cytoplasmic antibodies (ANCA), antimyeloperoxidase and antiproteinase
III (PR3), hepatitis B and C serology were negative. Urinalysis was normal. Her
peripheral blood chromosome analysis was consistent with mosaic Turner syndrome
(45,X/46,XX,
Subsequently,
she developed proteinuria and hematuria. A repeated indirect immunofluorescence
test for ANCA was positive with c-ANCA pattern, although PR3 antibodies were
negative by ELISA. The family refused renal biopsy.
Although
tissue diagnosis was not available, Wegener’s granulomatosis (WG) was
considered as the probable diagnosis. Cyclophosphamide (1mg/kg/day, p.o.) was
added to the oral steroid treatment. The following year was characterized by
frequently intervening severe respiratory tract infections despite
trimethoprim/sulphamethoxazole prophylaxis. Immunosuppressive treatment was
frequently put off because of these infections and she was hospitalized several
times due to persistent and recurrent pulmonary inflammation. The chest
radiograph suggested pulmonary vasculitis or infection and she was treated with
pulse methylprednisolone, intravenous antibiotic and antifungal agents multiple
times (Figure 1).
Renal biopsy
was performed one year later and revealed focal cresentric, diffuse segmental
and necrotizing ‘’pauci-immune’’ type glomerulonephritis. Immunofluorescence
studies showed no immune complex deposition. Direct laringoscopic examination
of the vocal cords showed granulomatous lesions. Biopsy revealed necrotic
material, inflammatory cells and gram positive cocci. Wegener’s granulomatosis
was diagnosed according to
She was
plasmapheresed three times a week and cyclophosphamide was started again when
her white blood count (WBC) was above 4000/mm3. At follow-up, she developed subcutaneous
nodules on the face, trunk and extremities (Figure 2). One of these nodules was
biopsied and a diagnosis was established.
DISCUSSION
Pulmonary
vascular inflammation can be seen in a variety of primary lung diseases and in
the setting of numerous systemic illnesses. Pulmonary vasculitis may be a
central feature of the pathologic process as in WG, Churg-Strauss syndrome,
microscopic polyangiitis and lymphomatoid granulomatosis. Henoch-Schoenlein
purpura, Behçet’s disease, giant cell arteritis, Takayasu’s disease,
leukocytoclastic vasculitis and cryoglobulinemia may also have a pulmonary
involvement, but quite rarely [2-4].
The presented
patient had recurrent and persistent inflammation in the upper and lower
respiratory tracts, renal biopsy verifying necrotizing pauci-immune type
glomerulonephritis and positive serology for c-ANCA. The clinical course very
similar to WG. The clinical presentation fulfilled the diagnostic criteria for
WG. She had upper respiratory tract involvement with severe epistaxis,
recurrent sinusitis and subglottic stenosis. Leukocytoclastic vasculitis,
segmental and pauci-immune type glomerulonephritis, positive serology for
c-ANCA, recurrent and persistent pulmonary inflammation and chest radiographs
showing diffuse interstitial infiltrates were all suggestive of WG [1,2,5]. On
the other hand, polyarteritis nodosa may present with similar renal features;
however, the upper respiratory tract involvement, and the pattern of ANCA was
incompatible. Her lung involvement was never in the form of asthma and she had
no eosinophilia. Anti-glomerular basement-antibodies were negative. She had no
features suggesting HSP, Behçet’s and Takayasu’s during her long follow-up.
Thus, her
clinical diagnosis was a probable WG although we had not shown the
granulomatous lesions in her biopsies and failed to show a high PR-3 ANCA titer. However, the final biopsy from the
nodules revealed a new diagnosis.
FINAL DIAGNOSIS
Light microscopic examination of the skin biopsy
showed a nodular lesion in subcutaneous fat tissue. In this lesion,
angiocentric and angiodestructive proliferation of lymphohistiocytic cells
principally involving small and medium sized vessels were observed. The
infiltrate was composed of various mononuclear elements including lymphocytes,
plasma cells and macrophages, with foci of bizzare lymphohistiocytic cells
demonstrating much pleomorfism and increased number of mitotic figures. Immunohistochemically, most of lymphoid cells
expressed CD3, and some of them expressed CD8. Between these cells, there were
CD68 positive histiocytes.
These histopathologic findings were consistent with
grade II angiocentric immunoproliferative lesion, that is, lymphoid granulomatosis
(LYG).
Our
patient had a multisystemic process, with clinical evidence of upper
respiratory tract, pulmonary, hepatic, cutaneous, renal and probable spleen
involvement consistent LYG.
LYG is a rare
angiocentric and angiodestructive lymphoproliferative disorder with prominent
pulmonary involvement [2,6]. It was initially described by Liebow et al. as a necrotizing pulmonary
vasculitis that may progress to lymphoma [6]. Skin, central nervous system and
kidneys are affected in one-third of the patients. Involvement of the upper
airways, eyes, liver, spleen, adrenal glands, pancreas, gastrointestinal tract,
heart and lymph nodes have also been documented [2,6-8]. The clinical course
may vary from spontaneous regression, resolution with treatment or progression
to lymphoma.
LYG is very
rare in childhood [6, 8, 9-11, 12-16]. In Liebow’s original series with 40
patients, only one patient was a child and in Katzenstein's series with 152
patients, 12 patients were under the age of 20 [6,8]. The clinical signs are
extraordinarily diverse, and the radiologic and laboratory findings are
nonspecific. Therefore, the diagnosis of LYG is usually missed or delayed. The
etiology of LYG is unknown. Recent studies have indicated that it is an
Epstein-Barr virus associated B cell lymphoproliferative disorder with a
background of reactive T lymphocytes [10, 17-19]. Immunodeficiency,
Epstein-Barr virus, genetic and familial factors have been proposed in the
pathogenesis [6-8,13, 15, 18-21]. There
are no specific laboratory findings in LYG.
Upper
respiratory tract involvement is a cardinal feature of WG, nearly reported in
92% of the patients although rarely observed in LYG [1,2,5,6]. Pulmonary involvement has been described in
all patients with WG and LYG [1,2,5,6,8]. Massive destruction of lung
parenchyma leading to respiratory insufficiency represented the major cause of
death in LYG [6,8,15]. Radiologic findings are not specific to help in
differential diagnosis. Multiple bilateral nodular infiltrates are present in 80% of cases in both WG and LYG [2,22].
Cavitation can be observed in 20 to 30% of cases in both diseases. Diffuse
interstitial infiltrates are the second most frequent radiologic finding,
present in 45% of the patients with LYG [22].
Renal
involvement has been described in 80% of the patients with WG and one-third of
the patients with LYG [1,2,5,6,8,15]. However clinically evident renal disease
like in our case has rarely been reported in LYG [15]. In Liebow’s initial
series, 45% of the cases showed nodular lesions with atypical lymphoreticular
infiltrates with necrosis and vasculitis [6]. A segmental necrotizing
pauci-immune type glomerulonephritis is a feature of WG, while glomerular
involvement is strikingly absent in LYG [6,8,15]. Hepatomegaly was reported in
12% of Katzenstein’s series and carried a worse prognosis [8].
Skin
involvement has been reported equally as 46% in both WG and LYG [5,15]. These
lesions included palpable purpura, ulcers, vesicles, papules and subcutaneous
nodules in WG and erythematous, macular or plaque-like lesions and rarely
subcutaneous nodules in LYG. Biopsy is important for early diagnosis when
cutaneous involvement is present, however our patient developed subcutaneous
nodules late in the course.
Liebow et al. considered LYG as a distinct and
separate disease entity although several features histologically resembled WG
[6]. A destructive inflammatory vasculitis is a feature of both LYG and WG,
however the composition of the infiltrate differs. An atypical infiltrate with
lymphoreticular cells with plasmocytoid features predominating over mature
lymphocytes and plasma cells, rare polymorphonuclear leukocytes (PMNL’s) or
eosinophils and intense proliferative activity are characteristic features of
LYG. The infiltrate in WG is composed chiefly of PMNL’s, histiocytes and
occasional eosinophils with a relative sparse population of lymphocytes and
plasma cells [6,8,15,20,23].
An optimal treatment protocol has not
been established for LYG yet and is somewhat similar to WG. Immunosuppressive
drugs and combined chemotherapy (cyclophosphamide, corticosteroids and
vincristine) have been applied [6-9,10,20]. After the diagnosis was
established, we have started chemotherapy for the presented patient.
Unfortunately, she died during chemotherapy due to pulmonary hemorrhage.
Surgery and
radiotherapy have been used as an adjunctive therapy [7,8,16,23]. Fauci et al. reported remissions lasting 5
years or more in approximately half of their 15 patients and concluded that
early diagnosis and prompt treatment could establish a good prognosis [7]. Koss
et al. reported no significant
difference in outcome of patients treated with corticosteroids, chemotherapy
and radiation [23]. Interferon-alpha 2b, which has antiviral, antiproliferative
and immunomodulatory effects, has been proposed as a new treatment modality and
achieved some favorable results [13,19].
CONCLUSION
Our case
strongly emphasizes the clinical similarities of WG and LYG and reveals the
diagnostic challenge and delay in patients with LYG. LYG should be considered
in the differential diagnosis of pulmonary vasculitis and mutisystemic clinical
findings, albeit very rare in the pediatric age group. As there are no specific
clinical, laboratory and radiologic findings for LYG, a definite diagnosis may
only be possible by histopathologic examination. Though it is often considered
as a fatal vasculitis without an evident response to treatment, early
recognition and treatment may prevent progression into a lymphoma.
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LEGENDS
Figure
1: Chest
radiograph showing bilateral diffuse infiltrates suggesting pulmonary
vasculitis or infection.
Figure
2: Subcutaneous
nodules on the lower extremity.
Figure
3 a, b:
Histopathologic examination the subcutaneous nodules showed polymorphous
angiocentric and angiodestructive inflammatory cells composed of histiocytes,
small lymphocytic cells, occasional large lymphoid cells or immunoblasts. These
lesions were compatible with lymphomatoid granulomatosis. Cytologic atypia was
observed in some of these lymphoid cells, therefore graded as II.
Figure 1.
Figure 2.
Figure 3a.
Figure 3b
