We worked through a case from the Human Diagnosis Project with a 57 yo M originally form Guatemala (moved to US 25 years ago) with a history of pre-DM and recently diagnosed and treated Lyme disease presenting with 2 months of persistent fever, chills, malaise, and myalgias. He received extensive work up, and everything turned (including TEE, LP, SPEP, rheum, BM biopsy, HIV) were negative. He had splenomegaly on exam, and CT CAP revealed hilar LAD + LLL tree-in-bud along iwth a 20cm spleen. The patient was ultimately diagnosed with DLBCL, AND cryptococcal pneumonia secondary to immunosuppression from his lymphoma!

Credit: Dr. Ron Cho, New York Medical College, Internal Medicine.

Fever of Unknown Origin

• Classic Definition
  • Fever > 38.3 °C on multiple occasions
  • Duration > 3 weeks
  • Uncertain diagnosis after 3 outpatient visits or 3 days in the hospital (revised, used to be 1 week inpatient investigation) or 1 week of “intelligent and invasive” ambulatory investigation
• Etiology
  • Infectious
    • TB is the single most common infection in most FUO series, can be extrapulmonary, military, or pulmonary. May occur concurrent in AIDS patient, leading to a more subtle presentation.
    • Abscess
    • Osteomyelitis
    • Bacterial endocarditis (2-5% of these are culture negative bacterial endocarditis, i.e. from Coxiella brunetii and tropheryma whipplei).
      • Super rare causes of endocarditis with difficult to grow culture: Mycoplasma, Legionella, Bartonella, Brucella, HACEK organisms
      • TEE is positive in > 90% of cases of FUO from infective endocarditis.
    • Viral i.e. EBV
  • Malignancy: Most common are lymphoma and leukemia.
    • NH Lymphoma
    • Leukemia
    • RCC
    • HCC
    • Myelodysplastic syndromes
  • Systemic Rheumatic disease
    • Adult onset Still’s disease: young and middle age adults, daily fevers, arthritis, evanescent rash.
    • GCA: Older patients
    • Polyarteritis nodosa, Takayasu, GPA, cryoglobulinemia
  • Others
    • Drugs: Antibiotics, H1 & H2 blocking antihistamines, antiepileptic drugs, NSAIDS, hydralazine, antithyroid drugs, digoxin.
    • Factitious fever: Psych, predominantly affects F and healthcare professionals
    • Disordered heat homeostasis after a stroke or from hyperthyroidism
    • Dental abscess
    • Multiple concurrent infections
    • Alcoholic hepatitis
    • VTE/PE
    • Hematoma
    • Hereditary periodic fever syndromes
  • Unidentified: 19% of cases are unidentified.
• Management/Diagnostic Principles
  • Get a detailed history, including fever pattern exposure history, sexual history, family history, medications.
  • Do not start empiric therapy unless pt is neutropenic or unstable, or you have a high-suspicions for GCA or culture negative endocarditis.

DLBCL

Epidemiology

• Most common type of NH Lymphoma, representing 25% of cases
• Median age: 64, 55% men. Also accounts for 25% of childhood NHL.
• Caucasians at higher risk and esp patients of Swedish and Danish ancestry
• Other risk factors: HIV, h/o radiation or chemotherapy

Pathophysiology

• Heterogenous group of tumors that arise from mature B cells in (90% of cases, the other 10% from T cells)
• Most common mutations found in DLBCL:
  • BCL6 gene mutation
  • BCL2 activation
  • MYC overexpression

Presentation

• Nodal and extra-nodal manifestation at time of diagnosis. Most common extra-nodal manifestation is bonemarrow or GI tract.
• Typically pts present with a mass, most commonly in the neck, abd, or mediastinum but it can manifest anywhere.
• Painless LAD might be present in 2/3 of cases.
• Less than 50% will have B-sx.
• Can present with pancytopenia. Might see elevated LDH, uric acid, and calcium.

Diagnosis

• Excision LN or tissue biopsy, excisional LN is preferred

Staging

• Ann Arbor Criteria
• 
  • Stage I – disease in single lymph node or lymph node region.
  • Stage II – disease in two or more lymph node regions on same side of diaphragm. Note: Stage II contiguous means two or more lymph nodes in close proximity (side by side).
  • Stage III – disease in lymph node regions on both sides of the diaphragm are affected.
  • Stage IV – disease is wide spread, including multiple involvement at one or more extranodal (beyond the lymph node) sites, such as the bone marrow (which is involved commonly), liver, pleura (thin lining of the lungs).
  • Spleen is considered nodal

Management

• • 1^st line is RCHOP (3 cycles) and local regional radiation, 6-8 cycles of R-CHOP is an acceptable alternative.
  • Emerging data, DA-EPOCH is better for younger patients < 60 yo and with certain phenotypes
  • Double Hit Lymphoma: Lymphoma resembling DLBCL but has MYC gene translocation AND rearrangement of BCL 2 or BCL 6. RCHOP still first line but overall prognosis is worse. DA-EPOCH-R might work better.