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

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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]
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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]
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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 

Role of Endobronchial Ultrasound in the Diagnosis and Management of Bronchogenic Cysts: Two Case Descriptions and Literature Review

Rene Franco-Elizondo MD

Soumya Patnaik MD

Kuan-Hsiang Gary Huang MD, PhD

Jorge Mora MD

Albert Einstein Medical Center

Philadelphia, Pennsylvania

Abstract

Imaging studies, such as high resolution computerized tomography (HRCT) and magnetic resonance imaging (MRI) facilitate the evaluation of mediastinal masses. However, the definite characterization of such masses can be ascertained only after tissue sampling is obtained and analyzed. Some mediastinal masses, like bronchogenic cysts, can be misdiagnosed as solid masses or lymphadenopathy in imaging studies, due to the variable densities of the cyst contents. More invasive tests, like fine needle aspiration or surgical resection of the bronchogenic cyst, may be necessary when HRCT fails to provide an initial diagnosis. We describe two such cases seen at our institution that highlight the implications of establishing a diagnosis of bronchogenic cyst with endobronchial ultrasound (EBUS) - trans-bronchial needle aspiration (TBNA) and discuss the possible therapeutic utility of EBUS-TBNA in select patients with bronchogenic cysts.

Abbreviation List

BAL - Bronchoalveolar lavage

CNS - Coagulase-negative Staphylococcus

CT – Computed tomography

EBUS - Endobronchial ultrasound

EUS – Endoscopic ultrasound

FOB - Fiberoptic bronchoscopy

HRCT - High resolution computerized tomography

MRI - Magnetic resonance imaging

RUL – Right upper lobe

TBNA - Trans-bronchial needle aspiration

VATS - Video-assisted thoracoscopic surgery

Introduction

Modern imaging, particularly high-resolution computed tomography (HRCT) and magnetic resonance imaging facilitate the evaluation of mediastinal masses. However, definite characterization is possible only after tissue sampling is obtained, typically through fine-needle aspiration or surgical resection. Herein, we report two cases of patients with mediastinal masses, where HRCT failed to provide a diagnosis. Bronchogenic cysts in both patients were ultimately diagnosed by endobronchial ultrasound (EBUS) and trans-bronchial needle aspiration (TBNA). The implications of establishing a diagnosis of bronchogenic cyst via EBUS-TBNA and therapeutic approaches are discussed.

Case 1

A 68-year-old African American woman with hypertension, diabetes mellitus type 2 and end-stage renal disease, on home hemodialysis, presented to the hospital with central stabbing chest pain, radiating to the back, accompanied by shortness of breath. An initial HRCT chest performed to rule out aortic dissection revealed a large subcarinal mass, measuring 2.3 cm x 6.5 cm x 3.8 cm (AP x transverse x height), that splayed the carina, exerting mass effect on the esophagus, raising suspicion of malignancy (Figure 1).

Figure 1. Subcarinal mass. Density ranged from 25-80 Hounsfield Units.

A separate 2.2 cm x 1.7 cm right paratracheal mass, mediastinal lymphadenopathy and many small prevascular lymph nodes were noted. These clinical and imaging findings were concerning for possible lymphoma.

A fiberoptic bronchoscopy (FOB), followed by blind TBNA of the subcarinal space using a Wang needle was attempted. Both, bronchoalveolar lavage (BAL) and TBNA were unrevealing. The patient was found to have persistent coagulase-negative Staphylococcus (CNS) bacteremia, with the first blood cultures being positive at the time of admission. A thorough evaluation, which included an echocardiogram and abdominal HRCT, failed to reveal a source of bacteremia, which was ultimately thought to be related to hemodialysis. Arrangements for outpatient EBUS evaluation of the mediastinal mass and lymphadenopathy were made and the patient was discharged.

A week later, she was readmitted for hypertensive emergency. EBUS was performed during this hospitalization and a cystic mass with heterogeneous-containing material was detected in the subcarinal space (Figure 2).

Figure 2 EBUS image of bronchogenic cyst and adjacent subcarinal lymph node.

The needle aspirate was sent for histological analysis and culture, but it was not possible to drain this cystic structure. Cytopathologic analysis showed bronchial and ciliated cells with abundant mucoid material and a diagnosis of bronchogenic cyst was made. Interestingly, the cultures from the aspirated material grew CNS. The patient was discharged with plans for a video-assisted thoracoscopic surgery (VATS) resection of the bronchogenic cyst as an outpatient.

Five days later, the patient was readmitted with symptoms that were concerning for sepsis, and was thus re-started on broad-spectrum antibiotics. She was found to have Enterobacter intermedius bacteremia. She subsequently underwent VATS, with direct aspiration of the bronchogenic cyst. A resection was not performed due to technical difficulties encountered during VATS. Purulent fluid was retrieved from the cyst and Enterobacter intermedius was identified upon analysis and culture of the cyst content. The patient had no further episodes of bacteremia after eight months of follow-up.

Case 2

A 43-year-old woman without significant past medical history was referred to our institute, for evaluation of a pretracheal lymph node seen on a chest HRCT (Figure 3) done for evaluation of new onset dyspnea and wheezing. Upon auscultation, a localized wheeze was noted with deep inspiration in the right upper chest. Her physical exam was otherwise unremarkable.

Figure 3. Chest CT showing subcarinal lymphadenopathy and mass. Density of mass 9-95 Hounsfield units.

A bronchoscopic exam with EBUS evaluation of lymphadenopathy was scheduled. On FOB, the patient was found to have an incidental endobronchial mass occluding the anterior segment of the right upper lobe. EBUS exam revealed an enlarged subcarinal lymph node (8 mm) with an adjacent cystic space containing homogenous hypoechoic material (Figure 4).

Figure 4. EBUS of bronchogenic cyst. A) Cyst prior to aspiration. B) Collapsed cystic cavity with enlarged lymph node now visible.

Both the lymph node and cystic space were sampled. Ten mL of serous fluid was aspirated from the cystic space, resulting in obliteration of the cavity, as visualized on the ultrasound (Figure 5).

Figure 5.Serous aspirate from cystic cavity.

Full mediastinal staging was done, and only station 11R lymph nodes were found to be enlarged and were sampled. Endobronchial biopsies, brushings and BAL were obtained from RUL endobronchial lesion. The patient was discharged home on empiric antibiotics (amoxicillin/clavulanate) for aspirated bronchogenic cyst. Subsequent fluid analysis revealed abundant macrophages and lymphocytes, consistent with cystic fluid content. Cultures of the fluid were positive for Streptococcus viridians. Lymph node sampling failed to reveal any evidence of malignancy. Interestingly, endobronchial mass biopsies, brushings and fluid cytology also failed to show evidence of malignancy. Only reactive inflammatory cells and benign bronchial elements were detected. The patient was continued on antibiotics for ten days without any evidence of infection.

A repeat bronchoscopy was performed to re-sample the endobronchial lesion. Benign elements were confirmed on the repeat biopsy. Follow up imaging has not been performed to evaluate fluid re-accumulation, since the patient has remained asymptomatic for two months.

Discussion

Mediastinal bronchogenic cysts are congenital anomalies of tracheobronchial origin; they are believed to be a result of an abnormal budding process during the development of foregut. They are often asymptomatic at presentation but can become symptomatic in 30% to 80% of cases due to infection or other complications like compressive efforts (1).

These cysts, being lined by secretary respiratory epithelium, consist of fluid of water density; however, the amount of proteinous mucus and calcium oxalate crystals in them can vary, affecting the imaging features on CT/MRI. A chest CT may reveal spherical masses with water or soft–tissue attenuation. A chest CT may misdiagnose them as soft-tissue masses in about 43% of patients. High attenuation on a chest CT can be a result of calcium oxalate or protein content, or can be due to infection of the cyst content (2, 3).

Due to the variable density in the cyst’s content, bronchogenic cysts can be misdiagnosed as masses or lymphadenopathy on non-invasive testing, as noted in our patients. EBUS can be of great help in diagnosing these lesions. Ultrasound provides an excellent delineation between tissues of different densities, and the absence of flow with color Doppler allows for differentiation from vascular structures. Ultrasonography allows a better delineation of cystic lesions and characterization of their contents (e.g. hypoechoic, isoechoic, heterogeneous, etc.), thereby providing useful diagnostic information. Needle aspiration of cyst contents can bring about not only cytological confirmation of the diagnosis, but also identification of complications such as infected bronchogenic cysts.

Our cases highlight the usefulness of EBUS in the diagnosis of bronchogenic cysts. In the first case, the diagnosis of bronchogenic cyst was made only after EBUS imaging and content aspiration were obtained, despite the initial chest HRCT specifically done to evaluate this mass. In the second case, EBUS imaging established the diagnosis in the absence of any suggestive findings on the HRCT.

The treatment of choice remains the complete surgical resection of the secreting mucosal lining, particularly in complicated cysts (11, 12). However, some authors have reported cases of successful treatment of bronchogenic cysts with EBUS-guided aspiration (4-8). In one case, a patient was followed up for eighteen months without evidence of recurrence (8). The rationale behind this approach is that complete drainage of the cyst obliterates the cyst cavity and prevents further fluid re-accumulation. In our first case, though complete drainage was not achieved with EBUS due to its thick mucoid content, aspiration of the cyst by VATS resulted in resolution without fluid re-accumulation. In our second case, resolution of the cyst was achieved via EBUS-TBNA drainage. These cases underscore the usefulness of aspiration of bronchogenic cysts as an alternative therapeutic approach to surgery in certain scenarios.

Contrary to the above mentioned cases, other case reports have pointed out life-threatening complications after bronchogenic cyst drainage with EBUS-guided FNA, such as pneumonia (9) or purulent pericardial effusion (10). As mentioned elsewhere, empiric antibiotic therapy should be given when a cystic lesion is drained via EBUS-TBNA (13). It should be noted, however, that in some of these case reports, infection post-EBUS-TBNA occurred despite giving empiric antibiotics (9), as in our first case.

The risk of infection should be underscored, as evidenced by the first case; particularly the less frequently reported possibility of bronchogenic cyst infection from bacteremia. The initial EBUS-TBNA cyst aspirate grew CNS, similarly to the blood cultures that were obtained prior to the blind TBNA sample of the mediastinal lesion. This suggests that the contamination of the cyst content could have been due to seeding from CNS bacteremia. However, the final VATS aspirate of the cyst grew Enterecoccus intermedius, which was likely to have been introduced by the EBUS-TBNA at the time of diagnosis. This infection occurred despite the use of antibiotics before and after the procedure. In this regard, the available literature is scant. In a study conducted by Steinfort et al. (14), incidence of bacteremia after EBUS-TBNA was found to be 7%, comparable to reported incidence of bacteremia from regular FOB. It is important to note that although none of these patients experienced clinical signs of infection, none of the biopsies were taken from cystic structures. Data evaluating EBUS-TBNA of mediastinal cystic lesions is conflicting. In a report of 22 patients undergoing EUS-TBNA of suspected mediastinal cyst and receiving periprocedural antibiotics, no infectious complications were found (15). However, several case reports of serious infectious complications after EBUS-TBNA have also been published (16).

Conclusion

Diagnosis of bronchogenic cysts cannot always be made with commonly used chest-imaging modalities such as X-ray or CT. EBUS has proven to be a useful diagnostic tool in the evaluation of some mediastinal masses. Although surgical resection remains the treatment of choice, complete aspiration, by VATS or EBUS, can be a successful therapeutic alternative in patients who are not candidates for surgery. However, the risks should be carefully assessed in each patient, with particular awareness of potential infectious complications. When this approach is taken, empiric antibiotics are recommended.

References

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Reference as: Franco-Elizondo R, Patnaik S, Huang K-H G, Mora J. Role of endobronchial ultrasound in the diagnosis and management of bronchogenic cysts: two case descriptions and literature review. Southwest J Pulm Crit Care. 2014;9(2):115-22. doi: http://dx.doi.org/10.13175/swjpcc096-14 PDF