC count, up to 61,000 within 1 week after the bone marrow exam.

Given her presentation, she was treated aggressively to elicit a rapid response and obtain disease control. She underwent systemic chemotherapy with rituximab, fludarabine, cyclophosphamide and mitoxantrone. The patient tolerated this treatment well and had a robust tumor lysis response, with the lactate dehydrogenase rising to more than 8,000. Interestingly, the patient’s pain in the extremities and lower back disappeared entirely by day 3 of chemotherapy and has not returned since the start of chemotherapy. After marrow recovery, the hemoglobin rose to 8.7 g/dL, platelets to 39,000 and WBC count to 4,600, with a normal differential. Her performance status has improved nicely with treatment, and she is on course for cycle two of systemic chemotherapy.

Case Discussion

The diagnosis of idiopathic thrombocytopenic purpura is generally a clinical one. In our patient’s case, she had a combination of her disease course, without alarm symptoms (eg, “B symptoms”), and laboratory data that were seemingly consistent with ITP. However, because she was unable to be weaned off of steroids, and with the unusual elements of the diffuse severe pains and the unexplained abdominal lymphadenopathy, a bone marrow biopsy was performed.

Generally, the literature has provided data supporting a baseline bone marrow exam in patients aged older than 60 years because of the presence of myelodysplasia in a relatively high percentage of patients. Given her younger age —as she was found to be gradually refractory to steroids, and with the lack of response to rituximab— a bone marrow exam was performed. The diagnosis of follicular lymphoma provided an explanation for her symptoms and her history (eg, the unexplained abdominal lymphadenopathy from 4 years ago). This was both intellectually and clinically satisfying because treatment, thus far, has been able to ameliorate most of the symptoms.

Follicular lymphoma is a heterogeneous disease, with a variety of treatment approaches. Relatively recent data have illuminated risk stratification of these patients, with the publication of the follicular lymphoma international prognostic index-2 (FLIPI-2) score. In this study, data were collected prospectively from more than 1,000 patients. Patients were treated with an assortment of approaches, including surgery, radiation, immunotherapy and chemoimmunotherapy. Five variables were found to inversely correlate with PFS. These risk variables are an elevated beta2-microglobulin; age older than 60 years; bone marrow involvement; longest diameter of an involved lymph node ≥6 cm; and anemia (hemoglobin ≤12 g/dL).

Based on these variables, patients were grouped into three risk groups: low (0 factors); intermediate (1-2 factors); and high (3-5 factors). Three-year PFS rates for these groups were 91%, 69% and 51%, respectively. In our patient’s case, the FLIPI-2 score would place her in the intermediate risk group (2 factors).

Even more recent data have provided more evidence about maintenance therapy for follicular lymphoma. At the ASH 2010 meeting, an abstract summarized the findings of a meta-analysis of the use of rituximab as maintenance therapy vs. either observation or treatment at disease relapse. Data were analyzed from more than 2,000 patients. This study showed that there is a statistically significant survival benefit in favor of maintenance rituximab usage (HR for death=0.75; 95% CI, 0.61-0.91). When separated into two groups — those who received rituximab after first induction vs. those who received rituximab after a second or later induction regimen — the survival advantage appeared to hold only for those receiving rituximab after relapse (ie, after a second or later induction regimen).

However, a PFS benefit was observed both in those patients who received rituximab after induction therapy (n=1,374; HR=0.53; 95% CI, 0.44-0.63) or after two or more induction therapies, or relapse (n=804; HR=0.63; 95% CI, 0.50-0.79).

Amit Mehta, MD, is attending physician at Regional Cancer Care, Durham, N.C., and is a member of the HemOnc Today Editorial Board.

For more information:

• Federico M. J Clin Oncol. 2009;27:4555-4562.
• Gupta R. Br J Haematol. 2007;139:265-268.
• Vidal L. Abstract #1798. Presented at: 52nd ASH Annual Meeting; Dec. 4-7, 2010; Orlando, Fla.