see also: Sjogren's Syndrome

Content compiled by Shiven Sharma (M2, Icahn Mt. Sinai SOM), Evgeniya Molotkova, and Dr. Henry Hoffman (March 9, 2025)

Study (Year)	Presentation	Recommendation re: SGUS (Salivary Gland UltraSound)	Key Takeaway(s)
Huper et al, 2024	SS patients with risk factors for lymphoma	Routine SGUS-based screening is not necessary in the absence of risk factors that may warrant additional imaging:  Risk Factors  Elevated cryoglobulins  Salivary gland masses  Persistent lymphadenopathy  Unexplained systemic B symptoms  Moderate/high systemic activity (as defined by a ESSDAI score ≥ 5)	Swedish study found no benefit from rigorous SGUS-based lymphoma screening in SS patients without the clinical symptoms listed. Suggest there is a risk that false-positive imaging may lead to additional imaging or invasive testing Cryoglobulinemia: 'persistent presences in serum of abnormal immunoglobulins (Igs) that precipitate at low temperatures and dissolve again on warming" (Desbois 2019) Systemic B symptoms: Fever (T>38ºC; 100.4ªF) / Weight loss (unexplained loss of >10% of body weight over past 5 months) / Sweats (presence of drenching night sweats) (Freedman 2025) ESSDAI score is a European (EULAR) "Sjogrens' syndrome disease activity index that was designed to measure disease activity"  (Seror 2015)
Wu et al,  2023	SS patients with risk factors for lymphoma	SGUS may be suggested for patients with known risk factors, defined as clinical and serological markers associated with an increased risk of lymphoma, including  Persistent parotid gland enlargement   Low C4 levels (hypocomplementemia) Cryoglobulinemia  Monoclonal gammopathy Lymphadenopathy   Higher disease activity	Supports targeted SGUS screening in patients with lymphoma-associated risk factors rather than general SS population
Zabotti et al, 2022	SS patients with persistent salivary swelling	SGUS-guided core needle biopsy (compared to open biopsy) is safe and accurate in diagnosing lymphoma  Ultrasound allows for direct visualization of suspicious lesions and targeting of said lesions for biopsy	Core needle biopsy obtained using SGUS guidance offers a safe and effective way to detect lymphoma in patients with SS presenting with salivary swelling
Jousse-Joulin et al, 2021	SS patients	SGUS findings may reveal risk factors for the development of lymphoma, but these findings (i.e., cystic lesions) are not pathognomonic for lymphoma  Doppler assessment of gland vascularization may be useful to detect at-risk lesions	These investigators appear to support ultrasound surveillance: “Suspicion of abnormal lymph nodes can be confirmed during a long term monitoring of pSS patients especially those with high risk of lymphoma development”  SGUS grade 3 lesions (complete gland destruction) may be associated with elevated lymphoma risk, but other clinical (SG swelling, organomegaly), epidemiological, biological (cryoglobulinemia, hypocomplementemia), and histopathological factors should be considered
Theander et al, 2013	Asymptomatic SS patients	SGUS findings of hypoechoic lesions within salivary glands were associated with clinical, serologic, histologic, and cytologic markers of lymphoma risk  Follow-up monitoring of lymphoma in SS patients may benefit from a more robust image scoring system (i.e. including Doppler assessment)	“SGUS may achieve broad acceptance for use in diagnosis, classification, and monitoring of primary SS, but the method and scoring may have to be adjusted to different clinical situations and needs.” (Theander et al, 2013)

 

Background

Sjogren’s Syndrome (SS) is a disorder characterized by immune-mediated salivary and lacrimal gland destruction manifesting as dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and salivary gland abnormalities (Brito-Zerón et al., 2007). The most common salivary gland abnormalities include xerostomia as well as gland swelling with pain. Gland imaging with CT, MRI, and ultrasound may identify both normal and abnormal lymph nodes, salivary gland enlargement, and lymphoepithelial lesions. Although SS is often associated with benign manifestations, the underlying B cell lymphoproliferative process, even in its non-malignant forms, creates a pathological environment that predisposes affected individuals to the development of lymphoid malignancies, particularly mucosa-associated lymphoid tissue (MALT) lymphoma (Titsinides et al., 2017).  

Historical research has explored the relationship between autoimmune disorders and non-Hodgkin’s lymphoma (NHL). A meta-analysis by Zintzaras et al. (2005), which examined cohort studies from 1974 to 2005, identified an association between B-cell lymphoproliferation and autoimmunity. This analysis found that the risk of developing NHL was highest in primary Sjögren’s syndrome (pSS), compared to a moderate risk in systemic lupus erythematosus (SLE) and a lower risk in rheumatoid arthritis (RA). The study also described patterns of NHL presentation in these conditions, noting that pSS-associated NHL was often indolent extranodal marginal zone B-cell lymphoma, or mucosa-associated lymphoid tissue (MALT) lymphoma, whereas NHL in RA more frequently appeared as the aggressive diffuse large B-cell type. 

 

Rationale for Surveillance 

The potential elevated risk of lymphoma in SS patients has spurred recommendations regarding routine surveillance. Chiu et al identified surveillance may be targeted to individuals with risk factors such as persistent glandular swelling, cryoglobulinemia, low C4, or monoclonal gammopathy (Chiu et al., 2017). Ultrasound has been specifically advocated for this purpose due to its non-invasive nature and reliability (Wu et al., 2023; Baqir et al., 2020).  

However, more recent studies, including Hüper et al. (2024), suggest that rigorous ultrasound-based screening for lymphoma in asymptomatic SS patients does not provide a significant survival benefit. These Swedish investigators raise questions about the utility of routine screening protocols in this population. The Sjogren’s Foundation has been reporte to be actively working to develop clinical guidelines for the management and treatment of lymphoma and other blood cancers in patients with SS. This is a clinically relevant topic that is continuing to gain attention (Vivino et al, 2016). 

Through this protocol we discuss the considerations for lymphoma screening in SS patients and highlights the various recommendations available in contemporary literature. 

 

Ultrasound Findings 

Ultrasound (US) is widely recognized for its utility to non-invasively assess glandular structures in patients with SS. Typical benign findings characteristic of SS include glandular heterogeneity with hypoechoic areas. Sequential ultrasound examinations can provide valuable insight into lesion progression, offering an alternative to invasive procedures by monitoring lesions that may not progress to warrant biopsy.  

US findings that have been reported to be suggestive of lymphoma include: 

• Hypoechoic or Anechoic Masses
  • Well-defined nodules or masses that differ in echogenicity from the surrounding tissue (Yachoui et al., 2017).  
• Heterogeneous Glandular Structure
  • Increased echogenicity and abnormal patterns, such as hypoechoic areas, septations, or irregular glandular architecture, may reflect benign lymphocytic infiltration or early malignant changes. Doppler findings, including increased vascularity or irregular blood flow patterns, may help differentiate malignant changes from benign lesions (Baqir et al., 2020). 
• Abnormal Vascularity
  • Doppler US may show increased blood flow or irregular vascular patterns in suspicious areas. Such an irregular pattern may include chaotic or disorganized vascular structures, in contrast to a regular pattern shown as well-defined, organized vascular flow typical of benign conditions (Zamora et al., 2016). 
• Mucosa Associated Lymphoid Tissue (MALT) Lymphoma-Specific US Patterns
  • In salivary gland MALT lymphoma, SGUS typically shows a shift from a diffuse pattern with multiple hypoechoic areas (as seen in benign conditions) to a more focal lesion that appears hypoechoic, has an oval shape, exhibits well-defined margins, and contains internal hyperechoic septa. This distinct pattern may help differentiate MALT lymphoma from other benign lymphoproliferative changes in SS (Vissink et al., 2024). 
• Shear Wave Elastography 
  • Through evaluation of the parotid glands comparing normals and 8 patients with non-Hodgkin's lymphoma (NHL) Bădărînză et al identified shear wave elastography findings of  higher stiffness of the NHL lesions leading to their conclusion that shear wave elastography 'can be used for early diagnosis, biopsy guidance, and, possible, for treatment monitoring" (Bădărînză 2020)

Gland enlargement has been reported as an important clinical finding that has lacked precise definition due to a lack of standardized measurement protocols (Hoffman et al., 2024). Gland enlargement in patients with Sjogren’s Syndrome may warrant investigation to determine its etiology. However, this finding must be interpreted in context, as benign conditions such as the common diabetic sialosis account for up to 25% of cases of glandular hypertrophy. In such cases, imaging modalities such as computed tomography (CT) may provide precise volumentric data. Less accurate but more readily accessible is the estimation of gland size provided by ultrasound analysis (Hoffman et al., 2024a).

 

Screening Suggestions

To Establish the Diagnosis of SS 

• As defined by the 2016 ACR/EULAR classification criteria, including ocular or oral dryness, serological markers (anti-SSA/Ro, anti-SSB/La), or biopsy-confirmed lymphocytic infiltration of the salivary glands (Wu et al., 2023 and Chiu et al. 2017).  
• Use of imaging techniques, such as parotid sialography, may enhance diagnostic accuracy and reduce the need for biopsies. Wang et al. (2024) demonstrated that parotid sialography has an 82.6% sensitivity and 71.5% specificity in diagnosing SS, supporting its use as a non-invasive diagnostic adjunct that still may warrant minor salivary gland biopsy.  
  • Wang et al proposed a staging model categorizing SS into early, active, and quiescent phases based on imaging and serological markers, which may help refine surveillance strategies (Wang et al., 2024).  
  • Nguyen et al performed a cluster analysis of 534 French patients with Sjogrens disease to identify three subgroups- with distinct disease evolution and prognosis - with one goal being to identify those with higher risk of lymphoma. Higher risk of lymphoma the BALS (B-cell active disases and low symptom burden) and HSA (high systemic disease activity) subgroups; with lower risk of lymphoma in the LSAHS subgroup (Nguyen 2024)
    • LSAHS subgroup (lower risk of lymphoma): Low Systemic Disease Activity with High Symptom Burden (common symptoms listed: pain, fatique, dryness, anxiety, and depression)  

Risk Factors for Lymphoma in Patients with Sjögren’s: Patients with any of the following are at increased risk: 

• Low C4 levels or cryoglobulinemia (Chiu et al., 2017); 
• Monoclonal gammopathy (Wu et al., 2023); and  
• Positive anti-SSA/Ro antibodies (Yachoui et al., 2017).  

Lip biopsy, showing lymphocytic infiltration of the minor salivary glands, can offer deeper insights into lymphoma risk: 

• High-Risk Findings: Biopsies demonstrating intense lymphoid infiltration, particularly germinal center formation, are more likely associated with malignant transformation than those without, specifically a 16-fold higher risk (Nocturne et al., 2021). These findings on lip biopsy may prompt more frequent or intensive screening (Jordan et al., 1995) 
• Lower-Risk Findings: Cases with mild, non-germinal center infiltration may correlate with a reduced lymphoma risk, potentially directing less frequent monitoring (Morel et al. 1993)

 

Surveillance

Baseline Assessment: 

• Initial Ultrasound: Ultrasound of the parotid, submandibular, and sublingual glands at diagnosis (Salivary Ultrasound)   
  • Parameters such as gland size, echogenicity, and vascularity should be documented (Wu et al., 2023).  
  • The evolving process of elastography may add quality to the evaluation. Elastography is a technique that involves measuring the stiffness of tissue, providing additional insights into glandular abnormalities. It provides diagnostic data that may aid in differentiating between benign and malignant lesions. (Klintworth et al., 2012) see also: Shear Wave Elastography - Quantitative Salivary Gland Ultrasonography
    • Typically, cancerous tissues tend to be stiffer (higher shear wave velocity) than normal or inflamed tissues (Jering et al., 2021). 

Follow-up Schedule: 

• Surveillance strategies may focus on two key approaches: patient-initiated self-monitoring and physician-assisted clinical surveillance.  
  • Patient-directed monitoring: 
    • Choi and colleagues found that bulky parotid gland tumors typically had poor prognosis at the time of diagnosis (presence of metastatic disease and high tumor grade). They argued for a patient-directed parotid gland self-evaluation protocol that would increase early detection and referral to treatment (Choi et al, 2021). 
  • Physician-assisted clinical surveillance: 
    • This may involve clinical palpation that could lead to imaging, preferably US with potential fine-needle aspiration (FNA) or core needle biopsy if indicated (Grist, 1990; Eom et al., 2015).   

 

Management of Suspicious Findings

Findings suggestive of lymphoma, such as nodular masses or abnormal vascularity, may lead to referral for further diagnostic tests, including fine needle aspiration (FNA), core needle biopsy (CNB), or additional imaging (e.g., MRI or PET-CT) sometimes progressing to open biopsy (Baqir et al., 2020; Zamora et al., 2016). 

Tissue Biopsy: Fine-needle aspiration (FNA) or core biopsy is commonly used to confirm a diagnosis of lymphoma, particularly in patients with significant ultrasound abnormalities. FNA and core biopsy are reported to be effective with ongoing debate about their relative merits. FNA is less invasive and offers rapid results, but core biopsy provides more tissue, potentially yielding more detailed information about the lymphoma subtype and its microenvironment, which can be useful for treatment planning (Wu et al., 2023). Both approaches have their advantages and limitations, and the choice between them often depends on the clinical scenario and available resources. Zabotti et al. (2022) demonstrated that ultrasound-guided CNB of the parotid gland is not only useful for lymphoma assessment but may also aid in the diagnosis of primary Sjögren’s syndrome (pSS). In their study, CNB provided adequate samples in 96.5% of cases, allowing for the evaluation of key histopathological markers such as focus score, lymphoepithelial lesions (LELs), and germinal centers (GCs). These findings suggest that CNB could play a broader role in pSS diagnosis and management, beyond its traditional use in lymphoma detection. The choice between FNA and CNB often depends on clinical suspicion, lesion characteristics, and available resources (Zabotti et al., 2022). 

PET-CT scans are useful for detecting metabolically active regions suggestive of malignancy. These scans may be beneficial when ultrasound shows suspicious findings that require further investigation (Baqir et al., 2020). 

Routine serological tests have been supported for use to monitor for elevated serum immunoglobulins, cryoglobulinemia, or persistent low C4 levels, which are associated with an increased risk of lymphoma in Sjögren’s Syndrome (Brito-Zerón et al., 2007). The decision to monitor and manage these factors may be deferred to rheumatology and/or medical oncology specialists, particularly for patients with additional complexities or elevated risk profiles. 

 

Conclusion

SGUS is advocated by some for the routine surveillance of patients with SS who are at risk for lymphoma. There is ongoing debate regarding the effectiveness of regular clinician-performed monitoring versus patient-conducted surveillance, especially among high-risk individuals. Proponents of clinician monitoring suggest that it may facilitate early detection to potentially lead to improved outcomes through heightened awareness. When US is used for surveillance, it typically serves as an initial evaluation, which can be followed by a sequence of repeated exams if stable, or may lead to additional diagnostic tests—such as biopsy, serological evaluation (including markers like beta-2 microglobulin and lactate dehydrogenase), and other imaging modalities—if abnormalities are detected. These follow-up assessments may be needed for confirming the presence of lymphoma and determining the extent of disease. (Yachoui et al., 2017). 

 

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