Discussion
PTC originates from the thyroid follicular epithelium and is the most common and well-differentiated thyroid malignancy, accounting for ~85% all thyroid cancer cases (4,13). Over the past decade, the incidence of PTC has risen markedly with advances in diagnostic techniques. PTC predominantly affects middle-aged women, and the disease typically follows an indolent course (4). The typical histopathological features include complex papillary structures and the characteristic ground-glass (‘Orphan Annie-eye’) nuclear appearance (3). FNA cytology under ultrasound guidance remains the cornerstone of preoperative diagnosis, providing high accuracy in identifying PTC (14). Immunohistochemistry serves as an adjunct in difficult cases, with PTC tumor cells frequently expressing thyroid-specific markers [such as thyroid transcription factor-1 and thyroglobulin (Tg)] and CKs (CK19, HBME-1 and galectin-3) (3,15). CLL, by contrast, is an indolent hematological malignancy that is characterized by the clonal proliferation of mature B lymphocytes, which represents the most common form of leukemia in adults (16). CLL primarily occurs in middle-aged and elderly individuals and is typically identified through peripheral blood lymphocytosis and generalized painless lymphadenopathy. Bone marrow biopsy and immunophenotyping are critical for achieving a definitive diagnosis (17,18). The typical immunophenotypic profile of CLL includes positivity for CD5, CD19 and CD23 (19,20). Overall, PTC is confined to the thyroid gland, progresses relatively slowly and carries a favorable prognosis. By contrast, CLL has a protracted clinical course, with long-term remission possible but a cure remaining elusive.
The simultaneous occurrence of PTC and CLL in the same patient is exceedingly rare, with only sporadic case reports documented in the literature (7,8). Such ‘dual primary’ malignancies have been described almost exclusively in isolated cases and small case series, with an estimated incidence of ~0.04%. In a large cohort study of 17,196 patients with PTC, only 0.04% were found to have a concomitant indolent B-cell lymphoma, underscoring its rarity (21). The coexistence of PTC and CLL may not be entirely coincidental. CLL-associated immune dysregulation provides a biologically plausible, although unproven, explanation for the development of a second primary solid tumor. CLL is accompanied by abnormalities across both humoral and cellular immune compartments, where patients with CLL have an increased risk of ‘secondary’ primary malignancies compared with the general healthy population (22). The most frequently reported secondary cancers in this context include cutaneous malignancies, other lymphoid neoplasms and various solid tumors, such as lung and bronchus cancer, colorectal cancer, kidney cancer, thyroid cancer and soft-tissue sarcoma. Notably, the relative risk of thyroid cancer among patients with CLL has been reported to be nearly 3 times greater compared with that in the general population (23). In a previous cohort study of 2,028 untreated patients with CLL, 11.2% developed a subsequent malignancy during follow-up, with the overall risk of secondary cancer being 2.2 times higher compared with that observed in the general population (24). These epidemiological observations support the concept that CLL-related immune failure may create a permissive host environment for the emergence such ‘secondary’ primary solid tumors, including PTC. Genetic predisposition may also serve a contributory role. Certain molecular alterations have been implicated in both diseases. The deleted in lymphocytic leukemia 1 gene, frequently deleted or downregulated in CLL, has been found to be upregulated in PTC, where it promotes thyroid cancer cell proliferation and invasion by sponging specific microRNAs (25). This raises the possibility that shared genetic or epigenetic alterations may contribute to the pathogenesis of coexisting PTC and CLL. Nevertheless, no definitive common pathogenic mutations have been established to date. Therefore, the concurrence of PTC and CLL is considered to be an opportunistic comorbidity arising from multiple contributing factors rather than a direct causal relationship (22,23).
In the present case, no recognized exogenous carcinogenic exposure was identified from the residential, occupational or lifestyle history of the patient, including ionizing radiation, radioactive materials, hazardous chemicals, smoking, alcohol consumption or known chronic infectious disease. Therefore, the coexistence of PTC and long-standing CLL is unlikely to be explained by a single environmental exposure. A more plausible interpretation is that the dual malignancies arose through a multifactorial process in which CLL-associated immune dysregulation may have lowered antitumor immune surveillance and facilitated the emergence of a second primary solid tumor. Beyond its identity as a clonal mature B-cell neoplasm, CLL is increasingly recognized as a systemic immune-disruptive disease, characterized by impaired humoral immunity, dysfunctional T-cell and natural killer-cell responses, altered antigen presentation, upregulated immune-checkpoint signaling and a tolerogenic tumor microenvironment (23,26). Recent reviews have further emphasized that immune dysfunction in CLL is persistent and clinically relevant, affecting not only infection susceptibility but also immune surveillance, immune-cell cross-talk and the broader risk of secondary malignancies (26,27). Together, these immune defects may impair antitumor surveillance and reduce host capacity to eliminate transformed epithelial cells, thereby creating a permissive milieu for secondary malignancies, including solid tumors, such as PTC.
Nevertheless, a direct causal relationship between CLL and PTC cannot be proven from a single case. The development of dual primary malignancies in the present patient is best interpreted as the result of interacting factors, including age-related accumulation of oncogenic alterations, sex-related susceptibility to PTC, possible genetic or epigenetic predisposition and CLL-related impairment of immune surveillance. Therefore, rather than representing metastatic spread or a single unifying pathogenic pathway, the present case likely reflects the biologically plausible coexistence of two independent primary malignancies in the setting of long-standing immune dysregulation. This interpretation also underscores the need for the careful evaluation of new solid lesions in patients with CLL, even when the hematological disease appears clinically indolent. A recent 2026 case of synchronous PTC and CLL presenting with cervical lymphadenopathy similarly emphasized that lymph node enlargement in patients with thyroid nodules may reflect hematological disease rather than metastatic thyroid carcinoma, whereby definitive histopathological and immunohistochemical assessment is essential for appropriate management (10).
The coexistence of thyroid carcinoma and hematological malignancy presents substantial diagnostic challenges. In the present case, the thyroid nodule was accompanied by widespread lymphadenopathy, a presentation that could easily suggest thyroid carcinoma with regional lymph node metastasis. However, further investigations revealed that the enlarged lymph nodes were not metastatic PTC but rather the result of CLL involvement. Lymphocytic infiltration is frequently observed in PTC tissue, particularly in association with Hashimoto's thyroiditis (28,29). By contrast, infiltration of the thyroid gland by CLL may closely mimic autoimmune lymphocytic infiltration under microscopy, making histological differentiation difficult (30). Therefore, in cases of thyroid carcinoma with dense monomorphic lymphocytic infiltration, clinicians should maintain a high index of suspicion for concomitant lymphoproliferative disorders, such as CLL. Immunohistochemistry and flow cytometry are indispensable adjuncts for establishing the correct lineage and avoiding diagnostic misclassification. Detection of monoclonal B-cell populations (such as clones co-expressing CD5, CD19 and CD23) by flow cytometry strongly supports the diagnosis of CLL (7,16). Histopathologically, immunohistochemistry enables separation of the two tumor components. In particular, PTC cells express epithelial and thyroid-related markers, whereas infiltrating lymphocytes express B-cell and CLL-associated markers (such as CD20, CD5 and CD23) but lack T-cell and germinal center markers. A recent report described the case of a patient with preexisting indolent SLL who developed suspicious cervical lymphadenopathy after thyroidectomy for PTC. FNA yielded only CLL-like lymphocytes, yet the aspirate demonstrated markedly elevated thyroglobulin levels, raising suspicion for occult PTC metastasis. Subsequent lymph node dissection confirmed the presence of metastatic PTC deposits within CLL-involved lymph nodes (9). This case, reported by Rejeb et al (9), highlights the diagnostic complexity of PTC coexisting with CLL, underscoring the need for the integration of tumor markers and when necessary, a repeat biopsy, to avoid misdiagnosis.
In the present case, the combined immunohistochemical and flow-cytometric findings established the thyroid lesion as PTC and the nodal disease as CLL. The distinct histomorphological and immunophenotypic profiles of the two lesions prevented misclassification of CLL-related lymphadenopathy as metastatic PTC and ensured appropriate staging and management. Although active surveillance is recognized in several international guidelines as a reasonable option for carefully selected patients with low-risk papillary thyroid microcarcinoma, management in the present case was individualized and was not dictated by tumor size alone (31–33). Recent reviews continue to support active surveillance as a safe and increasingly accepted option for carefully selected low-risk PTC, but also emphasize that eligibility depends on reliable imaging, the absence of suspicious nodal disease, patient preference and the feasibility of structured follow-up (34–36). According to Recommendation 42 of the Chinese Guidelines for the Diagnosis and Treatment of Thyroid Nodules and Differentiated Thyroid Cancer (Second Edition, 2023), thyroid lobectomy with isthmusectomy is strongly recommended, with moderate-quality evidence, for differentiated thyroid cancer lesions measuring <1 cm in the absence of high-risk features. Therefore, surgery represented a guideline-concordant management option rather than a departure from accepted care (37).
Crucially, the present case was not a straightforward case of an isolated, incidentally detected PTC. The patient had a 7-year history of CLL and presented with persistent, generalized lymphadenopathy involving the cervical, axillary, mediastinal, abdominal, pelvic and inguinal regions. In such a setting, preoperative risk stratification was particularly challenging, as enlarged lymph nodes could represent CLL involvement, occult PTC metastasis or coexistence of both processes within the same nodal basin. Although preoperative cytology and flow cytometry favored CLL-related nodal involvement, they could not fully exclude occult metastatic PTC, particularly in the setting of extensive cervical lymphadenopathy. Surgical resection with a central compartment lymph node dissection therefore provided definitive histopathological staging, excluded occult nodal metastasis in the dissected nodal basin and informed subsequent surveillance intensity.
In addition, patient preference was an important ethical and clinical consideration. The diagnosis of concurrent malignancies imposed a substantial psychological burden and the patient consistently expressed a strong preference for definitive surgical treatment rather than prolonged observation. After shared decision-making and multidisciplinary discussion involving the thyroid surgery and hematology teams, this patient-centered approach also enabled definitive pathological staging and remained consistent with the patient's informed values and psychological needs.
The prognosis of patients with concomitant PTC and CLL depends on the stage and biological behavior of each malignancy, in addition to the effectiveness of treatment (4). Overall, early-stage PTC, with papillary microcarcinoma as a representative subtype, is associated with a highly favorable prognosis. Papillary thyroid microcarcinoma (≤1 cm) has an exceptionally low mortality rate and >90% 10-year survival rate (38). CLL is an indolent lymphoma that can also have a prolonged natural history. Low-risk patients may survive for years with observation alone already sufficient (16). In the present case, the 64-year-old patient had a 0.3-cm papillary carcinoma with no lymph node metastases (stage pT1aN0M0) and was considered clinically cured following surgery. This specific CLL, which was diagnosed 7 years earlier, remained in a stable early stage, where no disease progression was observed during the 2-year follow-up. The patient has since maintained a good quality of life without additional therapy for CLL. However, the prognosis in similar cases may vary depending on tumor burden and pathological subtype of PTC. Sezer et al (8) reported the case of a patient with PTC who had local invasion and distant metastases alongside CLL and succumbed within 1 year postoperatively. In addition, in CLL, late-stage complications, such as Richter's transformation, which refers to the progression of CLL into aggressive diffuse large B-cell lymphoma, can markedly shorten survival time (39). These considerations highlight the necessity of comprehensive surveillance.
As a result of the present case, a multidisciplinary, long-term follow-up strategy is recommended. For the monitoring of thyroid carcinoma recurrence and metastasis, postoperative surveillance should include the periodic measurement of serum Tg and anti-Tg antibodies, in addition to high-resolution neck ultrasonography at least every 6–12 months. In patients who have undergone a total thyroidectomy, any unexplained rise in Tg or suspicious imaging findings should prompt further imaging (such as whole-body positron emission tomography-CT or iodine scans) to localize potential recurrent or metastatic disease (3,40). For the monitoring of hematological disease progression, in stable CLL, hematological evaluation with blood counts and relevant chemistries is recommended every 3 months. Key parameters include lymphocyte doubling time, cytopenias and constitutional symptoms, such as night sweats or weight loss. Early-stage asymptomatic disease is generally managed with observation, whilst rapid lymphocyte escalation, progressive lymphadenopathy or splenomegaly, or bone marrow failure warrant treatment initiation.
In summary, patients with concomitant PTC and CLL require sustained, multidisciplinary follow-up. Surveillance must focus not only on detecting the recurrence of thyroid carcinoma but also on monitoring the evolution of leukemia. With individualized follow-up plans and proactive management strategies, the majority of patients with this rare dual malignancy can achieve a good quality of life and prolonged survival time.