The Fear of Lymphadenopathy: Does It Portend Sarcoidosis or Lymphoma?

AUTHORS:
Eduardo Solbes, MD; Richart W. Harper, MD; and Samuel Louie, MD

CITATION:
Solbes E, Harper RW, Louie S. The fear of lymphadenopathy: Does it portend sarcoidosis or lymphoma? Consultant. 2016;56(11):1016-1020.

Lymphadenopathy (localized or widespread) that is found during routine physical examination, on chest radiographs, or on chest computed tomography (CT) scans, is a nonspecific finding, but it can elicit intense fear and anxiety from both the patient and the clinician.¹ Malignancy, particularly lymphoma, is immediately suspected whether the patient is young or old, but it should be the top concern in patients who are older than 50 years. However, it is a major pitfall to reach conclusions prematurely, even if the patient has preexisting risk factors, such as age, chronic obstructive pulmonary disease (COPD), tobacco smoking, or a history of cancer.

Lymphadenopathy: Differential Diagnosis

It is important to know which disease states or conditions lymphadenopathy can be associated with. We offer our mnemonic, MAGIC, to help keep the differential diagnosis of lymphadenopathy in mind during the initial assessment (Table 1). This acronym should be used with another mnemonic, the 5 T’s that cause superior and anterior mediastinal masses: (1) intrathoracic thyroid goiter; (2) tumors of the thymus, including thymoma (especially in cases of myasthenia gravis), thymic cyst, thymic carcinoma, and thymic carcinoid; (3) dilated thoracic aorta; (4) teratoma (mediastinal germ cell tumors); and (5) terrible lymphoma. Lymphoma is the clear link between the 2 acronyms.

The drugs linked to lymphadenopathy, pseudolymphoma, or drug-induced hypersensitivity syndrome are legion; Table 2 offers a very short list of commonly used prescription and nonprescription drugs.

It is a pitfall to forget that a number of very common diseases can cause benign, “reactive” lymphadenopathy, including COPD, bronchiectasis, and congestive heart failure (CHF). Cases of benign, reactive mediastinal lymphadenopathy have been uncovered on chest radiographs in patients with CHF.² Chest CT scans have confirmed multiple enlarged lymph nodes exceeding 10 mm—and their disappearance after treatment with diuretics and digitalis. In one report, lymph node histopathology obtained by mediastinoscopy consistently revealed noninflammatory, benign lesions that did not affect the node structure. The diagnostic approach to such lymphadenopathy should be guided by the radiologic regression seen on follow-up CT scanning after treatment for decompensated CHF.²

Reactive lymphadenopathy was detected on chest CT in 81% of 42 patients with bronchiectasis in one study.³ Nodes larger than 10 mm (the maximum size for normal nodes) were detected in 29% of patients. In the absence of other recognized causes of lymphadenopathy in these patients, these findings confirm reactive mediastinal lymph node enlargement in bronchiectasis.³

In a retrospective study,⁴ 89 COPD patients were found to have mediastinal and hilar lymphadenopathy in the absence of malignancy and pneumonia; 49% of patients showed enlarged lymph nodes. Lymph node enlargement was seen more often in the mediastinum (48%) than in the hilar region (20%). Enlarged lymph nodes were present in 49% of patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 COPD, 46% of those with GOLD stage 2 COPD, 58% with GOLD stage 3 COPD, and 50% of those with GOLD stage 4 COPD. These findings did not differ significantly. Severe airway wall thickening on chest CT, presumably from longstanding chronic bronchitis or even bronchiectasis, was significantly associated with lymphadenopathy in 64% of cases.⁴

One of the best ways to learn is by reviewing actual cases that are not discussed in textbooks or online references. We offer the following case to challenge conventional dogma about lymphadenopathy in clinical practice.

CASE REPORT

A 55-year-old woman with a history of follicle-center lymphoma of the head and neck, cutaneous granulomas, and suspected asthma was referred to our center after abnormal results of a positron emission tomography (PET)/CT scan. Her lymphoma initially had been diagnosed in 2012 and had been treated with radiation therapy. Subsequent PET/CT scans showed no evidence of disease.

In 2016, the patient developed palpable cervical lymphadenopathy. Repeated fludeoxyglucose F 18 (FDG) PET/CT scans demonstrated FDG-avid lymphadenopathy in the head and neck as well as the mediastinal and hilar regions (Figure). She underwent excisional biopsies of the tongue base and the right deep cervical lymph nodes. Biopsy results did not show evidence of lymphoma by pathology or by flow cytometry. She was subsequently referred to the pulmonary oncology clinic for diagnostic bronchoscopy with endobronchial ultrasonography (EBUS), given her mediastinal lymphadenopathy.

Figure. PET/CT scan showing FDG-avid bilateral hilar lymphadenopathy (left) and right paratracheal lymphadenopathy (right).

Results of EBUS-guided transbronchial fine-needle aspiration of the subcarinal and left hilar nodes showed only reactive lymphoid tissue, and transbronchial biopsy results from the left lower lobe showed nonnecrotizing granuloma and no evidence of lymphoma. None of the specimens showed acid-fast bacilli or fungi on staining, nor did any pathogen grow from bronchoalveolar lavage fluid cultures.

The patient was subsequently referred to a sarcoidosis clinic, where her recorded symptoms included resolving skin lesions on the hands and a mild cough. Further workup revealed normal results of a metabolic panel, a normal angiotensin-converting enzyme (ACE) level, and a complete blood cell count notable only for a leukocytosis of 12,000 cells/µL. Additional imaging workup included cardiac magnetic resonance imaging (MRI) based on heterogeneous FDG uptake in the heart. Cardiac MRI did not demonstrate any evidence of sarcoidosis. Pulmonary function tests (PFTs) showed normal spirometry results with a significant improvement in forced expiratory volume in the first second (FEV₁) after bronchodilators, normal lung volumes, and a normal carbon monoxide diffusing capacity (Dlco). Prednisone therapy was not initiated, and she follows up regularly with the sarcoidosis clinic.

SARCOIDOSIS

Sarcoidosis is a chronic, multisystem, inflammatory disease of uncertain etiology. Pathologically, it is characterized by tissue infiltration of mononuclear phagocytes, lymphocytes, and noncaseating granulomas. The current consensus opinion of sarcoidosis experts is that the disease results from exposure of genetically susceptible individuals to specific environmental antigens that are persistent and poorly digested by the host immune system.⁵ The presence of this antigenic stimulus triggers a T_H1 cellular immune response that results in granuloma formation. The antigens that have been implicated range from infectious causes such as viruses and bacteria to noninfectious causes such as pollen, soil, and metals.⁵

While sarcoidosis is typically a chronic disease that may last for years to decades, it may also take the form of an acutely presenting illness called Löfgren syndrome that typically presents with erythema nodosum and bilateral hilar lymphadenopathy that is self-limiting and requires no prednisone treatment. There are also likely a significant number of cases that remain clinically silent or that display a bilateral reticulonodular pattern with hilar prominence on chest radiographs and chest CT scans.

The highly variable prevalence estimates (from 5 to 40 per 100,000 population) highlight the fact that sarcoidosis does not affect the population uniformly.⁵ Epidemiologic investigations have consistently found that the time of peak incidence of sarcoidosis is in young adulthood (20- to 40-year-olds). Women appear to be disproportionately affected. African Americans have an incidence rate of sarcoidosis that is 11 times higher and a hospitalization rate for sarcoidosis that is 7.5 times higher than those of whites.⁵ Persons of Asian descent also appear to have 12 times higher incidence of sarcoidosis compared with white persons.⁵ Among the white population, Scandinavians tend to be disproportionately affected by sarcoidosis.⁵

Although sarcoidosis is a multisystem disease, certain organs are more commonly involved than others, giving rise to protean manifestations including fever and malaise; blurred vision, photophobia, and red eyes; cough, chest pain, and dyspnea; and rashes. However, hilar lymph nodes are most commonly involved as evident on abnormal chest radiograph findings, followed by the lungs (reticulonodular pattern), and then nonhilar lymph nodes (eg, right paratracheal nodes).⁵ Other organs that may be affected by sarcoidosis, albeit less commonly, are the liver, spleen, skin (lupus pernio, erythema nodosum), eyes (anterior > posterior granulomatous uveitis, often recurrent), kidneys (nephrocalcinosis), salivary glands (Heerfordt syndrome consists of uveitis, parotitis, and fever), bones, heart (heart block, arrhythmias), and the central nervous system (Bell palsy, neurosarcoidosis).⁵

SARCOIDOSIS AND LYMPHOMA COEXIST?

The coexistence of sarcoidosis and lymphoproliferative disease has been recognized since the 1930s.^6,7 In patients with chronic active sarcoidosis, lymphoma has been observed to occur from 5.5 to 11.5 times more frequently than in the general population. This relationship was noticed by Brincker in 1972,⁶ and he further described it in a case series of 46 patients in 1986,⁷ where he coined the term sarcoidosis-lymphoma syndrome. According to Brincker, the 3 salient characteristics of the sarcoidosis-lymphoma syndrome were as follows⁷:

1. In all but 2 cases, the diagnosis of lymphoma occurred after that of sarcoidosis. The median interval between diagnoses was 24 months.
2. The median age at sarcoidosis diagnosis was 41 years, which is 10 years older than in the general sarcoid population.
3. Hodgkin lymphoma occurred more frequently in sarcoidosis patients than would be expected if the relationship were truly fortuitous.

The proposed mechanisms of this syndrome involve alterations in the immune system initially triggered by chronic activation from sarcoidosis. Such mechanisms include increased mitotic activity of lymphocytes and subsequent genetic mutation in chronically inflamed tissue, and a decreased number of circulating helper T cells that leads to decreased identification and rejection of tumor cells and/or oncogenic viruses, thus allowing for lymphoproliferation.⁷ Other postulated mechanisms include that the treatment of sarcoidosis with corticosteroids may precipitate the development of steroid-sensitive lymphomas.⁸

Less commonly, sarcoidosis has also been observed to occur after a diagnosis of lymphoma. Brincker noted 2 cases in which this occurred; however, he thought that the relationship was coincidental. In a case series of 65 patients, lymphoma was the second most common malignancy preceding a sarcoidosis diagnosis.⁹ In a combined case series and literature review of 39 patients,¹⁰ the median interval between lymphoma and sarcoidosis diagnosis was 18 months. There was roughly equal representation of non-Hodgkin lymphoma and Hodgkin disease. As in Brincker’s study, this cohort of patients tended to be older at time of sarcoidosis diagnosis, with a median age of 49 years. Also noteworthy was that the sarcoidosis and lymphoma both tended to be milder: of the 41% of patients requiring treatment for sarcoidosis, 75% had a complete clinical response.¹⁰ Furthermore, 82% of patients in this study had no clinical manifestations of sarcoidosis at 16 months of follow-up, and the same percentage of patients had maintained complete remission of lymphoma at 48 months of follow-up.¹⁰

These observations are consistent with other studies that have shown sarcoid-like reactions to be associated with an improved prognosis in patients with Hodgkin disease.^11,12 There are several proposed mechanisms by which sarcoidosis may arise subsequent to lymphoma, including immune or inflammatory reactions to malignancy, adverse effects of chemotherapy, cell-mediated immune response to tumor antigens, and previously undiagnosed sarcoidosis.⁹ To date, none of the proposed mechanisms of the association between sarcoidosis and lymphoma have been proven, and this is an area that is open for further investigation.

AVOIDING DIAGNOSIS AND MANAGEMENT PITFALLS

The overlap of clinical symptoms and signs, organ involvement, and radiographic findings between sarcoidosis and lymphoma, as well as their possible coexistence, poses significant challenges for diagnosis and disease surveillance. In addition to the clinical history, physical examination findings, and laboratory evaluation findings, radiographic imaging (primarily contrast-enhanced chest CT scans and PET/CT scans) is a valuable tool used in the diagnosis and surveillance of both diseases.

The efficacy of FDG PET/CT in the diagnosis and surveillance of sarcoidosis has been studied. In a series of 20 patients with biopsy-proven sarcoidosis,¹³ FDG PET/CT showed 100% sensitivity in localizing sarcoidosis involving the lungs and sinonasal region. It showed 80% sensitivity in localizing sarcoidosis to the pharyngolaryngeal region. Overall sensitivity from 36 biopsy-proven locations was 78%, which increased to 87% when skin involvement was excluded. Five of the 20 patients in this study underwent a second FDG PET/CT scan after treatment with corticosteroids. Complete regression of disease was seen in 2 cases, incomplete regression of disease was seen in 2 cases, and disease progression was seen in 1 case.¹³

In another study, FDG PET/CT was shown to have a sensitivity of 87.5% for diagnosing cardiac sarcoidosis but a specificity of only 38.5%.¹⁴ In the same study, cardiac MRI showed a sensitivity of 75% and a specificity of 76.9%. 

While cardiac MRI is often used to evaluate for the presence of cardiac sarcoidosis, FDG PET/CT is the imaging modality most commonly used to evaluate for sarcoidosis in all other regions of the body, and it has also become an imaging modality commonly employed in various lymphomas based on its ability to provide both structural and functional information.¹¹

While PET/CT is a sensitive test, its lack of specificity is where making a diagnosis based heavily on imaging can lead to an erroneous diagnosis and the delivery of inappropriate treatment, while simultaneously delaying the correct diagnosis and implementation of appropriate treatment. Conditions that result in an increase in glycolysis, such as infection, inflammation, and granulomatous diseases, can result in increased FDG uptake and be mistaken for lymphomatous involvement.¹⁵

Similarly to our case above, the lack of specificity of FDG PET/CT for sarcoidosis is illustrated in a case report of a 52-year-old woman who presented with a 4-month history of fevers, night sweats, and a 50-pound unintentional weight loss.¹⁶ PET/CT showed avid uptake in the lymph nodes of the neck, mediastinum, and hila. Given the clinical history and diffuse lymphadenopathy on PET/CT, the primary concern was for lymphoma. However, biopsies of a subcarinal lymph node and bone marrow showed noncaseating granulomas consistent with sarcoidosis, and no evidence of lymphoma was seen. The patient was started on immunosuppression for presumed sarcoidosis, and the patient experienced clinical improvement. A follow-up PET/CT scan showed regression of disease activity.¹⁶

In conclusion, while the clinical history, physical examination, laboratory evaluation, and imaging serve vital roles in the diagnosis and surveillance of both sarcoidosis and lymphomas, these can be nonspecific, given that the clinical and radiographic features of these diseases may overlap, and that sarcoidosis and lymphoma may coexist within organs. In order to ensure that the proper diagnosis is made, referral to a specialist who is capable of obtaining tissue biopsy specimens for histopathologic examination should be pursued whenever a patient presents with new or recurrent lymphadenopathy. 

Eduardo Solbes, MD, is a fellow in the Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, at UC Davis Medical Center in Sacramento, California.

Richart W. Harper, MD, is a professor of medicine in the Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, at UC Davis Medical Center in Sacramento, California.

Samuel Louie, MD, is a professor of medicine in the Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, and director of the ROAD Center at UC Davis Medical Center in Sacramento, California.

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