Case Reports A Familial Lymphoproliferative Disorder Presenting with Primary Pulmonary Manifestations l - 3

BEVERLY BARTON ROGERS, ILEY BROWNING, HOWARD ROSENBLATT, KENNETH McCLAIN, JAMES KEMP, LOREN L. GLASSER, MARY V. GRESIK, CIRO SUMAYA, MILTON L. WAGNER, MARILYN S. POLLACK, and CLAIRE LANGSTON

Introduction Familiallymphoproliferative disorders have been described in association with a variety of heritable diseases. Hematologic malignancies occur in ataxia telangiectasia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severecombined immunodeficiency (1). In the X-linked lymphoproliferative syndrome (XLP), affected males show an abnormal response to Epstein-Barr virus (EBV), with a wide phenotypic expression, including agammaglobulinemia or hypogammaglobulinemia, chronic infection mononucleosis, and B-cell malignancies (2, 3). Abnormal proliferative responses to EBV have also been described in families without the XLP gene, and include fatal infectious mononucleosis (4) and overt B-celllymphoma (5). Familial T-cellleukemia has been associated with the human T-cell leukemia virus (6). We have studied a family in which three male siblings developed lymphoproliferative disorders with primary pulmonary involvement, apparently not related to EBV infec-

Father 2 I

Sibling 1

I

SUMMARY A familial Iymphoprollferatlve disorder presented in three male siblings with primary pulmonary Involvement manifested as either lymphoid Interstitial pneumonia or an anglodestructive polymorphous infiltrate morphologically resembling lymphomatoid granulomatosis. The polymorphous infiltrate consisted chiefly of mature T-cells with a few B-cells and plasma cells, and gene rearrangement studies failed to show clonallty. Epstein-Barr virus, frequently associated with proliferative lesions in males In the X-linked Iymphoprollferatlve syndrome, was not demonstrated in any of the pUlmonary lesions. An HLA haplotype shared among the affected siblings was Al, B8, DR4. The unusual clinical presentation plus the lack of Involvement by EBV In the pulmonary lesions suggests that this Is a previously undescribed familial Iymphoprollferatlve disorder. AM REV RESPIR DIS 1992; 145:203-208

tion. Two presented concurrently with lung biopsy findings resembling lymphomatoid granulomatosis (LYG) in which the perivascular infiltrate was composed chiefly of T-Iymphocytes. The third had lymphoid interstitial pneumonia (LIP) diagnosed at lung biopsy 6 yr prior to documented EBV infection. The absence of a relationship to EBV and the T-cell nature of thesesiblings'primarily pulmonary lymphoproliferative processes mitigates against this being an atypical pre-

Mother

Father 1 i

i

Sibling 2

Sibling 3

Sibling 4

Presentation 1981(7 yr)

5/1986(10 yr)

5/1986(7 yr)

9/1986(14 yr)

Diagnosis

LIP

AILILYG

AIULYG

1M

Treatment

Steroids cytoxan

Steroids cytoxan

Steroids cytoxan

None

Course

9/19861M with hypoglobulinemia; 12/1987 necrotizing CNS vasculitis; 1987-nodular infiltrates in CXR

9/1986 VAHS; died of overwhelming infection

Alive and well 6/1986; died of GI hemorrhage

Fig. 1. Summary of clinical and pathologic findings. AIULYG = angiocentric immunoproliferative lesionS/lym· phomatoid granulomatosis. LIP = lymphoid interstitial pneumonia.

sentation of XLP and supports our conclusion that this is a previously undescribed familiallymphoproliferative disorder with primary pulmonary manifestations.

Case Report Sibling I (figure I) presented in 1981at 7 yr of age with LIP (figure 2). He did not respond to initial prednisone treatment, but he improved with the addition of cytoxan, with resolution of symptoms. Therapy was discontinued in 1983,and he remained stable with normal immunoglobulins until September 1986 when he developed severe manifestations of infectious mononucleosis with fever, hepatomegaly, lymphadenopathy, and a lymphocytosis of 4,602lmm 3 • Monospot test was positive. He had a protracted clinical course, but he converted to a typical convalescent serologic pattern. Hypogammaglobulinemia developed and was treated intravenously with gamma globulin. His course was complicated in December 1987 by necrotizing vasculitis of the central nervous system. Radiographically,

(Receivedin originalform November 19, 1990and in revisedform May 28, 1991) 1 From the Departments of Pathology, Pulmonary Medicine, Immunology, Hematology/Oncology, and Radiology, Texas Children's Hospital and Baylor College of Medicine, Department of Microbiology and Immunology, Baylor College of Medicine, and the Department of Pathology, University of Texas Health Sciences Center, San Antonio, Texas. 2 Supported in part by Public Health Service Grant No. CA-40552 from the National Institutes of Health. 3 Correspondence and requests for reprints should be addressed to Dr. Beverly Barton Rogers, Department of Pathology, Women & Infants' Hospital, 101 Dudley Street, Providence, RI 02905.

203

204

CASE REPORT

associated hemophagocytic syndrome (VAHS)and died 4 months after initial presentation with disseminated candidiasis. Sibling 3 died 2 months after onset of pulmonary symptoms from massive gastrointestinal ulceration and hemorrhage. The only residual of Iymphoproliferative disease in either child at autopsy was in Sibling 3 who had foci of perivascular lymphocytes in the central nervous system and a mature Iymphoplasmacytic proliferative lesion in the ileum. Immunoperoxidase staining of the lung biopsies showed a predominance of T-Iymphocytes (figure 4C) with a helper to suppressor T-cell ratio of approximately2:1.T-cellreceptor rearrangements were done on extracted DNA from the lung biopsy of Sibling 3. Southern blotting (7) using probes from the T-cell beta and gamma genes(gift ofT. W. Mak) failed to show a clonal population ofT-cells. A panB-cell antibody (figure 40) showed a minor population of admixed B-cells containing both kappa and lambda light chains. Direct immunofluorescence for EBV using antibodies to EBNA 2-A protein and EBV Latent Membrane Protein (8) was negative. Southern blot analysis was also done on extracted DNA for the EBV genome using a probe from the BamHI-H fragment (gift of E. Kieff and T. Dambaugh) (7) and was negative. Sibling 4, a maternal half-brother of the three affected boys, also developed infectious mononucleosis in September 1986. He had a typical clinical course and recovered completely. The family history is negative for pulmonary disease, immunodeficiency, or vasculitis. The mother has two sisters and a brother. Her family history for the past two generations is negative for chronic pulmonary disease, early death in infants or males, or severeand unusual infections. There is no history ofany Iymphoproliferative diseases in either the mother's or father's family.

Fig. 2. Top panel. A mature Iymphoplasmacytic infiltrate is seen in the alveolar septa. characteristic of LIP Hematoxylin-eosin stain; magnification. 100. Bottonpanel. Sibling 1: 7 yr of age. Frontal chest film demonstrates diffuse. coarse linear-reticular infiltrates.

the pulmonary infiltrates had evolved from linear reticular infiltrates in 1981 to peripheral nodular infiltrates (figure 3, top panel). Sibling 2 presented in April 1986 with fever, pleural effusions, hypoxia, hypogammaglobulinemia, and ill-defined,peripheral pulmonary nodular infiltrates (figure 3, bottom panel). Sibling3 presented concurrently with low-grade fever, lethargy, persistent cough, and hypogammaglobulinemia. Open lung biopsies were done in both and showed similar angiocentric, nodular polymorphic infiltrates

resembling LYG(figure 4, A and B). Sibling 2 also had a liver biopsy that showed infiltrates surrounding portal vein branches similar to those seen in the lungs. Bacterial and viral cultures of both these lung biopsies were negative. Serologic evaluation did not show evidence of infection by cytomegalovirus, adenovirus, human immunodeficiency virus, Brucella, Mycoplasma, Coccidioides, Blastomyces, Aspergillus, or Francisella tularensis. They were treated with steroids and cytoxan, with radiographic and clinical improvement. Sibling 2 developed viral-

Serologic Evaluation of EBV Antibodies to EBV, including IgM(VCA), IgG (VCA), EA, and EBNA, were assayed using immunofluorescence techniques (9). Spontaneous transformation of peripheral blood lymphocytes (10)and viral secretion was determined by EBV isolation in tissue culture (11). Serologically, Siblings 2 and 3 did not show definite evidence of EBV infection. Neither had positive titers for EBVVCA(lgG). Sibling 3 had a single specimen positive for EBV-VCA(lgM) at a 1:10 dilution. However, his total IgM was elevated at that time, possibly resulting in a false positive result. Subsequent serologic tests for EBV-VCA(lgM) were negative. Results of EBV serologic evaluation for Sibling 1 and the mother and the father, are shown in table 1. Sibling 1 initially showed an increase in VCA (lgM) and VCA(lgG). The VCA(lgG) titer was 1:1,280, elevated over the normal acute response. His VCA(IgM) titer became negative, and his VCA(lgG) titer fell to the normal range. Although his course was protracted, his EBNA titer rose to normal levels during convalescence. Both parents were tested during the convalescent period of Sibling 1. The mother had a weakly positive EA titer, which has been seen in normal persons tested in the same laboratory (personal communication, Dr. Sumaya). Also, her evaluation showed a low VCA(lgM), with titers repeatedly between 1:5 and 1:10. The father had an EBNA titer of 1:5, a borderline low level for that same laboratory, seen in 5070 of normal males. Repeated evaluation has not shown an increase in titer. The father also showed spontaneous transformation of peripheral blood lymphocytes, seen in less than 10% of normal persons.

205

CASE REPORT

and aberrant lymphocyte subset phenotyping with monoclonal antibodies. He had normal percentages of B-cells (slg+, B4+, and Bl+) and T-cells (E-rosette -t , TlI +, and T3 +) with markedly depressed helper (T4+) and elevated suppressor (TS+ )T-cells (T4:TS = 0.2). In addition, there was marked depression of in vitro proliferation to standard lectins (PHC, Con-A, and PWM) and to specific antigens (Candida, tetanus, and SK-SD). Sibling 2 was initially evaluated at 10.5 yr, shortlyafter the diagnosis of LYG was made. His IgG was mildly depressed, 415mg/dl (nl 639 to 1,315),with normal IgA and an IgM at the upper limit of normal, 357 mg/dl (nl 56 to 352 mg/dl). Anti-A and anti-B isohemagglutinins werestrongly positive by saline and Coomb's methods, and delayed hypersensitivity skin tests (DHST) for Candida and tetanus were positive. Lymphocyte subset determinations showednormal percentages and absolute numbers of T-(E-rosette +, TlI -t-, and T3 + ) and B-cells (slg +, B4+, and Bl + ) with normal percentages and absolute numbers of suppressor and normal numbers but slightly increased percentages of helper T-cells resulting in a T4:TS ratio of 3.44 (nl O.S to 2.4). In vitro proliferation to the standard lectins PHA, Con-A, and PWM were well within the normal ranges. Sibling 3 was only partially evaluated prior to receiving cytoreductive therapy for rapidly progressive LYG. At initial evaluation, he had moderately depressed IgG = 366 mg/dl (n1631 to 1,29S)and normal IgA and IgM. His DHST were positive to Candida and tetanus, and anti-B isohemagglutinins were present by both saline and Coomb's methods. Lymphocyte phenotyping and in vitro proliferative responses were not obtained on Sibling 3 prior to his death. In summary, Sibling 1 demonstrated the most profound immune defects of both T- and B-cell function, and Siblings 2 and 3 showed more subtle defects, primarily in B-cell function, with mild depression of serum IgG levels.

HLA Antigen Typing HLA-A, B, and C serologic typing was performed using standard microcytotoxicity techniques (15) for all except Sibling 3. Because Sibling 3 was deceased at the time of analysis, his HLA-A, B, and C typing was done on previously established fibroblasts (16). HLA-DR typing was performed, using separated B-cells (17) and modified microcytotoxicity techniques for the best characterized antigens of the DR series (DRI-DRwlO). Serologic typing was also performed for DQwl, DQw2, and DQw3 and for the DRb3 gene polymorphic determinants DRw52 and DRw53. The results of these studies show haplotype AI, B8, DR4 in the father and the three affected siblings (table 2).

Discussion

Fig. 3. Top panel. Sibling 1: 13 yr of age. PA chest now demonstrates bilateral coarse nodular pattern. Bottom panel. Sibling2: 10 yr ofage (May 1986). Frontal chest film demonstrates diffuse. ill-defined pulmonarynodules. some of which suggest central breakdown. Large bilateral pleuraleffusions have been removed. Small effusion remaining on right.

Immunologic Evaluation Immunologic evaluations of the three affected siblings at various stages of disease were performed. Peripheral blood mononuclear cells were isolated (12), and proliferation in response to phytohemagglutinin, concanavalin-A, pokeweed mitogen, and SK-SD was assessed (13). Lymphocyte subset analysis was performed using sheep rosetting (14),

f1uoresceinated immunoglobulin, and flow cytometry (Ortho Pharmaceuticals, Raritan, NJ). Sibling I was studied initially during his acute EBV infection and had normal serum levels of IgG and 19A and elevated IgM, 511 mg/dl (nl 56 to 352 mg/dl), which persisted for several weeks. Immune evaluation 3 months later revealed depressed IgG, A, and M, cutaneous anergy to Candida, tetanus, and PPD,

This familial lymphoproliferative disorder, presenting with primary pulmonary manifestations, is unique in its combined clinical and pathologic findings. Angiocentric immunoproliferative lesions in the lung include lymphocytic vasculitis, LYG, and angiocentric large cell lymphoma (18).The pulmonary lesions in Siblings 2 and 3 most closely fit the morphologic description of LYG, a polymorphic angiocentric and angiodestructive process (table 3). Although some investigators have considered LYG to be a B-cell proliferative process (19),others have suggested that the cellular components are mostly mature T-cells, with a predominance of helper T-cells(20). The nodular proliferations of

206

CASE REPORT

Fig. 4. Microscopic examination of lung biopsies from Siblings 2 and 3 showed. A. Vasocentric lymphocytic infiltrates (Hematoxylin-eosin stain: magnification, 63). B. With extension into the vessel wall (H-E stain; magnification, 400). Immunoperoxidase staining shows the majority of cells staining positive with the pan-r-eef marker leu 4 & 58 (C), with only a minor population of cells staining with the pan-8-cell marker leu 14 (D).

Siblings 2 and 3 were not only morphologically similar to LYG but also showed a predominance of T-cells of a mixed helper and suppressor T-cell phenotype. Sibling 1presented with LIP 5 yr prior to his brothers' LYG. LIP has been associated with LYG in only one case (21). His LIP, treated and radiographically stable for years, has recently progressed,and now appears radiographically similar to his brothers. The underlying defect in this family is not known. These boysresemble patients with the XLP in some ways, but striking differences exist. XLP is an inherited disorder in which

affected males show an abnormal proliferative response to EBV, and sometimes other infectious agents (2, 3). A hypo proliferative phenotype may result in depression or a total lack of production of immunoglobulin, and a fatal mononucleosis syndrome may develop with an exuberant proliferation of lymphocytes.A hyperproliferative phenotype has also been described, and this results in lymphomas of the B-cell type (22). The proliferative lesions in these patients typically show evidence for EBVgenome. Affected males show deficient EBNA responses and depression of natural killer cell activity after EBV infection

TABLE 1 EPSTEIN-BARR VIRUS SEROLOGIC EVALUATION

VCA (lgM) VCA (lgG) EA E8NA Viral secretion Spontaneous transformation (PBl)

Sibling 1 (A:l)

Mother (l)

+1t/+ ND/±I+ ND/± ND/-

+ + +R +

Father (l)

+ ±

+

Norma! (A:E:L)

+1-1-1+1+ +1-1-I±I+ ttltl ± ttltl ±

De/inition 01 abbreviations: A = ac ute EBV infection; E = early convalescence: L = late convalescence; VeA = viral capsid antigen; EA = early antigen; EBNA = Epstein-Barr nuclear antigen.

(23). Also carrier females may have abnormal EBVantibody responses (24). In our family, there appears to be a similar predisposition for male siblings to develop lyrnphoproliferative disorders; however, their serologic responses to EBV were in the normal range, and EBV was not demonstrated in their pulmonary lesions. This lack of relationship to EBV is inconsistent with ascribing these lesions to XLP. Also, the pulmonary infiltrates consisted chiefly of T-cells, not B-cells as is characteristic of XLP. In XLP the carrier mother may show abnormal responses to EBV infection, but the father should be normal. In our family the father's unusual responses, a low-normal EBNA titer and transformed peripheral blood lymphocytes, may be present in a small percentage of the population, but their combined occurrence suggests an abnormality in serologic response to EBV. The mother had a positive EA titer, which also is uncommon, but it is seen in a small percent of the normal population. She also had a positive titer for VCA(IgM), which is normal only in acute infection. The significance of these unusual serologic studies in the face of normal clinical phenotypes of the parents remains to be determined.

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CASE REPORT

TABLE 2 Sibling 1 Al,B8(w6),DR4(DQw3,DRwS3) Al,B44(w4),DR4(DQw3,DRwS3) Sibling 2 Al,B8(w6),DR4(DQw3,DRwS3) A30,B13(w6),DR7 ± ((DQw2),DRwS3) Sibling 3 A1,B8(w6),(DR4(DQw3,DRwS3))* Al,B44,(DR4(DQw3,DRwS3»* Father A1,B8(w6),DR4(DQw3,DRwS3) A29,Bw4S(w6),DR1(DQw1) Mother Al,B44(w4),DR4(DQw3,DRwS3) A30, B13(w4),DR7(DQw2,DRwS3) Sibling 4 A1,B8(w6)DR3(DQw2,DRwS2) A30,B13(w4),DR7(DQw2,DRwS3) • The Class II HLA antigens assignments for this sibling are inferred since the fibroblasts were only typed for Class I antigens. The crossover frequency between HLA-B and HLA-DR is less than 1%.

Although EBV is most commonly associated with B-cellproliferations, the virus has also been demonstrated by in situ hybridization in the tumor cellsof malignant T-cellproliferations of the helper T-cellphenotype (25). In one such patient, an initial biopsy was suggestive of LYG;however, he was subsequently shown to have a lymphoma. Although our siblings did not have EBV genome in their

lung biopsies, the possibility exists that an abnormal response to another virus resulted in the abnormal mixed T-cell proliferation. Infectious agents other than EBVhave been implicated as possible causativeagents in familial T-Iymphocyte malignancy. Two siblings with evidence of human T-cellleukemia virus developed T-cell leukemia of the helper T-cell type (6). Another virus, human B lympho-

trophic virus (HBLV) has been implicated in T-cell proliferations including AIDS-related lymphoproliferations, angioimmunoblastic lymphadenopathy, peripheral T-celllymphorna, and immunoblastic lymphoma (26). Although it is unlikely that our patients had the HTLV-I virus, we cannot exclude infection with HBLV or some other unknown agent. The HLA haplotype AI, B8, DR4, which is present in the father and the three affected siblingsis rare, with a gene frequencyof 0.16% in North American Caucasians (27). The HLA haplotype AI, B8 has been shown to be present in increased frequency in patients with VAHS (28), a histiocytic proliferation triggered by viral infection. This association is supported in the family as VAHS occurred in Sibling 2. The father, although clinically well, carried an HLA AI, B8, DR4 haplotype and showed depressed serologic response to EBV with a low EBNA titer. Because Class I HLA molecules are involved in the presentation of viral antigens for initiation of an immune response, some inherited characteristic of the molecules may be involved in the abnormallymphoproliferative responses seen in this family. In summary, we have studied a family with a previously undescribed T-cell pulmonary lymphoproliferative disorder with a unique clinical and pathologic presentation. The proliferative abnormality was not associated with EBV; however, unusual serologic responses to EBV were documented in the clinicallyunaffected mother and father. The HLA haplotype AI, B8, DR4 was present in the father and in the affected siblings. The underlying defect is elusive, but the available evidence suggests a familial tendency towards abnormal T-cellresponses to an unidentified infectious or toxic agent.

TABLE 3 PRIMARY PULMONARY ANGIOCENTRIC IMMUNOPROLIFERATIVE LESIONS Benign Lymphocytic Vasculitis

Lymphomatoid Granulomatosis

Angiocentric Lymphoma

Morphology

Perivascular small lymphocytes and plasma cells

Polymorphic vascular infiltrate with atypical cells

Monotypic, pleomorphic vascular infiltrate

Necrosis

Minimal or absent

Ischemic necrosis

Ischemic necrosis

Ischemic necrosis

Polyclonal mature T-cells with predom inance of helper T-cells

Monoclonal

Polyclonal infiltrate consisting predominantly of T-cells (helper:suppressor T-cell ratio = 2:1)

Cell surface markers

Siblings 2 and 3 Polymorphic vascular infiltrate with atypical cells

Sile(s) of involvement

Lungs

Lungs and extrapulmonary sites (frequently skin and CNS)

Lungs with or without hilar lymph nodes

Primarily lungs with focal liver and brain infiltrates

Radiographic findings

Multiple nodular infiltrates

Multiple nodular infiltrates

Most commonly localized infiltrate

Multiple peripheral nodular infiltrates

Resolution with cyclophosphamide prednisone

Unknown

Variable

No

Yes

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CASE REPORT

Acknowledgment The writers acknowledge the expert technical assistanceof Mrs. BillieSmith in performing immunohistochemical stains. The T-cell rearrangement studies weredone in the laboratory of Dr. Gregory J. Buffone, and the EBVimmunofluorescent studies were done by Dr. Carolyn Alfieri in the laboratory of Dr. Elliott Kieff.

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to other "benign" lymphoproliferative disorders. Am J Clin Pathol 1980; 73:41-7. 20. Lipford EH Jr, Margolick JB, Longo DL, Fauci AS, Jaffe ES. Angiocentric immunoproliferative lesions: a clinicopathologicspectrum of post-thymic T cell proliferations. Blood 1988; 72:1674. 21. Weisbrot 1M. Lymphomatoid granulomatosis of the lung associated with a long history of benign lymphoepitheliallesions of the salivary glands and lymphoid interstitial pneumonitis. Am J Clin Pathol 1976; 66:792-801. 22. Morgan-Capner P, Morris JA, McIllmurray MB,Thomas JA, Crawford DH, Azin T. Immunohistochemicalstudies of lymphoproliferativelesions in a fatal case of Epstein-Barr virus infection. J Clin Pathol 1986; 39:1317-22. 23. Sullivan JL, Bryan KS, Brewster FE, Purtilo DT.Deficient natural killer cell activity in X-linked lymphoproliferative syndrome. Science 1980;210: 543-5. 24. Sakamoto K, SeeleyJK, Lindstein T, et al. Abnormal anti-Epstein Barr virus antibodies in carriers of the X-linked Iymphoproliferative syndrome and females at risk. J Immunol 1982; 128:904-7. 25. Jones JF, Shurin S, Abramowsky C, et al. Tcelllymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. N Engl J Med 1988; 318:733-41. 26. Satahuddin SZ, Ab1ashi DV, Markham PD. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986; 234:596-600. 27. Baur MP, Danilovs SA. Reference tables of two and three locus haplotype frequenciesfor HLAA, B, C, DR, BF and 010. In: Terasaki PI, ed. Histocompatibility testing 1980. Los Angeles: UCLA Tissue Typing Laboratory, 1980;994-1210. 28. McClain K, Gehrz R, Grierson H, Purtilo D, Filipovich A. Virus-associated hemophagocytic proliferations in children: frequent association with Epstein-Barr virus and congenital or acquired immunodeficiencies. Am J Pediatr Hemato1 Oncol 1988; 10:196-205.