Treatment of Lymphoma and Cardiac Monitoring during Pregnancy

Stella Pak, MD

Yan Yatsynovich, MD 

Damian Valencia, MD

Calvert Busch, MD

Emily Vannorsdall, MD

Department of Medicine

Kettering Medical Center

Kettering, OH USA

Abstract

Limited data is available regarding fetal-maternal outcomes with chemotherapy during pregnancy, including cardiovascular toxicity and evaluation thereof. Early cardiovascular evaluation and initiation of cardioprotective therapies should be considered. Herein, we report a case of a 33-year-old woman treated with R-CHOP chemotherapy for large B-cell lymphoma found to have some degree of reversible cardiac strain.

Introduction

There are no guidelines specific for cardiotoxicity monitoring in pregnant patients undergoing chemotherapy. Pregnant patients are more vulnerable to cardiovascular complications, such as congestive heart failure, from chemotherapy as their cardiovascular system is under considerable stress from increasing physiological demands in pregnancy. With elevated cardiac output and circulatory volume from baseline, these patients do not have much cardiopulmonary reserve to compensate for cardiac strains from chemotherapy side effects (1). Therefore, it would be critical for clinicians to be aware of increased risk of cardiovascular adverse effect from chemotherapeutic agents in pregnant patients. Herein, we report a case of a 33-year-old woman treated with R-CHOP chemotherapy for large B-cell lymphoma found to have some degree of reversible cardiac strain.

Case Presentation

An otherwise healthy 33-year-old Caucasian female, G2P1 at 24 weeks gestation presented with a chief complaint of cough, chest pressure, and swelling in the neck and face. Physical exam was notable for a negative Pemberton’s sign, two lymph nodes in the right supraclavicular region measuring approximately 2 cm without axillary or groin lymphadenopathy. Cardiac exam demonstrated distant heart sounds with a faint I-II/VI systolic murmur in the left second intercostal space, without presence of bruits or lower extremity edema. Lung exam was positive for occasional wheezing in the left lower lobe. Breast exam was normal. Initial chest x-ray (Figure 1) and computed tomography (CT) scan (Figure 2) of the chest revealed a mediastinal mass (11 x 9.2 x 8.7 cm) and a moderate sized pericardial effusion.

Figure 1. Roentgenogram of chest demonstrating a large mass on left lower lobe and pericardial effusion.

Figure 2. Computerized tomography of chest revealing a large homogeneous left mediastinal mass (92.1 mm X 87.1 mm).

Follow up CT-guided biopsy yielded a diagnosis of large B-cell lymphoma. Bronchoscopy done at that time demonstrated diffuse tracheal and bronchial involvement, likely pointing to primary mediastinal derivation of the tumor. Interestingly, the patient had a history of lymph node biopsy of two areas on her right lateral neck and right medial supraclavicular node; pathology reports were consistent with granulomatous disease at that time. Due to pregnancy, baseline positron emission tomography (PET)/CT was not performed, however, the patient did undergo staging with a CT scan of the chest and abdominal/pelvic and magnetic resonance imaging (MRI), both of which were negative for metastatic disease. Bone marrow biopsy obtained was negative for malignancy as well. Dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, oncovin, cyclophosphamide, hydroxydaunorubicin) was replaced with R-CHOP (rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, prednisolone) due to the teratogenic effects of etoposide. Embryologic toxicity has previously been observed with etoposide including skeletal abnormalities, exencephaly, encephalocele and anophthalmia. Monitoring of cardiac function was performed before, during and after treatment. Initial echocardiogram demonstrated preserved ejection fraction (EF) of 60% with a large pericardial effusion and early signs of tamponade. No strain studies were done prior to initiation of chemotherapy. The patient had undergone a total of six cycles with a good response. Upon treatment completion fluoro-D-glucose (FDG)-PET/CT did show persistent uptake mostly in the manubrium as well as a persistent mediastinal mass with a low standardized uptake values (SUV).

The patient had initially considered radiotherapy in her post-delivery course, but given her most recent PET scan with a Deauville score of less than 4, the patient decided to avoid radiation and opted for close follow-up with repeat imaging. The Deauville 5-point scoring system is an internationally accepted point based scale used to characterize fluorodeoxyglucose (FDG) avidity of malignant tumor mass as seen on FDG positron emission tomography (PET) scan. Scores between 1 and 2 are considered negative, a score of 3 is typically paired with other studies and clinical signs to determine progression of disease, a score of 4 and 5 are considered positive for malignancy progression. Her pericardial effusion had resolved with chemotherapy.

Echocardiographic cardiac strain evaluation performed during follow-up evidenced a drop in her longitudinal strains from 22.8 to -15% just prior to delivery. Ejection fraction remained preserved at >60%. Low-dose carvedilol was considered during treatment however patient was not agreeable. The patient had an uneventful delivery and strain studies post-delivery showed a stable -15% strain. Echocardiogram performed 6 months post-chemotherapy demonstrated an ejection fraction of 72% and normalization of longitudinal strain. In the light of chemotherapy with known cardiotoxic adverse effects, as well as pregnancy strain on cardiac function, the patient did well and underwent an uneventful course.

Discussion 

The majority of data on maternal and fetal cardiotoxic effects of chemotherapy during pregnancy is based on case reports and retrospective data collection (2).

Registry data seems to suggest that the incidence of toxic side effects is not significantly increased during pregnancy and in the current literature there is no mention of an increased frequency of heart failure or left ventricular dysfunction during pregnancy (3-5). A study by Van Calsteren et al. (6), suggested that serum levels of chemotherapy, including anthracyclines, measured in pregnant women, were lower compared with those in nonpregnant women although the differences were not statistically significant. Despite the lower serum levels, cardiotoxicity might have a more significant impact on the maternal cardiovascular system in a context of increased hemodynamic loading. The use of cardiotoxic medications during pregnancy requires further attention, however no standard cardiac follow-up protocols are currently in place (7).

There may be a need for clinical cardiac assessments and an echocardiographic functional evaluation, including cardiac strain monitoring, prior to starting chemotherapy and repeat echocardiographic evaluation prior to every dose. If changes in cardiac function are observed, less cardiotoxic treatments might be considered or cardioprotective agents could be used. In this particular patient population, baseline echocardiography with strain study is crucial. Evidence of abnormal strain study during any part of the treatment should prompt initiation of cardioprotective therapy as per standards of the current heart failure guidelines. In addition, we suggest consideration for close cardiac follow-up monitoring, including a repeat echocardiogram study at 12 months post completion of chemotherapy/radiotherapy treatment. It is still unclear whether prophylactic therapy with cardioprotective agents would be safe and beneficial in these patients. Though we may be able to extrapolate data from trials performed on non-pregnant patients undergoing therapy and apply it to this particular niche of patients. The 2013 ACC/AHA heart failure guidelines state that it may be reasonable to evaluate those who are receiving (or who have received) cardiotoxic chemotherapy agents for left ventricular dysfunction as well as use echocardiographic techniques or biomarkers to identify increased heart failure risk in those receiving chemotherapy (8). In addition, the 2012 European Society of Medical Oncology (ESMO) guidelines stress on importance of serials cardiac function monitoring at baseline, 3, 6 and 9 months during treatment and then at 12 and 18 months after initiation of treatment (9).

Today, there is still no clear consensus with regards to cardioprotective therapy in patients exposed to cardiotoxic agents. As of 2016, the ACC/AHA guidelines did not reflect any change in recommendations in this particular field. Risk-stratification and prophylactic cardioprotective therapy remain an ultimate goal in pregnant patients undergoing chemotherapy, but how that should be done is still being studied. Early cardiology involvement and possible early initiation of prophylactic heart failure therapy should be considered.

References

1. Fadol AP, Lech T, Bickford C, Yusuf SW. Pregnancy in a patient with cancer and heart failure: challenges and complexities. J Adv Pract Oncol. 2012 Mar;3(2):85-93. [PubMed]
2. Gziri MM, Amant F, Debiève F, Van Calsteren K, De Catte L, Mertens L. Effects of chemotherapy during pregnancy on the maternal and fetal heart. Prenat Diagn. 2012 Jul;32(7):614-9. [CrossRef] [PubMed]
3. Cardonick E, Dougherty R, Grana G, Gilmandyar D, Ghaffar S, Usmani A. Breast cancer during pregnancy: maternal and fetal outcomes. Cancer J. 2010;16(1):76-82. [CrossRef] [PubMed]
4. Van Calsteren K, Heyns L, De Smet F, et al. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol. 2010 Feb 1;28(4):683-9. [CrossRef] [PubMed]
5. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol. 2004 May;5(5):283-91. [CrossRef] [PubMed]
6. Van Calsteren K, Verbesselt R, Ottevanger N, et al. Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study. Acta Obstet Gynecol Scand. 2010 Oct;89(10):1338-45. [CrossRef] [PubMed]
7. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol. 2010 Oct;7(10):564-75. [CrossRef] [PubMed]
8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013 Oct 15;128(16):1810-52. [CrossRef] [PubMed]
9. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2012 Oct;23 Suppl 7:vii155-66. [CrossRef] [PubMed]

Cite as: Pak S, Yatsynovich Y, Valencia D, Bushch C, Vannorsdall E. Treatment of lymphoma and cardiac monitoring during pregnancy. Southwest J Pulm Crit Care. 2017;15(4):154-8. doi: https://doi.org/10.13175/swjpcc106-17 PDF 

October 2017 Pulmonary Case of the Month

Eric A. Jensen, MD

Department of Radiology

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 56-year-old woman presented with 3 days of non-productive cough, low-grade fever and severe right-sided pleuritic chest pain.

Past Medical History, Social History and Family History

She was diagnosed with coccidioidomycosis 5 years previously. She reports that she has had pneumonia every 6 to 12 months since her diagnosis with valley fever. She does not smoke. Family history is noncontributory.

Physical Examination

Her vital signs were unremarkable and she was afebrile but did cough frequently during the examination. Her lungs were clear and the rest of the physical examination was unremarkable.

Chest Radiography

She brings in two prior chest x-rays, one from 2011 (Figure 1, Panels A & B) and another from 2012 (Figure 1, Panel C).

Figure 1. Chest radiograph from 2011 (A & B) and from 2012 (C).

Which of the following best describes the chest x-rays? (Click on the correct answer to proceed to the second of five pages)

1. A repeat chest x-ray should be performed
2. A right lower lobe mass is present which appears to have enlarged from 2011 to 2012
3. There is a right lower posterior lung density
4. 1 and 3
5. All of the above

Cite as: Jensen EA. October 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;15(4):125-30. doi: https://doi.org/10.13175/swjpcc115-17 PDF

September 2017 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 67-year-old woman with history of chronic lymphocytic leukemia (CLL) was referred due to a 6-week history severe cough. Her CLL had recently relapsed and she was begun on ibrutinib (a small molecule drug that binds permanently to Bruton's tyrosine kinase) in addition to acyclovir, sulfamethoxazole/trimethoprim and allopurinol.

Past Medical History, Social History and Family History

Her CLL was initially diagnosed in 2009 and had responded to fludarabine, cyclophosphamide, and rituximab. She had no other chronic medical diseases. She smoked ½ pack per day but quit with the development of her cough. Family history was noncontributory.

Physical Examination

Her vital signs were unremarkable and she was afebrile but did cough frequently during the examination. There were shoddy small lymph nodes noted in both supraclavicular and axillary areas. Lungs were clear and the rest of the physical examination was unremarkable.

Laboratory Evaluation

Her complete blood count revealed her to be mildly anemic with a hemoglobin of 9.0 g/dL, an elevated white count of 33,700 cells/mcL with 88% lymphocytes, and a low platelet count of 60,000 cells/mcL. Her electrolytes were within normal limits and her blood urea nitrogen was 20 mg/dL, creatinine 1.1 mg/dL and uric acid 7.1 mg/dL.

Chest Radiography

A chest x-ray was performed (Figure 1).

Figure 1. Initial chest x-ray.

Which of the following is true? (Click on the correct answer to proceed to the second of five pages)

1. A pulmonary nodule is present in the left upper lobe (LUL)
2. Ibrutinib is well known to cause a chronic cough
3. Pneumonia is unlikely since she is afebrile
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. September 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;15(3):94-9. doi: https://doi.org/10.13175/swjpcc108-17 PDF

August 2017 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

The patient is a 60-year-old woman with dyspnea on exertion when she had a pulmonary embolism following knee surgery 3 years earlier. She smoked 1 pack per day for the past 40 years. She was seen at another hospital and had pulmonary function testing which showed only a DLco which was 66% of predicted. Serologic studies were negative for a rheumatologic disorder. A CT scan was also performed (Figure 1).

Figure 1. Representative images from thoracic CT scan in lung windows.

The CT scan was interpreted as showing a few small nodules and possible very early interstitial lung disease.

Which of the following are true? (Click on the correct answer to proceed to the second of five pages)

1. A pulmonary embolism can reduce the DLco
2. Her CT scan is characteristic of Langerhans cell histiocytosis
3. Smoking can reduce the DLco
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. August 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;15(2):54-60. doi: https://doi.org/10.13175/swjpcc096-17 PDF 

Tip of the Iceberg: 18F-FDG PET/CT Diagnoses Extensively Disseminated Coccidioidomycosis with Cutaneous Lesions

Benjamin B. Nia¹

Emily S. Nia²

Ngozi Osondu³

John N. Galgiani^3,4

Phillip H. Kuo^2,5

¹College of Medicine, University of Texas Medical Branch, Galveston, TX, USA.

²Department of Medical Imaging

³Department of Medicine, Section of Infectious Disease

⁴Valley Fever Center for Excellence

⁵Departments of Medicine and Biomedical Engineering

University of Arizona

Tucson, AZ, USA.

Abstract

We present a case of an immunocompetent 27-year-old African American man who was initially diagnosed with diffuse pulmonary coccidioidomycosis and started on oral fluconazole. While his symptoms improved, he began to develop tender cutaneous lesions. Biopsies of the cutaneous lesions grew Coccidioides immitis. Subsequent ¹⁸F-FDG PET/CT revealed extensive multisystem involvement including the skin/subcutaneous fat, lungs, spleen, lymph nodes, and skeleton. This case demonstrates the utility of obtaining an ¹⁸F-FDG PET/CT to assess the disease extent and activity in patients with disseminated coccidioidomycosis who initially present with symptoms involving only the lungs.

Report of Case

A 27-year-old African American man, who lived in the desert southwest of the United States for several years, with no significant past medical history presented with chest pain, weight loss, and shortness of breath. After two urgent care visits, he was admitted to the hospital with a chest radiograph showing bilateral pulmonary infiltrates (Figure 1).

Figure 1. Frontal (A) and lateral (B) chest radiography at hospital admission shows extensive reticulonodular opacities suspicious for atypical infection.

Bronchoscopy yielded Coccidioides spp., and immunodiffusion complement fixation (IDCF) was further confirmatory. Laboratory values showed elevated erythrocyte sedimentation rate (ESR) and mildly abnormal liver function tests. He was diagnosed with diffuse pulmonary coccidioidomycosis and discharged home on 400 mg of oral fluconazole per day. At initial follow-up appointment, he reported feeling significantly better with resolution of his chest pain. He was gaining weight and had increased physical activities. At three-month follow-up, he reported continued improvement but complained of three new “spots” on the skin of his lower abdomen (Figure 2).

Figure 2. Photograph of the cutaneous lesions at nine months (red arrows) that were also present at 3- and 6-month follow-up appointments.

On physical exam, the cutaneous lesions were not suspicious for disseminated infection so treatment was continued unchanged. At six-month follow-up, he displayed numerous cutaneous lesions that were now tender. A biopsy of a cutaneous lesion demonstrated Coccidioides spherules on microscopy. An ¹⁸F-FDG PET/CT scan was performed to assess the extent of disease and demonstrated FDG-avid disease involving the skin/subcutaneous tissue, lungs, spleen, multi-station lymph nodes, and the skeleton (Figure 3).

Figure 3. Coronal maximum-intensity projection (A) and axial fused (B) 18F-FDG PET/CT scan shows FDG-avid disease involving the spleen (blue arrow), osseous structures (green arrows), multiple lymph nodes stations (yellow arrows), and soft tissues, including the skin and subcutaneous tissues (red arrows).

After another month, the skin lesions improved and, on further questioning, the patient revealed that he had previously not been taking his fluconazole as prescribed. Because of the skeletal involvement uncovered by the PET/CT scan, the patient’s oral fluconazole dose was increased to 800 mg per day. At nine-month follow-up, patient reported continued improvement and resolution of majority of skin lesions, albeit with residual hyperpigmentation.  

Discussion

Coccidioidomycosis, or “Valley fever” is a fungal infection caused by inhalation of Coccidioides immitis or Coccidioides posadasii spores. Most infections cause little clinically apparent illness and result in lifelong immunity. Approximately one-third of infections produce pulmonary syndromes compatible with a community-acquired pneumonia, whereas <1% are complicated by potentially fatal blood-stream dissemination. Skin involvement is one of the most common manifestations of disseminated coccidioidomycosis. Other common sites of involvement include the bones, joints, and meninges. Unfortunately, nonspecific symptoms, the subacute nature of this disease, and lack of familiarity with this infection result in delayed diagnosis, increasing the risk of dissemination. Risk factors for disseminated coccidioidomycosis include African-American or Filipino ancestry, immunocompromised state, pregnancy, and discrete genetic defects. Coccidioides-endemic areas include parts of the southwestern United States, Central and South America (1,2).

¹⁸F-FDG PET/CT is an imaging modality most commonly utilized to stage malignancies and monitor response to therapy. ¹⁸F-FDG is a radioactive analog of glucose and is taken up by inflammatory cells. Detecting and monitoring infectious and inflammatory processes can be achieved with various imaging techniques, including computed tomography, magnetic resonance imaging, and ultrasonography. However, these techniques rely primarily on structural changes, and differentiation between active and indolent infections can be difficult. PET/CT’s whole-body coverage and high sensitivity can localize all sites of disease and assess level of disease activity (3,4).

This case demonstrates the utilization of ¹⁸F-FDG PET/CT to provide a comprehensive assessment of disease extent and activity in a patient with disseminated coccidioidomycosis. Diagnosing extent of disease is particularly important in this circumstance as osseous coccidioidomycosis predominantly results in osteolytic lesions that increase risk for fractures. Additionally, soft tissue assessment may reveal clinically occult soft tissue abscesses that may require surgical debridement (5). For this patient, the PET/CT scan results provided information that prompted medication dose escalation and emphasized the need for medication compliance. If disseminated coccidioidomycosis is suspected, PET/CT may provide value for the diagnostic evaluation in selected patients.

References

1. Odio CD, Marciano BE, Galgiani JN, Holland SM.Risk factors for disseminated coccidioidomycosis, United States. Emerg Infect Dis. 2017 Feb;23(2). [CrossRef] [PubMed]
2. Nguyen C, Barker BM, Hoover S, Nix DE, Ampel NM, Frelinger JA, Orbach MJ, Galgiani JN. Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clin Microbiol Rev. 2013;26(3):505-25. [CrossRef] [PubMed]
3. Zhuang H, Alavi A. 18-Fluorodeoxyglucose Positron Emission Tomographic Imaging in the Detection and Monitory of Infection and Inflammation. Semin Nucl Med. 2002;32:47-9. [CrossRef] [PubMed]
4. Basu S, Chryssikos T, Moghadam-Kia S, Zhuang H, Torigian DA, Alavi A. Positron emission tomography as a diagnostic tool in infection: present role and future possibilities. Semin Nucl Med. 2009;39:36–51. [CrossRef] [PubMed]
5. Gupta NA, Iv M, Pandit RP, Patel MR. Imaging manifestations of primary and disseminated coccidioidomycosis. App Radiol. 2015;44(2):9-21. Available at: http://appliedradiology.com/articles/imaging-manifestations-of-primary-and-disseminated-coccidioidomycosis (accessed 7/10/17).

Cite as: Nia BB, Nia ES, Osondu N, Galgiani JN, Kuo PH. Tip of the iceberg: ¹⁸F-FDG PET/CT diagnoses extensively disseminated coccidioidomycosis with cutaneous lesions. Southwest J Pulm Crit Care. 2017;15(1):28-31. doi: https://doi.org/10.13175/swjpcc069-17 PDF