PATHOLOGY
Immunoglobulin G4–Related Disease of the Hard Palate Nicholas Andrew, MBBS,* Daniel Kearney, MBBS,y Nicole Sladden, MBBS,z Alastair Goss, BDS, DDSc,x and Dinesh Selva, MBBSk A 71-year-old woman presented with erythematous, nontender, bilateral hard palate nodules of 6-month duration. Biopsy showed collagenous sclerosis and a follicular lymphoplasmacytic infiltrate among the minor salivary glands. Immunoglobulin G (IgG) and IgG4 staining showed 280 IgG4+ cells per high-power field and a ratio of IgG4+ to IgG+ cells of 0.8. The patient subsequently developed bilateral lacrimal gland and parotid gland enlargement associated with an increased serum IgG4 level of 3,031 mg/dL (#135 mg/ dL). Left lacrimal gland biopsy confirmed IgG4-related dacryoadenitis. The patient declined corticosteroid treatment for IgG4-related disease (IgG4-RD) and remained stable at 15 months after the first presentation. Spontaneous, partial resolution of the palatal lesion was observed during follow-up. IgG4-RD should be considered in the differential diagnosis of lymphoplasmacytic lesions of the hard palate. Crown Copyright Ó 2014 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons. All rights reserved J Oral Maxillofac Surg 72:717-723, 2014 Immunoglobulin G4–related disease (IgG4-RD) is a recently defined systemic condition characterized by tissue infiltration with IgG4-bearing plasma cells. It unites a wide range of inflammatory lesions from multiple organs that were previously thought to be unrelated. ‘ Classic’’ sites of IgG4-RD involvement are the pancreas, hepatobiliary tract, major salivary glands, lymph nodes, orbit, and lung.1 Minor salivary gland involvement has been reported rarely.2-4 To the best of their knowledge, the authors report the first case of IgG4-RD involving the minor salivary glands of the hard palate.
of type 2 diabetes, polymyalgia rheumatica, and ischemic heart disease. Incisional biopsy of the patient’s left nodule showed minor salivary glands and a dense lymphoplasmacytic infiltrate incorporating germinal centers, bands of collagenous sclerosis, and scattered eosinophils (Fig 2). The pathologic diagnosis was benign sialadenitis with a reactive lymphoid infiltrate. Because the patient was asymptomatic, no further treatment was undertaken. Retrospective IgG and IgG4 staining of this specimen showed 280 IgG4+ cells per high-power field (hpf) and a ratio of IgG4+ to IgG+ cells of 0.8 (Fig 3). These features were consistent with salivary gland IgG4-RD according to the consensus-based histologic diagnostic criteria proposed by Deshpande et al5 (Table 1). Ten months after the hard palate lesion was noted, the patient developed bilateral painless upper eyelid
Report of Case A 71-year-old woman presented with smooth, erythematous, nontender, rubbery, bilateral hard palate nodules of 6-month duration (Fig 1). She had a history *Associate Clinical Lecturer, Department of Ophthalmology and
kFoundation Chair, Department of Ophthalmology and Visual
Visual Sciences, University of Adelaide and South Australian Institute of Ophthalmology, South Australia, Australia.
Sciences, University of Adelaide and South Australian Institute of Ophthalmology, South Australia, Australia.
ySenior Consultant, Anatomic Pathologist, SA Pathology, Royal
Address correspondence and reprint requests to Dr Andrew:
Adelaide Hospital and Department of Surgical Pathology, Institute
Department of Ophthalmology and Visual Sciences, University of
of Medical and Veterinary Science, Adelaide, South Australia,
Adelaide, South Australian Institute of Ophthalmology, Level 8,
Australia.
Royal Adelaide Hospital, Adelaide, SA 5000, Australia; e-mail: nick.
zRegistrar in Anatomical Pathology, SA Pathology, Royal Adelaide
[email protected]
Hospital and Department of Surgical Pathology, Institute of Medical
Received July 25 2013
and Veterinary Science, Adelaide, Australia. xEmeritus Consultant, Oral and Maxillofacial Surgery Unit, Royal
Crown Copyright Ó 2014 Published by Elsevier Inc on behalf of the American
Adelaide Hospital and University of Adelaide, Adelaide, South
Association of Oral and Maxillofacial Surgeons. All rights reserved
Australia, Australia.
0278-2391/13/01207-X$36.00/0
Accepted August 26 2013
http://dx.doi.org/10.1016/j.joms.2013.08.033
717
718
IMMUNOGLOBULIN G4–RELATED HARD PALATE DISEASE
FIGURE 1. Photograph of bilateral hard palate nodules (arrows). Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
swelling. Serum IgG4 was markedly elevated at 3,031 mg/dL (#135 mg/dL). An autoimmune screen, including complete blood cell count, liver function tests, antinuclear antibodies, extractable nuclear antigens, and erythrocyte sedimentation rate, was within normal
limits. Magnetic resonance imaging (MRI) visualized diffuse enlargement of both lacrimal glands and both parotid glands, but the hard palate was normal in appearance. Biopsy of the left lacrimal gland confirmed this to be a manifestation of IgG4-RD (Figs 4, 5).
FIGURE 2. Hematoxylin and eosin stain of the patient’s left palatal lesion (magnification, 200). There is a dense lymphoplasmacytic infiltrate among the minor salivary glands (asterisks). Numerous eosinophils are present, 2 of which are indicated (arrows). Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
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ANDREW ET AL
FIGURE 3. A, Immunoglobulin G and (Fig 3 continued on next page.) Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
Computed tomographic (CT) scan of the patient’s neck, chest, abdomen, and pelvis showed no masses or lymphadenopathy. The patient was diagnosed with IgG4-RD involving both lacrimal glands, both parotid glands, and the minor salivary glands of the hard palate. The patient declined corticosteroid treatment for IgG4-RD and remained clinically stable at 15 months after first presentation. The hard palate lesion partially resolved spontaneously.
Discussion To the authors’ knowledge, this is the first published case of IgG4-RD involving the hard palate. The case fulfills the consensus-based histopathologic diagnostic criteria for salivary gland IgG4-RD (Table 1) and the comprehensive diagnostic criteria for ‘‘definite’’ IgG4RD (Table 2).5,6 Classic sites of IgG4-RD involvement are the pancreas, hepatobiliary tract, major salivary glands, lymph nodes, orbit, and lung.1 IgG4-RD of the perioral region is not uncommon, but is almost in-
variably localized to the major salivary glands. Mickulicz’s disease has recently been reclassified into the IgG4-RD spectrum and is defined as symmetric involvement of 2 pairs of submandibular, parotid, or lacrimal glands.7 Chronic sclerosing sialadenitis, also known as Kuttner tumor, is related to IgG4 in the vast majority of cases.7 IgG4-RD has been rarely described in the maxillary sinus, and although 1 case was associated with gingival erythema, the disease spared the gingival mucosa on biopsy.8 There has been 1 report of IgG4-RD of the tongue and a few reports of IgG4-RD of the labial mucosa,2-4 but the condition has not been reported elsewhere in the oral cavity. The pathogenesis of IgG4-RD is thought to involve an abnormal immune response to antigen, possibly an environmental allergen1; however, the rarity of the disease at sites of conjunctiva-associated lymphoid tissue seems inconsistent with this postulated mechanism. IgG4-RD of the major salivary glands is relatively common, whereas IgG4-RD of the oral mucosa
720
IMMUNOGLOBULIN G4–RELATED HARD PALATE DISEASE
FIGURE 3 (cont’d). B, immunoglobulin G4 immunohistochemical stains (brown) with hematoxylin nuclear counterstain (blue) (magnification, 200). There are 280 immunoglobulin G4–positive cells per high-power field (field area, 0.2 mm2) and the ratio of immunoglobulin G4–positive to immunoglobulin G–positive cells is 0.8. Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
appears to be rare. In the ocular adnexa, a similar dichotomous pattern is observed; IgG4-RD of the lacrimal glands is common, but IgG4-RD of the ocular conjunctiva has never been reported.1 Consensus-based histopathologic guidelines for the diagnosis of IgG4-RD were issued by Desphande et al5 after a 2011 international symposium on IgG4-RD. The hallmark feature of the condition is a lymphoplasmacytic infiltrate rich with IgG4-bearing plasma cells. For salivary gland lesions, more than 100 IgG4+ cells per hpf are considered indicative of the diagnosis.5 The criteria do not distinguish between major and minor salivary gland disease. The ratio of IgG4+ to IgG+ cells must be higher than 0.4 to correct for extreme tissue plasmacytosis. This ratio is considered the most reliable diagnostic marker and is more likely to be preserved after corticosteroid treatment or progressive sclerosis than the raw IgG4+ cell count.1 Lesions are thought to
undergo progressive sclerosis and, therefore, the overall appearance of lesions is dependent on the age of the lesion and the underlying microstructure of the involved tissue. Sclerosis typically assumes a whirling pattern (storiform sclerosis), but also may have a lamellar architecture (collagenous sclerosis).5 Obliterative phlebitis is purported to be a cardinal feature of IgG4-RD, but it is rarely detected in major salivary gland and lacrimal gland IgG4-RD and would not be expected in minor salivary gland biopsies.9 Obliterative phlebitis may be an organ-specific feature rather than a disease-specific feature of IgG4-RD. An eosinophilic infiltrate is common and was well shown in the present patient’s palatal and lacrimal gland biopsy specimens. Patients with IgG4-RD should have a systemic workup at diagnosis to assess the extent of disease and to screen for non-Hodgkin lymphoma (NHL). The risk of lymphoma is uncertain, but cases of NHL
721
ANDREW ET AL
Table 1. CONSENSUS-BASED HISTOLOGIC DIAGNOSTIC CRITERIA FOR SALIVARY GLAND IGG4-RD5
1
2
3
Characteristic histologic features ($1 feature required) a Dense lymphoplasmacytic infiltrate b Fibrosis, usually storiform in character c Obliterative phlebitis >100 IgG4+ cells per high-power field (3 fields with the largest number of IgG4+ plasma cells should be counted and averaged) IgG4+/IgG+ plasma cell ratio >40% Fulfillment of all 3 criteria is required for the histologic diagnosis of salivary gland IgG4-RD
Abbreviation: IgG4-RD, immunoglobulin G4–related disease. Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
arising in sites of histologically confirmed IgG4-RD have been rarely reported.1 The IgG4-RD literature is insufficient to authoritatively dictate a screening protocol, but screening tests at the authors’ center include physical examination, complete blood cell count, serum IgG4, liver function tests, and CT scan of the neck, chest, abdomen and pelvis. Radiologic
features of IgG4-RD in the head and neck include well-defined, enhancing mass lesions that are iso- to hypointense on T2-weighted MRI.10 Bony remodeling without cortical invasion and concentric enlargement of multiple cranial nerves may favor the diagnosis.11,12 Serum IgG4 concentration may have a role in prognostication because it is thought to correlate with disease volume and activity.1 However, serum IgG4 is an unreliable diagnostic marker because it is normal in up to 40% of biopsy-proved cases of IgG4-RD.1 Patients with IgG4-RD may have a mild eosinophilia, but inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) are typically normal. The natural history of IgG4-RD is varied, ranging from self-limited disease to recalcitrant inflammation requiring targeted chemotherapeutics.1 Management is tailored to the patient and usually follows a graduated approach. As shown by the present case, some lesions cause minimal morbidity and may settle after the debulking effect of biopsy. More commonly, inflammatory or mass effects necessitate treatment. Corticosteroids are considered first-line treatment for IgG4-RD and are usually associated with an excellent but unsustained response.1 Disease relapse during or shortly after prednisolone taper is common and patients may become steroid dependent.13 Targeted therapy with rituximab may be strikingly effective, even in
FIGURE 4. Hematoxylin and eosin stain of the left lacrimal gland biopsy (magnification, 40). There is a follicular lymphoplasmacytic infiltrate interspersed among bands of collagenous sclerosis (arrows). Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
722
IMMUNOGLOBULIN G4–RELATED HARD PALATE DISEASE
FIGURE 5. A, Immunoglobulin G and B, immunoglobulin G4 immunohistochemical stains (brown) with hematoxylin nuclear counterstain (blue) (magnification, 200). There are 270 immunoglobulin G4–positive cells per high-power field (field area, 0.2 mm2) and the ratio of immunoglobulin G4–positive to immunoglobulin G–positive cells is 0.79. Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
steroid-resistant cases.13 Rituximab is a monoclonal antibody against the protein CD20 and induces apoptosis in all mature B cells (normal and pathogenic); stem cells then regenerate the B-cell population. The adverse effects of rituximab include infusion reactions, reactivation of latent infections, and progressive multifocal leukeoencephalopathy.14 The duration of follow-up and the need for repeat staging are
determined by clinical suspicion and patient symptomatology because there are no consensus guidelines. In summary, the authors have described the first case of IgG4-RD involving the minor salivary glands of the hard palate. IgG4-RD should be considered in the differential diagnosis of lymphoplasmacytic lesions involving the hard palate.
ANDREW ET AL
Table 2. COMPREHENSIVE DIAGNOSTIC CRITERIA 6 FOR IGG4-RELATED DISEASE
1
2 3
Clinical examination showing characteristic diffuse/ localized swelling or masses in single or multiple organs Hematologic examination shows elevated serum IgG4 concentration ($135 mg/dL) Histopathologic examination shows a Marked lymphocyte and plasma cell infiltration and fibrosis b Infiltration of IgG4+ plasma cells: ratio of IgG4+/ IgG+ cells >40% and >10 IgG4+ plasma cells/hpf Definite, 1 + 2 + 3; probable, 1 + 3; possible, 1 + 2
Abbreviations: hpf, high-power field; IgG4, immunoglobulin G4. Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
References 1. Andrew N, Kearney D, Selva D: IgG4-related orbital disease: A meta-analysis and review. Acta Ophthalmol, 2012 [ePub ahead of print] 2. Doe K, Hohtatsu K, Lee S, et al. Case report: Usefulness of lip biopsy for the diagnosis of IgG4-related diseases with retroperitoneal fibrosis: Report of a case. Nihon Naika Gakkai Zasshi 100: 1645, 2011 (in Japanese)
723 3. Ogawa Y, Nakagawa M, Ishii W, et al: Lip biopsy in Mikulicz’s disease phenotype IgG4-related disease. Intern Med 52:1007, 2013 4. Baer AN, Gourin CG, Westra WH, et al: Rare diagnosis of IgG4related systemic disease by lip biopsy in an international Sjogren syndrome registry. Oral Surg Oral Med Oral Pathol Oral Radiol 115:e34, 2013 5. Deshpande V, Zen Y, Chan JK, et al: Consensus statement on the pathology of IgG4-related disease. Mod Pathol 25:1181, 2012 6. Umehara H, Okazaki K, Masaki Y, et al: Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 22:21, 2012 7. Himi T, Takano K, Yamamoto M, et al: A novel concept of Mikulicz’s disease as IgG4-related disease. Auris Nasus Larynx 39:9, 2012 8. Ono K, Shiiba M, Yoshizaki M, et al: Immunoglobulin G4-related sclerosing inflammatory pseudotumors presenting in the oral cavity. J Oral Maxillofac Surg 70:1593, 2012 9. Andrew N, Kearney D, Selva D: Applying the consensus statement on the pathology of IgG4-related disease to lacrimal gland lesions. Mod Pathol 26:1150, 2013 10. Fujita A, Sakai O, Chapman MN, et al: IgG4-related disease of the head and neck: CT and MR imaging manifestations. Radiographics 32:2012, 1945 11. Ginat DT, Freitag SK, Kieff D, et al: Radiographic patterns of orbital involvement in IgG4-related disease. Ophthal Plast Reconstr Surg 29:261, 2013 12. Katsura M, Mori H, Kunimatsu A, et al: Radiological features of IgG4-related disease in the head, neck, and brain. Neuroradiology 54:873, 2012 13. Khosroshahi A, Carruthers MN, Deshpande V, et al: Rituximab for the treatment of IgG4-related disease: Lessons from 10 consecutive patients. Medicine 91:57, 2012 14. Molloy ES, Calabrese LH: Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: Evolving role of biologic therapies. Arthritis Rheum 64:3043, 2012
Immunoglobulin G4–Related Disease of the Hard Palate Nicholas Andrew, MBBS,* Daniel Kearney, MBBS,y Nicole Sladden, MBBS,z Alastair Goss, BDS, DDSc,x and Dinesh Selva, MBBSk A 71-year-old woman presented with erythematous, nontender, bilateral hard palate nodules of 6-month duration. Biopsy showed collagenous sclerosis and a follicular lymphoplasmacytic infiltrate among the minor salivary glands. Immunoglobulin G (IgG) and IgG4 staining showed 280 IgG4+ cells per high-power field and a ratio of IgG4+ to IgG+ cells of 0.8. The patient subsequently developed bilateral lacrimal gland and parotid gland enlargement associated with an increased serum IgG4 level of 3,031 mg/dL (#135 mg/ dL). Left lacrimal gland biopsy confirmed IgG4-related dacryoadenitis. The patient declined corticosteroid treatment for IgG4-related disease (IgG4-RD) and remained stable at 15 months after the first presentation. Spontaneous, partial resolution of the palatal lesion was observed during follow-up. IgG4-RD should be considered in the differential diagnosis of lymphoplasmacytic lesions of the hard palate. Crown Copyright Ó 2014 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons. All rights reserved J Oral Maxillofac Surg 72:717-723, 2014 Immunoglobulin G4–related disease (IgG4-RD) is a recently defined systemic condition characterized by tissue infiltration with IgG4-bearing plasma cells. It unites a wide range of inflammatory lesions from multiple organs that were previously thought to be unrelated. ‘ Classic’’ sites of IgG4-RD involvement are the pancreas, hepatobiliary tract, major salivary glands, lymph nodes, orbit, and lung.1 Minor salivary gland involvement has been reported rarely.2-4 To the best of their knowledge, the authors report the first case of IgG4-RD involving the minor salivary glands of the hard palate.
of type 2 diabetes, polymyalgia rheumatica, and ischemic heart disease. Incisional biopsy of the patient’s left nodule showed minor salivary glands and a dense lymphoplasmacytic infiltrate incorporating germinal centers, bands of collagenous sclerosis, and scattered eosinophils (Fig 2). The pathologic diagnosis was benign sialadenitis with a reactive lymphoid infiltrate. Because the patient was asymptomatic, no further treatment was undertaken. Retrospective IgG and IgG4 staining of this specimen showed 280 IgG4+ cells per high-power field (hpf) and a ratio of IgG4+ to IgG+ cells of 0.8 (Fig 3). These features were consistent with salivary gland IgG4-RD according to the consensus-based histologic diagnostic criteria proposed by Deshpande et al5 (Table 1). Ten months after the hard palate lesion was noted, the patient developed bilateral painless upper eyelid
Report of Case A 71-year-old woman presented with smooth, erythematous, nontender, rubbery, bilateral hard palate nodules of 6-month duration (Fig 1). She had a history *Associate Clinical Lecturer, Department of Ophthalmology and
kFoundation Chair, Department of Ophthalmology and Visual
Visual Sciences, University of Adelaide and South Australian Institute of Ophthalmology, South Australia, Australia.
Sciences, University of Adelaide and South Australian Institute of Ophthalmology, South Australia, Australia.
ySenior Consultant, Anatomic Pathologist, SA Pathology, Royal
Address correspondence and reprint requests to Dr Andrew:
Adelaide Hospital and Department of Surgical Pathology, Institute
Department of Ophthalmology and Visual Sciences, University of
of Medical and Veterinary Science, Adelaide, South Australia,
Adelaide, South Australian Institute of Ophthalmology, Level 8,
Australia.
Royal Adelaide Hospital, Adelaide, SA 5000, Australia; e-mail: nick.
zRegistrar in Anatomical Pathology, SA Pathology, Royal Adelaide
[email protected]
Hospital and Department of Surgical Pathology, Institute of Medical
Received July 25 2013
and Veterinary Science, Adelaide, Australia. xEmeritus Consultant, Oral and Maxillofacial Surgery Unit, Royal
Crown Copyright Ó 2014 Published by Elsevier Inc on behalf of the American
Adelaide Hospital and University of Adelaide, Adelaide, South
Association of Oral and Maxillofacial Surgeons. All rights reserved
Australia, Australia.
0278-2391/13/01207-X$36.00/0
Accepted August 26 2013
http://dx.doi.org/10.1016/j.joms.2013.08.033
717
718
IMMUNOGLOBULIN G4–RELATED HARD PALATE DISEASE
FIGURE 1. Photograph of bilateral hard palate nodules (arrows). Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
swelling. Serum IgG4 was markedly elevated at 3,031 mg/dL (#135 mg/dL). An autoimmune screen, including complete blood cell count, liver function tests, antinuclear antibodies, extractable nuclear antigens, and erythrocyte sedimentation rate, was within normal
limits. Magnetic resonance imaging (MRI) visualized diffuse enlargement of both lacrimal glands and both parotid glands, but the hard palate was normal in appearance. Biopsy of the left lacrimal gland confirmed this to be a manifestation of IgG4-RD (Figs 4, 5).
FIGURE 2. Hematoxylin and eosin stain of the patient’s left palatal lesion (magnification, 200). There is a dense lymphoplasmacytic infiltrate among the minor salivary glands (asterisks). Numerous eosinophils are present, 2 of which are indicated (arrows). Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
719
ANDREW ET AL
FIGURE 3. A, Immunoglobulin G and (Fig 3 continued on next page.) Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
Computed tomographic (CT) scan of the patient’s neck, chest, abdomen, and pelvis showed no masses or lymphadenopathy. The patient was diagnosed with IgG4-RD involving both lacrimal glands, both parotid glands, and the minor salivary glands of the hard palate. The patient declined corticosteroid treatment for IgG4-RD and remained clinically stable at 15 months after first presentation. The hard palate lesion partially resolved spontaneously.
Discussion To the authors’ knowledge, this is the first published case of IgG4-RD involving the hard palate. The case fulfills the consensus-based histopathologic diagnostic criteria for salivary gland IgG4-RD (Table 1) and the comprehensive diagnostic criteria for ‘‘definite’’ IgG4RD (Table 2).5,6 Classic sites of IgG4-RD involvement are the pancreas, hepatobiliary tract, major salivary glands, lymph nodes, orbit, and lung.1 IgG4-RD of the perioral region is not uncommon, but is almost in-
variably localized to the major salivary glands. Mickulicz’s disease has recently been reclassified into the IgG4-RD spectrum and is defined as symmetric involvement of 2 pairs of submandibular, parotid, or lacrimal glands.7 Chronic sclerosing sialadenitis, also known as Kuttner tumor, is related to IgG4 in the vast majority of cases.7 IgG4-RD has been rarely described in the maxillary sinus, and although 1 case was associated with gingival erythema, the disease spared the gingival mucosa on biopsy.8 There has been 1 report of IgG4-RD of the tongue and a few reports of IgG4-RD of the labial mucosa,2-4 but the condition has not been reported elsewhere in the oral cavity. The pathogenesis of IgG4-RD is thought to involve an abnormal immune response to antigen, possibly an environmental allergen1; however, the rarity of the disease at sites of conjunctiva-associated lymphoid tissue seems inconsistent with this postulated mechanism. IgG4-RD of the major salivary glands is relatively common, whereas IgG4-RD of the oral mucosa
720
IMMUNOGLOBULIN G4–RELATED HARD PALATE DISEASE
FIGURE 3 (cont’d). B, immunoglobulin G4 immunohistochemical stains (brown) with hematoxylin nuclear counterstain (blue) (magnification, 200). There are 280 immunoglobulin G4–positive cells per high-power field (field area, 0.2 mm2) and the ratio of immunoglobulin G4–positive to immunoglobulin G–positive cells is 0.8. Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
appears to be rare. In the ocular adnexa, a similar dichotomous pattern is observed; IgG4-RD of the lacrimal glands is common, but IgG4-RD of the ocular conjunctiva has never been reported.1 Consensus-based histopathologic guidelines for the diagnosis of IgG4-RD were issued by Desphande et al5 after a 2011 international symposium on IgG4-RD. The hallmark feature of the condition is a lymphoplasmacytic infiltrate rich with IgG4-bearing plasma cells. For salivary gland lesions, more than 100 IgG4+ cells per hpf are considered indicative of the diagnosis.5 The criteria do not distinguish between major and minor salivary gland disease. The ratio of IgG4+ to IgG+ cells must be higher than 0.4 to correct for extreme tissue plasmacytosis. This ratio is considered the most reliable diagnostic marker and is more likely to be preserved after corticosteroid treatment or progressive sclerosis than the raw IgG4+ cell count.1 Lesions are thought to
undergo progressive sclerosis and, therefore, the overall appearance of lesions is dependent on the age of the lesion and the underlying microstructure of the involved tissue. Sclerosis typically assumes a whirling pattern (storiform sclerosis), but also may have a lamellar architecture (collagenous sclerosis).5 Obliterative phlebitis is purported to be a cardinal feature of IgG4-RD, but it is rarely detected in major salivary gland and lacrimal gland IgG4-RD and would not be expected in minor salivary gland biopsies.9 Obliterative phlebitis may be an organ-specific feature rather than a disease-specific feature of IgG4-RD. An eosinophilic infiltrate is common and was well shown in the present patient’s palatal and lacrimal gland biopsy specimens. Patients with IgG4-RD should have a systemic workup at diagnosis to assess the extent of disease and to screen for non-Hodgkin lymphoma (NHL). The risk of lymphoma is uncertain, but cases of NHL
721
ANDREW ET AL
Table 1. CONSENSUS-BASED HISTOLOGIC DIAGNOSTIC CRITERIA FOR SALIVARY GLAND IGG4-RD5
1
2
3
Characteristic histologic features ($1 feature required) a Dense lymphoplasmacytic infiltrate b Fibrosis, usually storiform in character c Obliterative phlebitis >100 IgG4+ cells per high-power field (3 fields with the largest number of IgG4+ plasma cells should be counted and averaged) IgG4+/IgG+ plasma cell ratio >40% Fulfillment of all 3 criteria is required for the histologic diagnosis of salivary gland IgG4-RD
Abbreviation: IgG4-RD, immunoglobulin G4–related disease. Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
arising in sites of histologically confirmed IgG4-RD have been rarely reported.1 The IgG4-RD literature is insufficient to authoritatively dictate a screening protocol, but screening tests at the authors’ center include physical examination, complete blood cell count, serum IgG4, liver function tests, and CT scan of the neck, chest, abdomen and pelvis. Radiologic
features of IgG4-RD in the head and neck include well-defined, enhancing mass lesions that are iso- to hypointense on T2-weighted MRI.10 Bony remodeling without cortical invasion and concentric enlargement of multiple cranial nerves may favor the diagnosis.11,12 Serum IgG4 concentration may have a role in prognostication because it is thought to correlate with disease volume and activity.1 However, serum IgG4 is an unreliable diagnostic marker because it is normal in up to 40% of biopsy-proved cases of IgG4-RD.1 Patients with IgG4-RD may have a mild eosinophilia, but inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) are typically normal. The natural history of IgG4-RD is varied, ranging from self-limited disease to recalcitrant inflammation requiring targeted chemotherapeutics.1 Management is tailored to the patient and usually follows a graduated approach. As shown by the present case, some lesions cause minimal morbidity and may settle after the debulking effect of biopsy. More commonly, inflammatory or mass effects necessitate treatment. Corticosteroids are considered first-line treatment for IgG4-RD and are usually associated with an excellent but unsustained response.1 Disease relapse during or shortly after prednisolone taper is common and patients may become steroid dependent.13 Targeted therapy with rituximab may be strikingly effective, even in
FIGURE 4. Hematoxylin and eosin stain of the left lacrimal gland biopsy (magnification, 40). There is a follicular lymphoplasmacytic infiltrate interspersed among bands of collagenous sclerosis (arrows). Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
722
IMMUNOGLOBULIN G4–RELATED HARD PALATE DISEASE
FIGURE 5. A, Immunoglobulin G and B, immunoglobulin G4 immunohistochemical stains (brown) with hematoxylin nuclear counterstain (blue) (magnification, 200). There are 270 immunoglobulin G4–positive cells per high-power field (field area, 0.2 mm2) and the ratio of immunoglobulin G4–positive to immunoglobulin G–positive cells is 0.79. Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
steroid-resistant cases.13 Rituximab is a monoclonal antibody against the protein CD20 and induces apoptosis in all mature B cells (normal and pathogenic); stem cells then regenerate the B-cell population. The adverse effects of rituximab include infusion reactions, reactivation of latent infections, and progressive multifocal leukeoencephalopathy.14 The duration of follow-up and the need for repeat staging are
determined by clinical suspicion and patient symptomatology because there are no consensus guidelines. In summary, the authors have described the first case of IgG4-RD involving the minor salivary glands of the hard palate. IgG4-RD should be considered in the differential diagnosis of lymphoplasmacytic lesions involving the hard palate.
ANDREW ET AL
Table 2. COMPREHENSIVE DIAGNOSTIC CRITERIA 6 FOR IGG4-RELATED DISEASE
1
2 3
Clinical examination showing characteristic diffuse/ localized swelling or masses in single or multiple organs Hematologic examination shows elevated serum IgG4 concentration ($135 mg/dL) Histopathologic examination shows a Marked lymphocyte and plasma cell infiltration and fibrosis b Infiltration of IgG4+ plasma cells: ratio of IgG4+/ IgG+ cells >40% and >10 IgG4+ plasma cells/hpf Definite, 1 + 2 + 3; probable, 1 + 3; possible, 1 + 2
Abbreviations: hpf, high-power field; IgG4, immunoglobulin G4. Andrew et al. Immunoglobulin G4–Related Hard Palate Disease. J Oral Maxillofac Surg 2014.
References 1. Andrew N, Kearney D, Selva D: IgG4-related orbital disease: A meta-analysis and review. Acta Ophthalmol, 2012 [ePub ahead of print] 2. Doe K, Hohtatsu K, Lee S, et al. Case report: Usefulness of lip biopsy for the diagnosis of IgG4-related diseases with retroperitoneal fibrosis: Report of a case. Nihon Naika Gakkai Zasshi 100: 1645, 2011 (in Japanese)
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