**7. Histopathological evaluation in IgG4-RD**

Histopathological evaluation is a crucial element of an accurate diagnosis of IgG4-RD due to their nonspecific clinical and laboratory features. Irrespective of the anatomic site, histopathologic presentation is similar and consists of five main histomorphological and immunohistochemical parameters evaluated in the tissue specimen (both biopsy and postoperative specimens) [1, 85, 86]:


Most of the analyzed cases do not show all histopathologic features characteristic for IgG4-RD. The presence of two or more of the parameters listed above suggests the diagnosis of IgG4-RD [1].

The inflammatory infiltrate in IgG4-related diseases primarily consists of mature plasma cells, dispersed T lymphocytes and focally aggregated macrophages. In some cases, eosinophils are observed [1].

It must be underlined that the isolated elevated IgG4+ plasma cell count is nonspecific and insufficient for the diagnosis of IgG4-RD. Elevated IgG4+ plasma cell count is observed in many cancers and infectious diseases, which is why a range of detailed clinical and laboratory tests is crucial in differential diagnosis [85, 86]. Full clinician and pathologist cooperation is indispensable as well since incomplete patient history may delay or in some cases even prevent establishing the accurate diagnosis.

**81**

IgG4-RD.

kappa light chains restriction [87].

*IgG4-Related Disease and the Spectrum of Mimics in Rheumatology*

potentially malignant lesions that may imitate IgG4-RD.

Fibrosis in IgG4-related diseases is very characteristic, being storiform with whorled or cart-wheel appearance [1, 56]. No cytologic atypia is observed within proliferating fibroblasts, which is an important element in differential diagnosis of

Obliterative phlebitis is the most specific but most rare histopathologic feature of IgG4-RD. In hematoxylin and eosin stained specimens a chronic intramural inflammatory infiltrate is observed with fibrosis and obliteration of the vessel lumen [1]. Elastic stain, which is a histochemical stain outlining the wall elements of the vessel damaged by the chronic inflammatory infiltration, may aid if it is difficult to accurately identify the pathologically altered and totally obliterated vein. The accurate histopathologic diagnosis of IgG4-RD can be made when two quantity parameters for IgG4+ plasma cells are observed at the same time [4]. According to the current recommendations, the number of IgG4+ plasma cells should be determined within three high-power fields with the highest density of IgG4+ plasma cells and then the average should be determined based on three measurements [1]. For the coreneedle biopsy specimen the minimal number of IgG4+ plasma cells is 10/HPF and one of the two histopathologic parameters (storiform fibrosis and/or obliterative phlebitis) must be observed. Different cutoffs are used for postoperative material, for example the cutoff within the resected salivary gland is >100 IgG4+ plasma cells/HPF [1, 56]. The key parameter, apart from elevated number of IgG4+ plasma cells is the accurate determination of IgG4+ plasma cells/total number of IgG+ plasma cells ratio. It is only the ratio of >40% that may suggest the diagnosis of IgG4-RD. The isolated elevated IgG4+ plasma cell number not accompanied by the required increase of IgG4+/IgG+ ratio does not meet the criteria for the diagnosis of

It must be stressed that plasma cells in IgG4-RD are polytypical. If a monotypical population of plasma cells is identified (even if it meets IgG4-RD criteria), a more extended histopathologic diagnosis for plasmacytic neoplasms is required—it is necessary to perform immunohistochemical staining for potential lambda and

From the point of view of histopathology and histopathologic-clinical correla-

The diagnosis of "histologically highly suggestive of IgG4-RD" requires the presence of a typical storiform fibrosis or obliterative phlebitis with a high number

Histopathologic diagnosis of "probable histologic features of IgG4-RD" is based only on a high number and elevated global percentage of IgG4+ plasma cells with the lack of typical storiform fibrosis or obliterative phlebitis. A detailed correlation

The third histopathologic category ("insufficient histopathologic evidence of IgG4-RD") is applied when microscopic examination does not show dense lymphoplasmacytic inflammatory infiltrate, storiform fibrosis, obliterative phlebitis or elevated number of IgG4+ plasma cells. It must be remembered though, that such diagnosis does not preclude IgG4-RD in a given patient since the primary lesion may

tions, three categories of diagnosis were enumerated [1, 56]:

• histologically highly suggestive of IgG4-RD;

• probable histologic features of IgG4-RD; and

of IgG4+ plasma cells and elevated IgG4/IgG ratio.

• insufficient histopathologic evidence of IgG4-RD.

with clinical, laboratory and radiological data is necessary.

not have been represented in the specimen taken for evaluation [1, 56].

The histopathological features of IgG4-RD in liver biopsy (**Figures 2**-**5**).

*DOI: http://dx.doi.org/10.5772/intechopen.83368*

#### *IgG4-Related Disease and the Spectrum of Mimics in Rheumatology DOI: http://dx.doi.org/10.5772/intechopen.83368*

*Chronic Autoimmune Epithelitis - Sjogren's Syndrome and Other Autoimmune Diseases...*

Retroperitoneal fibrosis was reported in 13% of patients with multi-organ involvement in the course of IgG4-RD. Most of the lesions were periaortic or located around iliac vessels. In 33% of patients, hydronephrosis was found, more commonly of one kidney than two [83]. Classifying all cases of IgG4-RD as Ormond's disease is controversial if not confirmed by histopathology, and requires a further well-designed medical analysis. However such a suggestion was made in one publication [84].

IgG4-RD is a disease of multiple systems. It may be located in one or in many organs at the same time. In case of suspected IgG4-RD, all other diseases which may mimic IgG4-RD should be excluded. For rheumatologists it is important to exclude in the differential diagnosis the following: neoplasms including solid lesions and lymphomas, inflammatory and infectious changes, sarcoidosis, vasculitis including granulomatous vasculitis, Sjӧgren syndrome, Castleman's disease, eosinophilic angiocentric fibrosis. As IgG4-RD may involve many organs, imaging diagnostics should always be carried out in order to determine all locations of the disease after diagnosis of the disease.

Histopathological evaluation is a crucial element of an accurate diagnosis of IgG4-RD due to their nonspecific clinical and laboratory features. Irrespective of the anatomic site, histopathologic presentation is similar and consists of five main histomorphological and immunohistochemical parameters evaluated in the tissue

4.increased number of IgG4+ plasma cells/HPF - different cutoffs depending on the anatomic site and the type of evaluated material (biopsy vs. postoperative

Most of the analyzed cases do not show all histopathologic features characteristic for IgG4-RD. The presence of two or more of the parameters listed above

The inflammatory infiltrate in IgG4-related diseases primarily consists of mature plasma cells, dispersed T lymphocytes and focally aggregated macrophages.

It must be underlined that the isolated elevated IgG4+ plasma cell count is nonspecific and insufficient for the diagnosis of IgG4-RD. Elevated IgG4+ plasma cell count is observed in many cancers and infectious diseases, which is why a range of detailed clinical and laboratory tests is crucial in differential diagnosis [85, 86]. Full clinician and pathologist cooperation is indispensable as well since incomplete patient history may delay or in some cases even prevent establishing the accurate diagnosis.

**6.8 Retroperitoneal fibrosis and IgG4-RD**

**6.9 Summary of the clinical picture**

**7. Histopathological evaluation in IgG4-RD**

1.dense lymphoplasmacytic infiltrate,

3.obliterative phlebitis,

specimen),

2.fibrosis with prominent storiform pattern,

5.IgG4+/IgG+ plasma cell ratio of >40%;

suggests the diagnosis of IgG4-RD [1].

In some cases, eosinophils are observed [1].

specimen (both biopsy and postoperative specimens) [1, 85, 86]:

**80**

Fibrosis in IgG4-related diseases is very characteristic, being storiform with whorled or cart-wheel appearance [1, 56]. No cytologic atypia is observed within proliferating fibroblasts, which is an important element in differential diagnosis of potentially malignant lesions that may imitate IgG4-RD.

Obliterative phlebitis is the most specific but most rare histopathologic feature of IgG4-RD. In hematoxylin and eosin stained specimens a chronic intramural inflammatory infiltrate is observed with fibrosis and obliteration of the vessel lumen [1]. Elastic stain, which is a histochemical stain outlining the wall elements of the vessel damaged by the chronic inflammatory infiltration, may aid if it is difficult to accurately identify the pathologically altered and totally obliterated vein.

The accurate histopathologic diagnosis of IgG4-RD can be made when two quantity parameters for IgG4+ plasma cells are observed at the same time [4]. According to the current recommendations, the number of IgG4+ plasma cells should be determined within three high-power fields with the highest density of IgG4+ plasma cells and then the average should be determined based on three measurements [1]. For the coreneedle biopsy specimen the minimal number of IgG4+ plasma cells is 10/HPF and one of the two histopathologic parameters (storiform fibrosis and/or obliterative phlebitis) must be observed. Different cutoffs are used for postoperative material, for example the cutoff within the resected salivary gland is >100 IgG4+ plasma cells/HPF [1, 56].

The key parameter, apart from elevated number of IgG4+ plasma cells is the accurate determination of IgG4+ plasma cells/total number of IgG+ plasma cells ratio. It is only the ratio of >40% that may suggest the diagnosis of IgG4-RD. The isolated elevated IgG4+ plasma cell number not accompanied by the required increase of IgG4+/IgG+ ratio does not meet the criteria for the diagnosis of IgG4-RD.

It must be stressed that plasma cells in IgG4-RD are polytypical. If a monotypical population of plasma cells is identified (even if it meets IgG4-RD criteria), a more extended histopathologic diagnosis for plasmacytic neoplasms is required—it is necessary to perform immunohistochemical staining for potential lambda and kappa light chains restriction [87].

From the point of view of histopathology and histopathologic-clinical correlations, three categories of diagnosis were enumerated [1, 56]:


The diagnosis of "histologically highly suggestive of IgG4-RD" requires the presence of a typical storiform fibrosis or obliterative phlebitis with a high number of IgG4+ plasma cells and elevated IgG4/IgG ratio.

Histopathologic diagnosis of "probable histologic features of IgG4-RD" is based only on a high number and elevated global percentage of IgG4+ plasma cells with the lack of typical storiform fibrosis or obliterative phlebitis. A detailed correlation with clinical, laboratory and radiological data is necessary.

The third histopathologic category ("insufficient histopathologic evidence of IgG4-RD") is applied when microscopic examination does not show dense lymphoplasmacytic inflammatory infiltrate, storiform fibrosis, obliterative phlebitis or elevated number of IgG4+ plasma cells. It must be remembered though, that such diagnosis does not preclude IgG4-RD in a given patient since the primary lesion may not have been represented in the specimen taken for evaluation [1, 56].

The histopathological features of IgG4-RD in liver biopsy (**Figures 2**-**5**).

#### **Figure 2.**

*Extensive fibrosis with storiform appearance and chronic inflammatory infiltrate (H*&*E, 200×).*

#### **Figure 3.**

*Extensive fibrosis with storiform appearance and chronic inflammatory infiltrate (H*&*E, 400×).*

**Figure 4.** *Immunohistochemical staining for CD138 revealed that majority of the cells are plasmocytes (hematoxylin, 200×).*

**83**

*IgG4-Related Disease and the Spectrum of Mimics in Rheumatology*

*A prominent component of IgG4+ plasmocytes (hematoxylin, 100×).*

Treatment of IgG4-RD is based on the experience of the attending physicians and opinions of the experts, as there are no large controlled clinical trials covering this problem so far. Moreover, the exact molecular pathomechanism of IgG4-RD is not known, so determination of targeted therapies is not possible at the moment. In every patient, treatment should be individually planned, depending on the location and organ damage, coexisting diseases and contraindications to immunosuppressive treatment. Another aspect of IgG4-RD therapy is that the disease tends to recur in case of treatment withdrawal. In the group of patients with the highest recurrence rate, increased baseline level of serum IgG4, IgE and eosinophils was observed [5]. At present, the experts recommend pharmacologic treatment in patients with active lymphoplasmatic infiltrations in histopathological examination. Surgery may be considered in patients with a long-lasting disease with predominant fibrosis, poorly responding to basic treatment [13, 83]. Therapy including careful observation without rapid initiation of treatment may be considered in moderate lymphadenopathy and with moderate enlargement of the submandibular salivary gland. In case of subclinical forms with involvement of the bile ducts, kidneys, aorta, retroperitoneal fibrosis, pancreas, pachymeningitis, pericarditis, treatment must be started even with a lack of clinical symptoms due to

According to international guidelines of IgG4-RD treatment, the first-line medicines are glucocorticoids: oral prednisone, at an initial dose of 0.6 mg/kg daily maintained for 2–4 weeks and gradually reduced for 3–6 months [83, 84]. In Japanese guidelines, glucocorticoids in small maintenance doses (5–10 mg daily) are recommended even for 3 years [88]. In case of recurrences, repeated administration of glucocorticoids is proposed in the above schedule [83]. Most of the patients show fast improvement after glucocorticoid use. As soon as after several weeks of treatment, improvement of functional parameters of the involved organs is observed, with a reduction of the infiltration mass and a decrease of serum IgG4 concentration. There are no publications which would constitute guidelines for the application of disease modifying antirheumatic drugs in patients not responding to or not tolerating treatment with glucocorticoids or who experience frequent disease

*DOI: http://dx.doi.org/10.5772/intechopen.83368*

**8. Treatment**

**Figure 5.**

progressive, irreversible organ damage.

*IgG4-Related Disease and the Spectrum of Mimics in Rheumatology DOI: http://dx.doi.org/10.5772/intechopen.83368*

**Figure 5.** *A prominent component of IgG4+ plasmocytes (hematoxylin, 100×).*
