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Lip Biopsy for IgG4 related disease - minor salivary gland biopsy for IgG4RD

Submitted by ebelding on Fri, 01/05/2024 - 09:47
minor salivary gland biopsy of lip using chalazion clamp
From "Application of Lip Biopsy for the Histological Diagnosis of Immunoglobulinavailable under the Creative Commons CC-BY-NC license and permits non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited

See Also Lip Biopsy for Sjogren's Syndrome (Minor Salivary Gland Biopsy) Using Chalazion Clamp

IgG4 Salivary Disease; Lip Biopsy of Minor Salivary Gland Histopathology for Sjogren's Syndrome (sjogren / sjogrens)

Created March 2024 by Emily Belding BA, MS (Univ of Iowa School of Medicine)

Definitions

IgG4-related disease (IgG4RD): An immune-mediated, fibroinflammatory systemic disease manifesting as tumefactive enlargement of organs with specific histopathologic features. (Nambiar, 2024). Signs and symptoms depend on the organ system involved. Common co-morbities include asthma, allergies and sinusitis. 

Background

IgG4-related disease is a multi-organ, inflammatory disorder characterized by lymphoplasmactyic infiltrates and fibrosis. IgG4-related disease can effect any organ. 

Wallace et al (Wallace, 2019) described four phenotypes:

  • Pancreato-hepato-biliary,
  • Retroperitoenal fibrosis and or/aortitis,
  • Head and Neck-limited disease and
  • Classic Milkulicz syndrome with systemic involvement. 

The diagnosis of IgG4RD requires correlation of clinical, radiologic and pathologic features.

Diagnosis is enhanced with analysis of affected tissue with biopsies often requiring either an open approach or core needle biopsy to obtain adequate tissue for analysis (Khosroshahi 2015).

Performing biopsies of sites such as kidney or pancreas can be technically difficult. Core biopsy of the submandibular gland has lesser morbidity, but may suffer from incomplete sampling. Lip biopsy (minor salivary gland sampling) has been proposed as a replacement for internal organ or major salivary gland biopsy. However, reports of the utility of lip biopsy for diagnosis of IgG4-related disease have been mixed (Pereira, 2022).

Both Tachibana et al (Tachibana, 2020) and Akiyama et al (Akiyama, 2016) found that lip-biopsy (minor salivary gland sampling) may be an option for the histopathological diagnosis of IgG4-related disease. Moriyama et al (Moriyama, 2016) identified that lip biopsy alone is not likely sufficient to establish the diagnosis of IgG4RD - but that it may be helpful when combined with clinical findings. These investigators reported low sensitivity (55.6%) and high specificity (100%) with overall accuracy reported at 70.0% of lip biopsy in evaluating for IgG4-related disease. Zhang et al (Zhang, 2020) reported a similar sensitivity (55.3%), specificty (100%) and accuracy (75.7%) in a comparison to submandibular gland core biopsy. Thus, they concluded that lip biopsy cannot replace submandibular gland biopsy in diagnosis of IgG4-related disease. 

Procedure (Minor Salivary Gland Biopsy): 

Multiple approaches have been reported - our approach focuses on use of a chalazion clamp assisted by use of viewing with loupe magnification -

minor salivary gland biopsy of lip using chalazion clamp

see: Lip Biopsy for Sjogren's Syndrome (Minor Salivary Gland Biopsy) Using Chalazion Clamp; Mental nerve and efforts to avoid numb lip from biopsy of minor salivary glands for Sjogrens

Consent: Lip biopsy under local anesthesia

  • Complications: mucocele, infection, bleeding and/or hematoma, scarring, transient or permenant numbness, and non-diagnostic biopsy. 

Room and Positioning: 

  • Minor procedure room
  • Semi-recumbent

Procedure: 

  • Brief time-out to identify patient and verify procedure. 
  • Anesthesia: apply 2% viscous lidocaine to gingivo-labial sulcus overlying the mental nerve. Inject 1-2cc of 2% lidocaine 1:100,000 epinephrine to the sulcus to block the mental nerve. Wait approximately 5 minutes (in our practice we wait longer in that a diagnostic ultrasound of the salivary glands is usually done in the interval).
  • Use a betadine swab to steralize the field. 
  • While an assistant inverts and places the lower lip under tension with the chalazion clamp in place (see protocol) , make a superficial incision along the direction of the mental nerve approximately 1-1.5 inches lateral to midline of the lip. 
    • Medial to lateral: halfway between the midline of the lip and angle of the mouth. 
    • Anterior to posterior: halfway between the vermillion border and the gums. 
  • Upon incision, several minor salivary glands may be visualized. 5-7 salivary glands should be excised. Use small foreceps to pick up the base of the gland and use gental upward traction to seperate from the underlying tissue with a scraping rather than cutting action of the scalpel or scissors to decrease risk of transgression of branch of mental nerve. 
    • After removal of the first minor salivary gland, the excisional window may be moved to visualized more glands.
  • Send glands to pathology on formalin and specify on container label that evaluation is to include assessment for IgG4-related disease. 
  • Achieve hemostasis with pressure, electrocautery or silver nitrate. 
  • Close incision with interrupted sutures with attention to avoid injury to mental nerve branches during closure. 

Post-operative Cares: 

  • Ice pack prn
  • Oral peroxide rinses prn

Histopathology:

Histopathological Features:

There are three major histopathologic features of IgG4-related disease (Nambiar, 2023):

  • Lymphoplasmacytic inflammation: The lesion is comprised of a majority lymphocytes. However, plasma cells or even eosinophils may be the predominant inflammatory cell typem (figure 1b). Germinal centers may or may not be present, (Deshpande, 2012)
  • Fibrosis with storiform pattern: The fibrosis is "irregularly whorled" and resembles the spokes of a wheel with spindle cells (fibroblasts or myofibroblasts) radiating from the center of the fibrosis. This pattern of fibrosis can be difficult to assess in limited samples, (Deshpande, 2012). 
  • Obliterative phlebitis: Inflammatory cells (lymphocytes and plasma cells) are found within the lumen and wall of the vessel causing obliteration of the lumen. Completely obliterated vessels can be challenging to detect on hematoxilin and eosin stains and may require an elastic stain (Van Gieson stain).    

A pathologic diagnosis of IgG4 disease has been reported to need two of the three major hisopathologic features. However, in minor salivary glands, only one feature may be sufficient for diagnosis as storiform fibrosis and obliterative phlebitis can be difficult to identify (Deshpande, 2012). Tanako et al (Tanako, 2016) found that storiform fibrosis was not present in any lip biopsy specimens in IgG4-RD patients.. Moriyama et al (2016) reported that none of the lip biopsies in patients identified with the diagnosis of IgG4-RD (identified by other criteria)  demonstrated obliterative phlebitis.

In the absence of identified obliterative phlebitis, findings supportive of IgG4RD (as per Deshpande, 2012) include:

  • Phlebitis without obliteration of the lumen
  • Increased eosinophilic infiltrate

In the 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria provided pathologic exclusion criteria for the diagnosis of IgG4-related disease (Wallace, 2019): 

  • Cellular features suspicious for malignancy
  • Markers consistent with inflammatory myofibroblastic tumor 
  • Dominant neutrophilic inflammation
  • Necrotizing vasculitis 
  • Prominent necrosis
  • Primary granulomatous inflammation
  • Pathologic features/markers of a histiocytic disorder

Quantitative assessment with IgG4 Immunostaining: 

A consensus statement addressing the pathology of IgG4-related disease reported that IgG4 immunostaining is critical for making the diagnosis of IgG4-RD (Deshpande, 2012). The diagnostic criteria to help establish IgG4RD includes the absolute number of IgG4+ plasma cells and the ratio of IgG4+ to total IgG but varies according to the organ evaluated and the type of specimen (biopsy vs excision). Currently, there is no established consensus regarding these number and ratio's in the evaluation of minor salivary gland biopsies.

 A report specific to IgG4RD in Japan identified that a IgG4+/IgG+ ratio of >40% found in any specimen is diagnositc for IgG4-RD (Deshpande, 2012). However, Deshpande ( 2012) reported that a IgG4+ / total IgG plasma cell ratio of  >40% in isolation was not sufficient to establish the diagnosis of IgG4RD in the absence of additional clinical, radiologic or histopathologic features. Zhang et al (2020) reported in their series of patients with established diagnosis of IgG4RD that the ratio of IgG4+/IgG+ plasma cells ranged from 56-93%. 

Figure 1: Lip biopsy in a 51 year-old female diagnosed with IgG4-related disease.

available under the Creative Commons CC-BY-NC license and permits non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited

Note: The lip biopsy specimen shows abundant lymphoplasmacytic infiltration with mild fibrosis (A and B). The plasma cells predominantly express immunoglobulin G4 (IgG4; >100/high-power field), and the IgG4/IgG ratio is > 40% (C and D). From "Application of Lip Biopsy for the Histological Diagnosis of Immunoglobulin G4-Related Disease." Tachibana T, et al. Ear Nose Throat J. 2022 Sep;101(8):547-551​ "This article is available under the Creative Commons CC-BY-NC license and permits non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.” 

References

Moriyama M, Ohta M, Furukawa S, Mikami Y, Tanaka A, Maehara T, Yamauchi M, Ishiguro N, Hayashida JN, Kawano S, Ohyama Y, Kiyoshima T, Nakamura S. The diagnostic utility of labial salivary gland biopsy in IgG4-related disease. Mod Rheumatol. 2016 Sep;26(5):725-9. doi: 10.3109/14397595.2016.1148225. Epub 2016 Mar 3. PMID: 26873153.

Zhang YY, Hong X, Wang Z, Li W, Su JZ, Chen Y, Gao Y, Yu GY. Diagnostic utility of submandibular and labial salivary gland biopsy in IgG4-related sialadenitis. Clin Rheumatol. 2020 Dec;39(12):3715-3721. doi: 10.1007/s10067-020-05097-1. Epub 2020 May 26. PMID: 32458243.

Tachibana T, Orita Y, Wani Y, Komatsubara Y, Kuroda K, Naoi Y, Gion Y, Makino T, Nishizaki K, Sato Y. Application of Lip Biopsy for the Histological Diagnosis of Immunoglobulin G4-Related Disease. Ear Nose Throat J. 2022 Sep;101(8):547-551. doi: 10.1177/0145561320971932. Epub 2020 Nov 4. PMID: 33147065.

Pereira GG, Pontes FSC, Soares CD, de Carvalho MGF, da Silva TA, Calderaro DC, Ferreira GA, Tanure LA, de Souza LL, Rodrigues-Fernandes CI, de Almeida OP, Fonseca FP, Pontes HAR. Oral and maxillofacial manifestations of IgG4-related disease: A clinicopathological study. J Oral Pathol Med. 2022 May;51(5):493-500. doi: 10.1111/jop.13296. Epub 2022 Apr 11. PMID: 35347770.

Deshpande, V., Zen, Y., Chan, J. et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 25, 1181–1192 (2012). https://doi.org/10.1038/modpathol.2012.72

Nambiar S, Oliver TI. IgG4-Related Disease. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499825/

Akiyama, M., Kaneko, Y., Hayashi, Y., & Takeuchi, T. (2016). IgG4-related disease involving vital organs diagnosed with lip biopsy: A case report and literature review. Medicine, 95(24), e3970. https://doi.org/10.1097/MD.0000000000003970

Varoni, E. M., Villani, G., Lombardi, N., Pispero, A., Lodi, G., Sardella, A., & Uglietti, D. (2020). Local complications associated with labial salivary gland biopsy for diagnosis of Sjögren's Syndrome: A retrospective cohort study. Journal of clinical and experimental dentistry, 12(8), e713–e718. https://doi.org/10.4317/jced.56562

Olsson, P., Ekblad F., Hassler, A., Bengtsson, M., Warfvinge, G., Mandl T., & Kvarnström, M.(2023) Complications after minor salivary gland biopsy: a retrospective study of 630 patients from two Swedish centres, Scandinavian Journal of Rheumatology, 52:2, 208-216, DOI: 10.1080/03009742.2021.1999671

Gerlag, D. M., & Tak, P. P. (2015). 32—Minimally invasive procedures. In M. C. Hochberg, A. J. Silman, J. S. Smolen, M. E. Weinblatt, & M. H. Weisman (Eds.), Rheumatology (Sixth Edition) (Sixth Edition, pp. 242–249). Mosby. https://doi.org/10.1016/B978-0-323-09138-1.00032-2

McCoy, S., Ike, R., "Labial Salivary Gland Biopsy." YouTube, uploaded by Robert Ike, 20 August 2018, https://www.youtube.com/watch?v=jIFkBjKSxas. 

Takano, K.,, Nomura, k., Abe, A., Kamekura, R., Yamamoto, M., Ichimiya, S., Takahashi, H., & Himi, T.(2016) Clinicopathological analysis of salivary gland tissue from patients with IgG4-related disease, Acta Oto-Laryngologica, 136:7, 717-721, DOI: 10.3109/00016489.2016.1154605

Khosroshahi A, Wallace ZS, Crowe JL et al (2015) International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol 67:1688–1699

Wallace, Z. S., Zhang, Y., Perugino, C. A., Naden, R., Choi, H. K., Stone, J. H., & ACR/EULAR IgG4-RD Classification Criteria Committee (2019). Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Annals of the rheumatic diseases, 78(3), 406–412. https://doi.org/10.1136/annrheumdis-2018-214603

Wallace, Z. S., Naden, R. P., Chari, S., Choi, H., Della-Torre, E., Dicaire, J. F., Hart, P. A., Inoue, D., Kawano, M., Khosroshahi, A., Kubota, K., Lanzillotta, M., Okazaki, K., Perugino, C. A., Sharma, A., Saeki, T., Sekiguchi, H., Schleinitz, N., Stone, J. R., Takahashi, N., … American College of Rheumatology/European League Against Rheumatism IgG4-Related Disease Classification Criteria Working Group (2020). The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis & rheumatology (Hoboken, N.J.), 72(1), 7–19. https://doi.org/10.1002/art.41120