©SEEd Tutti i diritti riservati Clinical Management Issues 2011; 5(Suppl 2) 75 Clinical Management Issues Case report A 70-year-old teacher, a good eater, didn’t drink any wine and any alcoholic drinks. His intestinal transit and his diuresis were nor- mal. He was a nonsmoker, a single and he didn’t take any therapy. In his past medical history we found hy- pertension, prostatic hypertrophy, appen- dectomy, and melanoma in the left arm in 2002. In November 2008 he was admitted to Hospital because of wheezing with fever chills, symmetrical arthralgias, and relevant asthenia. He was apiretic. Physical examina- tion revealed obtuseness chest and showed mean pleural effusion; the neurological examination showed that the patient was sound; the cranial nerve function was ob- served: the sensation, the muscle strength, and tenden reflex were normal. The heart sound was normal, and there were no oedema on lower extremities. In the abdomen we found no specific abnormalities and Blumberg sign was negative. There were IntroduCtIon Pure red cell aplasia (PRCA) describes a condition where the RBC precursors in bone marrow are nearly absent, while meg- akaryocytes and WBC precursors are usu- ally present at normal levels. In 1922, this condition was recognised by Kaznelson [1] as a different entity from aplastic anaemia. Pure red cell aplasia exists in several forms, and the most common one is an acute self- limited condition. Acquired pure red cell aplasia is chronic and is often associated with underlying disorders like thymomas [2], lymphomas [3], and autoimmune diseases. Initially a congenital form of pure red cell aplasia was described by Joseph in 1936 and by Diamond-Blackfan in 1938 [4]. Congenital pure red cell aplasia is a lifelong disorder, and it is associated with physical abnormali- ties. Both acquired and congenital pure red cell aplasia are occasionally refractory to therapy (Table I). Corresponding author Dott. Massimo Incagliato incagliatom@virgilio.it Caso clinico abstract We report a case of acquired pure red cell aplasia (APRCA) associated with carcinoma of the tongue: the first was considered a rare paraneoplastic syndrome. We point out that there is no case in literature with this association. After surgical operation (subglottic laryngectomy + right lymphadenectomy + laterocervical on the right) the transfusions required, at the beginning very frequent, decreased relevantly. This is a typical case where the paraneoplastic syndrome precedes the diagnosis of the primary carcinoma of the tongue (one year before what happens in bronchogenic carcinoma). Keywords: pure red cell aplasia, paraneoplastic syndrome, carcinoma of the tongue Un raro caso di aplasia eritroide pura che occulta un carcinoma squamoso della lingua CMI 2011; 5(Suppl 2): 75-79 1 Division of Internal Medicine, Hospital San Giacomo, ASLAL Novi Ligure (AL) 2 Division of Haematology, Hospital San Biagio, Alessandria 3 Department of Clinical and Laboratory investigation, Hospital San Martino, Genova Massimo Incagliato 1, Antonella Daffonchio 1, Lidia Celesti 1, Amedeo Bottero 1, Francesco Balbi 1, Massimo D’Ulizia 1, Emilia Ballestrero 1, Monia Costanzo 1, Valeria Primon 2, Amelia Leone 3, Giancarlo Gambarotta 1 an unusual case of secondary pure red cell aplasia (prCa) that occults a squamous carcinoma of the tongue ©SEEd Tutti i diritti riservati Clinical Management Issues 2011; 5(Suppl 2)76 An unusual case of secondary pure red cell aplasia (PRCA) that occults a squamous carcinoma of the tongue = 3.9 g/dl) [6]. For this test, in accordance with the criteria proposed by Light, this pleural effusion was considered an exudate [6]. Culture of infected pleural fluid yielded negative results. The echocardiography presented minimal pericardial effusion. The haematic tests revealed lymphocytes = 55% and neutrophils = 42%. Cytology find- ings were negative for neoplastic cells. Because of the negativity of the clinical examinations during hospitalisation, the pa- tient was transferred to the Thoracic Surgery, where he was subjected to pleural biopsy: the pathologic specimen showed a chronic pleuritis. During hospitalisation ticarcil- lin 4.5 mg × 3, prednisone 50 mg/die, and a gastroprotective drug were administered. The patient was discharged after 20 days with good resolution of the general clinical condition and an outpatient follow-up was arranged. At home the patient continued steroid treatment since there was the sus- pect of a possible form of autoimmune dis- ease (maybe systemic lupus erythematosus). This suspicion roused by the results of the following tests: positive antibody and native DNA, pleural effusion, and pericardial effu- sion associated with moderate megaloblastic anaemia, which was already present since some time. In March 2009 he was re-hospitalised in Department of Internal Medicine for se- vere megaloblastic anaemia (Hb = 5.8 g/dl; no skin lesions, the genitals were normal, and we found no rash and no lymphadenopathy. He was overweight. The blood tests revealed the results shown in Table II. Tuberculin skin testing (Mantoux test) and a single smear-sputum sample for My- cobatterium tuberculosis were negative. The urinalysis and proteinuria were normal. The testing stool for the presence of haemoglobin was negative. The electrocardiogram (ECG) showed a normal rhythm at a rate of 87 bpm. The cystoscopy explored prostate lobes, find- ing mucosal hyperaemia bleeding heavily at the passage of the instrument. The bladder mucosa was regular. The neck/thoracic Magnetic Resonance Imaging (MRI) detected a pleural effusion on the left. The MRI performed on the ab- domen showed gallbladder-renal calculi and prostatic hypertrophy. The chest CT con- firmed the gallbladder calculi and the abun- dant pleural effusion on the left, adding the detection of not dependent focal lesions of the remaining lung parenchyma. The tracheal and bronchial branches were normal, such as adrenal glands. The PET was negative. A thoracentesis was performed for pleural effusions: the ratio of pleural fluid to serum protein resulted greater than 0.5. The ratio of pleural fluid to serum lactate dehydroge- nase (LDH) was greater than 0.6. Pleural fluid LDH is greater than two thirds of the upper limits of normal serum value (protein “Congenital” form (diamond-Blackfan anaemia) acquired prCa Parvovirus B19 infection Transient aplastic crisis (TAC) in patients with shortened erythrocyte life span y Chronic type of bone marrow failure in immunosuppressed patients y Immunological suppression of erythropoiesis Antibody mediated y Antibody against red-cell progenitors • Transient erythroblastopenia in childhood (TEC) · Adult form · AB0-incompatibility following bone marrow transplantation · Antibody against erythropoietin • αβ or γδ T cell-mediated T-helper cell-mediated antibody production y MHC-restricted, recognition of red-cell progenitors y MHC-unrestricted recognition of red-cell progenitors y NK cell- or T cell-mediated MHC-unrestricted cytotoxicity y associated with pregnancy associated with certain drugs and toxins Initial manifestation of a pre-leukaemic syndrome table I Types of pure red cell aplasia. Modified from [5] ©SEEd Tutti i diritti riservati Clinical Management Issues 2011; 5(Suppl 2) 77 M. Incagliato, A. Daffonchio, L. Celesti, A. Bottero, F. Balbi, M. D’Ulizia et al The biopsy of the bone marrow revealed a 20% cellularity (hypocellular) and a nor- mal myeloid series. The erythroid series was aplastic, while the megakaryocytic one resulted hyperplastic. We found also inter- stitial infiltrates of lymphocytes for 25% of elements with immunophenotype CD3- CD20 positive (reactive lymphocytes), and CD34 cells 2%. The test for the PNH (Paroxysmal Nocturnal Haemoglobinuria) platelets = 150,000/mm3; MCV = 110 fl), dyspnoea, and tachycardia. The gastroscopy performed showed chronic gastritis, while the colonscopy was normal. A computed tomographic scanned neck, chest, abdomen with administration of con- trast material: the main pulmonary artery and the pulmonary arterial vasculature were normal, such as the lung parenchymal. parameter results normal range WBC 4,990/mm3 4,500-11,000/mm3 Neutrophils 40% - Lymphocytes 55% - Plts 150,000/mm3 150,000-350,000/mm3 Hb 10.5 g/dl 14-18 g/dl MCV 110 fl 80-100 fl ESR 31 mm/hour 2-10 mm/hour INR 1.1 0.8-1.2 Fibrinogen 278 mg/dl 175-400 mg/dl Glucose 97 mg/dl 70-110 mg/dl Urea 37 mg/dl 10-50 mg/dl Creatinine 1 mg/dl 0-1.5 mg/dl Total cholesterol 112 mg/dl < 200 mg/dl TAG 142 mg/dl 40-170 mg/dl Total bilirubin 0.8 mg/dl < 1 mg/dl Uric acid 5.7 mg/dl 3.6-8.5 mg/dl Ferritin 226 ng/dl 30-300 ng/dl Na+ 146 mEq/l 135-145 mEq/l K+ 4.4 mEq/l 3.4-4.8 mEq/l GOT 25 U/l 9-25 U/l GPT 24 U/l 7-30 U/l GGT 37 U/l 7-33 U/l ALP 50 U/l 40-115 U/l LDH 493 U/l 110-210 U/l PT 5.8 sec 11-16 sec Amylase 42 U/l 10-220 U/l Lipase 30 U/l 114-286 U/l Alpha fetoprotein 1.38 ng/ml < 10 ng/ml CEA 1.6 ng/ml < 5 ng/ml Ca 19-9 30 U/ml 0-40 U/ml CRP 0.3 mg/l < 8 mg/l ACE 7 nmol/ml 8-22 nmol/ml Vitamin B12 675 µg/dl 200-900 µg/dl Folic acid 13 ng/ml 3.1-17.5 ng/ml HIV Negative - HBV Negative - HCV Negative - ANA 1:640 - ENA Negative - LAC Negative - ACA Negative - B2GP1 Negative - Anti-dsDNA Positive - C3 In range C4 In range Rheumatoid factor In range Antibodies CCP In range table II Results of the blood tests performed ACA = Anti-Cardiolipin Antibody; ACE = Angiotensin Converting Enzyme; ALP = ALkaline Phosphatase; ANA = ANtinuclear Antibody; Antibodies CCP = antibodies anti-citrulline; B2GP1 = Beta 2 GlycoProtein 1 Antibody; C3 = C3 complement component; C4 = C4 complement component; Ca 19-9 = Carbohydrate antigen 19-9; CEA = CarcinoEmbryonic Antigen; CRP = C Reactive Protein; dsDNA = double-stranded DNA; ENA = anti-Extractable Nuclear Antigens; ESR = Erythrocyte Sedimentation Rate; GGT = Gamma-Glutamyl Transferase; GOT = Glutamic Oxaloacetic Transaminase; GPT = Glutamic Pyruvic Transaminase; HBV = Hepatitis B Virus; HCV = Hepatitis C Virus; HIV = Human Immunodeficiency Virus; INR = International Normalized Ratio; LAC = Lupus AntiCoagulant antibody; LDH = Lactate DeHydrogenase; MCV = Mean Corpuscular Volume; PT = Prothrombin Time; TAG = TriAcylGlycerol ©SEEd Tutti i diritti riservati Clinical Management Issues 2011; 5(Suppl 2)78 An unusual case of secondary pure red cell aplasia (PRCA) that occults a squamous carcinoma of the tongue subsequently radiotherapy. After radiothera- py a hyperhaemia on the head and neck and dysfagia appeared. During the following 6 months no tras- fusion was necessary and the patient main- tained the level of 9.5 g/dl of haemoglobin. Unfortunately, about 4 months after the patient had to receive transfusion every 20 days. dIsCussIon The description of this case is useful to point out the polymorphic features of para- neoplastic syndromes. In fact at the begin- ning there were suspected symptoms of systemic lupus erythematosus (SLE) but the examinations did not meet all the criteria of the American College of Rheumathology (Table III). Because of the above-mentioned symptoms a steroid therapy was given. Subsequently the patient was again admitted to the hospital for severe megaloblastic anaemia: radiolo- gical, endoscopic, and serological investiga- tions excluded causes of blood loss from the digestive tract, and eventual malabsorption and haemolysis. The bone biopsy showed a series of red cell aplasia with a lymphoid infiltrate of reactive elements consistent with this his- tological result; the patient was transferred to the Department of Haematology, where the investigations were completed with the study of cell cultures of the erythroid series, that showed no basal growth and stimula- tion of growth factors, thus confirming the diagnosis of PRCA, but it was not yet clear if there was a primary or a secondary form on the periferic blood was negative. The cy- togenetic revealed a XY karyotype. In bone marrow cultures there was a lack of growth of BFU-E (Burst Forming Unit-Erythroid) and CF U-GM (Colony Forming Unit- Granulocyte, Macrofage). Among the laboratory tests, the Parvovi- rus B19, the HIV, the CMV, and the EBV- Toxo Monotest were negative. There were no signs of haemolysis (LDH, haptoglobin, direct and indirect Coombs’ tests were nega- tive, schistocytes not on peripheral blood) and not obvious signs (clinical and labora- tory) of viral disease. The Epo-Hb electro- phoresis was in range, tumour markers were normal, and proteinaemia and serum elec- trophoresis were in range. After all examina- tions, we diagnosed pure red cell aplasia. In August 2009 we started immunosup- pressive therapy with cyclosporin and pred- nisone 25 mg + 200 mg + 250 mg/day with poor response (in fact the patient was trans- fused with two bags of erythrocytes every 15 days). From November 2009 to February 2010 testosterone undecanoate 50 mg was added to cyclosporin, with haemoglobin lev- els ranging from 7.2 and 8.9. In total, the patient was transfused with 40 bags of blood and ferritin 4,079 ng/dl. The 2nd of February 2010 during the am- bulatory monitoring appeared a swelling on the right laterocervical and on the tongue. Then the patient was sent to Maxillofacial Department where a biopsy was made and its specimen was later diagnosed of sq- uamous cell carcinoma on the base of the tongue pN2b pT4. Subsequently he was submitted to subglottic laryngectomy + right lymphadenectomy + right laterocervical and then there was a plastic reconstruction and serositis Pleurisy, pericarditis on examination or diagnostic ECG or imaging oral ulcers Oral or nasopharyngeal, usually painless; palate is most specific arthritis Nonerosive, two or more peripheral joints with tenderness or swelling photosensitivity Unusual skin reaction to light exposure Blood disorders Leukopenia (< 4 × 103 cells/µl on more than one occasion), lymphopenia (< 1,500 cells/µl on more than one occasion), thrombocytopenia (< 100 × 103 cells/µl in the absence of offending medications), haemolytic anaemia renal involvement Proteinuria (> 0.5 g/dl or 3+ positive on dipstick testing) or cellular casts aNAs (antinuclear antibodies) Higher titers generally more specific (> 1:160); must be in the absence of medications associated with drug-induced lupus Immunologic phenomena Anti-double-stranded DNA, anti-Smith (Sm) antibodies; antiphospholipid antibodies (anticardiolipin immunoglobulin G (IgG) or immunoglobulin M (IgM) or lupus anticoagulant); biologic false-positive serologic test results for syphilis, lupus erythematosus (LE) cells (omitted in 1997) neurologic disorder Seizures or psychosis in the absence of other causes Malar rash Fixed erythema over the cheeks and nasal bridge, flat or raised discoid rash Erythematous raised-rimmed lesions with keratotic scaling and follicular plugging, often scarring table III The 1982 American College of Rheumatology (ACR) criteria summarise features necessary to diagnose systemic lupus erythematosus (SLE). They are summarised here with a useful mnemonic: the acronym “SOAP BRAIN MD”. The presence of 4 of the 11 criteria yields a sensitivity of 85% and a specificity of 95% for SLE. It must be considered that individual features are variably sensitive and specific. Patients with SLE may present with any combination of clinical features and serologic evidence of lupus [7,8] ©SEEd Tutti i diritti riservati Clinical Management Issues 2011; 5(Suppl 2) 79 M. Incagliato, A. Daffonchio, L. Celesti, A. Bottero, F. Balbi, M. D’Ulizia et al A bone marrow biopsy control showed a slight increase of erythroid series: in this case we point out the absence in the litera- ture of associations between pure red cell aplasia and squamous cell carcinoma of the tongue and that the removal of the tu- mour, as it happens in many paraneoplastic syndromes, shows the improvement of the clinical picture. In this case the improvement of anaemia is connected to debulky cancer, to cytokines and to antibodies produced by the tumour. The diagnosis of a paraneoplastic syn- drome (PNS) may precede, follow or be concurrent with the diagnosis of a malig- nant tumour [9]. aCknowledgeMents We acknowledge Professor Eugenia Nicolicchia for the article reviewing and the Nursing Team of the Internal Medicine Department for the collaboration and the data collection. dIsClosure The Authors declare that they have no financial competing interests. of subclinical autoimmune disease (eryth- roblastopenia in SLE). In August 2009 the patient began a ther- apy with prednisone 25 mg and cyclosporin 600 mg/day; blood transfusions were re- quired every 15 days, as the steroid therapy alone was not sufficient to maintain accept- able levels of haemoglobin. In November 2009 the patient received 40 bags of transfused red cell concentrates and we decided therefore to associate also androgens (testosterone undecanoate) 50 mg and if after three months there was an improvement of haemoglobin, he could have started the serum anti-lymphocyte. In October 2010, because of the appear- ance of laterocervical and lingual enlarged lymphnodes, the patient was transferred to the Department of Maxillofacial Surgery, where the biopsy was diagnosed with sq- uamous cell carcinoma of the tongue pN2b pT4 (subglottic laryngectomy + right lym- phadenectomy + right laterocervical with a plastic reconstruction); subsequently a ra- diotherapy was performed. After surgery the patient wasn’t trans- fused for about 6 months. The haemoglob- in maintained the values of 9-9.8 g/dl and then the haemotransfusion was performed every 20 days. referenCes Karnelsom P. Zur Entseling der Bluptplattehen. 1. Verh Dtsh Ges Inn Med 1922; 34: 577 Nelson RP Jr, Pascuzzi RM. 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The 1982 revised criteria 7. for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7 Hochberg MC. Updating the American College of Rheumatology revised criteria for the 8. classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725 Toro C, Rinaldo A, Silver CE, Politi M, Ferlito A. Paraneoplastic syndromes in patients with 9. oral cancer. Oral Oncol 2010; 46: 14-8