Haematologica 2002; 87:(06)ECR21
[Medline] [prev] [index] [next]Two cases of intravascular lymphomatosis revealed by hypopituitarism.
Nicolas Schleinitz,# Emanuelle Bernit,# Karin Mazodier,# Aude Charbonnier,° Nicole Horchowski,* Lucile Andrac-Meyer,^ Véronique Veit,# Jean-Robert Harlé#
#Service de médecine interne, Hopital de la Conception, *Service d'anatomopathologie, Hopital de la Timone, ^Service d'anatomopathologie, Hopital Nord, 13385 Marseille Cedex; °Service d'hématologie, Institut Paoli Calmettes, 13273 Marseille Cedex, France.
Correspondence: Nicolas Schleinitz, Service de Medecine Interne, Pr JR HARLE, Hopital de la Conception, 13385 Marseille Cedex 05, France. Phone: 04.91.38.35.01. Fax: 04.91.38.14.33. E-mail: nschleintz@ap-hm.fr
Intravascular lymphomatosis (IVL) is a rare disorder with a poor prognosis. This entity was previously referred as "malignant angioendotheliomatosis" or "angiotropic large-cell lymphoma".1 It is an uncommon variant of large cell lymphoma in which the lymphomatous, usually B, or T-cells proliferate within the lumens of capillaries, small veins and arteries. General symptoms such as fever of unknown origin, malaise and fatigue are the most commonly reported manifestations, often combined with various neurologic and dermatologic signs.1-4 Lymph nodes and bone-marrow are usually free of lymphomatous cells. Circulating lymphomatous cells are rarely detected on blood smear analysis and elevated lactic dehydrogenase levels and/or positive direct Coombs' test with hemolytic anemia are the main biological abnormalities. Therefore, the diagnosis of IVL still remains a challenge and has been often made on postmortem examination. Here we report two cases initially combined with hypophyseal insufficiency, a rare manifestation of IVL.Case 1. A 69-year-old woman presented with low-grade fever, cough, myalgia, diffuse edema and hypodermal cutaneous lesions of the two legs. Neurological examination was non-focal without ophthalmologic disturbances. A slight mental status state change was observed. There was no lymphadenopathy or hepatosplenomegaly. Laboratory results showed: hemoglobin of 8.3 g/dL; platelets, 80,000/mm3; white cell count, 4,500/mm3; sedimentation rate, 92/105 mm/H; C reactive protein of 63 mg/L (normal value, <5) and polyclonal hypergammaglobulinemia. Blood smear analysis were unremarkable. Lactate dehydrogenase level was markedly increased at 2000 UI/L (normal value, 280-423). Hyponatremia (130 mEq/L) was associated with normal kalemia, renal and liver function tests. Bone marrow aspiration smear and biopsy were normal without abnormal lymphocytic infiltration. As shown in Table 1, hormonal levels revealed hypophyseal insufficiency with decreased serum levels of follicule stimulating hormone (FSH), luteinizing hormone (LH), and adrenocorticotrophic hormone (ACTH). Thyroid-stimulating hormone (TSH) was in the normal range despite low levels of free thyroxine. Cranial computed tomography (CT) and magnetic resonance imaging (MRI) of hypophysis were normal. Cytology, biochemical and microbiological analysis on cerebrospinal fluid were normal. Thoracic and abdominal CT scan revealed bilateral pulmonary interstitial infiltrates and infiltrative lesions of kidneys. Histologic examination of a hypodermal nodule revealed large mononucleated cells with multiple nucleoli within dermal and hypodermal small blood vessels. These cells were CD 20+ (L26, Dako) B-lymphoma cells (Figure 1A and B). The patient received systemic chemotherapy using cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for four months. Because of cardiac insufficiency developed, she received two supplementary cycles of systemic chemotherapy using cyclophosphamide, vincristine, prednisone and VP16 (COP-VP16). An array of evidence, such as the lack of lung infiltrates and kidneys abnormalities, the decrease of hormonal replacement treatment with normalization of TSH levels, suggested a complete remission. Four months later the patient presented with fever and acute respiratory distress syndrome. The patient died without histological proof of recurrence of IVL. No infection was found by serological and microbiological analysis. Post-mortem examination was not done.
Case 2. A 76-year-old man was admitted after a two-month history of progressive fatigue, night sweats, low-grade fever, anorexia and weight-loss. Clinical examination was normal and failed to detect hepatomegaly, splenomegaly or lymph node enlargement. Dermatological and neurological examination were normal, without sight disturbances. On laboratory tests, platelet count and hemoglobin level were normal; white cell count, 2,750/mm3; polymorphonuclear, 0,970/mm3; lymphocytes, 1,200/mm3. Blood smear examination was unremarkable. Sedimentation rate was at 63mm/H; C reactive protein was 108mg/L and LDH increased to 897 UI/L. A mild hyponatremia (130 mEq/L) was observed while kalemia was normal. As shown in Table I an hypophyseal insufficiency was found in this patient: LH, ACTH and TSH were decreased with low serum levels of cortisol and free thyrotoxin. Abdominal CT scan showed bilateral adrenal hyperplasia. Magnetic resonance imaging (MRI) showed an enlargement of the hypophyseal on T1 weighted images with an increased homogeneous signal by contrast MRI (Figure 2). Cytology, biochemical and microbiological analysis on cerebrospinal fluid were normal. Bone marrow aspiration showed infiltration by 10% of atypical lymphocytes. Bone marrow histological analysis was normocellular and revealed large lymphoid cells with irregular nuclear contours and multiple nucleoli located predominantly within the sinusoidal lumen by light microscopy. Immunohistochemical studies (CD20+) confirmed that these cells derived from the B lymphocyte lineage. The patient died from septicemia before initiation of chemotherapy. Post-mortem examination was not done.
IVL is an uncommon variant of large cell lymphoma derived from B-cells, or exceptionally T-cells, classified as a peripheral B-cell neoplasm in the WHO classification. It is considered as a high-grade non-Hodgkin's lymphoma. Diagnosis is often difficult, in part related to the usually reported relative sparing of lymph nodes, spleen and bone marrow . Therefore ante-mortem diagnosis is not the hallmark.2 Recognition of the disease is important and the poor prognosis must be tempered by the complete remission and long-term survival reported in patients treated by aggressive combination therapy.3 Currently, there is no available controlled study about IVL treatment. The recognition of IVL is based on non-specific clinical and biological features. Clinically, fever, weight loss, malaise with neurological abnormalities and skin manifestations are usually described and dominate the clinical presentation in case reports and series that have been reported to date.1-3 Neurological manifestation are variable including dementia or focal defects.4 Cutaneous nodules or plaques of various types include purpura, nodular plaque-like lesions, diffuse macular discoloration and more specific indurated telangiectasia.5 When skin lesions are present, their histological analysis is the easiest way to make the diagnosis of IVL. Endocrine glands, kidney, heart, liver, gastrointestinal tract, lungs or genitourinary tract could be also involved by IVL but are reported in fewer cases.2,6 Laboratory findings are usually an anemia with a positive Coombs' test and an increase of sedimentation rate and LDH levels.2 Both bone marrow infiltration7 and the observation of large lymphocytes with nuclear abnormalities on peripheral blood smear are reported only in few cases.8 The lymphomatous cells are preferentially localized in CNS and skin but are also found in endocrine glands and lung vessels. This suggests that tissue-specific vascular homing receptors are involved, and that the clinical heterogeneity of the disease could reflect the heterogeneity of the lymphomatous cell.9,10 The receptors involved in this defect of lymphocyte homing and lymphocyte interaction with endothelial cells, are, as jet, poorly identified.11 In our two patients, IVL was associated with general symptoms and devoid of clinical evidence of neurological involvement. In the first patient, skin, lung and renal abnormalities were associated with hypopituitarism. Normal MRI findings in this case does not exclude IVL infiltration. A normal hypophysis on MRI has been previously reported, despite a panhypopituitarism with IVL infiltration demonstrated on post mortem examination.2 The complete remission observed in this patient was obtained by CHOP/COP-VP16 associated with normalization of TSH concentration. We did not associate CNS radiotherapy because hypopituitarism was only secondary related to IVL. For the second patient, hypopituitarism appeared to be the only clinical manifestation. Despite histological confirmation we though that the hypophysis was involved by IVL, attested by the abnormal MRI findings. Few reports have been focused on endocrine gland dysfunction in IVL, reviewed by Krauss et al.12 Most reports described IVL in adrenal gland, hypophysis and also thyroid after histological post-mortem examination. In a study, 7 patients out of 15 were found to have a pituitary abnormality after post-mortem examination. Nevertheless, hypopituitarism was not formally demonstrated.13 The most frequent endocrine gland involvement seems to be unilateral or bilateral adrenal enlargement as a radiological finding, as in our second case. In these cases, formal evidence for corticosteroid insufficiency is rarely reported. In the literature, Krauss et al counted only 18 cases associated with endocrine dysfunction. Among these and his cases, hypopituitarism was demonstrated in 4 patients, adrenal insufficiency in 3 and hypothyroidism in one. In this report, we describe two cases of IVL with primary hypopituitarism at diagnosis. Endocrine gland dysfunction has been previously reported but hypopituitarism rarely demonstrated. It would be interesting to study the role of this endocrine dysfunction, perhaps under-recognized, in the development of the symptoms (weight loss, malaise) frequently observed in IVL. Finally, a demonstrated hypophyseal insufficiency, despite the absence of clinical or radiological evidence (i.e. our second patient) could lead to proposing a treatment against the central nervous system location of lymphoma in association with combined chemotherapy.References