—  SPECIALTY CONFERENCE  —

Neuropathology

Case 2 - Angiotropic Large Cell Lymphoma

Richard A. Prayson
Cleveland Clinic Foundation
Cleveland, OH


Click on each slide thumbnail image for an enlarged view
Clinical History
A 45-year-old woman presented with a 6 day history of ascending sensory loss and weakness of the left leg progressing to complete sensory loss, dense paraparesis of both legs and bladder/bowel incontinence. Other than Graves' disease, which was recently treated with iodine131 followed by thyroxine replacement, the patient's medical history was unremarkable. T2-weighted magnetic resonance imaging (MRI) showed a non-enhancing fusiform area of increased signal at at the thoracic (T2-3) level of the spinal cord and a single area of increased signal in the deep cerebral white matter. The patient was treated with an 8 day course of i.v. ACTH followed by a tapering oral prednisone regimen.


Case 2 - Figure 1 - Low magnification view of the cortex showing involvement of vessels in the leptomeninges as well as cortical parenchyma by the lymphomatous process (hematoxylin and eosin, original magnification 100x).
Case 2 - Figure 2 - High magnification appearance of lymphomatous cells within vascular lumina. Cells are marked by irregular nuclear contours and high nuclear to cytoplasmic ratio. Extension of lymphomatous cells beyond vascular walls was not observed (hematoxylin and eosin, original magnification 400x).


Case 2 - Figure 3 - The intervascular tumor cells stain positively with antibody to CD20 indicating a B-cell immunophenotype (CD20 immunostain, original magnification 400x).
Case 2 - Figure 4 - CD3 immunostain shows rare positive staining benign T lymphocyte cells within and around vessels in the leptomeninges. The tumor cells themselves do not stain with CD3 (CD3 immunostain, original magnification 250x).
One month later the patient presented with no significant improvement in symptoms. Neurological examination at this time found minimal hip flexor anti-gravity strength and no ankle dorsi-flexor anti-gravity strength of the lower extremities bilaterally with grade 1 spasticity. Vibration and joint position sense were absent to the level of the knee and hip joint, respectively. Reflexes in the lower extremities were pathologically brisk with positive Babinski's signs. Examination of the cranial nerves and upper extremities revealed no deficit. Relevant laboratory tests included the following (normal range in paretheses): hemoglobin, 159 g/l (120-160); leukocyte count, 5.24x109/1 (4.0-11.0) with neutrophils 82.6%, lymphocytes 11.1%; platelets, 145 K/ul (150-400); erythrocyte sedimentation rare, 1.0 mm/h (0.0-20.0); serum albumin, 3140 mg/dl (3276-4819); serum IgG, 582 mg/dl (747-1470); CSF protein, 45 mG/dl (15-45); CSF red cell count, 1 (0-1/ul); CSF white cell count, 1 (0-3/ul); CSF IgG, 4.0 mg/dl (0.6-4.4); CSF albumin 29.2 m/dl (9.3-31.3); CNS IgG synthesis, 1.6 mg/dl (0.0-30.0); IgG/albumin ratio, 0.14 (0.06-0.17); IgG index, 0.50 (0.00-0.61); lactate dehydrogenase (LDH), 1776 U/l (100-220): Oligoclonal bands, antinuclear antibodies (ANA), rheumatoid factor, syphilis serology (RPR, HA-TP) and SF cultures for bacteria, herpes virus and fungi were negative. Cytological examination of the CSF, bone marrow and peripheral blood did not demonstrate neoplastic cells. A repeat MRI scan of the spinal cord and brain showed numerous hyperintense lesions in the right periventricular white matter and thoracic spine (T2-3), interpreted as being consistent with demyelinating disease. Steroid therapy was commenced.

Despite steroid therapy, the patient was readmitted on several occasions for worsening paraplegia, sensory deficits, hearing loss and cognitive impairment. Further MRI studies of the brain showed no new interval changes.

Ten months after initial presentation, a sigmoid colostomy was performed for bowel atony and severe obstipation. Two weeks later, the patient was admitted for recurrent seizures, multiple electrolyte abnormalities, acute hepatic and renal failure and infected decubitus ulcers. Neurological examination demonstrated a right facial paresis, dysarthria, no anti-gravity strength in the lower extremities and positive Babinski's signs bilaterally. A sensory level at T8 was demonstrated and joint position/vibration was absent in both lower extremities. The patient continued to decline with worsening renal function, severe metabolic acidosis and multiple tonic/clonic seizures prior to death.

Diagnosis
Angiotropic large cell lymphoma (Intravascular large cell lymphoma).

Discussion
Angiotropic large cell lymphoma (ALCL) is a rare disorder characterized by a proliferation of malignant lymphoid cells within the lumens of small vessels, usually in the absence of extravascular tumor. Since its first report in 1959 by Pfleger and Tappeiner [1, 2] under the designation of angioendotheliomatosis proliferans systemisata, the entity has been reported under various names including angioendotheliomatosis or malignant angioendotheliomatosis [3, 4] , intravascular endothelioma [5], proliferating angioendotheliomatosis [6, 7] , systemic angioendotheliomatosis [8, 9] , and neoplastic angioendotheliomatosis [10, 11] .

About half of all cases of ACLC are diagnosed at autopsy [2]; of the patients that are diagnosed antemortem, most are discovered on skin biopsies. Less frequently, brain biopsies or microscopic examination of surgically resected organs result in the diagnosis. Because of the confinement of the neoplastic cells to vessel lumina, the disease is seldom, if ever, diagnosed without a biopsy. Only rarely are malignant lymphoid cells found in the cerebrospinal fluid [12] or circulating in the peripheral blood [13].

Men and women are affected with equal frequency and the mean age of onset is between 50-70 years [2, 13, 14, 15, 16] . About three fourths of patients present with predominant cutaneous (most commonly plaques or nodules on the extremities) and neurologic symptoms; however, involvement of a number of other organs has been report [2]. Nervous system manifestations are present in almost half of symptomatic patients and most commonly include progressive dementia, multifocal sensorimotor deficits, seizures and neuropathy [17, 18, 19, 20, 21, 22, 23, 24] . Multisystem involvement was found by Domizio et al in 90% of patients in whom autopsy findings were available [2]. Most of the symptomatology is related to vascular occlusion and subsequent organ infarction [10, 11, 12, 13, 14, 15, 16, 25] .

In a review of 40 cases by Wick et al, an average survival time of 13 months was reported [3]. Others have reported mean survival times as short as 5 months [2]. Most patients respond poorly to chemotherapy, including steroids and radiation therapy; however, variable successes with each of these treatment modalities has been reported [11, 12, 16, 26, 27, 28] .

The histopathology of angiotropic lymphoma is distinctive, and is composed of often distended vessels filled with a dense proliferation of atypical mononuclear cells with high nuclear to cytoplasmic ratios, scant cytoplasm and irregular nuclear contours. Fibrin/platelet thrombi with enmeshed tumor cells are often present, and the adjacent endothelium is devoid of significant atypia. Ischemic damage to the surrounding tissue may be present.

Much of the literature on ALCL has focused on the histogenesis. The diversity in the nomenclature of this entity is in part a reflection of the historical controversy surrounding the exact nature of the intravascular cells. An endothelial cell origin was advocated by some, based on the presence of cells in blood vessels and supposed electron microscopic findings of Weibel Palade bodies [10, 16] . Findings of apparent immunohistochemical staining with factor VIII-related antigen reported by Wick et al [3] and Kitagawa et al [16] seemed to provide further support to the argument that these cells were endothelial in nature. It is uncertain, though, whether the cells being characterized were not in fact the endothelial cells lining the vessel wall and not the intraluminal cells of question. Some of the observed factor VIII-related antigen positivity may be related to nonspecific adsorption of the antigen from serum or platelets [13].

Others have suggested that the neoplastic cells might represent either an occult carcinoma with intravascular proliferation or an intravacsular malignant histiocytosis [2, 29] . Immunohistochemical staining with lymphoid markers, Southern blot hybridization analyses for immunoglobulin gene rearrangement, and PCR studies offer undeniable evidence supporting a lymphoid origin [12, 14, 30, 31, 32] . Most have a B cell immunophenotype [2], but rare cases having a T-cell phenotype have been described [15, 32] . Cytogenetic analysis of the tumor cells by Molina et al found a number of chromosomal abnormalities [trisomy 7, 12, 18] , similar to those seen in other hematologic malignant neoplasms [31].

Further confusion in the literature has been caused by the existence of a benign form of angioendotheliomatosis, associated with bacterial endocarditis and caused by exogenous proteins such as cow's milk [33]. This disease represents an unrelated reactive and self-limited disorder which responds well to antibiotic and steroidal therapy. Angiocentric lymphoma (angioimmunoproliferative lesion type III) is a distinct entity and should not be confused with ALCL. Angiocentric lymphoma is a post-thymic T-cell neoplasia, characterized by a neoplastic T-cell infiltrate within the vessel wall and extending into surrounding tissues [34]. Other differential diagnostic considerations include disseminated intravascular carcinoma and acute leukemia. Carcinoma can be excluded with clinical history, an absence of a tissue mass and positive staining with keratin markers. Leukemia will involve peripheral blood and bone marrow and may stain with certain markers, such as myeloperoxidase.

The mechanism by which the lymphoid cells are attracted to vessels is not entirely understand. Endothelial cells express surface receptors which are involved with the attraction of lymphocytes to endothelial cells [35]. Likewise, in normal lymph nodes, lymphocytes have been found to have functional receptors for endothelial cells [36]. Perhaps some disruption or alteration in the lymphocytes-endothelial interaction may account for the predominant presence of the neoplastic lymphoid cells in vessels. Ponzoni et al recently noted an absence of CD29 and CD54 immunoreactivity in tumor cells [27]. Both of these proteins are known to be critical for lymphocyte trafficking and for transvascular lymphocyte migration. The absence of these markers in ALCL may contribute to its intravascular and disseminated distribution.

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