The histopathological spectrum of kidney biopsies in patients with thymoma and myasthenia gravis: a report of 24 biopsies from a single institution

Abstract

Background: Nephropathy in patients with thymic diseases such as thymoma and myasthenia gravis (MG) is rare and has been described mostly as isolated case reports. Here we evaluate a series of kidney biopsies from patients with thymoma and/or MG from a single institution in order to better define the spectrum and relative frequencies of thymic disease-associated nephropathies.

Methods: We conducted a retrospective case series study of 32 462 native kidney biopsies from January 2005 through December 2019 at Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Results: Twenty-four biopsy specimens (0.07%) from patients with a history of thymoma and/or MG were identified. Two patients had repeat biopsies. The most common pathologic diagnosis that could be immunologically attributed to thymic disease was minimal change disease (MCD; 45%), followed by tubulointerstitial nephritis (TIN; 14%), immune complex (IC)-mediated glomerulonephritis (9%), membranous nephropathy (5%) and immunoglobulin A (IgA) nephropathy (5%). Interestingly, 50% of the MCD and 67% of TIN cases concomitantly showed mild IgG-dominant IC deposition in mesangial areas and/or in tubular basement membranes. In the two patients with repeat biopsies, mild mesangial IC deposition developed in the MCD patient but disappeared in the TIN patient with the second biopsy. Pathologic diagnoses unlikely related to the underlying thymic disease were diabetic glomerulosclerosis (9%), acute tubular necrosis (9%) and monoclonal Ig deposition disease (5%).

Conclusions: Thymic disease is associated with a wide spectrum of kidney diseases affecting the glomerular and tubulointerstitial compartments, often with low-grade IC deposition. These findings suggest a role of immunologic dysregulation in the pathogenesis of thymic disease-associated nephropathy.

Keywords: immune complex deposition; minimal change disease; onconephrology; paraneoplastic syndrome; thymus; tubulointerstitial nephritis.

FIGURE 1:

(A and B) MCD (Patient 11). (A) Periodic acid–methenamine (PAM) silver stain shows an unremarkable glomerulus without hypercellularity (bar: 20 μm). (B) EM shows global podocyte foot process effacement with microvillous transformation (original magnification 7200×; bar: 2 μm). (C) Active TIN (Patient 3). Periodic acid–Schiff (PAS) stain shows lymphocytic inflammation in the interstitium and tubular walls (bar: 20 μm). (D and E) IC-GN (Patient 9). (D) PAS stain shows mild mesangial expansion with mild mesangial hypercellularity (bar: 40 μm). (E) Direct immunofluorescence for IgG reveals fine granular IgG staining in the mesangial area (bar: 20 μm). (F) MN (Patient 22). Direct immunofluorescence for IgG shows fine granular reactivity along glomerular capillary loops (bar: 20 μm). (G–I) IgAN (Patient 19). (G) PAS stain shows mild mesangial expansion without hypercellularity (bar: 20 μm). (H) Direct immunofluorescence for IgA exhibits fine granular staining in the mesangial area (bar: 20 μm). (I) EM shows electron-dense deposits in the mesangial area (original magnification 10 000×; bar: 1 μm). All electron micrographs stained with uranyl acetate and lead citrate.

FIGURE 2:

(A–C) MCD with IC deposition (Patient 16). (A) PAM stain shows an unremarkable glomerulus without hypercellularity (bar: 20 μm). (B) Immunofluorescence study shows fine granular mesangial IgG staining in a mild degree (bar: 20 μm). (C) EM shows global podocyte foot process effacement (original magnification 14 000×; bar: 1 μm). (D) MCD with IC deposition in the mesangial area and segmentally in the subepithelial area (Patient 10). EM reveals electron-dense deposits in subepithelial space (original magnification 19 000×; bar: 1 μm). (E) Granulomatous TIN (Patient 6). PAM stain shows interstitial areas with inflammatory cells and multinucleated giant cells (bar: 20 μm). (F–H) TIN with IC deposition in the mesangium and tubular basement membranes (Patient 8). (F) PAS stain shows active lymphocytic inflammation in interstitial area and tubular walls (bar: 20 μm). (G) Direct immunofluorescence for IgG shows fine granular staining in the mesangial area and focally in tubular basement membranes (bar: 20 μm). (H) EM shows small electron-dense deposits in the mesangial area (original magnification 15 000×; bar: 500 μm). All electron micrographs stained with uranyl acetate and lead citrate.

FIGURE 3:

(A and B) MCD without IC deposition (Patient 2; first biopsy). (A) EM shows global podocyte foot process effacement (original magnification 14 000×; bar: 1 μm). (B) Direct immunofluorescence for IgG shows negative staining in the glomerulus (bar: 30 μm). (C and D) MCD with IC deposition (Patient 2; second biopsy). (C) EM shows global podocyte foot process effacement with microvillous transformation (original magnification 3000×; bar: 2 μm). (D) Immunofluorescence study shows mild fine granular IgG staining in the mesangial area (bar: 30 μm). (E and F) TIN with IC deposition (Patient 3; first biopsy). (E) PAS stain shows lymphocytic interstitial inflammation with mild tubulitis (bar: 40 μm). (F) Direct immunofluorescence for IgG shows minimal fine granular staining in the mesangial area (bar: 30 μm). (G and H) TIN without IC deposition (Patient 3; second biopsy). (G) PAS stain shows the similar findings to (E) (bar: 40 μm). (H) Immunofluorescence study shows negative staining of IgG in the entire tissue (bar: 40 μm).

FIGURE 4:

(A) DGS (Patient 17). PAS stain shows mesangial expansion and segmental Kimmelstiel–Wilson nodules (bar: 20 μm). (B and C) ATN with focal myoglobin casts (Patient 20). (B) PAS stain shows epithelial flatting and necrosis with intraluminal PAS-negative amorphous material (bar: 20 μm). (C) Immunohistochemistry of myoglobin shows strong staining in the amorphous tubular cast (bar: 20 μm). (D–F) MIDD (Patient 21). (D) PAM stain shows a membranoproliferative pattern of glomerular injury (bar: 20 μm). (E) Direct immunofluorescence for kappa light chain shows negative reaction in a glomerulus (bar: 20 μm). (F) Immunofluorescence study shows positive lambda light chain staining in a glomerulus and tubular basement membranes (bar: 20 μm).

FIGURE 5:

Summary of renal pathology in patients with thymoma and/or MG. (A) 17 patients in this study: MCD [59% (10/17)], TIN [17% (3/17)], IC-GN [12% (2/17)], IgAN [6% (1/17)] and MN [6% (1/17)]. (B) 87 patients in previously reported cases: MCD [45% (39/87)], MN [20% (18/87)], LN [9% (8/87)], 1°FSGS [8% (7/87)], CRGN [8% (7/87)], IgAN [5% (4/87)] and Others [5% (4/87), which includes secondary FSGS, TMA, necrotizing angiitis and membranoproliferative GN]. (C) Overall 104 patients: MCD [47% (49/104)], MN [18% (19/104)], LN [8% (8/104)], 1°FSGS [7% (7/104)], CRGN [7% (7/104)], IgAN [5% (5/104)], TIN [3% (3/104)], IC-GN [1% (2/104)] and Others [4% (4/104)].