(Radiology. 1999;212:257-263.)
© RSNA, 1999
Autoimmune Lymphoproliferative Syndrome: A Syndrome Associated with Inherited Genetic Defects That Impair Lymphocytic Apoptosis—CT and US Features1
Nilo A. Avila, MD,
Andrew J. Dwyer, MD,
Janet K. Dale, RN, MPH,
Uri A. Lopatin, BA,
Michael C. Sneller, MD,
Elaine S. Jaffe, MD,
Jennifer M. Puck, MD and
Stephen E. Straus, MD
1 From the Diagnostic Radiology Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bldg 10, Rm 1C660, 10 Center Dr, MSC 1182, Bethesda, MD 20892-1182 (N.A.A., A.J.D.); the Laboratories of Clinical Investigation (J.K.D., U.A.L., S.E.S.) and Immunoregulation (M.C.S), National Institute of Allergy and Infectious Diseases, Bethesda, Md; the Laboratory of Pathology, National Cancer Institute, Bethesda, Md (E.S.J.); and the National Human Genome Research Institute, Bethesda, Md (J.M.P.). Received July 6, 1998; revision requested August 27; final revision received October 26; accepted January 19, 1999. Address reprint requests to N.A.A. (e-mail: navila@nih.gov).
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Abstract
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PURPOSE: To describe the imaging findings in patients with autoimmune lymphoproliferative syndrome (ALPS) and to relate the findings to the clinical and genetic features of this recently recognized syndrome.
MATERIALS AND METHODS: Retrospective or prospective reviews of the computed tomographic (CT) and ultrasonographic (US) studies and the clinical features in 19 consecutive patients with ALPS were performed.
RESULTS: Most patients presented in the 1st year of life with symptoms of adenopathy and hepatosplenomegaly. At the time of presentation to the institution, 12 patients had already undergone splenectomy, and 14 patients had developed autoimmune disorders. All patients had multifocal adenopathy, which was massive in some patients; 14 of 15 patients who underwent CT of the chest had an enlarged thymus, and all six patients who retained their spleens and who underwent imaging had splenomegaly. Ten of 18 patients who underwent liver imaging had hepatomegaly. The adenopathy at US was hyper- and/or isoechoic relative to the liver and thyroid and was enhanced at CT in some patients. All patients had defective lymphocytic apoptosis, or programmed cell death, which was due to specific Fas (APT1 [TNFRSF6]) mutations in 15 patients.
CONCLUSION: Patients with ALPS demonstrate nonspecific but often dramatic imaging findings of lymphoproliferative disorders, such as adenopathy, splenomegaly, thymic enlargement, and hepatomegaly. The stability of the clinical findings over months to years and the pattern of lymph node echogenicity may suggest the diagnosis of ALPS.
Index terms: Autoimmune lymphoproliferative syndrome, 99.39 • Familial conditions • Lymphatic system, CT, 99.12911, 99.12912 • Lymphatic system, diseases, 99.822 • Lymphatic system, US, 99.12983, 99.12984
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Introduction
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Apoptosis, or programmed cell death, maintains immune homeostasis by limiting lymphocytic accumulation and by minimizing reactions against self-antigens (1,2). Findings of recent studies have shown that defective lymphocytic apoptosis caused by specific genetic mutations manifests as a human disorder termed the autoimmune lymphoproliferative syndrome (ALPS) (3–6). ALPS manifests in early childhood. The defining clinical features of ALPS are chronic, diffuse, nonmalignant lymphadenopathy and splenomegaly of occasionally massive proportions. Autoimmune diseases, which include autoantibody-mediated hemolytic anemia and thrombocytopenia, manifest in most patients.
Splenectomy is commonly required to control the cytopenia caused by hypersplenism and acutely aggravated by these autoimmune phenomena. There is an expansion of a usually rare (<1%) population of double-negative (CD4-CD8-) T cells that expresses the 
ß T-cell receptor and of defective lymphocytic apoptosis in vitro (7,8). In most patients with ALPS, functional mutations can be identified in the gene APT1 (TNFRSF6), which encodes Fas, one of the key apoptosis-signaling proteins (3,4,6,9,10).
We conducted radiologic examinations in 19 consecutive patients with ALPS to relate the imaging findings to the clinical and genetic features of this syndrome and to determine whether the imaging findings might aid in diagnostic evaluation of ALPS.
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MATERIALS AND METHODS
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We performed retrospective or prospective reviews of the imaging studies in 19 consecutive patients with ALPS who presented to our institution, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Md, during their evaluations for ALPS and its complications. Six patients were examined at our institution before we developed the computed tomographic (CT) imaging protocol outlined in Materials and Methods; the imaging studies in these patients were reviewed retrospectively. Thirteen patients were examined prospectively after the initiation of the CT protocol outlined in Materials and Methods. All patients or parents of patients under 18 years of age consented in writing for the study of ALPS under internal review board–approved (National Institute of Allergy and Infectious Diseases, Bethesda, Md) protocols.
All imaging studies were reviewed by one radiologist (N.A.A.), who was blinded to the clinical and laboratory findings but who was aware of the diagnosis of ALPS. As patient schedules permitted, patients underwent CT of the neck (n = 12), chest (n = 15), abdomen (n = 15), or thymus (n = 15) by using a Highlite Advantage scanner (GE Medical Systems, Milwaukee, Wis). The CT images of the neck and thymus were obtained with 5-mm collimation, whereas the images of the chest and abdomen were obtained with 10-mm collimation. Thirteen of the 15 patients who underwent CT did so after intravenously receiving nonionic contrast material (iopamidol [Isovue 300]; Bracco Diagnostics, Princeton, NJ); two patients reported having allergic reactions in the past and did not receive intravenous contrast material.
CT findings were documented as follows: Lymph nodes were characterized according to size, site, and presence of enhancement. The thymus was measured in maximal craniocaudal, anteroposterior, and transverse dimensions; thymic thickness (the largest dimension perpendicular to the long axis of the thymus) was also measured and was compared with standards that were previously published (11). The maximal craniocaudal dimensions of the liver and spleen, when they had not been surgically removed, were recorded.
Eight patients underwent abdominal ultrasonography (US) that was performed with either a model 128 or a model 128 XP unit (Acuson, Mountain View, Calif); from the US images, the presence and echogenicity of abdominal lymphadenopathy were recorded. Five patients underwent gray-scale and color Doppler US of the submental lymph nodes; the size, echogenicity, and presence of internal vascularity of the nodes were recorded.
The patients' clinical charts were reviewed (by J.K.D. and U.A.L.). Pertinent clinical, genetic, and demographic data were recorded. The clinical and genetic features of ALPS in nine patients had been previously reported by Sneller et al (6).
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RESULTS
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Nineteen patients were examined; 12 were female patients, and seven were male patients. The age at which the patients first presented with symptoms of adenopathy or splenomegaly ranged from birth to 5 years; a majority of the patients (n = 10) presented before their first birthday. At the time of referral to our institution, the patients had a median age of 10 years (age range, 1–39 years). Thus, they had had clinical evidence of marked lymphoproliferation for a median of 7.2 years (range, 0.7–37.0 years).
Of the 19 patients, seven had persistent splenomegaly that was determined at clinical examination, and 12 patients had already undergone splenectomy, 10 patients had hepatomegaly, and 14 patients had documented autoimmune disorders (Table 1). All patients met the criteria for ALPS by virtue of their chronic lymphoproliferation, increased double-negative T-cell percentages, and defective lymphocytic apoptosis in vitro.
Fifteen patients had defined mutations in the gene encoding Fas. These mutations occur throughout the gene but cluster with the gene region that codes for the cytoplasmic death–signaling domain. Four patients were presumed to have had unrecognized defects in other genes that regulate apoptosis (6).
Cervical Lymph Nodes
CT images of the neck showed submental lymph nodes (which ranged from 1.0 to 4.0 cm in maximal diameter for the largest lymph node in each patient) and cervical lymph nodes (which ranged from 1.0 to 3.0 cm in maximal diameter) in all 12 of the patients who underwent CT of the neck (Fig 1). Enhancement of the submental nodes was seen in two patients, and enhancement of the cervical nodes was seen in five patients. All five patients who underwent US of the submental lymph nodes showed enlarged submental and cervical lymph nodes that were either isoechoic or slightly less echogenic than was the thyroid gland and that were either minimally or moderately vascular at color Doppler evaluation (Figs 2, 3).
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Figure 1a. CT images of the neck in a 4-year-old patient with ALPS. (a) Axial section at the level of the mandible shows extensive cervical adenopathy (arrow). (b) Axial section at the base of the neck shows extensive supraclavicular adenopathy (large arrow) and submental adenopathy (small arrow).
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Figure 1b. CT images of the neck in a 4-year-old patient with ALPS. (a) Axial section at the level of the mandible shows extensive cervical adenopathy (arrow). (b) Axial section at the base of the neck shows extensive supraclavicular adenopathy (large arrow) and submental adenopathy (small arrow).
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Figure 2. Transverse gray-scale US image of the neck in a 16-year-old patient with ALPS shows an enlarged lymph node (arrow) with echogenicity similar to that of the thyroid gland. CCA = common carotid artery, JV = jugular vein, LN = lymph node, THY = thyroid.
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Figure 3. Transverse color Doppler US image of the submental region in a 10-year-old patient with ALPS shows moderate vascularity (arrows) within the submental lymph nodes.
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Histologic findings of cervical lymph node biopsy specimens typically showed florid, reactive follicular hyperplasia and paracortical expansion, with immunoblasts, plasma cells, and a markedly expanded CD3+CD4-CD8- subset of T cells (Fig 4).
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Figure 4a. Histologic results from a cervical lymph node biopsy in a patient with ALPS shows florid reactive hyperplasia and a markedly expanded CD3+CD4-CD8- subset of T cells. (a) Photomicrograph obtained with hematoxylin-eosin staining shows preservation of the lymph node architecture (curved arrow), marked reactive follicular hyperplasia, and paracortical expansion (straight arrow), with immunoblasts and plasma cells. (b–d) Photomicrographs obtained following staining of lymph node sections for (b) CD3, (c) CD4, and (d) CD8 show extensive accumulation of T cells (arrow) in the paracortical region. The absence of staining for (c) CD4 or (d) CD8 in the lymph node photomicrographs shows that most CD3+ cells are CD4- and CD8-. (In a–d, original magnification, x100.)
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Figure 4b. Histologic results from a cervical lymph node biopsy in a patient with ALPS shows florid reactive hyperplasia and a markedly expanded CD3+CD4-CD8- subset of T cells. (a) Photomicrograph obtained with hematoxylin-eosin staining shows preservation of the lymph node architecture (curved arrow), marked reactive follicular hyperplasia, and paracortical expansion (straight arrow), with immunoblasts and plasma cells. (b–d) Photomicrographs obtained following staining of lymph node sections for (b) CD3, (c) CD4, and (d) CD8 show extensive accumulation of T cells (arrow) in the paracortical region. The absence of staining for (c) CD4 or (d) CD8 in the lymph node photomicrographs shows that most CD3+ cells are CD4- and CD8-. (In a–d, original magnification, x100.)
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Figure 4c. Histologic results from a cervical lymph node biopsy in a patient with ALPS shows florid reactive hyperplasia and a markedly expanded CD3+CD4-CD8- subset of T cells. (a) Photomicrograph obtained with hematoxylin-eosin staining shows preservation of the lymph node architecture (curved arrow), marked reactive follicular hyperplasia, and paracortical expansion (straight arrow), with immunoblasts and plasma cells. (b–d) Photomicrographs obtained following staining of lymph node sections for (b) CD3, (c) CD4, and (d) CD8 show extensive accumulation of T cells (arrow) in the paracortical region. The absence of staining for (c) CD4 or (d) CD8 in the lymph node photomicrographs shows that most CD3+ cells are CD4- and CD8-. (In a–d, original magnification, x100.)
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Figure 4d. Histologic results from a cervical lymph node biopsy in a patient with ALPS shows florid reactive hyperplasia and a markedly expanded CD3+CD4-CD8- subset of T cells. (a) Photomicrograph obtained with hematoxylin-eosin staining shows preservation of the lymph node architecture (curved arrow), marked reactive follicular hyperplasia, and paracortical expansion (straight arrow), with immunoblasts and plasma cells. (b–d) Photomicrographs obtained following staining of lymph node sections for (b) CD3, (c) CD4, and (d) CD8 show extensive accumulation of T cells (arrow) in the paracortical region. The absence of staining for (c) CD4 or (d) CD8 in the lymph node photomicrographs shows that most CD3+ cells are CD4- and CD8-. (In a–d, original magnification, x100.)
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Chest and Abdominal Lymph Nodes
CT images of the chest and abdomen obtained in 15 patients showed lymph nodes in the following sites: axillary, in 15 patients, often with multiple lymph nodes that ranged in size from 0.9 to 3.8 cm; mediastinal, in 12 patients (size range, 0.5–5.0 cm); periportal, in three patients (size range, 1.8–4.0 cm); retroperitoneal, in 12 patients (size range, 0.8–3.0 cm); mesenteric, in 10 patients (size range, 0.8–3.0 cm); pelvic, in four patients (size range, 1.5–2.0 cm); and inguinal, in 10 patients (size range, 0.6–1.8 cm). Lymph nodes in the following anatomic locations showed CT enhancement: axillary, in 10 patients; retroperitoneal, in two patients; mesenteric, in one patient; and inguinal, in nine patients (Fig 5).
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Figure 5a. Axial CT sections of the chest and abdomen in an 11-year-old patient with ALPS show enhancing axillary, retroperitoneal, and inguinal lymph nodes. (a) Section near the origin of the great vessels from the aortic arch demonstrates enhancement of axillary adenopathy (arrowheads). Also note mediastinal adenopathy (arrow) in the pretracheal space, which separates the right brachiocephalic vein and the brachiocephalic artery. (b) Precontrast study below the left renal vein shows retroperitoneal lymph nodes (arrow). (c) Postcontrast study below the left renal vein demonstrates mild enhancement of the retroperitoneal nodes (arrow). (d) Section at the level of the acetabuli shows enhancement of the inguinal nodes (arrows).
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Figure 5b. Axial CT sections of the chest and abdomen in an 11-year-old patient with ALPS show enhancing axillary, retroperitoneal, and inguinal lymph nodes. (a) Section near the origin of the great vessels from the aortic arch demonstrates enhancement of axillary adenopathy (arrowheads). Also note mediastinal adenopathy (arrow) in the pretracheal space, which separates the right brachiocephalic vein and the brachiocephalic artery. (b) Precontrast study below the left renal vein shows retroperitoneal lymph nodes (arrow). (c) Postcontrast study below the left renal vein demonstrates mild enhancement of the retroperitoneal nodes (arrow). (d) Section at the level of the acetabuli shows enhancement of the inguinal nodes (arrows).
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Figure 5c. Axial CT sections of the chest and abdomen in an 11-year-old patient with ALPS show enhancing axillary, retroperitoneal, and inguinal lymph nodes. (a) Section near the origin of the great vessels from the aortic arch demonstrates enhancement of axillary adenopathy (arrowheads). Also note mediastinal adenopathy (arrow) in the pretracheal space, which separates the right brachiocephalic vein and the brachiocephalic artery. (b) Precontrast study below the left renal vein shows retroperitoneal lymph nodes (arrow). (c) Postcontrast study below the left renal vein demonstrates mild enhancement of the retroperitoneal nodes (arrow). (d) Section at the level of the acetabuli shows enhancement of the inguinal nodes (arrows).
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Figure 5d. Axial CT sections of the chest and abdomen in an 11-year-old patient with ALPS show enhancing axillary, retroperitoneal, and inguinal lymph nodes. (a) Section near the origin of the great vessels from the aortic arch demonstrates enhancement of axillary adenopathy (arrowheads). Also note mediastinal adenopathy (arrow) in the pretracheal space, which separates the right brachiocephalic vein and the brachiocephalic artery. (b) Precontrast study below the left renal vein shows retroperitoneal lymph nodes (arrow). (c) Postcontrast study below the left renal vein demonstrates mild enhancement of the retroperitoneal nodes (arrow). (d) Section at the level of the acetabuli shows enhancement of the inguinal nodes (arrows).
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US of the abdomen revealed lymph nodes in seven of the eight patients who underwent abdominal US; in all seven patients, the lymph nodes were isoechoic when compared with the liver and were periportal in seven patients and retroperitoneal in four patients. One of the seven patients also had some periportal lymph nodes that were hyperechoic relative to the liver parenchyma (Fig 6).
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Figure 6. Longitudinal US image of periportal adenopathy in a 9-year-old patient with ALPS shows lymph nodes that are isoechoic (short arrow) and hyperechoic (long arrow) relative to the liver. (Crosshairs indicate location of calipers.)
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Thymic Enlargement
The thymus was enlarged in 14 of the 15 patients who underwent CT of the chest. The thymus thickness was above the normal, published, age-related standards (11), and the thymic attenuation was similar to the attenuation of muscle in these 14 patients. The thymus was diffusely enlarged and preserved a triangular shape in seven of these patients, had lobulated contours in two patients, and had a multinodular appearance in the other five patients (Figs 7, 8). Patient 17, a 20-year-old woman, had almost complete fatty replacement of the thymus, with a few remaining nodular areas that measured less than 0.5 cm in maximal diameter.
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Figure 7. Axial CT image at the level of the anterior mediastinum in a 4-year-old patient with ALPS demonstrates a diffusely enlarged thymus (arrow).
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Figure 8. Axial CT image at the level of the anterior mediastinum in a 9-year-old patient with ALPS demonstrates an enlarged thymus (arrow) with a multinodular appearance.
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Liver
Ten of the 19 patients had hepatomegaly at clinical examination (Table 1). Eighteen patients underwent imaging of the liver; 15 underwent only CT, and three underwent only US (Table 2). The maximal craniocaudal dimension of the liver was measured (Table 2). Ten of the 18 patients who had undergone liver imaging had imaging proof of hepatomegaly, according to the published age-adjusted standards (12). No focal liver lesions were found.
Spleen
All 19 patients had splenomegaly detected at clinical examination or by determining medical history (Table 1). Eighteen patients underwent imaging of the spleen; 15 patients underwent only CT, and three patients underwent only US (Table 2). Twelve of the 18 patients had undergone splenectomy. The spleen was diffusely enlarged in all six patients who had not undergone splenectomy. No focal splenic lesions were identified.
Indications for splenectomy included the following: hypersplenism, severe hemolytic anemia, refractory thrombocytopenia, and suspicion of lymphoma. Histologic examination of the splenic specimens showed lymphoid hyperplasia of the white pulp with histologic features similar to those of the involved lymph nodes, that is, expansion of the white pulp with reactive follicles.
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DISCUSSION
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ALPS is a disorder of lymphocytic apoptosis that results in splenomegaly, adenopathy, and autoimmune phenomena. The syndrome manifests in early childhood, often with massive splenomegaly and chronic lymphadenopathy. This prompts consideration of several lymphoproliferative disorders, including infectious diseases and malignant lymphoma, before the histologic, cellular, genetic, and immunologic features of ALPS allow its definitive diagnosis.
Our results suggest that the US and CT features of the adenopathy may help in the distinction of ALPS from other lymphoproliferative processes, including malignant lymphoma. First, the adenopathy and splenomegaly may persist with only moderate alterations in size for many years. In the present series, which to our knowledge is the largest series of patients with ALPS reported to date, the median duration of lymphoproliferation at the time of imaging was 7.2 years. Although we have just begun a longitudinal evaluation of these patients, their medical histories, including their requirement of splenectomy years to decades earlier, verify the chronicity of the condition. Our initial impression suggests that, if anything, the adenopathy becomes relatively less prominent after childhood.
Second, in seven of eight patients who underwent US, the abdominal adenopathy was isoechoic or hyperechoic relative to the liver and was distinct from the adenopathy of malignant lymphoma, which is usually hypoechoic (13). Of less use in the differential diagnosis is that in all 13 patients who underwent contrast-enhanced CT, some of the lymph nodes enhanced (this has been previously described in patients with Castleman disease, tuberculosis, or reactive hyperplasia), which suggests an infectious or reactive cause. However, the same finding has also been reported in some patients with neoplasms, such as lymphoma and melanoma (14,15).
The radiologic similarities between the adenopathy in ALPS and the adenopathy in more conventional reactive and infectious processes parallel the histologic findings. In ALPS, the histologic features of the lymph nodes resemble those of viral lymphadenitis, except for the conspicuous absence of histiocytes normally seen to contain apoptotic debris. The lymph node architecture is preserved. There is florid follicular hyperplasia and paracortical expansion by a mixed infiltrate that includes CD3+CD4-CD8- T cells (5,6). This combination of follicular hyperplasia and paracortical expansion, with CD4- and CD8- T cells that express the ß T-cell receptor in the lymph nodes and spleen, appears unique to ALPS and, hence, constitutes a virtually certain pathognomonic histologic feature.
There is insufficient long-term clinical follow-up of patients with ALPS to predict their ultimate outcome. Most patients with ALPS experience autoimmune complications—commonly hemolytic anemia and thrombocytopenia—although autoimmune neutropenia, glomerulonephritis, autoimmune hepatitis, and Guillain-Barré syndrome have been seen. Most patients eventually require splenectomy, usually for hypersplenism, severe hemolytic anemia, or refractory thrombocytopenia.
Some patients have developed postsplenectomy sepsis with encapsulated bacteria, including Streptococcus pneumoniae and Haemophilus influenzae. There is, however, no other recognized predisposition to infections in patients with ALPS. Although adenopathy may be massive, the lymphoproliferative aspect of ALPS per se does not affect vital organ function. Whether patients with ALPS are predisposed to malignancy remains to be proved, but isolated cases have been confirmed in extended studies of ALPS kindreds (3,6).
Apoptosis is a crucial cellular mechanism that normally limits lymphocytic accumulation and the potential for some aberrant clones that can react against self-antigens to persist (1,2). In ALPS, lymphocytic apoptosis is disrupted by heritable defects in genes that regulate it. This disruption results in the accumulation in lymphoid organs of mature, activated CD4- and CD8- lymphocytes that have escaped apoptosis. These lymphocytes, together with additional reactive cells, produce the microscopically massive follicular hyperplasia and/or paracortical expansion and the macroscopic adenopathy, splenomegaly, and hepatomegaly that are characteristic of ALPS.
Similarly, the autoimmune phenomena can be explained by the faulty apoptosis of T and B cells, the failure to eliminate mature T cells with receptors that recognize self-antigens, the excess of helper T cells for self-reactive B cells, the excess of B cells with self-reactive potential, the excessive release of cytokines that induce lymphocytes to exhibit autoimmune phenomena, or by a combination of these mechanisms (16).
The clinical and immunologic features in patients with ALPS resembled those of mice with mutations that impair lymphocytic apoptosis. This observation provided the first clue to the factors involved in the cause of ALPS (5). The demonstration that most ALPS patients have alterations in Fas, the same gene product that is abnormal in a strain of mice with a similar disorder, established the nature of ALPS (3,4).
It is apparent that not all patients with ALPS have Fas mutations. Mutations in other apoptosis genes are being sought. Our recent study of one large family revealed the pattern of inheritance of the mutation and its variable clinical consequences (17). Of 11 family members in four generations with the identical Fas mutation and with defective lymphocytic apoptosis in vitro, three members were entirely asymptomatic, five members had one or more features of ALPS, and three members had the full-blown syndrome.
Patients with autoimmune lymphoproliferative syndrome demonstrate nonspecific imaging findings of lymphoproliferative disorders (adenopathy, splenomegaly, thymic enlargement, and hepatomegaly); the stability of the clinical findings over months to years and the pattern of lymph node echogenicity may suggest the diagnosis. Imaging examinations have various roles in managing ALPS: (a) providing accurate measures of organ involvement, (b) depicting lymphoproliferation that can elude clinical examination, (c) and helping to rule out other unanticipated or complicating conditions.
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Footnotes
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Abbreviation: ALPS = autoimmune lymphoproliferative syndrome
Author contributions: Guarantor of integrity of entire study, N.A.A.; study concepts, S.E.S., N.A.A.; study design, N.A.A.; literature research, S.E.S., N.A.A.; clinical studies, M.C.S., E.S.J., J.K.D., S.E.S.; experimental studies, J.M.P.; data acquisition, J.K.D., U.A.L.; data analysis, N.A.A., U.A.L.; manuscript preparation, A.J.D., N.A.A., S.E.S.; manuscript editing and review, all authors.
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Hematology,
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Abstract
Introduction
