Treatment-related peripheral small cell lung carcinoma in a Hodgkin lymphoma survivor
- 1 Internal Medicine, UNC Health Southeastern, Lumberton, North Carolina, USA
- 2 Internal Medicine, Campbell University Jerry M Wallace School of Osteopathic Medicine, Lillington, North Carolina, USA
- 3 Medicine, Duke University School of Medicine, Durham, North Carolina, USA
- Correspondence to Dr Prathyusha Gudapati; prathyusha.gudapati@hotmail.com
Abstract
Hodgkin lymphoma (HL) survivors have an increased risk of developing subsequent treatment-related primary malignancies. In the last few decades, advances in knowledge, radiotherapy, chemotherapy and autologous stem cell transplantation have led to the transformation of lethal malignancy into highly curable malignancy, thereby improving outcomes. With prolonged survival, the risk of developing subsequent treatment-related late adverse effects, such as malignancies, steadily increases over time. Herein, we present the first case of a treatment-related second primary stage IV peripheral small cell lung carcinoma in a female HL survivor who was also diagnosed with right breast cancer 13 years after HL treatment and 1 year before her lung cancer diagnosis.
Background
Hodgkin lymphoma (HL) is a rare haematological malignancy of lymphatic origin that accounts for 0.4% of new cancer diagnoses and 0.3% of cancer-related deaths annually.1 HL primarily affects young adults, particularly males, and has a bimodal age distribution, with prominent peaks at 20–39 years and 60 years or beyond.1 HL is diagnosed based on the identification of characteristic Reed Steinberg cells and is divided into classic HL and nodular lymphocyte-predominant HL based on presentation, behaviour, morphology and immunophenotype.2 Early HL is basically treated with chemotherapy with or without radiotherapy (RT), whereas recurrent HL is treated with chemotherapy with stem cell transplant or radiation therapy.3 Over the past few decades, the relative survival rates of HL patients have steadily increased because of advances in early detection, supportive care and treatment. Consequently, there is an increased risk of developing treatment-related late adverse effects, such as malignancies, with the majority of cases occurring 5 years after treatment.4 HL survivors are at an increased risk of developing thoracic malignancies, such as breast and lung cancers, particularly after chest RT.4 The risk of developing subsequent malignancies within 5 years of the first treatment-related malignancy is significantly elevated.4 Small cell lung cancers in never smokers are relatively rare and treatment-related peripheral small cell lung cancers in never smokers are yet to be reported. A literature review was conducted using PubMed, and no prior reports of treatment-related primary peripheral small cell lung cancer in HL were found. Herein, we report the first case of treatment-related second primary peripheral small cell lung cancer in an HL survivor.
Case presentation
A female in her 50s with generalised weakness and altered mental status was presented to our hospital. The associated symptoms included intermittent mentation changes, appetite changes, weight loss and headaches for weeks prior to presentation. Her medical history revealed that she was diagnosed with nodular sclerosing HL with extranodal or solid organ involvement, for which she received chemotherapy with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD), which resulted in progressive disease. She subsequently underwent salvage chemotherapy with ifosfamide, carboplatin and etoposide and an autologous bone marrow transplant. She experienced biopsy-proven recurrence (Stage RIIA) 2 years after salvage therapy and underwent radiation therapy with fractions of 1.8 Gy qd–36 Gy to the mantle field and 25.2 Gy to the para-aortic nodes and spleen. A screening mammogram performed 13 years later, revealed that she had a right breast mass, which was later diagnosed as oestrogen receptor-positive (ER+) and progesterone receptor-positive invasive ductal carcinoma, with a pT1c, pNo, cM0 pathological stage. Her treatment options became limited because of her prior HL treatment. She underwent a mastectomy and is currently on anastrozole therapy for breast cancer. Her family has a history of breast cancer in her cousin and colon cancer in her father. Her vital signs were significant for tachycardia, with a heart rate of 114.
Investigations
Acute kidney injury with a creatine of 1.7 (baseline 0.7–0.9) and leucocytosis with a white count of 14.6 K/mm3 were discovered during laboratory workup. A head CT scan without contrast revealed neoplasm metastasis. A CT scan of the chest, abdomen and pelvis revealed metastatic disease in the liver with 1.2 cm right hepatic lobe hypodense lesion and throughout the thoracic cavity with left lower base mass with internal cavitation, left infrahilar and mediastinal lymphadenopathy (figure 1). MRI of the spine was performed without spinal involvement. MRI of the brain revealed the presence of multiple bilateral sub-cm rim-enhancing lesions (figure 2). Transthoracic needle aspiration biopsy of the left lower base mass revealed a microscopic morphology and neuroendocrine features that were consistent with stage IV B, cM1c small cell carcinoma. Immunohistochemistry confirmed that the tumour exhibited neuroendocrine differentiation, with positivity for cytokeratin 7, thyroid transcription factor 1, synaptophysin and CD56.
Coronal view of contrast-enhanced CT scan of the chest (Computed Tomography Angiography Pulmonary Embolus protocol) demonstrating left lung base mass (green arrow pointing to lung base mass) (lung window).
Axial Apparent Diffusion Coefficient diffusion-weighted MRI of brain demonstrating posterior right frontal lobe and right occipital lobe metastatic lesions (green arrows pointing to metastatic lesions).
Differential diagnosis
A preliminary diagnosis of metastatic breast cancer was made based on the CT findings, MRI findings, and a recent history of breast cancer. This was subsequently diagnosed as metastatic peripheral small cell lung cancer.
Treatment
After a multidisciplinary tumour board discussed the patient’s case, the decision was made to place her on systemic chemotherapy with a carboplatin area under the curve of 5, 100 mg/m² of etoposide and 1500 mg of durvalumab to be administered over 3 days every 21 days, with plans to examine the intracranial and extracranial response. The patient had severe adverse reaction to her second cycle of chemotherapy, and the treatment was stopped. She completed a palliative radiation therapy to treat brain metastasis resulting from small cell lung cancer. She received 10 fractions of 300 cGy (ie, a total of 3000 cGy) using an opposed lateral field arrangement with 6 MV photons. She was not eligible for any further treatment with cytotoxic agents after palliative RT due to Eastern Cooperative Oncology Group (ECOG) performance status of 3.
Outcome and follow-up
The patient achieved clinically significant symptomatic relief from palliative RT.
Discussion
HL is a rare but highly curable adult haematological malignancy. The risk factors for HL include age (adulthood), male gender, previous childhood or early adulthood Epstein-Barr virus infection, and family history of HL.3 However, the prognostic factors are age, sex, erythrocyte sedimentation rate, haematocrit, the extent of abdominal involvement and the absolute number of nodal site involvements.3 The mainstay of HL treatment is chemotherapy with or without radiation. Over the last few decades, the treatment regimen has improved, resulting in better outcomes. Treatment-related long-term adverse effects are more likely to develop as survival rates improve. Between the 1970s and 1990s, HL patients received extended-field radiation therapy (EFRT), which included mantle, extended mantle and subtotal nodal RT (figure 3).5 It is well known that HL patients who have been treated with EFRT have an increased risk of developing subsequent malignancies.4 6–11 Several prospective studies have demonstrated that involved-field radiation therapy (IFRT) with 35 Gy RT for HL is as effective as EFRT with 35 Gy and reduces toxicities.12–14 Additionally, IFRT was predicted to substantially reduce the risk of treatment-related malignancies.15 16 Radiation therapy for HL has evolved from EFRT to IFRT because of the results of these trials and the aim of reducing long-term radiation-related adverse effects.
Radiation therapy fields used in treatment of classical Hodgkin lymphoma, image created by PG. RT, radiotherapy.
Chemotherapy with mechlorethamine, vincristine, procarbazine and prednisolone (MOPP) remained the mainstay of treatment for several years. However, MOPP fell out of favour because of severe systemic toxicities, an increased risk of acute myeloid leukaemia and sterility, and ABVD became the first-line chemotherapy regimen.17 Retrospective studies have also linked chemotherapy with alkylating agents, such as mechlorethamine, vincristine and procarbazine, to the development of subsequent malignancies independent of RT.10 11 Patients who have received RT are at an increased risk of ER + breast cancer, whereas patients who have received combination therapy are at an increased risk of lung cancer.8 18 Additionally, chemotherapy and RT have dose-dependent and additive effects on the development of treatment-related lung cancer.11 19 Female patients who develop breast cancer as their treatment-related first primary malignancy have an increased risk of developing treatment-related second primary malignancies.6 Treatment-related lung cancers are diagnosed at either stage III or stage IV and are associated with poor outcomes.7 9 Non-small cell lung cancers are the most common histological type of these lung cancers, accounting for 70%–81% of cases in retrospective studies.10 19
Despite the growing awareness of treatment-related subsequent malignancies in HL survivors, there is still limited data on surveillance strategies, making it challenging. Furthermore, risk factors such as smoking status, environmental exposures, and genetics were not taken into account in previous studies. Therefore, the existing evidence does not show a benefit in mortality from low-dose CT-based lung cancer screening in HL survivors who have never smoked or from early breast cancer screening in patients who received mantle field RT at age greater than 30. However, the landscape of HL treatment has changed significantly in the last two decades because of multiple studies demonstrating the role of RT and chemotherapy with alkylating agents in the development of subsequent malignancies, with the goal of minimising these risks. Hence, the risk of developing subsequent treatment-related malignancies will decrease with time. Although the above-mentioned prospective studies have demonstrated that IFRT reduces the incidence of subsequent malignancies by 35%–65% with the same treatment dose of 35 Gy, data on further risk reduction with a decrease in the radiation dose/target volume of IFRT are still scarce.
Our case highlights the increased risk of subsequent malignancies in HL survivors who received mantle/extended field radiation. The occurrence of her second and third malignancies was attributed to her prior mantle field RT in the absence of other aetiological factors, such as alcohol and tobacco use, environmental exposure and genetic susceptibility. In conclusion, we report the first case of treatment-related second primary peripheral small cell lung cancer in a female HL survivor in her 50s.
Patient’s perspective
I am tired of being admitted to the hospital almost every week because of my unbearable headaches, memory lapses, weakness, and bone pain. I would prefer to choose any treatment that will alleviate my symptoms and allow me to live out the rest of my life with dignity.
Learning points
-
Hodgkin lymphoma survivors are at an increased risk of developing subsequent treatment-related late adverse effects.
-
Treatment-related lung cancers are diagnosed at an advanced stage and are associated with poor outcomes.
-
Chemotherapy with alkylating agents and radiotherapy have dose-dependent and additive effects on the development of treatment-related lung cancer.
Ethics statements
Patient consent for publication
Acknowledgments
We would like Thank Ms. Jane Moran, librarian CUSOM for independently verifying literature review using PubMed.
Footnotes
-
Contributors PG performed literature search, drafted, formatted and reviewed the manuscript. She sought patient’s consent for publication. MA was involved in the patient care and approved the final manuscript.
-
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
-
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
-
Competing interests None declared.
-
Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
Use of this content is subject to our disclaimer