None, D. P. D. J. & None, D. C. T. R. (2025). Clinicopathological Study Of Head And Neck Lesions With Respect To Fnac, Histopathology And Haematogical Profile. Journal of Contemporary Clinical Practice, 11(12), 1049-1059.
MLA
None, Dr Poonam Dasharath Jadhav and Dr. Chetan Tukaram Rathod . "Clinicopathological Study Of Head And Neck Lesions With Respect To Fnac, Histopathology And Haematogical Profile." Journal of Contemporary Clinical Practice 11.12 (2025): 1049-1059.
Chicago
None, Dr Poonam Dasharath Jadhav and Dr. Chetan Tukaram Rathod . "Clinicopathological Study Of Head And Neck Lesions With Respect To Fnac, Histopathology And Haematogical Profile." Journal of Contemporary Clinical Practice 11, no. 12 (2025): 1049-1059.
Harvard
None, D. P. D. J. and None, D. C. T. R. (2025) 'Clinicopathological Study Of Head And Neck Lesions With Respect To Fnac, Histopathology And Haematogical Profile' Journal of Contemporary Clinical Practice 11(12), pp. 1049-1059.
Vancouver
Dr Poonam Dasharath Jadhav DPDJ, Dr. Chetan Tukaram Rathod DCTR. Clinicopathological Study Of Head And Neck Lesions With Respect To Fnac, Histopathology And Haematogical Profile. Journal of Contemporary Clinical Practice. 2025 Dec;11(12):1049-1059.
Background: Head and neck lesions encompass a wide spectrum of inflammatory, infectious, benign, and malignant conditions that require accurate diagnosis for appropriate clinical management. Fine needle aspiration cytology (FNAC) is a minimally invasive, cost-effective, and rapid diagnostic technique widely employed for the initial evaluation of head and neck swellings. Correlation with histopathological findings and haematological parameters may further enhance diagnostic assessment and facilitate differentiation between various pathological conditions.Aim and Objectives: To evaluate the clinicopathological spectrum of head and neck lesions and assess the diagnostic utility of FNAC by determining its sensitivity, specificity, and diagnostic accuracy in correlation with histopathological findings, along with evaluating haematological variations in patients with lymphadenopathy.Results: A total of 320 patients with head and neck lesions were evaluated, comprising 129 males (40.31%) and 191 females (59.69%), with the highest proportion belonging to the 21–30-year age group (26.25%). Lymph node lesions were the most common (50.94%), followed by thyroid (32.50%) and salivary gland lesions (5.63%). Adequate FNAC samples were obtained in 295 cases (92.19%). Among lymph node lesions, tuberculous lymphadenitis (45.03%) predominated, followed by reactive lymphadenitis (32.45%). Colloid goitre (67.35%) was the most common thyroid lesion, while pleomorphic adenoma (35.29%) predominated among salivary gland lesions. Haematological evaluation revealed lymphocytosis with normal total leucocyte count in 30.88% of patients with tuberculous lymphadenitis, while increased leucocyte counts were observed in eight patients with suppurative lymphadenitis. Histopathological correlation was available in 42 cases, demonstrating 88.10% diagnostic concordance. FNAC exhibited a sensitivity of 88.89%, specificity of 96.97%, positive predictive value of 88.89%, negative predictive value of 96.97%, and overall diagnostic accuracy of 95.24% for malignancy detection among histopathologically verified cases.Conclusion: FNAC is a reliable, minimally invasive, and effective initial diagnostic modality for evaluating head and neck lesions, demonstrating high diagnostic accuracy for malignancy detection in histopathologically verified cases. Histopathological correlation remains essential for definitive diagnosis in selected cases, while haematological investigations provide complementary information in patients with lymphadenopathy. The limited number of histopathologically verified cases warrants cautious interpretation of diagnostic performance estimates
Keywords
Fine Needle Aspiration Cytology
Head and Neck Lesions
Histopathology
Clinicopathological Correlation
Haematological Profile
Lymphadenopathy
Tuberculous Lymphadenitis
Thyroid Lesions
Diagnostic Accuracy
Sensitivity and Specificity
INTRODUCTION
Head and neck lesions constitute a diverse group of pathological conditions frequently encountered in clinical practice. These lesions may arise from lymph nodes, thyroid gland, salivary glands, skin, subcutaneous tissue, and other soft tissue structures. They encompass a wide spectrum of inflammatory, infectious, reactive, benign neoplastic, and malignant disorders (1). The clinical presentation varies considerably depending on the anatomical location, underlying pathology, and duration of the disease. Although many head and neck swellings are benign, some may represent primary malignancies or metastatic deposits. Therefore, early identification and accurate diagnosis are essential for appropriate patient management, treatment planning, and prognosis (2,3).
The evaluation of head and neck lesions involves a comprehensive clinical examination supported by cytological, histopathological, and laboratory investigations. Clinical assessment provides important information regarding the location, size, consistency, mobility, tenderness, and progression of the swelling (4). However, clinical findings alone may not reliably differentiate between inflammatory, benign, and malignant conditions. Consequently, additional diagnostic investigations are necessary to establish the nature of the lesion and guide further management (5).
Fine needle aspiration cytology (FNAC) is a simple, minimally invasive, rapid, and cost-effective diagnostic technique widely employed in the initial evaluation of head and neck swellings. It can be performed as an outpatient procedure with minimal discomfort and a low risk of complications (6). FNAC enables cytomorphological assessment of lesions involving lymph nodes, thyroid, salivary glands, and superficial soft tissues. It is particularly useful in distinguishing non-neoplastic lesions from neoplastic conditions and identifying lesions requiring further investigation or surgical intervention. Nevertheless, diagnostic limitations may arise because of inadequate sampling, overlapping cytological features, and the inability to assess tissue architecture (7,8).
Histopathological examination plays a crucial role in establishing a definitive tissue diagnosis and confirming cytological findings. It provides detailed information regarding cellular morphology, tissue architecture, invasion, and pathological characteristics of the lesion (9). Comparative evaluation of FNAC findings with histopathological diagnoses helps determine the diagnostic accuracy, sensitivity, and specificity of cytology. Such correlation is essential for identifying false-positive and false-negative results and understanding the diagnostic limitations of FNAC in different categories of head and neck lesions (10,11).
Haematological investigations provide additional information regarding the systemic manifestations of various pathological conditions, particularly lymphadenopathy. Parameters such as haemoglobin concentration, total leucocyte count, differential leucocyte count, and peripheral blood smear findings may demonstrate alterations associated with infectious, inflammatory, and malignant disorders. These investigations complement clinical and cytopathological findings and may contribute to a better understanding of the underlying disease process (12,13).
An integrated clinicopathological approach combining clinical examination, FNAC, histopathological evaluation, and haematological investigations may improve the overall diagnostic assessment of head and neck lesions (14). The present study was undertaken to evaluate the spectrum of head and neck lesions diagnosed by FNAC, correlate cytological findings with histopathological diagnoses, and assess variations in haematological parameters among patients presenting with lymphadenopathy. Additionally, the study aimed to determine the diagnostic accuracy, sensitivity, and specificity of FNAC and evaluate its utility as an outpatient diagnostic procedure in the assessment of head and neck lesions.
AIMS AND OBJECTIVES
Aim: To evaluate the clinicopathological spectrum of head and neck lesions and assess the diagnostic utility of fine needle aspiration cytology (FNAC) in correlation with histopathological findings and haematological profiles.
Objective: To determine the diagnostic accuracy, sensitivity, and specificity of FNAC in head and neck lesions by comparing cytological findings with histopathological diagnoses and evaluating haematological variations in patients with lymphadenopathy.
MATERIALS AND METHODS
The present prospective cytological study was conducted in the Department of Pathology from July 2009 to September 2011, comprising 320 patients presenting with head and neck lesions. Patients referred to the cytology section from outpatient departments and inpatient wards with a clinical diagnosis of head and neck lesions were included in the study. A detailed clinical history was obtained, followed by general, systemic, and local examinations. The location, size, shape, consistency, borders, mobility, and other relevant characteristics of the lesions were recorded. Written informed consent was obtained before performing fine needle aspiration cytology (FNAC).
FNAC was performed using a sterile 23-gauge needle and a 5 mL disposable syringe following standard aspiration techniques. The non-aspiration technique was employed wherever appropriate, particularly for superficial lesions. Aspirated material was spread onto clean glass slides, and smears were prepared using standard procedures. Wet-fixed smears were fixed in 90% ethanol and stained with haematoxylin and eosin (H&E). Ziehl–Neelsen staining was performed in suspected cases of tuberculosis. Cytological smears were examined microscopically and classified according to their morphological characteristics. Histopathological examination was performed on available tissue specimens using routine paraffin embedding, sectioning, and H&E staining. Cytological findings were subsequently correlated with histopathological diagnoses.
For haematological evaluation, peripheral venous blood samples were collected in EDTA tubes. Haemoglobin concentration, total leucocyte count, differential leucocyte count, and peripheral blood smear examination were performed using standard laboratory procedures. Haematological findings were evaluated particularly in patients presenting with lymphadenopathy. The cytological spectrum of head and neck lesions was assessed, and FNAC findings were compared with corresponding histopathological diagnoses to evaluate diagnostic accuracy, sensitivity, and specificity. The overall utility of FNAC as an outpatient diagnostic procedure for head and neck lesions was also assessed.
RESULTS
Table 1. Age and Sex Distribution of Patients with Head and Neck Lesions (N = 320)
Age group (years) Male (n) Female (n) Total (n) Percentage (%)
0–10 24 10 34 10.63
11–20 25 32 57 17.81
21–30 21 63 84 26.25
31–40 21 34 55 17.19
41–50 14 27 41 12.81
51–60 7 13 20 6.25
61–70 15 11 26 8.13
>70 2 1 3 0.94
Total 129 191 320 100.00
In the present study, among 320 patients, 129 (40.31%) were males and 191 (59.69%) were females. The highest number of patients belonged to the 21–30-year age group (84; 26.25%), followed by 11–20 years (57; 17.81%), 31–40 years (55; 17.19%), 41–50 years (41; 12.81%), 0–10 years (34; 10.63%), 61–70 years (26; 8.13%), 51–60 years (20; 6.25%) and >70 years (3; 0.94%). The male-to-female ratio was approximately 1:1.48.
Table 2. Anatomical Distribution of Head and Neck Lesions and Adequacy of FNAC Samples (N = 320)
Anatomical site Total cases (n) Distribution (%) Adequate FNAC (n) Inadequate FNAC (n) Adequacy rate (%)
Lymph node 163 50.94 151 12 92.64
Thyroid gland 104 32.50 98 6 94.23
Salivary gland 18 5.63 17 1 94.44
Skin and subcutaneous tissue 13 4.06 13 0 100.00
Soft tissue 11 3.44 8 3 72.73
Miscellaneous 11 3.44 8 3 72.73
Total 320 100.00 295 25 92.19
In the present study, lymph node lesions were the most common (163; 50.94%), followed by thyroid (104; 32.50%), salivary gland (18; 5.63%), skin and subcutaneous tissue (13; 4.06%), soft tissue (11; 3.44%) and miscellaneous lesions (11; 3.44%). Adequate FNAC samples were obtained in 295 (92.19%) cases, while 25 (7.81%) were inadequate. Site-wise adequate and inadequate samples were 151 and 12 for lymph nodes, 98 and 6 for thyroid, 17 and 1 for salivary glands, 13 and 0 for skin and subcutaneous tissue, 8 and 3 for soft tissue, and 8 and 3 for miscellaneous lesions, respectively. The corresponding adequacy rates were 92.64%, 94.23%, 94.44%, 100%, 72.73% and 72.73%.
Table 3. Cytological Spectrum of Lymph Node Lesions on FNAC (n = 151)
Cytological diagnosis n %
Reactive lymphadenitis 49 32.45
Tuberculous lymphadenitis 68 45.03
Granulomatous lymphadenitis 2 1.32
Suppurative lymphadenitis 14 9.27
Metastatic squamous cell carcinoma 12 7.95
Metastatic adenocarcinoma 2 1.32
Metastatic ductal carcinoma 1 0.66
Metastatic papillary carcinoma 1 0.66
Metastatic malignant melanoma 1 0.66
Metastatic undifferentiated carcinoma 1 0.66
Total 151 100.00
In the present study, among 151 lymph node lesions, tuberculous lymphadenitis was the most frequent diagnosis (68; 45.03%), followed by reactive lymphadenitis (49; 32.45%), suppurative lymphadenitis (14; 9.27%) and granulomatous lymphadenitis (2; 1.32%). Metastatic squamous cell carcinoma was identified in 12 (7.95%) cases, metastatic adenocarcinoma in 2 (1.32%), and metastatic ductal carcinoma, papillary carcinoma, malignant melanoma and undifferentiated carcinoma in 1 (0.66%) case each. Metastatic malignancies collectively accounted for 18 (11.92%) cases.
Table 4. Haematological Profile in Relation to Cytological Diagnosis of Lymph Node Lesions (n = 151)
Cytological diagnosis Normal TLC and DLC Normal TLC with neutrophilia Normal TLC with lymphocytosis Increased TLC with normal DLC Increased TLC with neutrophilia Increased TLC with lymphocytosis
Reactive lymphadenitis 32 3 5 7 2 0
Tuberculous lymphadenitis 45 0 21 1 1 0
Granulomatous lymphadenitis 1 0 0 1 0 0
Suppurative lymphadenitis 4 0 2 1 6 1
Metastatic squamous cell carcinoma 12 0 0 0 0 0
Metastatic adenocarcinoma 2 0 0 0 0 0
Metastatic ductal carcinoma 1 0 0 0 0 0
Metastatic papillary carcinoma 1 0 0 0 0 0
Metastatic malignant melanoma 1 0 0 0 0 0
Metastatic undifferentiated carcinoma 1 0 0 0 0 0
Total 100 3 28 10 9 1
TLC: Total leucocyte count; DLC: Differential leucocyte count.
In the present study, normal total and differential leucocyte counts were observed in 100 patients, comprising 32 with reactive, 45 with tuberculous, 1 with granulomatous, 4 with suppurative lymphadenitis and all 18 with metastatic lesions. Normal TLC with neutrophilia occurred in 3 reactive cases, while normal TLC with lymphocytosis occurred in 28 cases (5 reactive, 21 tuberculous and 2 suppurative). Increased TLC with normal DLC was observed in 10 cases (7 reactive, 1 tuberculous, 1 granulomatous and 1 suppurative), increased TLC with neutrophilia in 9 cases (2 reactive, 1 tuberculous and 6 suppurative), and increased TLC with lymphocytosis in 1 suppurative case.
Table 5. Cytological Spectrum of Thyroid Lesions on FNAC (n = 98)
Cytological diagnosis n %
Colloid goitre 66 67.35
Colloid cyst 3 3.06
Inflammatory cyst 2 2.04
Lymphocytic thyroiditis 9 9.18
Granulomatous thyroiditis 1 1.02
Follicular neoplasm 16 16.33
Papillary carcinoma 1 1.02
Total 98 100.00
In the present study, among 98 thyroid lesions, colloid goitre was the most common cytological diagnosis (66; 67.35%), followed by follicular neoplasm (16; 16.33%) and lymphocytic thyroiditis (9; 9.18%). Colloid cyst was identified in 3 (3.06%) cases, inflammatory cyst in 2 (2.04%), while granulomatous thyroiditis and papillary carcinoma were identified in 1 (1.02%) case each.
Table 6. Cytological Spectrum of Salivary Gland Lesions on FNAC (n = 17)
Cytological diagnosis n %
Acute sialadenitis 5 29.41
Chronic sialadenitis 4 23.53
Pleomorphic adenoma 6 35.29
Oncocytoma 1 5.88
Benign salivary gland lesion 1 5.88
Total 17 100.00
In the present study, among 17 salivary gland lesions, pleomorphic adenoma was the most frequent cytological diagnosis (6; 35.29%), followed by acute sialadenitis (5; 29.41%) and chronic sialadenitis (4; 23.53%). Oncocytoma and benign salivary gland lesion were identified in 1 (5.88%) case each. No malignant salivary gland lesions were reported.
Table 7. Cytological Spectrum of Skin, Subcutaneous Tissue, Soft Tissue and Miscellaneous Head and Neck Lesions (n = 35)
Anatomical category Cytological diagnosis n %
Skin and subcutaneous tissue Epidermal cyst 6 46.15
Dermoid cyst 1 7.69
Benign adnexal tumour 1 7.69
Squamous cell carcinoma 5 38.46
Subtotal 13 100.00
Soft tissue Lipoma 6 54.55
Haemangioma 1 9.09
Rhabdomyosarcoma 1 9.09
Inadequate aspirate 3 27.27
Subtotal 11 100.00
Miscellaneous Epidermal inclusion cyst 1 9.09
Benign cystic lesion 1 9.09
Squamous cell carcinoma of tongue 3 27.27
Malignant round cell tumour 1 9.09
Spindle cell lesion 1 9.09
Poorly differentiated carcinoma 1 9.09
Inadequate aspirate 3 27.27
Subtotal 11 100.00
Total 35
In the present study, among 13 skin and subcutaneous lesions, epidermal cyst accounted for 6 (46.15%), squamous cell carcinoma for 5 (38.46%), and dermoid cyst and benign adnexal tumour for 1 (7.69%) each. Among 11 soft tissue lesions, lipoma was identified in 6 (54.55%), haemangioma and rhabdomyosarcoma in 1 (9.09%) each, and inadequate aspirates in 3 (27.27%). Among 11 miscellaneous lesions, squamous cell carcinoma of the tongue and inadequate aspirates accounted for 3 (27.27%) each, while epidermal inclusion cyst, benign cystic lesion, malignant round cell tumour, spindle cell lesion and poorly differentiated carcinoma accounted for 1 (9.09%) case each.
Table 8. Site-Wise Cytohistopathological Correlation of Head and Neck Lesions (n = 42)
Anatomical site Histopathology available (n) Concordant (n) Discordant (n) Concordance (%)
Lymph node 9 6 3 66.67
Thyroid 20 18 2 90.00
Salivary gland 4 4 0 100.00
Skin and subcutaneous tissue 4 4 0 100.00
Soft tissue 2 2 0 100.00
Miscellaneous 3 3 0 100.00
Total 42 37 5 88.10
In the present study, histopathological correlation was available for 42 of 295 adequate FNAC cases (14.24%), while 253 (85.76%) lacked histopathological correlation. Of the 42 verified cases, 37 (88.10%) showed concordance and 5 (11.90%) showed discordance. Concordant and discordant cases were 6 and 3 among 9 lymph node lesions (66.67% concordance), 18 and 2 among 20 thyroid lesions (90%), 4 and 0 among 4 salivary gland lesions (100%), 4 and 0 among 4 skin and subcutaneous lesions (100%), 2 and 0 among 2 soft tissue lesions (100%), and 3 and 0 among 3 miscellaneous lesions (100%).
Table 9. Diagnostic Accuracy, Sensitivity, Specificity and Predictive Values of FNAC in Detecting Malignancy Compared with Histopathology (n = 42)
A. Comparison of FNAC and Histopathological Diagnosis
FNAC diagnosis Histopathologically malignant (n) Histopathologically benign (n) Total (n)
Malignant 8 (TP) 1 (FP) 9
Benign 1 (FN) 32 (TN) 33
Total 9 33 42
TP: True positive; FP: False positive; FN: False negative; TN: True negative.
In the present study, among 42 histopathologically verified head and neck lesions, 9 were malignant and 33 were benign on histopathology. FNAC diagnosed 9 cases as malignant, comprising 8 true-positive and 1 false-positive cases, while 33 cases were diagnosed as benign, comprising 32 true-negative and 1 false-negative cases. Overall, FNAC correctly classified 40 of 42 cases (95.24%) according to their benign or malignant status.
B. Diagnostic Performance of FNAC
Diagnostic parameter Formula Result (%)
Sensitivity TP/(TP + FN) × 100 88.89
Specificity TN/(TN + FP) × 100 96.97
Positive predictive value TP/(TP + FP) × 100 88.89
Negative predictive value TN/(TN + FN) × 100 96.97
Diagnostic accuracy (TP + TN)/Total × 100 95.24
False-positive rate FP/(FP + TN) × 100 3.03
False-negative rate FN/(FN + TP) × 100 11.11
In the present study, FNAC demonstrated a sensitivity of 88.89% and specificity of 96.97% for detecting malignancy among 42 histopathologically verified head and neck lesions. The positive predictive value was 88.89%, while the negative predictive value was 96.97%. The overall diagnostic accuracy was 95.24%, with a false-positive rate of 3.03% and a false-negative rate of 11.11%.
DISCUSSION
The present study evaluated the clinicopathological spectrum of head and neck lesions, emphasizing the diagnostic utility of fine needle aspiration cytology (FNAC), its correlation with histopathological findings, and associated haematological variations. Among 320 patients, females predominated (59.69%), with a male-to-female ratio of 1:1.48. The highest proportion belonged to the 21–30-year age group (26.25%). Kaur et al. (2023), in their study of 242 head and neck lesions, similarly demonstrated the importance of FNAC in evaluating lesions across different age groups (4). The present findings highlight the considerable burden of head and neck swellings among young adults, particularly females.
Regarding anatomical distribution, lymph node lesions were the most frequent (50.94%), followed by thyroid lesions (32.50%), salivary gland lesions (5.63%), and skin and subcutaneous lesions (4.06%). Kaur et al. (2023) also reported lymph nodes as the predominant anatomical site, followed by thyroid lesions, supporting the present observations (4). Similarly, Nirmala et al. (2023) emphasized the usefulness of FNAC in evaluating neck swellings involving lymph nodes, thyroid glands, salivary glands, and soft tissues (6). The overall FNAC sample adequacy rate in the present study was 92.19%, demonstrating its feasibility as an initial diagnostic investigation.
Among 151 adequately diagnosed lymph node lesions, tuberculous lymphadenitis was the predominant finding (45.03%), followed by reactive lymphadenitis (32.45%) and suppurative lymphadenitis (9.27%). Metastatic malignancies accounted for 11.92%, predominantly metastatic squamous cell carcinoma. Haematological evaluation revealed normal total and differential leucocyte counts in 100 patients (66.23%). Lymphocytosis with normal total leucocyte count was observed in 30.88% of patients with tuberculous lymphadenitis, while increased leucocyte counts occurred in eight patients with suppurative lymphadenitis. Silva et al. (2025) investigated the usefulness of full blood count parameters in differentiating benign and malignant lymphadenopathy, supporting the relevance of haematological assessment as an adjunct to cytological evaluation (13).
Among 98 thyroid lesions, colloid goitre predominated (67.35%), followed by follicular neoplasm (16.33%) and lymphocytic thyroiditis (9.18%). Among 17 salivary gland lesions, pleomorphic adenoma was the most frequent diagnosis (35.29%), followed by acute sialadenitis (29.41%). Rameeza and Hemalata, in their study of 104 salivary gland lesions, demonstrated the diagnostic usefulness of FNAC in distinguishing inflammatory and neoplastic conditions (7). Kasinathan et al. (2023) also evaluated FNAC accuracy through histopathological correlation in salivary gland lesions, emphasizing the importance of tissue confirmation when required (10).
Histopathological correlation was available for 42 cases, with concordance observed in 37 (88.10%). Concordance was 90% for thyroid lesions and 66.67% for lymph node lesions. FNAC demonstrated a sensitivity of 88.89%, specificity of 96.97%, positive predictive value of 88.89%, negative predictive value of 96.97%, and diagnostic accuracy of 95.24% for malignancy detection. AlGhamdi et al. (2021) reported 90.3% sensitivity, 100% specificity, and 91.4% diagnostic accuracy in salivary gland masses, providing comparable evidence of FNAC's diagnostic performance (11).
Overall, the present study demonstrates that FNAC is a valuable initial diagnostic modality for head and neck lesions. Histopathological correlation improves diagnostic confidence, while haematological assessment provides complementary information in patients with lymphadenopathy. However, histopathological verification was available for only 42 cases, limiting the generalizability of the calculated diagnostic performance
CONCLUSION
he present study concludes that fine needle aspiration cytology (FNAC) is a valuable, minimally invasive, and reliable diagnostic modality for evaluating head and neck lesions. Among 320 patients, lymph node lesions were the most common (50.94%), followed by thyroid lesions (32.50%). Tuberculous lymphadenitis and colloid goitre were the predominant cytological diagnoses in their respective anatomical categories. FNAC demonstrated an overall sample adequacy rate of 92.19%, with 88.10% concordance between cytological and histopathological diagnoses among 42 verified cases. The sensitivity, specificity, and diagnostic accuracy for malignancy detection were 88.89%, 96.97%, and 95.24%, respectively. Haematological evaluation revealed variations in leucocyte counts and differential patterns, particularly in tuberculous and suppurative lymphadenitis. These findings highlight the complementary roles of FNAC, histopathology, and haematological investigations in diagnosis. However, the limited histopathological verification emphasizes the need for cautious interpretation and further studies involving larger, systematically verified patient populations.
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