Complex case suspicious for lymphoma but rules in as Sarcoidosis.
I give the NEJM summary up to the diagnosis at at bottom.
https://www.nejm.org/doi/full/10.1056/NEJMcps2304844
CHAT GPT4 DISCUSSES THE CASE TO THIS POINT.
The patient's medical history, physical examination findings, and investigative results all point towards a diagnosis of Sarcoidosis. This systemic granulomatous disease often involves multiple organ systems, most commonly the lungs, skin, and lymph nodes, but can potentially affect any organ.
The noncaseating granulomas found in the excisional biopsy of the right groin lymph node, along with the extensive lymphadenopathy observed on CT and PET scans, are consistent with sarcoidosis. The lung nodules, skin changes, joint pains, elevated ACE levels, and her family history further support this diagnosis. Sarcoidosis is indeed known for its association with tattoos and could explain the skin changes overlying the tattoos.
The negative interferon gamma release assay, lack of necrosis in the biopsied lymph node, absence of pulmonary symptoms typical of tuberculosis, and the fact she has not traveled outside of Massachusetts make tuberculosis an unlikely diagnosis.
Lymphoma was another important consideration due to the systemic symptoms and lymphadenopathy. However, flow cytometry did not reveal any evidence of a lymphoproliferative disorder, and no malignant cells were found in the lymph node biopsy.
Systemic Lupus Erythematosus (SLE) was also a possibility given the patient's joint pains and rashes. However, the absence of other typical manifestations (such as photosensitivity, alopecia, Raynaud's phenomenon, or oral ulcers) and negative antinuclear antibody test make this less likely.
The next steps would be a multidisciplinary approach to manage her symptoms and the disease itself. This includes pulmonary function tests, ophthalmological evaluation, skin biopsy (if not already performed) from the affected areas, bone density test (due to the risk of osteoporosis in long-term sarcoidosis), and potentially cardiac evaluation as sarcoid can affect the heart. A treatment plan including corticosteroids or other immunosuppressive agents might be considered, based on the severity and extent of the disease. Regular follow-ups would be necessary to monitor her symptoms and the effect of treatment. Lifestyle modifications including smoking cessation will also be beneficial. Finally, genetic counseling may be of value given the family history of sarcoidosis.
Your analysis is correct. Here is how the case continues, beyond the point that you read above.
In this case, the combination of histologic findings (including an absence of cancer or infection), radiographic signs, and cutaneous manifestations are diagnostic of sarcoidosis.
Prednisone was prescribed at a dose of 40 mg daily, and the patient had rapid abatement of her abdominal and pulmonary symptoms. She reported no palpitations, lightheadedness, or syncope; an electrocardiogram showed no conduction abnormalities. An ophthalmologic evaluation showed no uveitis or retinal abnormalities such as “candle wax dripping” lesions (perivenous exudates associated with periphlebitis in patients with acute ocular sarcoidosis). Biopsy cultures were negative for mycobacteria after 60 days.
The patient did well for 1 year but had a recurrence of symptoms after completing a prednisone taper. Prednisone treatment was restarted, and the patient was transitioned to methotrexate (a glucocorticoid-sparing immunosuppressant)
ChatGPT4 CLOSING REMARKS
This is a classic presentation of sarcoidosis, a systemic granulomatous disease that can affect any organ system but most commonly involves the lungs and lymph nodes. The patient’s symptoms such as abdominal pain, unintentional weight loss, night sweats, skin changes, and the presence of a nonproductive cough and dyspnea suggest multi-organ involvement.
Sarcoidosis often presents with non-specific symptoms, as seen in this case, making the diagnosis challenging. The presence of non-necrotizing granulomas in biopsy samples from involved tissues is a hallmark of sarcoidosis but is not specific. Exclusion of other causes, such as infections or malignancy, is a crucial part of the diagnostic process.
It is interesting to note the patient's response to prednisone, the initial first-line therapy for sarcoidosis. Prednisone can effectively control the symptoms and inflammation associated with sarcoidosis. However, as in this case, some patients may require more prolonged treatment or additional immunosuppressive medications, like methotrexate, due to recurrence of symptoms after initial tapering of prednisone.
Methotrexate has been shown to have a steroid-sparing effect, and its use can help mitigate the long-term side effects of corticosteroids. It is generally well-tolerated and effective in the management of sarcoidosis. Regular monitoring is essential to check for potential adverse effects, such as hepatotoxicity and myelosuppression.
In summary, this case illustrates the diagnostic challenges of a disease with a highly variable presentation, and the importance of a systematic approach to investigation, including histological confirmation and exclusion of differential diagnoses. It also highlights the potential for relapse in sarcoidosis and the need for individualized long-term management plans.
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors’ commentary follows.
A 32-year-old woman presented to the emergency department with a 6-month history of worsening abdominal pain. She rated the pain as 10 on a 10-point scale of severity; the pain was localized to the epigastrium and was characterized as intermittent and cramping in nature, without substantial radiation. It was not associated with eating or exertion but was associated with unintentional weight loss of 20 lb (9 kg). She reported chills, night sweats, a nonproductive cough, and intermittent dyspnea and wheezing that did not respond to inhaled albuterol. She reported that she had not had fever, headaches, vision changes, chest pain, nausea, emesis, changes in bowel habits, or genitourinary symptoms. Her menstrual cycles were normal.
Localized gastrointestinal disorders (e.g., gastritis, peptic ulcer disease, and pancreatitis) could cause chronic abdominal pain but would not explain this patient’s systemic symptoms. Chills, sweats, and weight loss suggest a systemic infectious, inflammatory, or neoplastic disease. An indolent infection, such as tuberculosis or histoplasmosis, could also explain her pulmonary symptoms. A cancer, such as a lymphoma, could cause a similar constellation of symptoms as a result of pulmonary and abdominal lymphadenopathy. Additional symptoms suggestive of autoimmune disease (Raynaud’s phenomenon, arthritis, oral ulcers, and eye or skin changes), infectious exposures, and a family history of inflammatory disease or cancer would help refine the differential diagnosis.
The patient noted intermittent joint pain in both hands but reported no color changes in the fingers or pain elsewhere in her limbs. She reported that she had had skin changes on her legs over the course of 6 months, with nonpainful bumps present at the sites of recent tattoos. She did not have dry eyes, dry mouth, oral ulcers, pleuritic chest pain, photosensitivity, or alopecia. Her medical history was notable for gastroesophageal reflux disease and constipation. She had no history of surgery. Her medications included acetaminophen twice daily for abdominal pain, with only modest effect. She had no known allergies. She identified as Black and lived in Boston; she worked as a patient care assistant and did not travel outside of Massachusetts. She was sexually active with one male partner and used condoms consistently. She had smoked a half pack of cigarettes daily for 13 years, and only rarely used marijuana or vaped. She had no known exposures to inhaled particulates such as silica or metal dusts, including beryllium. She consumed eight alcoholic drinks per week. She reported that she did not use other drugs. There was no family history of cancer or gastrointestinal disease; an aunt had sarcoidosis.
Reflux and constipation could contribute to the abdominal pain but would not explain her night sweats and weight loss. The absence of travel outside Massachusetts reduces concern for an endemic mycosis such as histoplasmosis, but her health care occupation increases her risk of tuberculosis. Although her alcohol consumption modestly exceeds “healthy” intake (<7 drinks per week in women), it is unlikely to cause alcohol-related complications at this age. Skin changes involving tattoos can be seen in infectious and inflammatory or granulomatous conditions, most classically in sarcoidosis; the family history increases concern for sarcoidosis.
Figure 1.
Skin Changes.
The patient’s oral temperature was 36.5°C, the heart rate 62 beats per minute, the blood pressure 122/66 mm Hg, the respiratory rate 16 breaths per minute, and the oxygen saturation 98% while she was breathing ambient air. Her height was 163 cm, and her weight was 58 kg, for a body-mass index (the weight in kilograms divided by the square of the height in meters) of 21.8. She was well-appearing, without cachexia. The conjunctivae, oropharynx, and parotid glands were normal. There was nontender lymphadenopathy bilaterally in the cervical, supraclavicular, axillary, and inguinal chains. Cardiac and pulmonary examinations were normal. The abdomen was soft and nondistended, with mild tenderness to deep palpation in the epigastrium without rebound, guarding, organomegaly, or other masses. The limbs showed mild tenderness to palpation in the left elbow and right knee, with a full range of motion and no erythema, swelling, or effusion; the remaining joints were unremarkable. The neurologic examination was normal. The patient’s skin was warm and dry; scattered firm, slightly eroded, nontender, erythematous and violaceous papules were present on the arms and legs, with a cluster at the right knee and overlying bilateral tattoos on the legs (Figure 1).
Although diffuse lymphadenopathy may reflect infectious or inflammatory processes, lymphoma is of particular concern. The combination of arthralgias, lymphadenopathy, and rashes could be explained by systemic lupus erythematosus even without Raynaud’s phenomenon, photosensitivity, or alopecia. The erythematous papular rash could be caused by an infection such as borreliosis or mycobacterial disease, cancers such as cutaneous marginal-zone lymphoma or T-cell lymphoma, or a dermal inflammatory reaction. An association with tattoo ink is characteristic of sarcoidosis but can also be seen in the context of cutaneous pseudolymphoma (benign lymphoproliferation in response to cutaneous antigens) or infections related to local inoculation.
Results of liver-function tests and levels of serum electrolytes, creatinine, calcium, lipase, and thyroid-stimulating hormone were normal, as were the prothrombin time and partial thromboplastin time. The white-cell count was 5240 per microliter, with 36.1% neutrophils (reference range, 48 to 76), 36.8% lymphocytes (reference range, 18 to 41), 11.6% monocytes (reference range, 4 to 11), and 14.5% eosinophils (reference range, 0 to 5); the hemoglobin level was 13.6 g per deciliter, and the platelet count 338,000 per microliter. The erythrocyte sedimentation rate was 50 mm per hour (reference range, 0 to 20), and the C-reactive protein level was normal. The lactate dehydrogenase level was 294 U per liter (reference range, 135 to 225), the angiotensin-converting enzyme level 146 U per liter (reference range, 16 to 85), and the total IgG level 2243 mg per deciliter (reference range, 700 to 1600). An interferon gamma release assay for tuberculosis was negative, as was syphilis immunoglobulin testing. Serologic testing for hepatitis A, B, and C viruses, human immunodeficiency virus, antinuclear antibody, antineutrophil cytoplasmic antibodies, and anti–double-stranded DNA antibody were negative; levels of C3 and C4 were normal. Urinalysis was normal, and a urine pregnancy test was negative.
Many of these tests suggest nonspecific increased activation of the immune system. An elevated erythrocyte sedimentation rate with a normal C-reactive protein level can be seen in the context of infections, autoimmune diseases such as systemic lupus erythematosus, and cancers with overproduction of immunoglobulins (e.g., Waldenstrom’s macroglobulinemia and multiple myeloma). Eosinophilia can occur with cancers, including lymphomas; in inflammatory disorders, such as sarcoidosis; or in infections (typically parasitic infections, but also others, including fungal infections). An elevated serum level of angiotensin-converting enzyme is also nonspecific and inadequate for a diagnosis of sarcoidosis; it can be elevated in the context of Hodgkin’s lymphoma, coccidioidomycosis, and berylliosis, among other conditions. The negative interferon gamma release assay makes tuberculosis less likely, but this assay can be falsely negative in patients with disseminated tuberculosis. Negativity for antinuclear antibody essentially rules out systemic lupus erythematosus. The absence of proteinuria or hematuria rules out glomerulonephritis. Overall, I remain concerned about lymphoma, with sarcoidosis as a likely alternative diagnosis.
Figure 2.
CT and PET Scans of the Chest, Abdomen, and Pelvis.
Chest and abdominal computed tomography (CT) performed after administration of contrast material (Figure 2A through 2D) showed diffuse thoracic and extensive bulky peritoneal and retroperitoneal lymphadenopathy, as well as subcentimeter nodular lower-lobe pulmonary opacities that were consistent with a possible “galaxy sign” (i.e., coalescent pulmonary granulomas that create a mass-like appearance) (Figure 2A). Whole-body positron-emission tomography (PET) showed intensely hypermetabolic lymph nodes in the cervical, retropharyngeal, mediastinal, internal mammary, subcarinal, axillary, abdominopelvic, periaortic, mesenteric, iliac, and inguinal regions. Additional hypermetabolic lesions were noted in areas of bone, lung, and skin (Figure 2E through 2H).
Extensive lymphadenopathy is highly suggestive of a lymphoproliferative disorder, particularly lymphoma, and the hypermetabolism seen in the PET scan further supports this diagnosis. Lymphadenopathy from a metastatic solid tumor, such as breast or lung cancer, is unlikely in this young patient without evidence of a primary tumor. Hypermetabolic lymphadenopathy can also be associated with infectious or inflammatory processes, including disseminated bacterial or fungal infections or autoimmune responses, as in systemic lupus erythematosus. Sarcoidosis remains possible, given the symmetric mediastinal and bilateral hilar lymphadenopathy, and could also explain the skin and bone involvement; sarcoidosis is also a well-recognized cause of a galaxy sign, although this finding can also occur in other conditions, such as tuberculosis. Before a diagnosis of sarcoidosis is made, lymphoma should be ruled out by definitive histologic examination.
Figure 3.
Right Inguinal Lymph-Node Tissue with Diffuse Granulomatous Changes.
The patient underwent excisional biopsy of a right groin lymph node. Flow cytometry of the tissue specimen showed no evidence of a lymphoproliferative disorder. Pathological analysis showed lymph-node effacement by nonnecrotizing granulomatous lymphadenitis without malignant cells (Figure 3). Gram and acid-fast staining was negative, as were bacterial and fungal cultures.
Effacement of lymph-node architecture by granulomas with a nonnecrotizing core is characteristic of, but not specific for, sarcoidosis. Fungal and mycobacterial infections should be ruled out with microbiologic cultures and stains. Multiple biopsy specimens may be needed to identify tuberculosis; however, this patient’s risk of tuberculosis is relatively low, and classically both tuberculosis and fungal infection would appear histologically as necrotizing (caseating) granulomas. Sarcoid-like granulomatous reactions may also be seen in association with Hodgkin’s lymphoma, non-Hodgkin’s lymphomas, seminoma in men, and a variety of carcinomas; clinical correlation is essential to exclude this possibility
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