Primary Lung Adenocarcinoma as a Second Neoplasm Following Chronic Lymphocytic Leukemia: A Case Report

Abstract

Chronic lymphocytic leukemia (CLL) and its variant, small lymphocytic lymphoma (SLL), are common adult leukemias characterized by the accumulation of mature monoclonal B lymphocytes. CLL primarily involves peripheral blood, spleen, and lymph nodes, whereas SLL predominantly affects lymph nodes. Patients with CLL/SLL are at increased risk of developing second primary malignancies, including lung cancer, highlighting the need for ongoing surveillance. We report the case of an 83-year-old man with a history of CLL/SLL who developed pulmonary adenocarcinoma. He presented weight loss and constitutional symptoms; imaging revealed retroperitoneal and mesenteric lymph node conglomerates along with a lung lesion. Histopathology confirmed SLL in the lymph nodes and primary mucinous adenocarcinoma of the lung. Evidence shows a heightened risk of second primary neoplasms in CLL/SLL, particularly among patients exposed to alkylating agents. This case emphasizes the role of demographic and treatment-related factors—such as male sex, advanced age, smoking history, and therapeutic regimens—in secondary cancer development. Vigilant monitoring and a multidisciplinary approach tailored to individual risk are essential for early detection and optimal management in this population.

Introduction

Chronic lymphocytic leukemia (CLL) is a neoplasm characterized by the accumulation of mature monoclonal B lymphocytes with an aberrant immunophenotype, typically expressing CD5 and CD23. These cells are found in peripheral blood (>1,500/mm³), spleen, or lymph nodes. When lymph nodes are predominantly involved, the disease is termed small lymphocytic lymphoma (SLL). ¹ CLL/SLL is the most common chronic leukemia in adults, with an incidence of 4.9 per 100,000 inhabitants, increasing with age and a mean diagnosis at 70 years. Its clinical course varies from asymptomatic cases not requiring therapy initially to aggressive forms that may evolve into high-grade lymphoma (Richter transformation). ²

One well-documented phenomenon in patients with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an increased risk of developing a second primary neoplasm (SPN). Population-based studies report that 11–36% of patients develop an SPN after a CLL/SLL diagnosis, with a mean latency of approximately 10 years.^3,4 This risk is significantly higher in patients treated with chemotherapy compared with those managed expectantly. The reported incidence of pulmonary carcinoma in this setting ranges from 2% to 16%.^3,5 We present the case of a male patient with a history of CLL/SLL who subsequently developed pulmonary adenocarcinoma.

Case Presentation

We present the case of an 83-year-old male with a medical history of type 2 diabetes mellitus and CLL/SLL, diagnosed six years earlier. He was treated with bendamustine and rituximab until two years ago and has since remained under regular clinical follow-up. Additionally, the patient had a long-standing history of active smoking. Family history of malignancy was not documented in the available medical records, and no relevant familial cancer history was reported during the patient’s clinical evaluation or follow-up.

At a routine outpatient visit, he reported weight loss and constitutional symptoms, including weakness and fatigue. Physical examination revealed no palpable lymphadenopathy or hepatosplenomegaly. Laboratory studies at admission showed marked leukocytosis, monocytosis, anemia, and elevated lactate dehydrogenase (LDH) levels (Table 1).

Table 1.

Admission Laboratory Report

Parameter	Value	Reference value	Units
White Blood Cell Count	276.790	4.230-9.070	/uL
Lymphocytes	242.160	1.320-3.570	/uL
Neutrophils	4.250	1.780-5.380	/uL
Monocytes	29.200	300-820	/uL
Eosinophils	180	40-540	/uL
Basophils	410	10-80	/uL
Hemoglobin	9.30	13.7 - 17.5	g/dL
Hematocrit	29.60	40.1-51	%
Mean Corpuscular Volume	109.60	79-92.2	Fl
Mean Corpuscular Hemoglobin	34.40	25.7-32.2	Pg
Mean Corpuscular Hemoglobin Concentration	31.40	32.3-36-5	g/dL
Platelets	251.000	163.000-337.000	/uL
Blood Urea Nitrogen	27.50	8-23	mg/dL
Creatinine	1.64	0.67-1-17	mg/dL
Total Bilirubin	0.27	0-1-4	mg/dL
Direct Bilirubin	0.28	0-0.3	mg/dL
Lactate Dehydrogenase	307	135-225	U/L
Alanine Aminotransferase	7.0	0-41	U/L
Aspartate Aminotransferase	15.40	0-38	U/L
Albumin	4.48	3.5-5.2	g/dL

He was admitted to the hospital with a suspected relapse, and further investigations were initiated to evaluate the disease’s progression. On admission, his vital signs were as follows: blood pressure 100/77 mmHg, heart rate 77 beats per minute, respiratory rate 20 breaths per minute, oxygen saturation 98%, and temperature 36°C. The remainder of the physical examination was unremarkable, with no detectable lymphadenopathy. Cardiac auscultation revealed regular heart sounds without murmurs, and pulmonary examination demonstrated symmetric breath sounds bilaterally.

A comprehensive staging workup with an abdominal computed tomography (CT) revealed a large retroperitoneal and mesenteric lymph node conglomerate measuring 12.5 x 5.5 cm (Figure 1). Chest CT demonstrated a spiculated nodule in the posterior basal segment of the right lower lobe (2.5 x 1.9 cm) and bilateral hilar lymphadenopathy, with the largest node measuring 1.8 x 1.0 cm in the right hilum (Figure 2). A laparoscopic biopsy of the retroperitoneal conglomerate was performed, and the thoracic surgery team carried out a thoracoscopic wedge resection of the lung lesion.

Figure 1.

Abdominal computed tomography scan. A large retroperitoneal and mesenteric lymph node conglomerate measuring 12.5 x 5.5 cm is evident

Figure 2.

Chest computed tomography scan, cuts with lung window (A) coronal, (B) sagittal, and (C) lateral where a spiculated nodule in the posterior basal segment of the right lower lobe measuring 2.5 x 1.9 cm is observed (yellow arrow) (D) Windowing for the mediastinum where a low paratracheal lymph node is appreciated (red arrow)

Histological examination of the retroperitoneal lymph nodes showed complete effacement of the nodal architecture by small neoplastic lymphoid cells in a diffuse pattern. Immunohistochemistry was positive for CD20, PAX5, BCL2, CD5, and CD23, and negative for CD10, BCL6, SOX11, and Cyclin-D1, consistent with SLL. The Ki-67 proliferation index was 20% (Figure 3).

Figure 3.

Retroperitoneal lymph node. Small cell lymphocytic lymphoma. (A) Cells with a small amount of cytoplasm, rounded nuclei, condensed chromatin, without evident mitotic activity, mixed with few cells with prolymphocytic appearance corresponding to retroperitoneal lymph node. Diagnosis: Small cell lymphocytic lymphoma (H&E staining, 10x) (red arrow). (B and C) Expression of PAX-5 (blue arrow) and CD5 (green arrow) in tumor lymphocytes (Immunohistochemistry study 10x). (D) Nuclear expression of KI-67 is 20% (Immunohistochemistry study 10x) (black arrow)

In the lung wedge resection, a poorly defined yellowish, opaque nodular lesion with mucoid material measuring 2.5 x 2.0 x 1.7 cm was identified. Histological sections revealed an invasive neoplasm composed of glands and papillary projections lined by intestinal-type mucinous epithelium. The neoplastic cells expressed Thyroid Transcription Factor-1 (TTF-1), CDX2, Napsin A, MUC1, and MUC5, consistent with primary mucinous adenocarcinoma of the lung with enteric differentiation (Figure 4).

Figure 4.

Lung. Right lower lobe. Wedge biopsy. Immunohistochemical study. Well-differentiated primary pulmonary mucinous adenocarcinoma (G1), with enteric differentiation. Negative resection margin of pleura and parenchyma. (A) Well-differentiated primary pulmonary mucinous adenocarcinoma (G1), with enteric differentiation, (H&E staining, 10x) (red arrow). (B) Production of cytoplasmic mucin, green color (Movat staining, 40x) (blue arrow). (C) MUC-1 expression in tumor cells, brown color (immunohistochemistry 10x) (green arrow). (D) MUC5AC expression in tumor cells, brown color (immunohistochemistry 40x) (black arrow)

Given the presence of mediastinal lymphadenopathy, the patient underwent staging with endobronchial ultrasound (EBUS) to exclude metastatic adenocarcinoma. Cytological samples from stations 4R, 7, and 11R demonstrated involvement by SLL, showing the same immunophenotype as the retroperitoneal lymph nodes (Figure 5). The patient also developed a right pleural effusion, for which thoracentesis was performed. Flow cytometry of the pleural fluid confirmed CLL/SLL infiltration (Figure 6).

Figure 5.

Lymph node stations 7, 4R, and 11R. EBUS-TBNA. Immunohistochemical study. Stations 7, 4R, and 11R are compromised by infiltration of lymphoma/chronic lymphocytic leukemia. (A–C) Monotonous population of hematolymphoid origin cells observed (H&E staining, 4x, 10x, and 40x) (red arrow). (D) Intense expression of CD20 observed in neoplastic B lymphocytes (Immunohistochemical technique, 10x). Stations 7, 4R, and 11R compromised by infiltration of mature B-cell neoplasia, lymphoma/chronic lymphocytic leukemia

Figure 6.

Flow Cytometry, EBUS of station 7 subcarinal: Pathological population of 94% low SSC (side scatter). T lymphocytes: 2.8%. (A) In green (black arrow), non-neoplastic CD3-positive T population. In black (red arrow), CD20-positive pathological B population. (B) In black (red arrow), monoclonal Kappa B population. Infiltration of 94% low complexity monoclonal mature B cells. (C) In black (red arrow), CD20-positive and CD10-negative pathological B population. (D) In black (red arrow), CD20-positive and CD5-positive pathological B population. (E) In black (red arrow), CD20-positive and CD23-positive pathological B population. (F) In black (red arrow), CD20-positive and CD200-positive pathological B population

The oncology team ultimately determined that the lung adenocarcinoma was localized (T1c, N0, M0; clinical stage IA), and neoadjuvant therapy was not required. The patient underwent successful surgical resection of the lung nodule with negative margins and no complications, and no additional treatment was indicated for the adenocarcinoma. For hematologic disease control, therapy with rituximab and the tyrosine kinase inhibitor acalabrutinib was reinstated.

The patient was discharged for outpatient follow-up and ongoing management of CLL/SLL. At the latest follow-up, the patient remains lung cancer–free for 24 months. During the most recent oncology visit, a palliative care approach was initiated in collaboration with the oncology team for the management of chronic symptoms, including persistent pain. He remains on baseline therapy, with improvement in his overall clinical condition.

Discussion

The development of second primary neoplasms (SPNs) is a well-recognized phenomenon among cancer survivors, accounting for approximately 16% of tumors diagnosed in the United States. This highlights the need for continuous surveillance and long-term management to enable early detection of new malignancies.^6,7 Contributing factors include improved survival rates, prior treatments such as radiotherapy, and comprehensive follow-up with routine imaging, which increases the likelihood of identifying additional neoplasms. ⁸ Regarding the demographics predisposed to SPN development, older men between 50 and 79 exhibit increased risk. However, some reports suggest a higher incidence in individuals under 60, with an average latency period of 5 to 10 years.^3,7

In patients with CLL/SLL, multiple studies have demonstrated a significantly increased risk of second primary malignancies, with standardized incidence ratios ranging from 1.2 to 1.79.^4,7,9-11 The most frequently reported tumors include Kaposi’s sarcoma, cutaneous melanoma, prostate carcinoma, and lung carcinoma. Additionally, an elevated risk of secondary hematolymphoid neoplasms has been described, particularly acute lymphoblastic leukemia and acute myeloid leukemia. ³

The behavior of lung carcinoma in patients with CLL/SLL has been scarcely reported in the literature. In a 20-year cohort analysis, Parekh et al. found that 2% of patients with CLL/SLL developed lung carcinoma, predominantly of the non-squamous type. The average age at lung cancer diagnosis was 68 years, approximately seven years after the diagnosis of CLL/SLL, and notably, 86% of these patients had a history of smoking. ⁵

Immunohistochemistry enabled the identification of synchronous CLL and lung adenocarcinoma, underscoring its essential role in routine diagnostic evaluation. While immunohistochemistry remains a cornerstone for tumor classification and lineage determination, emerging evidence supports the added value of genomic profiling in selected complex oncologic scenarios. A recently published case report of a patient with CLL and concurrent lung adenocarcinoma demonstrated how comprehensive genomic profiling altered the initial diagnosis, with potential therapeutic implications. The present case complements these findings by illustrating that immunohistochemistry alone may provide sufficient diagnostic certainty in selected clinical contexts, while also highlighting the importance of individualized, multidisciplinary decision-making to determine when expanded molecular diagnostic strategies are necessary. ¹²

The immunosuppressive state induced by CLL/SLL is thought to contribute to SPN development, involving alterations in adaptive immunity (reduced complement levels), humoral immunity (hypogammaglobulinemia), and cellular immunity (inactivation of CD8+ and CD4+ cytotoxic T lymphocytes, increased regulatory T cells, and preferential differentiation of monocytes into the M2 subtype with tolerogenic activity).^13-15 Elevated absolute monocyte counts have been associated with increased proliferation and prolonged survival of neoplastic lymphoid cells in CLL/SLL, representing a prognostic marker of poorer clinical outcomes. ¹⁶

Standard treatment for CLL/SLL includes alkylating agents (e.g., fludarabine, bendamustine), monoclonal antibodies (rituximab, obinutuzumab), tyrosine kinase inhibitors (ibrutinib, acalabrutinib), and BCL-2 inhibitors such as venetoclax. ² While early evidence did not suggest an increased risk of secondary neoplasms with these therapies, ⁹ more recent studies have demonstrated that alkylating agents, in particular, are significantly associated with an elevated risk of SPN development. ¹⁷

The impact of rituximab–bendamustine therapy on indolent B-cell lymphomas has been specifically evaluated. Dote et al. reported a significantly increased risk of secondary neoplasms (odds ratio 1.33) in patients treated with this regimen compared to those receiving rituximab monotherapy or combination therapies such as RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), or RTHPCOP (rituximab, pirarubicin, cyclophosphamide, vincristine, prednisolone). Importantly, no significant differences in overall mortality were observed between treatment groups. ¹⁸

Thus, it is plausible that multiple factors—including age, prior treatments, and smoking history—contributed to the development of pulmonary adenocarcinoma in this case. Despite limitations, such as the retrospective nature of data collection from medical records, this report adds to the understanding of the clinical behavior of this entity.

Conclusion

In conclusion, patients diagnosed with CLL/SLL are at a heightened risk of developing a second primary neoplasm, underscoring the importance of vigilant clinical monitoring during disease follow-up. The convergence of risk factors such as male gender, age at diagnosis, smoking history, and the administration of Rituximab-Bendamustine therapy likely played a significant role in the onset of lung adenocarcinoma after the diagnosis of CLL/SLL.