Lymphomas

HODGKIN LYMPHOMA

Zachary H. Word

Craig Moskowitz

Epidemiology

Represents ˜12% of lymphomas
˜8-9K cases annually in US, resulting in ˜1300 death
Typically affects younger pts (20s-30s) but can also affect older adults

Biology/Pathology

2 major types:
- Classical HL
- NLPHL
Classical HL characterized pathologically by the Reed-Sternberg Cell, a large, bilobed, or multinucleated cell that classically has an “owl’s eyes” appearance & stains (+) for CD15 & CD30
Subtypes of Classical HL include: Nodular sclerosis (most common), lymphocyte rich, mixed cellularity, & lymphocyte depleted. Tx does not differ among these subtypes
NLPHL is a more indolent disease characterized by the Lymphocytic & Histiocytic cell, a Reed-Sternberg variant that stains negative for CD15 & CD30, but (+) for CD20

Workup

Excisional bx preferred for initial dx; core-needle bx may be adequate, FNA typically inadequate
Cross-sectional imaging w/PET/CT
BM bx required for complete staging
Echo if anthracycline to be used, PFTs if bleomycin to be used

Staging

Cotswolds modification of the Ann Arbor Staging System (Lister TA, et al. J Clin Oncol 1989;7:1630)

STAGE	Description
I	Single LN or nodal group
II	2 or more nodal groups on the same side of the diaphragm
III	LN groups on both sides of the diaphragm
IV	Disseminated extranodal disease
MODIFIER	Description
B	“B” sx: Unexplained fever, wt. loss (≥10% of wt.) or night sweats (drenching)
A	Absence of “B” sx
X	Bulky disease (≥10 cm or 1/3 of intrathoracic diameter)
E	Extranodal extension: Limited involvement of an extralymphatic organ contiguous w/a nodal site
S	Spleen involvement

Risk Factors

The IPS includes 7 RFs for adverse outcome (N Engl J Med 1998;339:1506):

Serum albumin <4 g/dL

Hb <10.5 g/dL

WBC ≥15K

Age ≥45

Male sex

Stage IV

Lymphocyte count <600/mm³ or <8% of WBC
Other RFs include: B-sx, elevated ESR, bulky disease, mixed-cellularity or lymphocyte depleted histology, abdominal or pulmonary hilar involvement & increasing number of nodal sites

Management: Early Stage Disease

Includes Stages I-IIA, nonbulky
Standard combined modality Rx w/2-4 cycles of ABVD & 20-30 Gy ISRT results in PFS ˜85% & OS >90% (J Clin Oncol 2003;21:3601; N Engl J Med 2012;366:399).
ABVD = doxorubicin, bleomycin, vinblastine, & dacarbazine
Additional RT (10 Gy) is given to sites of bulky disease
2 cycles of ABVD & 20 Gy of IFRT equally effective in a select group of early stage pts (“early favorable”) who have no clinical RFs (N Engl J Med 2010;363:640)
Repeat PET post-tx for response assessment

Management: Advanced Stage Disease

“Adv Stage” includes stages III-IV. Some groups include bulky disease of any stage and/or Stage IIB w/unfavorable factors
ABVD chemotherapy for 6 cycles is standard in North America. Pts w/bulky disease receive ISRT of 30-36 Gy
Escalated BEACOPP improves FFTF & possibly OS in pts w/unfavorable RFs (eg, IPS ≥4), but is more toxic than ABVD (N Engl J Med 2003;348:2386)
Limited data for benefit of consolidative RT (J Clin Oncol 2004;22:62) but typically reserved for bulky disease in current era of improved salvage Rx
Post-tx PET for response assessment. Interim PET (after cycle 2) predicts outcome, but still considered investigational (J Clin Oncol 2007;25:3746)

Toxicity

BPT results in cough, shortness of breath, PFT (↓ DLCO) & imaging abnormalities
Monitoring includes clinical surveillance ± routine PFTs
RFs for BPT (J Clin Oncol 2005;23:7614):
- ABVD chemotherapy
- ↑ Age
- Use of granulocyte growth factors (G-CSF)
Risk of infxn low even in neutropenic pts not receiving G-CSF tx delays should be avoided whenever possible. Neutropenia does not necessitate a dose delay or reduction

Management: Relapsed Classical Hodgkin Lymphoma

Most pts should receive salvage chemotherapy such as ICE or DHAP ± accelerated TLI/STLI w/boost (J Clin Oncol 1993;11:1062) followed by consolidative autologous stem cell transplant if responsive
RFs for adverse outcome post relapse (Blood 2001;97:616):
- Remission duration <12 mos
- B-sx
- Extranodal disease
Role of allogeneic transplant is unclear
Brentuximab vedotin has 75% RR in post-ASCT setting
Multiple combination chemotherapy regimens have reported activity in multiply relapsed pts

Nodular Lymphocyte Predominant Hodgkin Lymphoma

Indolent, relapsing neoplasm w/different natural hx & tx paradigm than classical HL
Most commonly early stage; better prognosis than classical HL
RT alone, or in combination w/chemotherapy effective in early stage disease
Rituximab containing chemotherapy (eg, R-CHOP) effective in adv stage

Survivorship

2° Malignancies overtake HL as the greatest risk of mortality in about 20 y post tx
Annual breast screening should begin 8-10 y after RT that included some of the breast (no later than age 40) in women who receive it. MRI together w/mammography for women that receive RT between ages 10 & 30 is the standard screening for women at high risk for breast CA
Annual chest imaging recommended for pts at increased risk of lung CA due to tobacco use, receipt of alkylating agents, or chest RT
Cardiovascular RFs should be screened for & modified
TSH annually in pts who received RT to the neck

FOLLICULAR LYMPHOMA

Zachary H. Word

Epidemiology

Most common indolent lymphoma & 2nd most common lymphoma overall, representing ˜25% of NHLs
More common in Caucasians than other races, incidence ↑ w/age. Equal incidence in men vs. women

Biology/Pathology

Composed primarily of small cleaved lymphocytes that grow in a follicular pattern resembling that of nl 2° lymphoid tissue
Variable numbers of larger centroblasts are typically present, w/↑ number indicating higher grade
Grade I, II, & IIIA share the tx paradigm outlined below. Grade IIIB is treated as DLBCL
Immunophenotypically, FL cells classically express the B-cell Ags CD-19 & CD-20, the follicular center Ag CD-10, & the anti-apoptotic protein BCL-2. They do not express T-cell Ags, including CD-3 or CD-5 (the latter is often aberrantly expressed in CLL/SLL or MCL)
Overexpression of BCL-2, an anti-apoptotic protein, is mediated by the t(14:18) w/c juxtaposes the BCL-2 gene to the Ig heavy chain locus in a large majority of cases. Translocation not sufficient to diagnose FL
As w/other lymphomas, incisional or excisional bx is preferred for initial dx
The term “follicular center cell lymphoma” is nonspecific & may refer to FL or DLBCL

Staging and Workup

Ann Arbor Staging w/Cotswolds modifications, as for HL (J Clin Oncol 1989;7:1630)
Staging primarily consists of cross-sectional imaging w/either a CT scan of chest/abdomen/pelvis ± neck or a PET scan
PET particularly useful if there is concern for transformed disease or to confirm limited distribution in early stage
Peripheral nodal areas evaluated w/PEx
BM bx needed to complete staging, but can be deferred if observation or standard Rx for adv disease is planned
CBC, comprehensive profile, LDH, HIV & hepatitis B & C serologies should also be sent

Risk Factors
FLIPI	FLIPI2
Age >60 y	Age >60 y
Stage ≥III	Node >6 cm
Hb <12	Hb <12
>4 nodal areas involved	+ BM
↑ LDH	↑ β2M

Prognostic Models

As w/other lymphomas, stage alone confers limited prognostic info
2 main prognostic models have been reported: The FLIPI (Blood 2004;104:1258) & the FLIPI2 (J Clin Oncol 2009;26:4555)

Outcomes
FLIPI Score	5-y OS (%)		FLIPI 2 Score	5-y PFS
0-1	90.6	Low Risk	0	79.5
2	77.6	Intermediate Risk	1-2	51.2
3-5	52.5	High Risk	3-5	18.8

Management: Stages I-II

ISRT alone results in 10-y RFS of ˜40% w/Stage I pts faring better than Stage II (J Clin Oncol 1996;14:1282). The current recommended dose is 2400 cGy
Observation is also reasonable in selected cases w/systemic or local Rx being employed when indicated by NCCN/GELF criteria, as for Stages III-IV

Management: Asymptomatic Stages III-IV (or intra-abdominal Stage II)

Generally considered incurable w/standard therapies, & no survival advantage has been demonstrated w/earlier initiation of Rx
Observation alone is recommended for most asymptomatic pts
Observed pts are usu followed w/serial clinical exams & periodic CT (not PET). Optimal timing of scans not determined, may vary according to individual pt characteristics
Median time to initiation of Rx in observed pts is ˜3 y
Rituximab monotherapy increases time to first chemotherapy, but not survival (ASH Annual Meeting 2010;116:Abstract 6)

Management: Symptomatic Stages III-IV (or bulky Stage II), Front-line

Enrollment in clinical trial should be encouraged
Commonly accepted indications for Rx include: Any node >7 cm, or 3 nodes >3 cm, sx, cytopenias, fluid collections (ascites, pleural effusions), organ impairment & leukemic phase of disease (J Clin Oncol 1998;16:2332)
Multiple front-line therapeutic options. Choice of Rx is based on pt & disease characteristics, including: Volume & distribution of disease, age, & functional status of the pt, potential need for rapid response, potential concern for transformed disease (see below)
Rituximab is a monoclonal Ab directed at the B-cell Ag CD-20. Efficacy has been shown w/both single-agent & combination Rx
Rituximab monotherapy (4 weekly doses) is used 1° in pts w/low volume disease. ORR ˜70-75%, CR ˜40-45% in untreated pts (J Clin Oncol 2005;23:1103)
More often, rituximab is added to chemotherapy. Standard regimens include R-CHOP, R-CVP, R-Bendamustine, & R-Fludarabine. Addition of rituximab to chemotherapy improves RR, PFS, & OS over chemo alone. No single regimen is preferred; individual pt factors guide decision

Maintenance & Consolidation Therapy

Maintenance dosing of rituximab after completing initial Rx improves PFS (J Natl Cancer Inst 2011;103:1799)
Rituximab re-tx at the time of progression results in similar TTTF, but uses less rituximab than maintenance (ASH Annual Meeting 2011;118, Abstract 6)
RIT also improves PFS but not OS. It converts some PRs to CRs (J Clin Oncol 2008;26:5156)

Relapsed or Refractory Disease

Transformed disease should be excluded w/PET ± bx
Asymptomatic relapsed pts can be observed, as w/untreated pts
Choice of 2nd-line Rx influenced by degree & duration of response to initial Rx. Front-line regimen can be re-used if remission duration was long
Rituximab remains effective in relapsed pts. The single agent ORR is ˜45%, but it’s more commonly combined w/chemotherapy
Very low-dose RT (400 cGy) may provide excellent local control & palliation in 70% of relapsed refractory pts
Radioimmunotherapy
Pts w/a short duration of remission may be considered for consolidation w/stem cell transplant after the 2^nd– or subsequent-line Rx
Choice of autologous or allogeneic transplant is made individually; usu based on such factors as pt age & comorbidity, availability of a suitable donor, & the biology & behavior of the lymphoma

Histologic Transformation

There is a ˜3%/y risk of transformation from FL to DLBCL, usu characterized by rapid nodal enlargement & rising LDH, + systemic sx
Bx required to diagnose transformation. PET may be useful in determining a site for bx. SUV values >10-13 suggest transformation (Ann Oncol 2009;20:508)
No intervention has been demonstrated to prevent transformation
Transformed disease is treated similar to de novo DLBCL, except that ISRT alone may be considered in selected pts

MARGINAL ZONE LYMPHOMA (MZL)

Andrew M. Intlekofer

Andrew D. Zelenetz

Pathogenesis

Thought to arise from chronic Ag stimulation due to infectious pathogens or other causes of inflammation, including autoimmune diseases
Variety of chromosomal translocations can result in Ag-independent activation of NF-κB pathway (important signal for B cell survival)
Whole genome sequencing of splenic MZL has identified recurrent somatic Mts of genes encoding chromatin-modifying enzymes & proteins in the NOTCH, NF-κB, & MYD88 pathways (JEM 2012;209:1537; NEJM 2012;367:826)

Epidemiology

Comprise approximately 10% of all NHLs

Clinical Presentation

MZL can affect diverse anatomical sites & presentation varies accordingly
Localized sx: Epigastric pain (gastric), abdominal pain or bowel obstruction (intestine), cough (bronchial), orbital mass, salivary gland mass, thyroid mass, breast mass, skin nodules or rash, abdominal distension or early satiety due to splenomegaly (splenic MZL), LAN (nodal MZL)
Systemic sx: B sx (wt loss >10%, fevers, sweats) uncommon, fatigue, bruising

Subtypes of Marginal Zone Lymphoma
Type	Disease Site	Associated Ag
ENMZL/MALT lymphoma	Gastric (most common)	Helicobacter pylori
	Intestine	Campylobacter jejuni
	Orbital/ocular	Chlamydia psittaci
	Salivary/lacrimal gland	Sjögren disease
	Thyroid	Hashimoto thyroiditis
	Joint/synovial tissue	Relapsing polychondritis
	Cutaneous	Borrelia afzelii
	Lung	Unknown
Splenic MZL	Spleen	HCV

Diagnostic Evaluation

Bx required: Either excisional/incisional or core plus FNA w/flow cytometry, splenic MZL often diagnosed on splenectomy specimen
Histology: Polymorphous infiltrate of small lymphocytes, centrocyte-like B cells, & plasma cells; reactive follicles; lymphoepithelial lesions (epithelial tissues)
Immunophenotype: CD19+, CD20+, CD22+, κ or λ restricted, surface Ig+, often cytoplasmic Ig+, CD5−, CD10−, CD23−/+, CD43−/+, CD103−, CyclinD1−
Cytogenetics/FISH: Most common t(11;18) (BIRC3:MALT1) → a/w H. pylori neg gastric ENMZL; t(1;14), t(14;18) (note this is IgH:MALT1), t(3;14); del13q; del7q
Molecular diagnostics for clonal IgH rearrangement (proves malignancy)
Lab evaluation: CBC w/diff, CMP, LDH, HBV sAg/cAb, HCV Ab, HCV PCR, HIV, SPEP/IFE (paraprotein often present), quant immunoglobulins
BM aspirate & core bx: Send for flow cytometry, splenic MZL classically shows “intrasinusoidal” lymphocytic infiltrations
Imaging: CT C/A/P w/contrast; may need MRI orbits (ocular) or neck (salivary); FDG PET not routinely required
Special considerations for gastric ENMZL:
- → Endoscopy ± EUS w/core bx required, stain specimen for H. pylori
- → If H. pylori negative by histopath, then perform H. pylori stool Ag test, urea breath test, or H. pylori blood Ab test

Staging

Ann Arbor Staging (for nodal, splenic, & nongastric ENMZL):
- Stage I = single LN region or single extranodal site (IE)
- Stage II = multiple LN on one side of diaphragm
- Stage III = multiple LN on both sides of diaphragm
- Stage IV = LN plus extranodal sites or multiple extranodal sites
- A = no B sx, B = B sx (fevers, drenching sweats, wt loss >10% BW)
- X = mass >10 cm
Lugano Staging System (for gastric ENMZL) (Ann Oncol, 1994; 5:397):
- Stage IE = confined to GI tract
- Stage IIE = regional LN or adjacent organ involvement
- Stage IIIE-IV = disseminated extranodal or supradiaphragmatic LN involvement

Principles of Treatment

In some cases, tx of underlying etiology can result in MZL regression
- → H. pylori eradication w/abx for gastric ENMZL (not effective if translocations present or if there is muscularis or perigastric LN involvement)
- → HCV Rx for splenic MZL
- → Doxycycline for ocular or cutaneous ENMZL
Localized disease is common in MZL, so RT is an important tx modality (usu IFRT = involved field RT)
Localized disease is potentially curable so treat even asx pts
Adv stage MZL is a chronic disease (not curable), therefore decision to treat is based on presence of 1 or more GELF criteria (same as follicular lymphoma): ≥3 nodal sites each ≥3 cm in size, any involved site ≥7 cm in size, B sx, splenomegaly, pleural effusion or ascites, cytopenias (WBC <1, Plt <100), malignant cells in blood (>5000)
Transformation: 5-10% pts transform to aggressive large cell lymphoma, heralded by rapid ↑ LN, new B sx, or ↑↑ LDH, dx by FDG PET scan & bx LN w/↑ SUV, tx like DLBCL (eg, R-CHOP)

Treatment Approaches
Subtype	Stage	Status	Tx
Nodal MZL	Ann Arbor I or II	NA	IFRT
	Ann Arbor III or IV	GELF−	Observe
		GELF+	Treat like follicular lymphoma (eg, ritux, R-CVP, R-CHOP, BR)
Splenic MZL	Ann Arbor IV (always)	HCV+	Treat HCV (even asx pts)
		Asx No cytopenias	Observe
		Sx or cytopenias	Splenectomy
			Rituximab
Gastric ENMZL	Lugano IE or IIE	H. pylori+	H. pylori eradication
		H. pylori− or failed H. pylori tx	IFRT
	Lugano IIIE or IV	GELF−	Observe
		GELF+	Treat like follicular lymphoma
Nongastric ENMZL	Ann Arbor I or II	NA	IFRT
			Surgical resection (in certain cases)
	Ann Arbor III or IV	GELF−	Observe
		GELF+	Treat like follicular lymphoma
R, rituximab; C, cyclophosphamide; V/O, vincristine; H, doxorubicin; P, prednisone; B, bendamustine; note BR may be less efficacious for MZL than for other indolent lymphomas; see StiL trial; JCO 30, 2012; suppl; abstr 3