Prevalence and Malignant Involvement of Calcified Intrathoracic Lymph Nodes in Patients Undergoing Endosonography

Prevalence of Intrathoracic Lymph Node Calcifications and Metastatic Involvement in Patients Undergoing Endosonography for Diagnosis and/or Mediastinal Staging of Intrathoracic Malignancy: a Cross-sectional Pilot Study

The presence of calcifications, which is a relatively common feature in intrathoracic lymph nodes, typically contributes to confer them a heterogeneous aspect during endosonographic B-mode examination, but their prevalence and a possible association between calcifications and metastatic involvement has never been systematically evaluated. We hypothesize that, in patients undergoing mediastinal diagnosis or staging of suspected/known lung cancer/intrathoracic malignancies, the prevalence of lymph node metastases is similar in calcified and non-calcified lymph nodes.

Study Overview

• Status: Completed
• Conditions: Lung Cancer; Tuberculosis; Lymphadenopathy; Sarcoidosis
• Intervention / Treatment: Device: Endosonography B-mode examination

Detailed Description

The presence of calcifications, which is a relatively common feature in intrathoracic lymph nodes, typically contributes to confer them a heterogeneous aspect during endosonographic B-mode examination, but a possible association between calcifications and metastatic involvement has never been systematically evaluated. The most likely reason why this possible association has been overlooked up to now is that the presence of calcifications in intrathoracic lymph nodes has long been thought to be the consequence of the prior involvement from granulomatous diseases (i.e., tuberculosis or sarcoidosis), and as such has been considered a sign of benignity. However, the presence of lymph node calcifications at ultrasound examination is a known predictor of lymph node metastasis in patients with some specific tumours, such as the papillary thyroid carcinoma or the squamous cell carcinoma of head or neck. Furthermore, recent radiological-pathological studies have shown that metastatic foci from lung cancer are observed in up to 19% calcified mediastinal lymph nodes identified at CT in surgical candidates. Finally, a recently published EBUS study has reported, for the first time, a very strong association between a very specific pattern of mediastinal lymph node calcification, known as "starry sky sign", and metastasis from pulmonary, colonic and breast adenocarcinoma. Interestingly, the starry sky sign is characterized by the presence of few to countless dot-like calcifications which are too small to be seen at CT and can be identified only during EBUS B-mode examination.

To the best of our knowledge, no studies have been carried out to assess the correlation between the presence and the ultrasound pattern of lymph node calcifications and lymph node metastasis from lung cancer or other intrathoracic malignancies.

• Study Type: Observational
• Enrollment (Actual): 362

Contacts and Locations

Study Locations

• Italy
  • Roma, Italy
    • Fondazione Policlinico Universitario A. Gemelli IRCCS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with known or suspected lung cancer or other intrathoracic malignancy with indication to endosonography for diagnosis or staging of intrathoracic lymph nodes according to currently accepted international guidelines

Description

Inclusion Criteria:

• Age >18 years at the time of the procedure
• Known or suspected lung cancer or other intrathoracic malignancy based on imaging (CT and/or PET/CT)
• Endosonography (EBUS and/or EUS) indicated for intrathoracic lymph node assessment/sampling according to national and international guidelines: 1) enlarged (> 1 cm on its short axis at CT) and/or PET positive lymph node; and/or 2) conditions at risk for occult mediastinal metastases, such as: i) central primary tumor; ii) primary tumor > 3 cm; iii) PET negative primary tumor; iv) ipsilateral hilar metastasis (cN1 status).

Exclusion Criteria:

• Inability or unwillingness to consent
• Compromised upper airway (i.e., concomitant head and neck cancer with upper airway obstruction; critical central airway obstruction from any cause)
• Contraindication for temporary interruption of the use of antiplatelet (excluded aspirin) or anticoagulant drugs
• American Society of Anesthesiologists grade 4

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Crossover
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Endosonography group; Patients with known or suspected lung cancer or intrathoracic malignancy with indication to endosonography for diagnosis or staging of intrathoracic lymph nodes according to currently accepted international guidelines	Device: Endosonography B-mode examination; Endobronchial ultrasound (EBUS) or Endoscopic with bronchoscope (EUS-B) B-mode examination and sampling, when indicated, of lymphadenopathy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
prevalence of metastatic involvement in intrathoracic lymph nodes featuring calcifications of any type	The prevalence of malignancy in patients with calcified intrathoracic lymph nodes will be calculated on a per lymph node basis and will be compared with the prevalence of malignancy observed in non-calcified lymph nodes	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The prevalence of metastatic involvement from lung cancer linked to 5 predefined patterns of lymph node calcification at B-mode ultrasound examination carried out during endosonography	These are the 5 patterns of calcification: a) single macrocalcification; b) multiple macrocalcifications; c) single microcalcification or local cluster of microcalcifications involving a limited area (< 20%) of the lymph node; d) few (< 10) scattered microcalcifications not distributed in a local cluster; e) countless, punctate (< 1 mm) non shadowing foci distributed across the whole lymph node (starry sky sign).	6 months
The interobserver agreement for the identification of 5 predefined patterns of lymph node calcification at endosonographic B-mode ultrasound examination	At the end of the study, two experienced endosonographers from different units/centers, blinded to the clinical, radiological (CT, PET) and pathological details, will be provided a video-clip of each calcified lymph node and will be asked to classify the pattern of calcification.	1 month
The prevalence of actionable mutations in the overall cohort of calcified lymph nodes identified with endosonography	This prevalence will be calculated on a per patient basis and will be compared with the prevalence of actionable mutations in a group of consecutive patients with non-calcified lymph nodes submitted to endosonography in the same study period and with the same indications and inclusion/exclusion criteria	1 month

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Investigators: Principal Investigator: Rocco Trisolini, MD, Catholic University of the Sacred Hearth

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2021
• Primary Completion (Actual): April 30, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: February 3, 2021
• First Submitted That Met QC Criteria: February 3, 2021
• First Posted (Actual): February 8, 2021

Study Record Updates

• Last Update Posted (Estimate): January 10, 2023
• Last Update Submitted That Met QC Criteria: January 9, 2023
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Lymphoproliferative Disorders; Lymphatic Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Lymphadenopathy; Sarcoidosis
• Other Study ID Numbers: 3872

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No