IgG4-Related Disease with Selective Testicular Involvement- A Rare Entity: Case Report with Review of Literature
Asbah SHAMS1, Abhijit DAS1, Madhu SINHA1, Natasha GULATI1, Man Mohan MEHNDIRATTA2, Manish KAUSHIK3, Puneet GUPTA4
1Department of Pathology, Janakpuri Super Speciality Hospital Society, NEW DELHI, INDIA
2Department of Neurology, Janakpuri Super Speciality Hospital Society, NEW DELHI, INDIA
3Department of Surgery, Guru Gobind Singh Government Hospital, NEW DELHI, INDIA
4Department of Cardiology, Janakpuri Super Speciality Hospital Society, NEW DELHI, INDIA
Keywords: IgG4-related disease, Testis, Plasma cells, Fibrosis
Immunoglobin-G4 related disease (IgG4-RD) is an auto-immune inflammatory condition where patients present with a tumour-like mass that
shows infiltration by plasma cell and subsequent fibrosis. It is a systemic condition that primarily involves the salivary glands, pancreas, kidneys,
aorta, and retroperitoneum amongst other organs. Testicular involvement is a rare occurrence in this disease entity. A 55-year old male patient
presented with the complaints of pain and swelling in the right scrotal region. Right-sided orchidectomy was carried out which on histopathology
showed features suggestive of IgG4-RD which was later confirmed on immunohistochemistry. Whole body MRI revealed that no other organ
was involved in the disease process in this patient. IgG4-RD has a variable clinical course and considerable overlap with its differentials. Imaging
studies and serum IgG4 levels are neither confirmatory nor customarily diagnostic in every case. The only confirmatory diagnostic investigation
is histopathological examination, which shows infiltration of IgG4+ plasma cells and fibrosis in the involved tissue. Whenever a mass-forming
lesion with typical histomorphological features is encountered with involvement of multiple organs/anatomic sites, IgG4-related disease should
be considered among the differentials, and clinicians of all disciplines should be familiar with this disease entity.
IgG4-related disease (IgG4-RD) is a systemic, autoimmune,
inflammatory condition, characterised by fibrosis of
the affected organ and its infiltration by IgG4+ plasma
cells, forming a tumour-like mass (1). It primarily
involves the pancreas, salivary glands, kidneys, aorta and
retroperitoneum amongst other organs (2). Testicular
involvement is rare in this disease entity. We report a
case of a 55-year old male, who presented with rightsided
scrotal pain and swelling of short duration which
progressed to a hard testicular lump. An orchidectomy
followed and upon histopathological examination of the
specimen, a diagnosis of IgG4-RD with solitary testicular
involvement was rendered. Awareness of this clinical
entity is imperative since it is steroid-responsive and early
diagnosis and management can prevent undue morbidity.
A 55-year old diabetic male presented with complaints of
pain and swelling in the right scrotal region along with
fever for five days. Ultrasound of the scrotum revealed fine internal septae and free fluid in the right scrotal sac along
with features of right-sided epididymitis and funiculitis. The
testes on both sides were apparently normal on ultrasound
). Consequently, in view of the ultrasound findings
and clinical examination, the patient was diagnosed
with right-sided acute epididymo-orchitis with localised
cellulitis. Injectable broad spectrum antibiotics were started
along with other supportive measures but the swelling
remained persistent with conservative management. On
clinical suspicion of pyocele, the patient was scheduled
for incision and drainage. Intra-operatively it was noted
that there was involvement of tunica albuginea by the
inflammatory process as well as exposure of testicular
pulp tissue. In consideration of necrotic testicular tissue,
a suspicion of malignancy was raised and patient was later
planned for right orchidectomy and the specimen was
submitted for histopathological examination.
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|Figure 1: Ultrasound of scrotum shows both testes normal in size, shape and echotexture. Right scrotal sac shows mild free fluid with
multiple fine internal septations.
On gross examination, the specimen measured 5x4x3 cm.
It consisted of the pulp of testes and epididymis, which
on cut section showed a central tan-coloured necrotic
area and peripheral whitish/fibrotic area (Figure 2).
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|Figure 2: Right-sided orchidectomy
specimen, grossly and on cut
section, showing central necrotic
area and peripheral whitish
Microscopic examination revealed distorted testicular
parenchymal tissue with peritubular storiform fibrosis
and a rich plasma cell infiltrate. A focal area of epididymal
tissue and a separately lying tunica albuginea was also seen
with marked fibrosis and chronic inflammatory infiltrate,
predominantly comprising of plasma cells (Figure 3A-D).
As histomorphological features were highly suggestive of
IgG4-RD, immunohistochemistry for IgG4-positive plasma
cells was carried out which revealed > 50 IgG4+ plasma
cells per high-power field. Serum IgG4 was elevated (4.67
g/L; normal: 0.03-2.0 g/L). Hence the diagnostic criteria for
IgG4-RD (3) were met and the diagnosis was confirmed.
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|Figure 3: A) Dense lymphoplasmacytic infiltrate along with fibrosis in the interstitium distorting the normal testicular parenchyma
(H&E; x20). B) Obliterative phlebitis (H&E; x100). C) Rich plasma cell infiltrate (H&E; x400). D) Immunohistochemistry for IgG4+
plasma cells (IHC; x200).
Thereafter a comprehensive whole body work-up
including whole body MRI was performed to determine the
involvement of other organs but no systemic involvement could be ascertained. Furthermore, his liver, kidney and
thyroid function tests as well as lipid profile and serum
amylase and lipase were found to be within the normal
range. Hence, it was concluded that this was a case of IgG4-
related disease where the solitary site of involvement was
the right testicle. The patient is doing well on follow up.
IgG4-RD can present with lesions in a variety of anatomic
sites, either synchronously or metachronously, but is shown
to have similar histomorphology which is characteristic of
the disease (4). Observed to be a disease of age fifty years
and above, it is more commonly seen in men than in
women, especially in disease affecting the kidney, pancreas
and retro-peritoneum (1, 5, 6).
The etiology of IgG4-RD is unclear. Non-HLA genes like
cytotoxic T-lymphocyte antigen-4 (CTLA-4) and tumour
necrosis factor-α have also been implicated. T-follicular
helper cells along with T-follicular regulatory cells help
in B cell differentiation and class switching, resulting in
proliferation of IgG4-secreting plasmablasts and longlived
plasma cells. CD4-positive T cells are central to the
disease. Their clonally expanded population is seen in both
peripheral blood and fibrotic lesions and shows active
involvement in development of fibrosis. The T helper type
2 (Th2) pathway, which is responsible for eosinophilic
infiltration by IL-5 release, is no longer considered central
to disease pathogenesis (1, 5, 7).
The two consistent clinical findings are tumefactive lesions
and allergic manifestations like atopy, eczema, asthma and peripheral blood eosinophilia (1, 5, 6, 7). The most
commonly reported organ to be involved in IgG4-related
disease is the pancreas (8, 9). The involvement of salivary
glands by IgG4-RD is common and may be in the form of
Mikulicz disease or Kuttner tumour. Various other organs
associated with IgG4-RD are the retroperitoneum, kidney,
thyroid, aorta, lung, lymph nodes, prostate and orbit. In
kidneys, along with hydronephrosis, tubulointerstitial
nephritis and membranous nephropathy have also been
reported (5, 8). Thyroid gland affected by IgG4-RD shows
extensive fibrosis which may extend to extra-thyroidal
tissues. Additionally, inflammatory pseudotumour and
multifocal fibrosclerosis of the orbit, lacrimal gland,
sinuses, and respiratory tract have been described (7).
Intrascrotal involvement by IgG4-RD has been reportedly
limited to para-testicular structures, mostly in the form
of a pseudotumour. Most of these cases had systemic
disease with more than one organ involvement (10-13).
Wenniger was the first to report testicular involvement in
IgG4-RD in a patient with IgG4-related pancreatico-biliary
disease and retroperitoneal fibrosis (14). Tokura and
colleagues encountered a case of hydrocele testis, which on
histopathology showed features of vaginalitis (15). Another
study reported a case of IgG4-RD with selective testicular involvement having dense lymphoplasmacytic infiltrate
around seminiferous tubules and IgG4 cell count 120-130/
hpf. However, serum IgG4 levels were within normal limits
The gold standard diagnostic modality for this entity is
histopathological examination. Diagnosis requires elevated
IgG4+ plasma cells in the tissue and two out of these three
characteristic histo-morphological features (Figure 4): 1)
dense infiltrate of lymphocytes (predominantly T cells) and plasma cells, 2) storiform fibrosis, 3) obliterative
phlebitis. IgG4+ plasma cell infiltration as shown by
immunohistochemistry (more than 10 IgG4+ plasma
cells per high power field) is considered less useful than
the IgG4+ /IgG plasma cells ratio (cutoff>40%) (17). To
establish the disease, in an organ/site not known to be
previously involved by IgG4-RD, the following diagnostic
criteria are set up: 1) typical histomorphology (as previously
described) along-with high IgG4 + plasma cells in tissue
and high IgG4/IgG ratio, 2) elevated serum IgG4 levels, 3)
adequate response to steroid therapy, 4) involvement of
other organs/sites with IgG4-related disease (10).
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|Figure 4: Schematic representation to describe pathogenesis and histomorphological features of IgG4-RD.
Elevated serum IgG4 levels (>135 mg/dl) are not
mandatory for diagnosis but have shown consistent
association with disease activity and show suppression
after steroid therapy. IgG4-related disease responder index
(RI) is a recently devised measure to ascertain the disease
activity and monitor relapses during therapy. The use of
imaging studies like CT scan, MRI and FDG-PET scan
(18F-fluorodeoxyglucose positron emission tomography)
is common for disease evaluation and depends on the organ
involved and availability. Treatment with glucocorticoids
is considered the first-line of management in patients with
active disease. Response is prompt and is noted within
days to weeks while remission is usually achieved within
few months. IgG4-RD has been shown to have a chronic
relapsing course and monitoring of disease activity is hence
of prime importance. Recently, rituximab was introduced
for treatment of this disease entity and shows promise (18).
In conclusion, IgG4-RD can present as a tumour-like mass
in a number of organs/anatomic sites. It may stay indolent
for years or develop organ damage in a short period of
time. Imaging studies cannot reliably distinguish between
this entity and malignancy. Serum IgG4 levels may not be
elevated in every case but they still serve as a marker for
disease activity. Since the span of this illness encompasses
a number of medical specialities, familiarity with this
entity is imperative and it should be considered in the
differential of any mass-forming lesion that shows typical
histomorphology of this disease.
CONFLICT of INTEREST
The authors declare no conflict of interest.
The authors received no financial support for the research,
authorship, and/or publication of this article.
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