David M. Menke

Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: A retrospective study

PURPOSE To evaluate the relationship between use of methotrexate in rheumatoid arthritis patients and development of hematologic malignancies. PATIENTS AND METHODS We retrospectively analyzed all patients registered at the Mayo Clinic from 1976 through 1992 with rheumatoid arthritis (n = 16,263) cross-indexed with patients registered during the same period with a hematologic malignancy (n = 21,270). Adult patients were selected who had rheumatoid arthritis, were treated with a disease-modifying antirheumatic drug, and subsequently developed a hematologic malignancy. RESULTS Thirty-nine patients met the selection criteria. Twelve of them had been given methotrexate. The characteristics of those who received methotrexate, including the type of hematologic malignancy, did not differ from those of patients who received other disease-modifying antirheumatic drugs. CONCLUSIONS Hematologic malignancies are uncommon in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, including methotrexate. There does not appear to be a relationship between the peak or cumulative dose or the duration of methotrexate therapy and the subsequent development of hematologic malignancy. The histologic types of hematologic malignancy seen in the methotrexate-treated patients did not differ from those of patients treated with other disease-modifying antirheumatic drugs.

The spectrum of localized amyloidosis: A case series of 20 patients and review of the literature

Localized deposition of amyloid may occur in individual organs, in the absence of systemic involvement. The reason for localized deposition is unknown, but it is hypothesized that deposits result from local synthesis of amyloid protein, rather than the deposition of light chains produced elsewhere. We identified 20 cases of localized amyloidosis at our institution between 1993 and 2003. There were 11 males and nine females in the group. The mean age at the time of diagnosis was 65.5 years. Organs involved included skin, soft tissues, oropharynx, larynx, lung, bladder, colon, conjunctiva, and lymph node. In six of nine patients typed, the amyloid light chain was lambda. In those patients where follow-up was available (mean 7.6 years), none developed systemic disease. Localized amyloidosis occurs in a variety of organ systems. Evolution into systemic amyloidosis was not seen in our series of patients, supporting the hypothesis of local production of amyloid protein in these cases.

The clinical spectrum of Castleman's disease.

Castlemans disease (CD) is a rare, poorly understood lymphoproliferative disease. The spectrum of symptoms and course of disease are broad, but there is no large study describing the natural history of this disease. Basic clinic and laboratory data from the records of 113 patients with CD evaluated at the Mayo Clinic and University of Nebraska were abstracted. The impact of these variables on overall survival (OS) from time of diagnosis was evaluated. Sixty patients had multicentric disease. Of the patients with multicentric CD, 32% had criteria sufficient for a diagnosis of POEMS syndrome. For all patients, 2, 5, and 10‐year OS was 92%, 76%, 59%, respectively. Most of the factors identified as risk factors for death on univariate analysis cosegregated with diagnostic criteria for POEMS syndrome, which supported the concept of four categories of CD, which are (along with their 5‐year OS): (1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%). We have demonstrated that CD represents a spectrum of disease that can be differentiated by simple prognostic factors that provide a framework for further study. Am. J. Hematol. 2012.

Symptomatic Gastric Amyloidosis in Patients With Primary Systemic Amyloidosis

We reviewed the clinical records of 769 patients with primary systemic amyloidosis who had been examined at Mayo Clinic Jacksonville (Jacksonville, Florida) or Mayo Clinic Rochester (Rochester, Minnesota) during a 12-year period (1978 through 1989). Of these 769 patients, 59 (8%) had biopsy-established gastrointestinal amyloidosis, and 8 (1%) had symptomatic gastric amyloidosis. All eight patients with symptomatic gastric amyloidosis had hematemesis or prolonged nausea and vomiting in association with weight loss. Additional findings were gastroparesis (in three patients), gastric tumor (in one), and gastric outlet obstruction (in one). Macroglossia was present in two patients, and multiple myeloma was diagnosed in three. Six of the eight patients had coexisting small bowel amyloidosis and weight losses of 6.5 to 22.5 kg. Congo red staining identified gastric amyloid in the media of blood vessels in all cases. All cases stained selectively for lambda (seven cases) or kappa (one) light chain. All eight patients died; the median duration of survival after diagnosis was 13.8 months (range, 0.5 to 39.5). Death was due to cardiac failure (three patients), renal failure (two), chronic gastrointestinal obstruction and severe cachexia (two), or hepatic failure (one). Chemotherapy was given to seven patients but was only partially effective for ameliorating symptoms in one.

A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia

The most common causes of macrocytic anemias in the adults are (1) alcoholism, (2) liver diseases, (3) hemolysis or bleeding, (4) hypothyroidism, (5) folate or vitamin B12 deficiency, (6) exposure to chemotherapy and other drugs, and (7) myelodysplasia. A carefully obtained history and examination with evaluation of a peripheral blood smear and reticulocyte count should be performed in most patients with macrocytosis. Serum vitamin B12 and folate levels, serum thyroid studies, liver function studies, and bone marrow aspirate and biopsy with cytogenetic analysis are frequently required to confirm a diagnosis suspected on the basis of the initial evaluation.

Analysis of the Human Herpesvirus 8 (HHV-8) Genome and HHV-8 vIL-6 Expression in Archival Cases of Castleman Disease at Low Risk for HIV Infection

Lymph nodes from 44 patients with Castleman disease (CD) without risk factors for HIV infection were analyzed with polymerase chain reaction (PCR), in situ hybridization (ISH), and immunohistochemical analysis for human herpesvirus 8 (HHV-8) and viral interleukin-6 (vIL-6). PCR detected HHV-8 genome in 2 of 4 cases; ISH detected it in 9 of 16 cases. HHV-8 vIL-6 peptides were detected in 2 of 44 cases. vIL-6- and ISH-positive cells were found in large transformed and small lymphocytes of the follicular mantle, respectively. Of 9 cases of plasma cell (PC) CD that demonstrated HHV-8 genome by PCR or ISH, 1 expressed vIL-6. Clonal populations of PCs in CD by immunohistochemical analysis or immunoelectrophoresis of serum and urine were associated with neuropathy. HHV-8 vIL-6 detection was associated with poor survival and lack of HHV-8 IL-6, with low risk for subsequent lymphoma. Although HHV-8 genome was detected in a considerable number of patients with PC CD, vIL-6 expression was infrequent. Expression of HHV-8 vIL-6 in CD may indicate poor prognosis in patients at risk for lymphoma who may prospectively require more aggressive treatment. The lack of vIL-6 expression in CD with HHV-8 genome suggests that human IL-6 rather than vIL-6 may be the principal pathogenic cytokine.

Localized Lymphoplasmacellular Pancreatitis Forming a Pancreatic.Inflammatory Pseudotumor

Inflammatory pseudotumors (IPTs) of the pancreas are rare. To our knowledge, we report the first case of a pancreatic IPT composed of dense lymphocytic and plasmacellular infiltrates that histologically resembled a primary lymphoplasmacytic lymphoma of the pancreas. In addition, it is the first pancreatic IPT analyzed for latent Epstein-Barr virus, an agent implicated in the pathogenesis of IPTs of the liver and spleen.

Lymphomas in Patients With Connective Tissue Disease Comparison of p53 Protein Expression and Latent EBV Infection in Patients Immunosuppressed and Not Immunosuppressed With Methotrexate

Cell cycle dysregulation as measured by p53 protein expression and latent Epstein-Barr (EBV) infection are important in the pathogenesis of lymphoma, particularly in immunosuppressed patients. Although latent EBV commonly is detected in lymphomas arising in patients with connective tissue disease who are immunosuppressed with methotrexate, p53 protein expression has not been reported. We compared the immunohistologic expression of p53 protein and the incidence of latent EBV infection in lymphomas arising in patients with connective tissue disease treated and not treated with methotrexate. Increased p53 staining was detected in 10 of 11 lymphomas arising in patients after methotrexate therapy vs 5 of 11 in patients not treated with methotrexate. Latent EBV was detected in 7 of 13 lymphomas arising in patients after methotrexate therapy vs 2 of 11 in patients not treated with methotrexate. Concordant p53 expression and latent EBV were detected in 5 of 7 lymphomas arising after treatment with methotrexate, including 1 that regressed after methotrexate therapy was withdrawn. These findings suggest that cell cycle dysregulation and EBV-related transformation are important in the pathogenesis of lymphomas arising in patients with connective tissue disease who are immunosuppressed with methotrexate.

Diagnosis of recurrent rectal carcinoma by EUS-guided fine-needle aspiration

Detection of recurrent malignancy in an anastomosis may be difficult. Endosonography is useful in the staging of malignant diseases of the GI tract.1,2 It has recently been demonstrated that endosonography, performed at set intervals after resection of gastric or esophageal cancer, is accurate in the detection of early recurrence.3 Early detection of rectal cancer recurrence may have a decisive impact on management. We report two cases of anastomotic recurrence of adenocarcinoma of the rectum detected by EUS with fine-needle aspiration (EUSFNA).

Primary Lymphoma of the Spinal Cord

Non-Hodgkins lymphomas arising in the spinal cord are extremely rare. Only eight single case reports have been well confirmed in the literature. Herein we describe a 59-year-old woman with symptoms attributable to a spinal cord lesion. Physical examination revealed neurologic deficits but no evidence of tumor elsewhere. Although several imaging studies were performed, only magnetic resonance imaging with use of gadolinium revealed the exact site and extent of the lesion. Laminectomy and direct examination of the spinal cord disclosed a discolored region at the level of the 11th thoracic vertebra. A biopsy specimen was obtained, and pathologic examination revealed an intermediate grade, mixed cell lymphoma of T-cell origin. Radiotherapy was administered to the lesion and adjacent region of the spinal cord with use of 6-MV photons and an anteroposterior-posteroanterior technique; the total dose was 45 Gy in 23 fractions. No chemotherapy was given. After 3 years of follow-up, the neurologic signs and symptoms were stable, and repeated magnetic resonance imaging with use of gadolinium showed no residual tumor. In addition to the case report, we review the literature on primary lymphomas of the central nervous system and discuss treatment recommendations.