SOLVING CLINICAL PROBLEMS IN BLOOD DISEASESA physician or group of physicians considers presentation and evolution of a real

clinical case, reacting to clinical information and data (boldface type). This is

followed by a discussion/commentary.

If at first you don’t succeed: Try, try againMahwash Saeed,1* Morel Rubinger,1,2 Arshad Ahsanuddin,3 Carmen Morales,3

Brian Penner,1 David Robinson,1 Hani El-Gabalawy,1 and Ryan Zarychanski1,2

A 51-year-old gentleman presented to a rheumatolo-gist with a 3 week history of fevers, diarrhea, arthral-gias, and generalized pruritis. Blood work revealedmild anemia (hemoglobin 13.5 g/dL). The erythrocytesedimentation rate (ESR) was within normal limits.Given the acuity of onset, rash, and arthralgias, parvo-

virus B19 was suspected. Cytomegalovirus, Epstein Barrvirus, adenovirus, and coxsackievirus were also possiblegiven these presenting signs and symptoms. Systemiclupus erythematosus, rheumatoid arthritis, adult onset Still’sdisease, or another connective tissue disease could not beexcluded. A reactive gastrointestinal disorder was lesslikely, but possible considering the history of diarrhea.Over the following 2 weeks, the patient’s clinical con-

dition deteriorated and he presented to an emergencydepartment. His temperature was 99.5 degrees Fahren-heit and his pulse was 115 bpm. All other vital signswere within normal limits. The physical examinationrevealed a lacy macular rash over the arms and ante-rior chest wall. There was no palpable lymphadeno-pathy or organomegaly.The patient reported a 3 week history of weight loss, but

denied chills or night sweats. He had no risk factors forhuman immunodeficiency virus infection (HIV) or hepatitis.Travel history included trips to Cuba in the year precedingpresentation.Laboratory testing revealed elevated liver trans-

aminases (aspartate aminotransferase (AST) 69 U/L, al-anine aminotransferase (ALT) 182 U/L, gamma glutamyltransferase (GGT) 95 U/L), and evidence of systemicinflammation (C-reactive protein (CRP) 64 mg/L, ESR25 mm/hr, ferritin 328 lg/L). Serum lactate dehydrogen-ase (LDH) (357 U/L) and bilirubin were elevated (totalbilirubin peaked at 92 lmol/L, direct at 92 lmol/L). Acomplete blood count at admission to hospitalrevealed hemoglobin of 11 g/dL (Mean corpuscular vol-ume (MCV) 86 fL), platelets of 69 3 109/L, and a whiteblood cell count of 2.3 3 109/L, with a normal whitecell differential.The patient looked distinctly unwell, with new pancytope-

nia, hyperbilirubinemia, elevated liver enzymes, and signsof systemic inflammation. Infection was suspected, but inthe absence of intravenous drug use, high risk sexualbehavior, or blood transfusions, HIV, or hepatitis wasunlikely. With no history of immunosuppression or evidenceof pulmonary pathology cytomegalovirus infection wasimprobable. Bacterial infections, including Streptococcuspyogenes, syphilis, bartonella, or mycobacteria were con-sidered. The presenting symptoms were not characteristicof a specific connective tissue disease.Microbiologic cultures from blood, urine, and cerebral

sinus fluid were negative for bacteria, fungi, and acid-fast bacilli. Immune serology including antinuclear anti-body, double stranded DNA, perinuclear antineutrophilcytoplasmic antibody, cytoplasmic antineutrophil cyto-

plasmic antibody, anti-smooth muscle, and assays forextractable nuclear antigens (anti-Ro, anti-La, anti-Scl-70, and anti-Jo-1 antibodies) were normal. Complementlevels were decreased (C3 5 0.13 g/L, C4 5 0.04 g/L).Protein electrophoresis revealed an increase in polyclo-nal immunoglobulins. Viral serology was negative forHepatitis A, B, or C, parvovirus B19, and HIV. Serologyand PCR for Epstein Barr and cytomegalovirus werenegative. Computed tomographic scans of the thorax,abdomen, and pelvis revealed mild hepatosplenomegalyand normal sized lymph nodes throughout the abdomenand thorax. The patient’s liver transaminases continuedto rise in hospital and the pancytopenia progressed.An infectious etiology could not be identified and immune

serology was negative. The patient’s rapid clinical decline, inassociation with rising transaminases and progressive pancy-topenia, was concerning for a hematological malignancy,and/or hemophagocytic syndrome. In an attempt to secure adiagnosis, liver and bone marrow biopsies were performed.A transjugular liver biopsy revealed no evidence of

neoplastic infiltration, and no evidence of autoimmunehepatitis or viral inclusion bodies. The bone marrowbiopsy and aspiration was of normal cellularity, andunremarkable morphology (Fig. 1). A slight increase inplasma cells was noted. Bone marrow cultures werenegative for bacteria, acid-fast bacilli, fungi, and viruses.The patient’s hemoglobin declined steadily in hospital, in

the absence of blood loss, while the LDH and unconjugatedbilirubin increased. The absolute reticulocyte count was254 3 109/L, serum haptoglobin was <0.01 lmol/L, andthe direct antiglobulin test (DAT) was positive for IgG.Thrombocytopenia worsened; the platelet nadir was 13 3109/L on day 6 of hospital admission.Based on the positive DAT (IgG), low haptoglobin and

increased reticulocytes, a diagnosis of warm autoimmune he-molytic anemia (AIHA) was established. Ample megakaryo-

Conflict of interest: Nothing to report.

*Correspondence to: Mahwash Saeed, CancerCare Manitoba, ON2051-675McDermot Ave. Winnipeg, Manitoba R3E 0V9, Canada. Tel.: 1204-787-2108. Fax: 1204-786-1096. E-mail: umsaeedm@cc.umanitoba.ca

Contract grant sponsors: Canadian Institutes for Health Research, Cancer-Care Manitoba.

Additional Supporting Information may be found in the online version of thisarticle.

1Department of Internal Medicine, University of Manitoba, Winnipeg, Mani-toba, Canada; 2Department of Medical Oncology and Haematology. Cancer-Care Manitoba, Winnipeg, Manitoba, Canada; 3Department of Pathology,University of Manitoba, Winnipeg, Manitoba, Canada

Received for publication 12 July 2011; Revised 13 October 2011; Accepted 19October 2011

Am. J. Hematol. 87:295–297, 2012.

Published online 22 October 2011 in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/ajh.22236

AJH Educational Material

VVC 2011 Wiley Periodicals, Inc.

American Journal of Hematology 295 http://wileyonlinelibrary.com/cgi-bin/jhome/35105

cytes in the bone marrow, along with peripheral thrombocyto-penia, were consistent with immune thrombocytopenia (ITP).AIHA occurring in combination with ITP (Evans Syn-

drome) may be secondary to infection, autoimmune dis-orders, connective tissue disease, drugs, and malignancy(particularly lymphoproliferative disorders and chronic lym-phocytic leukemia). Laboratory testing and tissue pathology,however, remained unrevealing while an offending drugcould not be identified.Due to continued clinical deterioration, including

increasing liver transaminases, declining renal func-tion, worsening pancytopenia, and a profound sys-temic inflammatory response syndrome (SIRS), highdose methylprednisolone (1 g, intravenously, for 3days) was prescribed. Within 7 days, all of the patient’ssigns and symptoms, including the macular skin rash,systemic inflammation, thrombocytopenia, and meas-ures of organ dysfunction had resolved, except for amild, well compensated hemolytic anemia (hemoglobin12–13 g/dL). The patient was discharged from hospitalon a tapering dose of oral prednisone.Over the following 4 months the patient slowly returned

to his baseline state of health. However, when the dose ofprednisone was tapered to 10 mg/day, he had recrudes-cence of his original symptoms, including fatigue, fever,diarrhea, and the pruritic skin rash on his arms and chest.The patient was also found to have palpable cervicaladenopathy, and developed a decompensated hemolyticanemia that rendered him transfusion dependent. Theabsolute reticulocyte count fell from 254 3 109/L on hisoriginal admission to 7 3 109/L. A repeat bone marrowbiopsy demonstrated the selective loss of red cell precur-sors, but was otherwise unremarkable (Fig. 2). In additionto Evans syndrome, the patient was diagnosed with purered cell aplasia (PRCA).The persistence and severity of his illness, in the ab-

sence of positive rheumatologic serology, made a primaryautoimmune condition unlikely. New cervical adenopathywas especially concerning for a lymphoproliferative dis-order; however, Castleman’s or Kikuchi’s disease was diag-nostic considerations. Multi-centric Castleman’s Disease,which is often associated with systemic symptoms, is clas-sically associated with HIV infection, but our patient wasconfirmed to be HIV negative.The patient was admitted to hospital with fever, neck

pain, diarrhea, and dehydration. Repeat CT scans of the

neck, chest, abdomen, and pelvis were performed. Hewas once again treated with high dose steroids, but withmarginal improvement in his symptoms. Due to progres-sive cervical, supraclavicular, and axillary lymphade-nopathy, in conjunction with enlarging splenomegaly,an axillary lymph node biopsy was performed. Tissuepathology was consistent with mixed cellularity classi-cal Hodgkin lymphoma (Fig. 3). The patient was treatedwith six cycles of ABVD (adriamycin, bleomycin, vincris-tine, dacarbazine). His early treatment course wascomplicated by pulmonary emboli and Pneumocystisjiroveci pneumonia, both requiring hospitalization. Alllaboratory indicators of Evans syndrome and PRCAresolved with the first cycle of therapy. A post-treatmentpositron emission tomographic (PET) scan showed noevidence of residual disease.

DiscussionHodgkin’s lymphoma (HL), was originally described in

1832, and was the first of the malignant lymphomas to berecognized as a distinct entity [1]. In the United States, theincidence of HL is 2.8 per 100,000 men and women peryear [2]. Contrary to the rising incidence of non-Hodgkinlymphoma (NHL), the incidence of HL has remained stableover the past 70 years [3,4].The most common manifestation of Hodgkin’s lymphoma

is persistent and painless lymphadenopathy, commonly inthe neck, supraclavicular fossa, or mediastinum, less oftenin the axilla [5]. Rare manifestations of HL, present in lessthan 1% patients at diagnosis, include paraneoplastic neu-rologic deficits, renal disease (e.g., glomerulonephropathiesand nephritic syndrome), or various immunologic abnormal-ities including autoimmune disorders [5].Autoimmune conditions, preceding or existing concomi-

tant with a new diagnosis of HL or NHL, are uncommon,but have been described. Hematologic manifestationsinclude AIHA [6,7], ITP [8,9], PRCA [10–12], and autoim-mune neutropenia (AIN) [8,13]. Non-hematologic autoim-mune conditions include thyroiditis, hepatitis, myastheniagravis, and polymyalgic syndromes [14]. These proteanmanifestations of a single disorder can pose a significantchallenge to clinicians and represent a source of frustrationto patients.AIHA in patients with HL occurs with a reported

frequency ranging from 0.2% to 3% [15,16]. Although anunusual feature of HL, especially at presentation, AIHA is

Figure 1. Normal bone marrow aspirate with trilineage representation and no evi-dence of neoplasia. Arrowheads indicate erythroid precursosrs (Wright-Giemsa,633 Oil Immersion, Olympus AxioCam ICc3). [Color figure can be viewed in theonline issue, which is available at wileyonlinelibrary.com.]

Figure 2. Bone marrow with selective loss of erythroid precursors, consistentwith PRCA (Wright Giemsa, 633 Oil Immersion, Olympus AxioCam ICc3). [Colorfigure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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often associated with advanced stage disease [9,10,16,]. In1980, Levine et al. retrospectively analyzed 71 HL casesfor DAT positivity and found positive DAT tests in 7 (10%)patients, all with advanced (Stage III or IV) disease, and‘‘B’’ symptoms [15]. While this small study failed to make astrong association between the presence of Coombs posi-tivity and poor prognosis in HL, it did emphasize the poten-tial for HL in cases of unexplained AIHA.Although autoimmune phenomena have been described

in association with HL for several decades, the mechanismsresponsible for their occurrence are poorly understood.Reed–Sternberg cells are known to induce aber-rant production of cytokines and chemokines, resulting ina prominent inflammatory response in involved tissues[10,17,18]. Autoimmune paraneoplastic cytopenias associ-ated with chronic lymphocytic leukemia have been mecha-nistically described as an immune dysregulation resulting inthe loss of tolerance to self-antigens, which in turn leads toimmune-based cytopenias [17]. Perhaps in HL, also a germi-nal B-cell center disorder, a similar mechanism exists [19].Acute therapy of autoimmune paraneoplastic disorders is

non-specific and aimed at initial disease control with highdose steroids and supportive care. Definitive treatmentinvolves treatment of the underlying lymphoma [19,20].Although there are cases of successful control of ITP asso-ciated with HL using cyclophosphamide and azathioprine,no cases describe successful control of AIHA with thesesame immunosuppressive regimens [20]. Improvement inITP with the use cyclophosphamide may have been relatedto partial treatment of the underlying HL. Several reportshave also described AIHA and ITP associated with HLbeing controlled, at least transiently, by splenectomy alone[19,21]. Generally, autoimmune symptoms abate with spe-cific lymphoma treatment, but can recur, especially in thesetting of relapsed disease [10,16,20]. Several cases ofAIHA, Evans Syndrome, and PRCA have been described

in association with NHL [22]. It appears that, in this settingas well, it is the treatment of the underlying NHL that defini-tively treats the concurrent cytopenias. The use of pro-longed steroids to control autoimmune symptoms is notwithout risk, including steroid-induced hyperglycemia,osteoporosis, and increased risk of life threatening oppor-tunistic infections, such as Pneumocystis jiroveci as in thecase presented.HL is a treatable and often curable malignancy, even in

advanced stage disease. Autoimmune disorders precedingor occurring concurrently with HL can complicate the diag-nosis and management of both disease processes. Physi-cians should maintain a high index of suspicion for lympho-proliferative disorders when confronted with a patient withpersistent or combined autoimmune disorders, especially inthe setting of new lymphadenopathy. Close observation andpersistence with a tissue diagnosis may be necessary tosecure an eventual diagnosis of a lymphoproliferative dis-order. The most effective treatment of autoimmune dis-orders in this setting remains treatment of the underlyingmalignancy.

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Figure 3. Mononuclear variant Hodgkin cells, consistent with mixed cellularityclassical Hodgkin Lymphoma (a,b: Hematoxylin and Eosin, 403, arrowheadsbelow Hodgkin cells; (c): CD30 immunohistochemical stain highlighting Hodgkincells, 403; (d): CD15 immunohistochemical stain highlighting Hodgkin cells, 403;Olympus AxioCam ICc3). [Color figure can be viewed in the online issue, which isavailable at wileyonlinelibrary.com.]

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