# Clinical Cases: Lymphomas

## Case 1: Classical Hodgkin Lymphoma

### Patient Presentation
**Demographics:** 24-year-old male

**Chief Complaint:** Painless neck mass and night sweats for 6 weeks

**History of Present Illness:**
The patient noticed a painless lump in his left neck 6 weeks ago that has been slowly enlarging. He reports drenching night sweats requiring him to change his shirt, occurring 3-4 times per week. He has lost 15 pounds over the past 2 months without trying. He also reports generalized pruritus. He denies fever, cough, or shortness of breath. He is otherwise healthy with no significant medical history.

**Physical Examination:**
- Vital signs: BP 120/75, HR 78, RR 14, Temp 37.0C
- General: Thin but otherwise healthy-appearing young man
- HEENT: Left supraclavicular and cervical lymphadenopathy (4 cm, rubbery, non-tender)
- Cardiac: Regular rhythm, no murmurs
- Lungs: Clear to auscultation
- Abdomen: No hepatosplenomegaly
- Skin: Excoriations from scratching, no rash

### Workup and Results

**Laboratory:**
- WBC: 8,500/uL with normal differential
- Hemoglobin: 11.8 g/dL (mild anemia)
- Platelets: 385,000/uL
- ESR: 65 mm/hr (elevated)
- LDH: 280 U/L (upper normal)
- Albumin: 3.2 g/dL (low)

**Excisional Lymph Node Biopsy:**
- Reed-Sternberg cells present
- Large cells with bilobed nuclei ("owl eyes")
- Background of lymphocytes, eosinophils, plasma cells
- Nodular sclerosis pattern with fibrous bands

**Immunohistochemistry:**
- CD15: Positive
- CD30: Positive
- CD20: Negative
- CD45: Negative
- EBV (EBER): Negative

**Staging Workup:**
- PET-CT: Avid lymphadenopathy in left neck and mediastinum (10 cm mediastinal mass)
- No disease below diaphragm
- Bone marrow: Negative

### Clinical Image

![Reed-Sternberg Cell](case_01_image.jpg)

*Histologic section demonstrating a classic Reed-Sternberg cell with its characteristic bilobed nucleus, prominent eosinophilic nucleoli, and "owl-eye" appearance, surrounded by a reactive inflammatory infiltrate.*

### Diagnosis
**Classical Hodgkin Lymphoma, Nodular Sclerosis Type - Stage IIB (Bulky)**

Staging:
- Ann Arbor Stage II (both sides of neck = 2 regions, same side of diaphragm)
- B symptoms present (night sweats, weight loss >10%)
- Bulky disease (mediastinal mass >10 cm)
- Early-stage unfavorable

### Treatment Plan
1. **Pre-treatment evaluation:**
   - Pulmonary function tests (baseline for bleomycin)
   - Echocardiogram (baseline for anthracycline)
   - Fertility preservation discussion (sperm banking)

2. **Chemotherapy:**
   - ABVD x 4-6 cycles (Adriamycin, Bleomycin, Vinblastine, Dacarbazine)
   - OR A+AVD (brentuximab vedotin replacing bleomycin) if available

3. **Interim PET assessment:**
   - PET-CT after 2 cycles
   - If PET-negative: May reduce therapy
   - If PET-positive: Consider escalation

4. **Radiation:**
   - Involved-site radiation therapy after chemotherapy
   - Particularly important for bulky mediastinal disease

5. **Response-adapted approach:**
   - End-of-treatment PET to confirm complete remission
   - Long-term surveillance for relapse

6. **Prognosis:**
   - Early-stage unfavorable: 85-90% cure rate
   - Young age and nodular sclerosis favorable features

### Teaching Points
1. Reed-Sternberg cells with CD15+/CD30+ and CD45- define classical Hodgkin lymphoma
2. B symptoms (fever, night sweats, weight loss >10%) indicate worse prognosis
3. Hodgkin lymphoma spreads contiguously through lymph node groups
4. PET-CT is essential for staging and response assessment
5. ABVD is standard therapy with excellent cure rates even in advanced disease
6. Bleomycin pulmonary toxicity requires baseline and monitoring PFTs
7. The mediastinum is commonly involved in nodular sclerosis type (most common subtype)

---

## Case 2: Diffuse Large B-Cell Lymphoma (DLBCL)

### Patient Presentation
**Demographics:** 65-year-old female

**Chief Complaint:** Rapidly growing abdominal mass and weight loss

**History of Present Illness:**
The patient noticed abdominal fullness and early satiety 4 weeks ago. She has had progressive abdominal distension with a palpable mass. She reports 18-pound unintentional weight loss, drenching night sweats, and low-grade fevers over the past 6 weeks. She also has fatigue and decreased appetite. She has no history of lymphoma or autoimmune disease.

**Physical Examination:**
- Vital signs: BP 118/72, HR 92, RR 18, Temp 37.8C
- General: Cachectic-appearing elderly woman
- HEENT: No lymphadenopathy
- Cardiac: Regular rhythm
- Lungs: Decreased breath sounds at right base
- Abdomen: Distended with large palpable right-sided mass (15 cm), mild ascites
- Extremities: 1+ pitting edema bilateral lower extremities

### Workup and Results

**Laboratory:**
- WBC: 6,200/uL
- Hemoglobin: 10.2 g/dL
- Platelets: 145,000/uL
- LDH: 1,250 U/L (markedly elevated)
- Creatinine: 1.8 mg/dL (elevated)
- Uric acid: 10.5 mg/dL (elevated)

**CT Abdomen/Pelvis:**
- 18 cm heterogeneous retroperitoneal mass
- Moderate ascites
- Right hydronephrosis from ureteral compression
- Mesenteric lymphadenopathy

**PET-CT:**
- Intensely FDG-avid retroperitoneal mass (SUV max 28)
- Additional FDG-avid lymph nodes in mediastinum
- No bone marrow involvement

**Core Needle Biopsy:**
- Diffuse infiltrate of large atypical lymphoid cells
- High mitotic rate
- Areas of necrosis

**Immunohistochemistry:**
- CD20: Positive (strong)
- CD10: Positive
- BCL6: Positive
- MUM1: Negative
- BCL2: Positive
- Ki-67: 85%
- MYC: 40% (not rearranged)

**FISH:**
- BCL2 rearrangement: Positive
- MYC rearrangement: Negative
- BCL6 rearrangement: Negative

**Cell of Origin:** Germinal Center B-cell (GCB) subtype

**IPI Score:**
- Age >60: 1 point
- LDH elevated: 1 point
- Stage III/IV: 1 point
- ECOG ≥2: 1 point
- Extranodal sites >1: 0 points
- Total: 4 points (High-intermediate risk)

### Clinical Image

![DLBCL Histology](case_01_image.jpg)

*Histologic section of diffuse large B-cell lymphoma showing diffuse infiltrate of large atypical lymphoid cells with high nuclear-to-cytoplasmic ratio, prominent nucleoli, and frequent mitotic figures.*

### Diagnosis
**Diffuse Large B-Cell Lymphoma - GCB Subtype, Stage III, IPI High-Intermediate**

Key features:
- Aggressive B-cell lymphoma
- GCB subtype (better prognosis than ABC)
- Not double-hit (MYC not rearranged)
- Advanced stage with B symptoms

### Treatment Plan
1. **Pre-treatment:**
   - Ureteral stent placement for hydronephrosis
   - Aggressive hydration for tumor lysis prevention
   - Allopurinol or rasburicase

2. **First-line therapy:**
   - R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
   - 6 cycles, every 21 days
   - Consider addition of polatuzumab vedotin (Pola-R-CHP)

3. **Interim assessment:**
   - PET-CT after 2-4 cycles
   - End-of-treatment PET for response

4. **CNS prophylaxis:**
   - Consider intrathecal methotrexate or high-dose MTX given high LDH and renal involvement

5. **Relapsed/refractory:**
   - Salvage chemotherapy + autologous transplant if chemosensitive
   - CAR-T cell therapy (axicabtagene ciloleucel or tisagenlecleucel) if refractory

6. **Prognosis:**
   - IPI 4 points: ~50% 5-year survival
   - GCB subtype is favorable
   - Response to initial therapy is most important prognostic factor

### Teaching Points
1. DLBCL is the most common non-Hodgkin lymphoma (~30% of NHL)
2. Aggressive behavior requires prompt diagnosis and treatment
3. Cell of origin (GCB vs ABC) impacts prognosis; GCB is more favorable
4. Double-hit lymphoma (MYC + BCL2/BCL6) requires more intensive therapy
5. R-CHOP has been standard for 20+ years; new additions like polatuzumab improving outcomes
6. IPI score predicts prognosis based on 5 clinical factors
7. CAR-T therapy has transformed outcomes in relapsed/refractory disease

---

## Case 3: Follicular Lymphoma

### Patient Presentation
**Demographics:** 58-year-old male

**Chief Complaint:** Incidentally discovered lymphadenopathy during routine physical

**History of Present Illness:**
During a routine physical examination, the patient's physician noted enlarged lymph nodes in his neck and groin. The patient had noticed some neck fullness but attributed it to weight gain. He is completely asymptomatic with no fever, night sweats, weight loss, or fatigue. He has no prior history of lymphoma and no family history of hematologic malignancy.

**Physical Examination:**
- Vital signs: BP 128/78, HR 72, RR 14, Temp 36.8C
- General: Well-appearing man in no distress
- HEENT: Bilateral cervical lymphadenopathy (2-3 cm, rubbery, non-tender)
- Axillae: Small bilateral lymphadenopathy
- Cardiac: Regular rhythm
- Lungs: Clear
- Abdomen: No hepatosplenomegaly
- Inguinal: Bilateral lymphadenopathy (2 cm)

### Workup and Results

**Laboratory:**
- WBC: 7,400/uL with normal differential
- Hemoglobin: 14.5 g/dL
- Platelets: 225,000/uL
- LDH: 185 U/L (normal)
- Beta-2-microglobulin: 2.8 mg/L (mildly elevated)

**Excisional Lymph Node Biopsy:**
- Nodular/follicular growth pattern
- Mixture of centrocytes (small cleaved cells) and centroblasts
- Centroblasts <15 per high-power field

**Immunohistochemistry:**
- CD20: Positive
- CD10: Positive
- BCL2: Positive (aberrant)
- BCL6: Positive
- CD5: Negative
- Cyclin D1: Negative
- Ki-67: 20%

**FISH:**
- t(14;18) IGH-BCL2: Positive

**Grading:**
- Follicular lymphoma, Grade 1 (0-5 centroblasts/HPF)

**PET-CT Staging:**
- Multiple FDG-avid lymph nodes above and below diaphragm
- Largest node 4 cm in right groin
- Bone marrow involvement (confirmed on biopsy)

### Clinical Image

![Follicular Lymphoma](case_01_image.jpg)

*Histologic section of follicular lymphoma demonstrating characteristic nodular/follicular architecture with neoplastic follicles composed of centrocytes and centroblasts, BCL2 positive staining confirms aberrant overexpression.*

### Diagnosis
**Follicular Lymphoma, Grade 1, Stage IVA**

Key features:
- t(14;18) BCL2-IGH translocation
- Indolent lymphoma
- Stage IV (bone marrow involvement)
- Asymptomatic at presentation
- Low FLIPI score (good prognosis)

### Treatment Plan
1. **Initial approach - Watch and Wait:**
   - No treatment indication currently
   - Patient is asymptomatic
   - No cytopenias, no bulky disease, no impending organ compromise

2. **Indications for treatment (when to start):**
   - Symptomatic disease
   - Cytopenias from marrow involvement
   - Rapid progression
   - Bulky disease or impending organ compromise
   - Patient preference

3. **When treatment needed:**
   - Bendamustine + Rituximab (BR) preferred for most
   - OR R-CHOP for aggressive presentation
   - Rituximab maintenance after chemoimmunotherapy

4. **Surveillance:**
   - Physical exam and labs every 3-6 months
   - CT scan if clinical change
   - Watch for symptoms of transformation (sudden growth, B symptoms, rising LDH)

5. **Prognosis:**
   - Indolent course with median survival >15 years
   - NOT curable with standard therapy but long survival expected
   - Risk of transformation to DLBCL (~2-3% per year)

### Teaching Points
1. Follicular lymphoma is defined by t(14;18) BCL2-IGH translocation causing BCL2 overexpression
2. BCL2 prevents apoptosis, leading to accumulation of long-lived B cells
3. Watch and wait is appropriate for asymptomatic patients - treatment does not improve survival
4. Grading based on centroblast count; Grade 3B is treated like DLBCL
5. Transformation to aggressive DLBCL occurs at 2-3% per year
6. Rituximab maintenance prolongs remission after chemoimmunotherapy
7. Disease is typically incurable but most patients live many years