Sarcoid Lymphoma Syndrome
As subspecialists, often times we are consulted to help with diagnostics and or management of an acute or chronic disease process. Many times we perform diagnostics and initiate treatment and then defer a large majority of the care, if not all, back to the patient's primary care physician who referred the patient. We may see them on a routine basis but often times not as frequent as the primary care doctor. Sometimes we defer them back to their primary care physician and do not see them again unless another acute issue arises. And then, there are certain situations in which we essentially take over all care for the patient's diagnosis and continue to follow and treat for the specific disease process; not expecting the primary care physician to play a large role in the treatment.
Now, some primary care physicians may not like that last sentence, as they want to be involved in all aspects of their patient's care for all issues. But sometimes, certain things should be "left to the professionals" as they say. That will be a controversial statement among my colleagues I am sure. Most of the time this is not the case, and a patient's primary care doctor is still the patient's primary treating physician.
I recently had an experience with a particular patient with sarcoidosis in which it was not clear who was "running the show". Sarcoidosis is one of those disease states in which I would never just defer back to primary care. Not because it is overly complicated or the primary care doctors are not familiar with the disease process; they are. But because of the fact that sarcoidosis is a bit of a chameleon.
Sarcoidosis is described as a great imitator. It can involve any organ of the body and can present itself in many different ways. Most commonly we see sarcoidosis with lung involvement. Lung nodules or infiltrates can be seen. Frequently mediastinal lymphadenopathy is noted. Many times a person with sarcoidosis would also potentially have the skin or joint involvement, but again, it can involve any organ including the heart and brain which is much more difficult to diagnose and treat. Frequently, there can be retinal involvement which is why it is recommended that a patient with sarcoidosis see a good ophthalmologist for pupil dilation and a good retinal exam. Lab work can frequently have subtle differences. Classically, lab analysis with sarcoidosis is described as an elevated ACE level and may have hypercalcemia but this is not always the case and these labs cannot be used for absolute confirmation or refuting the diagnosis.
So, back to our patient. He had been appropriately diagnosed with sarcoidosis with lymph node resection showing classic pathologic findings of sarcoidosis with noncaseating granulomas. He responded appropriately to standard treatment with low-dose prednisone but his chest x-ray and mediastinal lymphadenopathy did not improve as much as his peripheral lymphadenopathy did. Pulmonary function tests improved with treatment. Everything suggested that the patient was responding appropriately to standard of care sarcoidosis treatment with the exception of his lung progress lagging behind his peripheral sarcoid symptom improvement. I had documented and discussed with the patient that if we did not see further improvement on imaging at our next appointment in a few months that we would need to consider secondary causes for the abnormalities noted on chest imaging. We would have to consider repeating bronchoscopy with lung biopsy and lymph node biopsy.
Unfortunately, the patient decided not to keep his follow-up appointment. Despite multiple attempts at contacting the patient, with repeated phone calls, to reschedule a follow-up appointment, the patient he did not show. Certified letters were sent to him and his primary care physician stating that the patient had missed appointments and needed to get back in to be seen in our office. The patient was predominantly being seen by the nurse practitioner at his primary care doctor's office who clearly was not aware that the patient was not following up with his pulmonologist for his sarcoidosis. He was seen several times for worsening shortness of breath and cough, in his primary care doctor's office over the next 6-9 months, and diagnosed with acute bronchitis and COPD exacerbations but consideration of sarcoidosis flare or another diagnosis was not considered. Primary care notes suggested that sarcoidosis was recognized as an ongoing diagnosis but it was clear that they thought the pulmonologist was still managing this. They were not aware that the patient was not keeping his follow-up appointments.
The problem was, his symptoms were not related to acute bronchitis or COPD exacerbations. Unfortunately, it was also not associated with a simple sarcoidosis flare. There was in fact a secondary process going on. He had developed a high-grade lymphoma. Luckily, he eventually was admitted to the hospital for what was initially diagnosed as pneumonia failing outpatient therapy. He had a diagnostic bronchoscopy with lung and lymph node biopsy which confirmed Hodgkin’s lymphoma with Reed-Sternberg cells on pathology. He was started on appropriate lymphoma treatment by oncology and has done very well and is in remission. Unfortunately, however, getting on treatment for his cancer was delayed due to lack of appropriate follow up and consideration for bronchoscopy at an earlier timeframe. Sometimes, when things aren’t going to plan, it is time to reconsider the initial diagnosis and start over. Sarcoidosis is a tricky disease and mimics other diseases, so in cases where treatment is not going to plan I have a low threshold to consider repeating biopsies.
There is an association with sarcoidosis and lymphoma and this is the main reason that I would never just defer a sarcoidosis patient back to primary care for complete management after diagnosis. It is not often seen and it is very difficult differentiating it from progression of sarcoidosis. In the literature this process is termed Sarcoid-Lymphoma-Syndrome; SLS. Case reports date back to the 1960s. Number of cases and studies available are not robust enough to give power to the studies to detect a clear mathematical risk of this rare entity, but reviewing the literature, it is suggested, a patient with sarcoidosis has a 2.0-5.5 relative risk of developing lymphoma.
In reviewing the literature, sarcoid-lymphoma syndrome, SLS, nearly always follows a diagnosis of sarcoid as opposed to sarcoid following the diagnosis of lymphoma. Hodgkin's lymphoma appears to be the predominant associated lymphoma in patients with SLS, and these patients tend to be diagnosed with sarcoidosis at an earlier age. This has suggested to investigators that early presentation of sarcoidosis might represent a paraneoplastic syndrome. Upon literature review, it has been suggested, patients with SLS who develop non-Hodgkin's lymphoma, NHL, tend to have a higher risk of developing high-grade NHL with an odds ratio of 2.3 compared to low-grade NHL or T-cell lymphomas.
Differentiating sarcoidosis and lymphoma by imaging is difficult. Both sarcoid and lymphoma are FDG avid, so PET imaging has been difficult to use for clarification. It has been suggested a biphasic PET imaging over the course of a few hours may be effective at differentiated cancer from benign tissue as glucose uptake by inflammatory tissue appears to be more rapid than malignant tissue. Lymphoma and lung cancer have significantly increased uptake at 2 hours compared to other malignant and nonmalignant disorders. This has led to the suggestion of a 2-hour delay as most appropriate for trying to distinguish malignant from benign disorders with PET imaging. PET imaging in sarcoidosis tends to be more of a homogeneous lymph node uptake suggesting asymmetric nodal uptake should lead one to consider malignant causes. Other possibilities for differentiation would be combination PET scan with gallium imaging. Mononuclear phagocytes in tissues involved by sarcoidosis take up gallium.
Given the difficulty in differentiating sarcoidosis and lymphoma, tissue diagnosis is essential. For this reason, patients with sarcoidosis need to have persistent follow-up with repeat imaging over time. If a person shows signs of progression or non-response to standard sarcoid treatment regimens, consideration of repeat diagnostics should be entertained. Diagnostic procedures such as bronchoscopy, endobronchial ultrasound, EBUS, and on occasion’s mediastinoscopy can obtain tissue for pathologic confirmation. EBUS, a less invasive endoscopic procedure for lymph node biopsy has predominantly replaced mediastinoscopy in recent years for lymph node biopsy.
Sarcoidosis is an inflammatory disease most simply described as the immune system going into overdrive, causing cells to group together and to clumps called granulomas. More than 90% of the cases affect the lungs and lymph nodes in the chest but sarcoidosis can affect any organ in the body. Every case of sarcoidosis is unique and sarcoidosis is described as a great imitator of other disease processes. Many times patients do not have any symptoms and the disease is initially entertained based on imaging such as chest x-ray which was taken for another reason. I would describe sarcoidosis as a disease of thirds, in that, a third of patients improve without treatment, a third of patients remain stable and a third of patients will progress and worsen without therapy.
Patients with sarcoidosis have increased inflammation in the body which can cause symptoms that are flulike such as cough, shortness of breath, wheezing, chronic fatigue, night sweats or joint pain. Patients with sarcoidosis may also present with a skin rash, joint pain or stiffness, eye irritation, kidney stones or abnormal lab work with elevated calcium in the blood or elevated liver function tests.
The exact cause of sarcoidosis is unknown. It is felt that it may be related to an infection or other exposure to something in the environment which may trigger an immune system overreaction and development of noncaseating granulomas. It is important to point out that sarcoidosis is not contagious.
People of African and Scandinavian descent are slightly more likely to develop sarcoidosis and it is more prevalent in women than men. Individuals with exposure to dusty or moldy environments may have increased risk of developing sarcoid.
Sarcoidosis is predominantly a manageable disease but does require regular follow-up and monitoring.
