Autoimmune lymphoproliferative disorder in an adult patientNK Desai, S Morkhandikar, S Bajpai, AR Pazare
Department of Medicine, Seth G.S. Medical College and KEM Hospital, Parel, Mumbai, India
A 50-year-old male patient presented with fever, epistaxis and multiple lymphadenopathy since 15 days. In the light of the above presentation a complete workup was initiated to exclude common conditions like tuberculosis, acquired immunodeficiency syndrome, lymphoid malignancy and sarcoidosis. After excluding common conditions a biopsy of cervical lymph node demonstrated reactive lymphadenitis with paracortical hyperplasia. Immunohistochemistry demonstrated double negative lymphocytes (CD4-, CD8-). A diagnosis of autoimmune lymphoproliferative disorder syndrome (ALPS) (probable) was made and patient was started on 1 mg/kg of steroids. Patient showed a dramatic improvement with respect to general wellbeing, fever and regression of lymphadenopathy. This entity of ALPS has been recently identified and classified; most of the reports are from the pediatric population. To the best of our knowledge ours is one of the few cases of this entity being reported in an adult patient from India.
Keywords: Autoimmune lymphoproliferation, Castleman′s disease, double negative lymphocytes, lymphadenopathy
The modern classification system for hematological malignancies cannot be applied to some cases of lymphoproliferation as they do not meet the classical pathological definition of malignancy. Some patients present with clinical features in which the results of biopsies deduce a pathological diagnosis that prompts the use of words like atypical or suspicious of malignancy, leaving the physician with incomplete information on how to treat this condition. We present a case report of a patient with multiple lymphadenopathy and splenomegaly which on workup was diagnosed as autoimmune lymphoproliferative disorder (ALPS).
A 50-year-old male presented with a 15-day history of fever, fatigue, epistaxis, petechial hemorrhages and multiple cervical lymph adenopathy. On inquiry patient was asymptomatic prior to the onset of symptoms without any pre-morbid conditions. There was no family history of autoimmune diseases and lymphoma. On examination there was pallor, petechiae, splenomegaly and multiple cervical, axillary and inguinal lymph node enlargements which were non-tender, firm without evidence of any matting or sinus formation. The largest lymph node was 4 x 3 cm, in the cervical region. A detailed nose examination was done to rule out local cause of epistaxis, which was normal. In light of the above findings a diagnosis of lymphoma was made clinically with the possibility of tuberculosis, sarcoidosis, Castleman's disease and acquired immunodeficiency syndrome as other differentials.
A complete hematological workup revealed bicytopenia with hemoglobin of 8.8 gm/dl and platelet count of 80000 cells/mm 3 , total leucocyte count being 11300 cells/mm 3 with normal differentials. Erythrocyte sedimentation rate of 75 mm was recorded at the end of 1 h by Westergren's method. HIV, angiotensin converting enzyme, serum protein electrophoresis, anti nuclear antibody, Coombs test, viral markers for hepatitis B and C were all negative. Bone marrow aspiration and cytology, coagulation parameters, liver and renal function test were completely within normal range. Immunoglobulin G levels were 2225 mg/dl.
Ultrasound of abdomen showed multiple mesenteric and paraortic lymph nodes with splenomegaly. Computerized tomography confirmed the ultrasound findings with multiple mediastinal lymph nodes without any pulmonary parenchymal pathology.
Lymph node biopsy of the left cervical lymph node demonstrated reactive lymph adenitis with paracortical hyperplasia. There was no evidence of any malignant cells, necrosis or giant cells. Immune histochemistry for B and T cells markers did not show any abnormality.
Peripheral blood flow cytometry showed double negative T cells (DNT), (CD4 -, CD8 -) 3.5%. Patient continued to worsen with high-grade fever, epistaxis and severe malaise. Empirically, antibiotics were started to which the patient did not respond. Platelets and packed cells were given as cytopenias continued to worsen with lowest hemoglobin of 4.3 gm% and platelets of 40,000.
A diagnosis of autoimmune lymphoproliferative disorder (ALPS) was made in the light of clinical, hematological and pathological presentation. As per revised diagnostic criteria our patient had probable ALPS as our patient had presence of both required and secondary accessory criteria. Patient was started on oral prednisolone 1 mg/kg/day. Within one week patient showed a dramatic improvement clinically in form of disappearance of fever, decrease in size of lymph nodes and hematologically, platelet count increased and bleeding subsided. The patient was discharged on six weeks of steroids followed by gradual tapering. Last follow-up of patient after two months of corticosteroids was normal and he was asked to follow up every month to see for development of lymphoma and steroid toxicity.
Lymphoid tissues have limited ways of generating a histological response to any agent. These include follicular hyperplasia, plasmacytosis, eosinophilia, proliferation of immunoblasts, T-zone expansion and sinus histiocytosis. Many of the uncommon lymphoproliferations are related to an abnormal immune response to some inciting stimulus. There are underlying conditions which can cause atypical lymphoproliferations [Table 1].  To enumerate a few:
Autoimmune lymphoproliferative syndrome (ALPS) is a recently described entity in which patients develop generalized lymphadenopathy, hepatosplenomegaly, hypergammaglobulinemia, B cell lymphocytosis and autoimmune characteristics. The autoimmune manifestations include hemolytic anemia, Guillain-Barrι syndrome, urticarial rash, glomerulonephritis, and idiopathic thrombocytopenic purpura.  The patients mostly manifest between six months to 18 years.
The etiology of the lymphadenopathy in most patients with ALPS is related to an impairment of apoptosis due to inherited heterozygous mutations in the fas gene (tumor necrosis factor receptor gene superfamily member 6-TNFRSF6, CD95, APO-1, APT-1), which is referred to as ALPS Type I. ,, Rare cases have been described of ALPS Type II (mutations in caspase 10) and Type III, wherein no mutation has been identified, however, a functional deficiency of fas-mediated apoptosis has been observed. ,
The pathology of this disorder is characterized by an expansion of double negative T cells (CD4-, CD8-) in the paracortical regions of the lymph nodes.
The incidence of these patients developing into lymphomas is quite significant, thus one needs to keep an eye and follow up these patients for the same. A study of Strauss et al., has observed and stated this fact in their cohort. 
Disease definition and classification of ALPS
A definitive diagnosis is based on the presence of both required criteria plus one primary accessory criterion [Table 2].  A probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion.
being a rare and newly reported entity there is a lack of sufficient data regarding definitive management; steroids are first-line management. Steroids and immunoglobulins have been used for the treatment of such patients but once the steroid therapy is stopped in most cases the symptoms recur.
Rituximab is relatively contraindicated in ALPS because it can precipitate common variable immune deficiency.  Data exists for treatment with mycophenolate mofetil and sirolimus.  These agents are used often in patients who need chronic therapy.
Allogenic bone marrow transplant has been done in patients with complete fas deficiency who seemed to have reached a cure with the same. ,
[Table 1], [Table 2]