2. OVERVIEW
Non-Hodgkin’s lymphomas (NHL) are a heterogeneous group of
lymphoproliferative disorders originating in B-lymphocytes, T-lymphocytes or
natural killer (NK) cells.
3.
4. Categories A, B, X, E, CS and PS.
The four stages of NHL can be divided into categories.
• The A category indicates that patients have not experienced fever, exaggerated
sweating and weight loss.
• The B category indicates that patients have fever, excessive sweating and weight
loss.
• The X category indicates bulky disease (large masses of lymphocytes).
• The E category indicates areas or an organ involved other than the lymph nodes or
has spread to tissues beyond, but near, the major lymphatic areas.
• The CS indicates clinical stage
• The PS indicates the pathological stage as indicated by laparotomy
5. EVALUATION OF PATIENT’S WITH NON HODGKIN’S LYMPHOMA
1. HISTORY AND PHYSICAL EXAMINATION
2. BLOOD STUDIES
i. COMPLETE BLOOD COUNT
ii. SERUM LACTATE DEHYROGENASE
iii. LIVER FUNCTION STUDIES AND BLOOD CHEMISTRIES
iv. HEPATITIS SEROLOGY AND HUMAN IMMUNODEFICIENCY VIRUS
TESTING
3. BONE MARROW ASPIRATE AND BIOPSY
4. IMAGING STUDIES
i. CHEST RADIOGRAPH
ii. COMPUTED TOMOGRAPHY OF CHEST, ABDOMEN , HEAD AND NECK,
PELVIS WHERE INDICATED
iii. POSITRON EMISSION TOMOGRAPHY/GALLIUM SCANNING
5. APPROPRIATE ENDOSCOPIC STUDIES
6. UPPER GASTROINTESTINAL SERIES/SMALL BOWEL WHERE INDICATED
6. PROGNOSTIC FACTORS
1.Tumor stage
2. Phenotype (B-cell, T-cell or natural killer (NK) cell/null-cell)
3. Histology (i.e. low-, intermediate-, or high-grade)
4. Symptoms
5. Patient age
6.Comorbidities
Other prognostic variables investigated have included performance status, tumor size, number
of nodal or extranodal sites, LDH, β2- microglobulin levels, serum albumin, hemoglobin, and
proliferation indices.
7. International Prognostic Index (IPI) The IPI is a scoring system that uses known risk
factors to predict overall survival and guide treatment decisions.
Five adverse prognostic risk factors for IPI
Age >60 years
Ann Arbor stage III/IV
>1 extranodal site
Serum lactate dehydrogenase (LDH) level >normal
Eastern Cooperative Oncology Group (ECOG) performance status ≥2
One point is assigned to each of the previously listed characteristics present in a patient with
aggressive NHL. Scores range from 0 to 5.
8. TREATMENT OVERVIEW
1. The initial therapy and intensity of treatment indicated for a patient are based
on the subtype and stage of disease.
2. In general, the goal of treatment is to induce a “complete remission”; that is, to
eliminate all evidence of disease. Patients who go into remission are
sometimes cured of their disease.
3. Treatment can also keep NHL in check for many years, even though imaging
or other studies show remaining sites of disease. This situation may be
referred to as a “partial remission.”
9. 4. In general, chemotherapy and radiation therapy are the two principal forms of
treatment for NHL.
5. Although radiation therapy is not often the sole or principal curative therapy, it is
an important additional treatment in some cases.
6. Stem cell transplantation and a watch-and-wait strategy are also used to treat
some NHL subtypes.
7. Other forms of treatment are emerging, and some are already approved for
specific forms of NHL.
10. PRINCIPLES OF TREATMENT
SURGERY:
• Surgery is widely used to establish a diagnosis by biopsy.
• That may involve a major surgical operation, such as exploratory laparotomy for
the diagnosis of stomach, intestinal, retroperitoneal, or mesenteric lymphoma.
• This is becoming much less common, however, with the use of endoscopic and
laparoscopic techniques.
• With an established diagnosis of lymphoma, surgical resection as primary
treatment should be a rare event, with radiotherapy and chemotherapy forming
the mainstays of treatment.
11. Radiation Therapy
1. Malignant lymphomas are, in general, uniquely sensitive to ionizing radiation.
For the great majority of anatomic locations, the sensitivity of the tumor is
greater than that of the corresponding normal tissue, usually by a considerable
amount.
2. Traditionally, wide or extended field radiotherapy treatments such as ‘Mantle’
and ‘Inverted Y’ were used as primary treatment for lymphomas with good
cure rates but late toxicity, particularly to the heart, lungs and breasts.
3. With treatments now combining chemotherapy and adjuvant radiotherapy,
data have accumulated to support the use of local radiotherapy instead of
extended fields, to reduce toxicity by sparing normal tissues.
12. • There are three possible approaches to using smaller volume treatments. Since lymphatic
spread involves nodes adjacent to the primary site of disease first, locoregional treatment
that includes elective adjuvant irradiation of the first node stations may be given (IFRT).
The CTV includes the GTV, which is the primary site, and adjacent nodes as CTV (a
situation analogous to treatment of uninvolved nodes in head and neck cancer).
• Alternatively, only the initial macroscopic volume of disease (GTV), whether in lymph
node (involved nodal INRT), or an organ (sometimes called involved site ISRT) is treated
with a GTV-CTV margin.
• Finally, the residual GTV following chemotherapy, defined by PET-CT, could be the basis
of the target volume. In published reports the target volumes used may combine aspects of
these different conceptual approaches.
16. UNILATERAL CERVICAL OR
SUPRACLAVICULAR
Arms position: Akimbo or at sides
Upper Border: 1 to 2 cm above the
lower tip of the mastoid process
and midpoint through the chin.
Lower Border: 2 cm below the
clavicle.
Lateral Border: To include the
medial two-thirds of the clavicle.
17. Medial Border:
(a) If the SCL nodes are not
involved, the border is placed at
the ipsilateral transverse processes
except when medial nodes close
to the vertebral bodies are seen on
the initial staging neck CT scan.
For medial nodes the entire
vertebral body is included.
(b) When the SCL nodes are
involved, the border should be
placed at the contralateral
transverse Processes
18. Blocks:
A posterior cervical cord block is required only if cord dose exceeds 45 Gy.
Mid-neck calculations should be performed to determine the maximum cord dose,
especially when the central axis is in the mediastinum.
A laryngeal block should be used unless lymph nodes were present in that location. In
that case the block should be added at 20 Gy.
19. Bilateral Cervical/Supraclavicular Region
Both cervical and SCL regions
should
be treated as described in the
preceding slide regardless of
the
extent of disease on each side.
Posterior cervical cord and
larynx
blocks should be used
20. MEDIASTINUM
The mediastinum is divided into:
Upper mediastinum - extends to the carina and includes paratracheal and
paraoesophageal LN, pre-aortic LN, LN in the aorto-pulmonary window.
Middle mediastinum - the lymph node areas at the level of the carina:
tracheobronchial LN, bronchopulmonary LN (lung hila), LN adjacent to base of
heart, subcarinal LN.
Lower mediastinum - the lymph node areas clearly below the carina along the
esophagus, the lower descending thoracic aorta and the spine and also between
heart and sternum (retrosternal)
21. FIELD
Arms position: Akimbo or at sides. The arms-up position is optional if the axillary nodes
are involved.
Upper Border: C5-6 interspace. If SCL nodes are also involved, the upper border should be
placed at the top of the larynx.
Lower Border: The lower of: (a) 5 cm below the carina or (b) 2 cm below the pre-
chemotherapy inferior border
Lateral Border: The post-chemotherapy volume with 1.5 cm margin.
Hilar Area: To be included with 1 cm margin unless initially involved, in which case the
margin should be 1.5 cm.
22. AXILLARY AREA
Arms position: Arms akimbo or arms up.
Upper Border: C5-6 interspace.
Lower Border: The lower of the two: (a) the tip of the scapula or (b) 2 cm below the
lowest axillary node.
Medial Border: Ipsilateral cervical transverse process.
Lateral Border: Flash axilla.
23. MANTLE FIELD
Indications: Only given if extensive lymph node involvement in the supra-diaphragmatic region
i.e. IFRT amounting to mantle irradiation.
25. SPECIAL POINTS ABOUT DIFFERENT NODAL
REGIONS
Jugular group:
Mid-jugular and lower jugular nodes lie anterior to the lateral border of thyroid
cartilage and trachea and can get underdosed by incorrect use of laryngeal blocks.
Placing the block 1-2 cm below from thyroid notch to lower border of cricoid is safe.
Axillary group:
On AP Chest X-ray, mid axillary nodes are along the lateral edge of rib-cage.
The apical nodes coincide with the lateral borders of the 1st , 2nd and 3rd rib.
The lowest level of the nodes are marked by the level of anterior 4th IC space.
The lateral margin is described on patient by the junction of the lateral margin of
pectoralis major muscle with the deltoid.
26. Superior mediastinal: High risk nodes lying anterior to the thoracic mid-plane and
superior to carina.
Inferior mediastinal: important nodes are
Posterior Intercostal
Juxtavertebral ( along the thoracic duct, anterior to vertebral bodies)
Para-esophageal nodes.
Diaphragmatic nodes form a circle along the base of heart,
• Anterior: behind xiphoid
• Right pericardial: posterolateral to right heart border in apposition to the right
phrenic nerve and IVC.
• Left pericardial: posterolateral to left heart border along left phrenic nerve.
Because of posterolateral position, they have to be quite large to produce changes
in cardiac silhouette on chest x ray.
Inclusion of these nodes requires a margin of 1cm to cardiac shadow.
27. POSITIONING
Akimbo (A position):
Supine with maximum extension of the neck, Arms abducted, forearm flexed and resting at the
waist. Classical position described by Fletcher.
Extended (E position):
Arms abducted, forearms extended.
Up overhead (U position):
Overhead arm abduction, forearm flexion
A. Up overhead , B. Extended, C. Akimbo
28. • The patient is placed supine with maximum extension of the neck and arms above the
head, or at 90 degree angle towards the side, or in ‘akimbo’ position, i.e., hands on the
waist.’
• In the arms above the head position, the axillary nodes were brought further away from
the chest .This helped in a more generous lung shielding.
• In the “akimbo” position, the humeral heads can be shielded and also it minimized the
effect of tissue folds in supraclavicular/low neck regions.
• Neck should be in extension to exclude the oral cavity and teeth from the RT field and to
decrease the dose to the mandible.
31. SIMULATION
• Counseling patient.
• Position supine with laser aligned along midline.
• Arms slightly abducted.
• Demarcation of gross palpable lymph nodes with lead wire.
• Simulation of treatment field:
Superior border: along the inferior portion of the ramus of mandible and the
mastoid. Neck in slight extension to get chin, mandible , ear lobe and a point 2-
3 cm above mastoid tip in same line.
Inferior border: at the anterior attachment of diaphragm i.e. D10-11 or clinically
about 4 cm above xiphoid.
Lateral borders: generous coverage of axillae, just beyond humeral head.
Mid-point: usually falls at or slightly below suprasternal notch.
32. SHIELDING
Lung blocks :
Made separate for anterior and posterior.
Upper border in anterior : 2 cms below medial clavicle, and a thin lung band
is left at the lateral clavicles.
Upper border in posterior : a thin band is left under the clavicles as the
infraclavicular LNs are located anteriorly.
Lateral Borders : a 1 cm band is left in costal curves which extends until the
5th or 6th costa and finishes horizontally in chest wall.
Medial Border :1.5-2cm margin around lateral border of tumor
33. • For 6 MV photons, with 5 cm lead ( 4 HVL) lung dose is 10- 15% of given dose.
• Increasing lead thickness reduces lung dose only minimally, but weight of block becomes
cumbersome.
• Partial transmission blocks may be used if pulmonary irradiation is also required.
• Head of Humerus is shielded both anteriorly and posteriorly.
• Larynx is shielded anteriorly
34. Laryngeal blocks:
Laryngeal shield can be used in the anterior portal extending from the thyroid notch to cricoid about 1-1.5
cm wide.
In presence of bulky mid and lower jugular nodes, laryngeal shield may be delayed or omitted till
regression occurs.
• Heart is shielded below the hilar level without including the mediastinal LN‟s both anteriorly and
posteriorly.
• Spinal cord shielding is done in midline for dosages >40Gy. Posterior spinal cord block - 1.5-cm- wide
block is placed from top of field to bottom of C7 vertebral body in posterior mantle field
• A small block is put at the inferior border of spinal cord posteriorly.
• Oral cavity is shielded if the superior border includes the oral cavity.
The central axis of the field is usually at the sternal notch or close to it.
• The central axis, points 10 cms left and right of it, and the inferior border, should be marked with a
tattoo to check during the daily setup and to allow the possibility of infradiaphragmatic RT at later stages.
35.
36. MINIMANTLE AND MODIFIED MANTLE FIELD
Mantle without irradiation of the
mediastinum due to low risk of
involvement.
MINIMANTLE
Bilateral cervical (neck),
supraclavicular and
axillary fields (excludes
mediastinal and lung)
38. PRESCRIPTION
Beam energy:
Can be treated with cobalt 60 or 6 MV photons.
Most mantle field sizes are 35 x 35 cm at 100 SSD.
Some times 40 x 40 cm needed requiring extended SSD and treatment at trolley level.
• Larger depth, better PDD, better homogeneity.
• With larger distances any small error in positioning or
measure of blocks will cause be magnified.
Patient position has to be changed (supine and prone) resulting in set up errors.
39. DOSIMETRY
Basic beam data available for rectangular or square fields only.
Methods described to use these data for irregularly shaped fields like mantle → Large, involve
irregular surface contour and use of various blocks.
By Clarkson’s method.
Based on the principle of SAR (scatter air ratio) which depends on field size and shape and can
be calculated separately from the primary component which is independent of field size and
shape.
40. MANTLE: DEPTH DOSE CALCULATION
SAR (Scatter air ratio):
The ratio of scattered dose at a given point in the phantom to the dose in the free
space at the same point.
Independent of SSD but depends on beam energy, field size and depth.
SARs have been tabulated as functions of depth and radius of a circular field at that
depth.
Correction for SSD variation within the field due to the difference in separation at
mediastinum Vs neck → 10-20 % difference in dose delivered.
Correction for tissue heterogeneity along the beam e.g. lung correction factor
depending upon the energy.
41. The standard site points calculated are the neck, supraclavicular region, axillae, mediastinum
and cord doses at the superior, central axis and inferior border. The cervical, axillary and
mediastinal doses are calculated at the midplane. The supraclavicular dose is calculated at a
depth of 3cm, and the cord doses are calculated at the cord depth, measured from the lateral
radiograph or the treatment planning CT Scan.
42. A common technique is the one in which the posterior mantle is the mirror image of the
anterior mantle field. The technique has the disadvantage that the superior border lies quite
high and the beam has to traverse the part of cerebellum and may exit in oropharynx and oral
cavity.
Most of the disease lies in the anterior half of the body so that treatment is weighted 3:2
anterior: posterior, thereby producing slightly higher doses in the anterior half of the field.
This also reduces the dose to spinal cord and reduces the cervical and thoracic bone marrow
dose to a level assuming recovery. The superior border of the posterior mantle is placed at the
level of thyroid notch.
POSTERIOR MANTLE
43. DOSE POINTS:
8 points demarcated for dose calculation.
The field centre, mid-mediastinum, inferior mediastinum at 3 cm above the
lower border, left lower neck, mid neck at the level of thyroid cartilage, upper
neck 3cm within the superior border, a mid- axillary point and a low axillary
border 3 cm above the inferior axillary border.
The neck points are placed on the anterior border of SCM.
In cases of specific areas of interests points may be added.
Lead markers are placed at these points so that they are represented on the
simulator film for calculation.
• SSD is measured at all the points .
• This is required for depth dose
calculation by scatter-air ratio technique.
44. LUNG CORRECTION
Lung density much lower than normal tissue density.
Decrease attenuation → increased transmission to tissues
Decreased contribution to scatter → decreased dose delivered to tissues beyond.
Net effect: increased transmission.
Depends on energy of beam and field size.
45. Pre auricular node/waldeyer’s ring
Portal used to irradiate waldeyer’s
ring(nasopharynx, tonsil and base of tongue)
and upper neck node.
Lower border: thyroid notch
Superior border: 1cm above the zygomatic
arch
Posterior border coincides with tragus and
bends posteriorly to encompass
sternocleidomastoid muscle
Anterior border extends from orbital rim
towards the second molar region, it then
bends along the mandible to encompass the
submental nodes.
46. Subdiaphragmatic fields:
PARA-AORTIC AREA
Upper Border: Top of T11 and at least 2 cm
above pre-chemotherapy volume.
Lower Border: Bottom of L4 and at least 2 cm
below pre-chemotherapy volume.
Lateral Borders: The edge of the transverse
processes and at least 2 cm from the post-
chemotherapy volume.
47. Spleen/ Splenic pedicle
1. The spleen is irradiated through anterior and posterior opposing
fields weighted 3:2 from the posterior. The splenic fields are
separated by 1cm from the para-aortic portals.
2. If a splenectomy has been done, the splenic chain of lymph nodes is
treated only if the spleen or splenic hilar nodes are positive.
3. If the surgeon has failed to mark the splenic hilus with the metal
clips, one has to outline a larger field to encompass the suspected
involved region.
4. The splenic pedicle is irradiated entirely through a small posterior
portal which is separated 1 cm from the para-aortic node field.
48. Indications of total abdominal irradiation
Patients who are admitted with bulky abdominal nodes (larger than 6cm)or documented
disease outside conventional treatment portals are thought ot be at a greater risk of
unusual nodal involvement (eg. Mesentric nodes) and for extranodal extension( eg.
Gastrointestinal tract) and should be considered for total abdominal irradiation.
Total abdominal irradiation is delivered through parallel opposed lateral fields that
encompasses the entire peritoneal reflection plus the inguinal and femoral nodes.
49. Superior border : dome of diaphragm (nipples
Inferior border : inferior border of the obturator foramen( pubis symphysis )
Lateral border : to the lateral peritoneal reflection
50. Pelvic fields
The pelvic nodes are most often irradiated for subclinical disease. In case where the
pelvis is irradiated only for the prophylactic reason the mantle and para-aortic
nodes/spleen, splenic pedicle treatment is usually completed and then a 1 month
break is allowed for the general recuperation of the patient and marrow recovery
before completion of the pelvic section.
However if the gross disease is located in the pelvis it is best to start with the therapy
in the abdominal section; the mantle would be the last section to be treated. This
prevents reseeding from gross disease in the abdomen.
51. If pelvic and para-aortic fields are treated simultaneously, it is possible to join them
together in one elongated field referred to as inverted Y shaped field.
The majority of high risk nodes lie in the anterior three-fifths of the pelvis and the
preferred plan is to weight the fields 3:2 in favour of anterior portal.
The nodes below the inguinal ligament are treated only from the anterior field, and the
posterior pelvic field does not extend below the pubic rim. The superficial inguinal nodes
lie at 1 or 2 cm but deep femoral nodes lie at 4 – 5 cm from the skin surface.
52. Superior border – matched with paraaortic field (upper border of L5)
Inferior border – lower border of ischial tuberosity
Laterally - field shaped with blocks to spare iliac wing bone marrow without
compromising coverage of iliac lymph nodal chain
Central block - 4 cm block extending from the inferior edge of field & superiorly to
sacroiliac joint to protect bladder and rectum
55. For girls and women of fertile age, shielding of the ovaries and/or ovariopexy should
be considered. Ovariopexy is the surgical relocation of the ovaries out of the small
pelvis to the midline behind the uterus. Surgical clips should indicate where the
ovaries are located. Only then is it possible to exclude the ovaries from the target
volume.
56. Inguinal/Femoral/External Iliac Region
Upper Border: Middle of the sacroiliac joint.
Lower Border: 5 cm below the lesser trochanter.
Lateral Border: The greater trochanter and 2 cm lateral to
Medial Border: Medial border of the obturator foramen with at least 2 cm medial to
involved nodes. If common iliac nodes are involved the field should extend to the L4-5
interspace and at least 2 cm above the initially involved nodal border.
initially involved nodes.
57. TOTAL LYMPHOID IRRADIATION
It includes all lymphoid region of the body both nodal and
extranodal.
TOTAL NODAL IRRADIATION includes nodal areas on both
sides of the diaphragm.
58. TOTAL BODY IRRADIATION
TBI is a special radio therapeutic technique that delivers to a patient’s whole
body, a uniform dose within (+/-)10% of the prescribed dose. Megavoltage
photon beams , either Co-60 Gamma rays or Megavoltage X-rays are used for
this purpose.
Clinical TBI categories Depending on the specific clinical situation , TBI techniques are
divided into the following four categories:
1:High dose TBI, with dose delivery in a single session or in up to six fractions of 200
cGy each in three days (total dose 1200 cGy);
2: Low dose TBI, with dose delivery in 10–15 fractions of 10–15 cGy each;
3. irradiation, with a dose of 8 Gy delivered to the upper or lower half body in a single
session;
4:Total nodal irradiation, with a typical nodal dose of 40 Gy delivered in 20 fractions.
59. BEAM ENERGY
The choice of photon beam energy is dictated by patient thickness and the
Specification of dose homogeneity.
Dose prescription point The TBI dose is prescribed to a point inside the body, referred to as
the dose prescription point (usually at the midpoint at the level of the umbilicus).
Normal Tissue Shielding Shielding of normal tissues must be carefully Considered
in TBI because shielding may potentially reduce the dose to the target volume
60. IFRT
When primary radiotherapy without chemotherapy is given (e.g. stage I follicular non-
Hodgkin lymphoma), IFRT is used to include the uninvolved first node station in the
CTV as well as the macroscopically involved GTV.
The CTV is designed using the initial volume of involved lymph nodes, i.e. the initial
GTV as shown on staging CT, MRI and FDG-PET-CT scans. These scans need to be
taken in the radiotherapy treatment position, whenever possible, for accurate co-
registration with subsequent CT planning scans which are taken after chemotherapy.
When primary radiotherapy is given, the GTV is present both clinically and on imaging.
After chemotherapy there may be a complete response (PET and CT negative) with no
GTV, or a partial response with a residual GTV.
61. The original GTV is outlined on the post-chemotherapy CT planning scan using the
co-registered initial CT and PET scans.
The patient’s anatomy will have altered with response to chemotherapy, and the
principle is to cover the site of original disease, but to reduce toxicity by excluding
wherever possible normal tissues that were displaced, but not involved by tumour.
For both IFRT and INRT of the mediastinum, the pre-chemotherapy volume is used
for the superior–inferior extension and the post-chemotherapy volume for the axial to
reduce dose to blood vessels, heart, coronary arteries and lung which may have
returned to their normal position.
Where there was definite tumour infiltration into adjacent tissues at diagnosis, the
whole volume should still be included.
62. The CTV for IFRT includes the clinically and radiologically involved lymph nodes as
imaged at presentation (GTV) with the adjacent lymphatics and uninvolved first
node station.
A CTV-PTV margin is added to allow for organ motion which will vary for different
sites, for example it should be 5 mm for mediastinal nodes.
A further 5–10 mm margin is used for daily variations in set-up, the exact value
determined according to individual departmental protocols, making a total CTV to
PTV margin of 10–15 mm.
63. INRT/ISRT
This target volume is based on initial macroscopic disease pre-chemotherapy (GTV),
rather than on lymph node region, and is defined using initial CT and PET scans co-
registered with subsequent CT planning scans. If the initially involved nodes are no
longer visible after a complete response, the CTV is the initial site of involvement.
For neck, mediastinum and para-aortic nodes, a GTV-CTV margin of 20 mm in the
cranio-caudal and 10mm in other dimensions is used. For hilar, SCF and common iliac
nodes, a GTV-CTV margin of 10 mm in the anteroposterior (AP) and 20mm in other
directions is used.
64. • For axillary, external and internal iliac, inguinal and femoral nodes, a GTV-CTV margin
of 20 mm is used in all directions. These variable margins are based on observation
and designed to exclude initially displaced normal structures which have returned to
their usual position.
• A CTV-PTV margin of 5–10 mm in 3D is added according to anatomical site and
departmental set-up error measurements.
• INRT may be used for adjuvant radiotherapy after chemotherapy.
• If only a partial remission is obtained, a residual GTV will be defined on post-
chemotherapy CT scans. This is used to create a boost CTV, which is the GTV plus a
10–15 mm margin used to deliver extra irradiation to residual disease.
65. EXTRANODAL SITES:
When primary radiotherapy is given for stage IE non-Hodgkin lymphoma, the GTV is
usually the whole of the involved organ such as stomach, orbit or breast with an
appropriate margin for microscopic disease to create the CTV.
For a solid organ, the volume is designed using the original GTV with a GTV-CTV
margin of 15 mm in the cranio-caudal dimension.
In the AP and lateral dimensions the residual, not initial, GTV are included with a 15
mm 3D margin to minimise normal tissue doses.
CTV-PTV margins vary according to the mobility of the organ, e.g. for stomach a 20
mm cranio-caudal margin may be used to allow for respiration.
66. There is no evidence yet to change the established practice of treating the whole of
Waldeyer’s ring, the parotid gland or whole brain after chemotherapy and large
margins may still be allowed (30mm cranio-caudal) for bone lymphoma.
For splenic irradiation, CT scanning is used to localise the target volume (whole
spleen) and organs at risk which include the left kidney and stomach although doses
are below tolerance.
No GTV-PTV margin is needed as even partial organ radiotherapy is effective
67.
68. ■ Non-Hodgkin lymphoma
Primary radiotherapy for stage I, IE, II, IIE low grade disease
24–30 Gy in 12–15 daily fractions given in 21⁄2–3 weeks (or 4 Gy in 2 daily fractions).
Radiotherapy after chemotherapy for all other histologies
30 Gy in 15 daily fractions given in 3 weeks.
Palliative treatment
20 Gy in 5 daily fractions given in 1 week. 30 Gy in 10 daily fractions given in 2 weeks. 4 Gy in
2 daily fractions.
Splenic irradiation
10–12 Gy in fractions of 0.5–1.5 Gy given up to three times/week.
If blood counts are initially very low, treatment is started cautiously with low doses given once a
week with full blood count check before each treatment.
69. Dose of Radiation Therapy When Used Alone
The diseases most often studied were what we now know as DLBCL and FL, with a reasonable
amount of information also available for MALT lymphomas. On the other hand, diseases such
as PTCL, MCL, and ALCL have never been analyzed separately, so one is forced to extrapolate
from the data for DLBCL and FL.
The classic articles in this regard are from Stanford University and Princess Margaret Hospital.
Fuks and Kaplan in 1973 reported that doses in the range of 44 Gy achieved local control of FL
in >95% of instances.
For diffuse histiocytic lymphoma (corresponding roughly to DLBCL), local failure rates,
however, were in the range of 20% to 30%, regardless of the dose of RT delivered. These data
have been widely misinterpreted as suggesting or justifying a dose of 50 Gy for DLBCL. In fact,
they suggest a subset of resistant disease in the range of 20%, regardless of the dose of RT
delivered.
70. A series of articles from Princess Margaret Hospital also addressed this issue.
Dose–response curves were constructed for both diffuse histiocytic lymphoma (mostly
DLBCL) and FL.
For DLBCL patients with medium- or large-bulk disease, defined as 2.5 to 5 cm in size and
>5 cm, respectively,
50% local control rate at a dose of 20 Gy
70% local control rate at a dose of 30 Gy
80% local control rate at a dose of 40 Gy with a plateau thereafter, and no apparent
improvement with additional dose.
For patients with small volume (<2.5 cm) DLBCL, a local control rate >90% was achieved
regardless of dose.
For patients with nodular (follicular) disease, doses in the range of 25 to 35 Gy produced a
local control rate >90%.
71. Patients with tumor size >6 cm were treated with combined modality therapy
(CMT).
It was suggested that doses of at least 40 Gy were necessary in these
circumstances for optimal local control, although the data demonstrated
local failure in 1 of 51 patients treated with >40 Gy as part of a CMT
program versus 4 of 70 patients treated with doses of 30 to 40 Gy.
72. Dose of Radiation Therapy in a Combined Modality
Therapy Program
For DLCBL, almost all patients, including those with localized disease, are treated with CMT,
now typically R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
chemotherapy followed by RT. Thus, a more relevant question than the dose of RT required
for local control in patients treated with RT alone is the required dose in a CMT program.
There are many phase II reports in the literature of CMT for DLBCL with rather widely varying
doses of RT used.
The Vancouver group reported 308 patients with stage I and II DLBCL treated with CHOP (and
related combinations) followed by involved field radiotherapy (IFRT) to doses of 30 to 35 Gy (2
to 3 Gy per fraction). The 10-year cause-specific survival rate was 82%. In-field local failures
occurred in 3% of patients.
73. Investigators at the MD Anderson Cancer Center reviewed 469 patients with DLBCL treated
between 2001 and 2007 with R-CHOP (6 to 8 cycles) with or without RT.
Forty percent had stage I or II disease and 60% had stage III or IV. Overall, 30% had
consolidation IFRT following CR to chemotherapy with doses of 30 to 39 Gy.
Local control was achieved in 100% of patients with all relapses outside the RT field.
75. Chemotherapy
• Chemotherapy forms the mainstay of treatment for the great majority of patients with
NHL, because these diseases are most often generalized. As with radiation, malignant
lymphomas are, in general, very responsive to chemotherapy.
• This responsiveness, unfortunately, does not translate to cure of the patient in most
instances.
• Of all the pathologic variants of NHL in the WHO classification, consistent curability with
advanced disease is seen only in patients with DLBCL and to a lesser extent in some
patients with PTCL and ALCL.
• Some of the more “indolent” lymphomas such as FL do not appear curable with
conventional chemotherapy. A few patients with advanced indolent disease may be curable
with an allogeneic transplant.
76. • A large variety of drugs are available for the treatment of malignant lymphomas, including
alkylating agents such as cyclophosphamide, corticosteroids, vinca alkaloids, purine
analogs, and anthracyclines.
• They are typically used in combination in order to circumvent problems of drug
resistance. The most widely used combination for the treatment of DLBCL has been CHOP.
• For patients with advanced DLBCL, this combination produces an approximate 50% to
60% CR rate, just over half of which are durable responses, for an overall cure rate of
approximately 30% to 40%.
• Results are significantly improved by the addition of the anti-CD20 antibody rituximab, so
that R-CHOP has rapidly become the new standard.
77.
78.
79.
80.
81. Immunotherapy
1. Perhaps the most promising new approach to the treatment of NHL has been the
recent development of effective immunotherapy.
2. The malignant lymphomas express a variety of surface antigens, most notably
the B-cell antigen CD20.
3. The ubiquitous presence of the CD20 antigen in many varieties of B-cell
lymphomas led to the genetic engineering of a human chimeric anti-CD20
antibody rituximab.
4. In contrast to prior murine derived monoclonal antibodies, rituximab is quite well
tolerated in humans. Rituximab was the first antibody of any type to receive U.S.
Food and Drug Administration (FDA) approval (1997) for the treatment of any
human malignancy.
5. There are few data on the treatment of high–tumor burden disease with single-
agent rituximab. Among patients with low-burden disease, overall response rates
have ranged from 47% to 74%.
82. Rituximab has been an important addition to traditional drug therapy programs. It is
approved to treat diffuse large B-cell lymphoma as well as indolent lymphoma patients
with
1. Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single
agent
2. Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line
chemotherapy
3. Nonprogressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a
single agent, after first-line cyclophosphamide, vincristine, and prednisone (CVP)
chemotherapy
4.Advanced follicular, CD20-positive, B-cell NHL as a single-agent maintenance
treatment, after response to initial treatment with Rituxmab plus chemotherapy
(induction treatment).
83. o In relapsed or refractory indolent lymphomas, treatment with rituximab results in overall
response rates of nearly 50%, with a median response duration of approximately 1
year.
o To improve on response rates and duration of response, additional doses of rituximab
have been administered as “maintenance therapy.” The median event-free survival is
prolonged with this approach, especially for previously untreated patients.
o In previously treated patients, the total duration of benefit from rituximab appears to be
the same whether patients receive maintenance rituximab on a scheduled basis or
reinduction with rituximab only at the time of disease progression.
84. Rituximab maintenance also impacts progression-free survival among patients
treated with chemotherapy alone and those receiving rituximab plus
chemotherapy.
Among previously untreated patients with follicular lymphoma who responded to
immunochemotherapy (R-CVP [rituximab, cyclophosphamide, vincristine,
prednisone], R-CHOP, or R-FCM [rituximab, fludarabine, cyclophosphamide,
mitoxantrone]), rituximab maintenance resulted in a significant improvement in
progression-free survival over observation in the PRIMA phase III trial (6-year;
59% vs 43%; P < .0001), recently updated by Salles and colleagues
85. .Chemotherapy with and without rituximab.
For patients with high–tumor burden disease and/or symptoms, the addition of
rituximab to chemotherapy has resulted in major improvements in clinical outcome,
including overall survival.
Four phase III trials comparing combinations of chemotherapy and rituximab with
chemotherapy alone in previously untreated patients have all shown benefit for the
combination, establishing chemoimmunotherapy as the standard of care for
symptomatic patients or those with high–tumor burden disease.
Overall response rates and either median time to treatment failure or event-free
survival were superior in the chemoimmunotherapy arm in every series. An overall
survival benefit has been demonstrated in three of the four trials and in the high-risk
subset of the fourth study.
86. • The combination of bendamustine (Treanda) and rituximab was compared with R-CHOP
as first-line therapy in previously untreated patients with follicular, indolent, and mantle
cell lymphomas, resulting in significantly longer median progression-free survival (69.5
months vs 31.2 months; HR = 0.58).
• Bendamustine plus rituximab was less myelosuppressive than R-CHOP and resulted in
fewer infections, less peripheral neuropathy, and fewer episodes of stomatitis.
• This combination has become the backbone for the new US intergroup trial in which
rituximab-bortexomib-bendamustine is compared with rituximab-bendamustine.
• The importance of minimal residual disease in follicular lymphoma is not known. There
have been recent studies analyzing minimal residual disease, and other prospective trials
are ongoing.
87. • The anti-CD20 radioimmunoconjugates Y-90 ibritumomab (Zevalin) and I-131
tositumomab (Bexxar) both deliver ionizing radiation to target cells and their neighbors
and have proved to be relatively easy to administer, safe, and effective.
• In previously treated patients, Y-90 ibritumomab, a high-energy beta-emitter, yielded an
overall response rate of 80% for relapsed or refractory follicular or transformed CD20+
B-cell NHL, with a median duration of response of 14 months. For patients whose
disease is refractory to rituximab, response rates with Y-90 ibritumomab are high (74%
overall response rate), but the median duration of response is relatively short (6.4
months; range, 0.5 months to 25+ months).
• The dose-limiting feature of this approach is hematologic toxicity. Short-lived
myelosuppression occurs 7 to 9 weeks post treatment.
• {Dosing is based on weight (0.4 mCi/kg), with a reduction (0.3 mCi/kg) for those with mild thrombocytopenia (platelet count <
100,000/µL). When used to consolidate first partial or complete remission, Y-90 ibritumomab prolonged progression-free survival
from 1.1 to 4.1 years.}
88. • I-131 tositumomab is both a gamma- and a beta-emitter and is individually
dosed on the basis of dosimetry to deliver 75 cGy of total-body irradiation.
Similar to Y-90 ibritumomab, it is effective in both heavily pretreated relapsed
and refractory patients.
• Heavily pretreated patients with refractory low-grade or transformed NHL had
an overall response rate of 65% (20% complete response rate), with a median
duration of response of 6.5 months.
• These rates were notable in view of a response rate of only 28% in the
preceding chemotherapy regimen.
• Like Y-90 ibritumomab, I-131 tositumomab is associated with predictable
myelosuppression.
• Secondary myelodysplasia and leukemia have occurred in patients treated
with radioimmunotherapy, but only in patients previously treated with
chemotherapy and thereby already at risk.
89. Interferon-α
The use of interferon (IFN)-α in follicular lymphoma has been extensively
investigated both in combination with chemotherapy and as maintenance therapy,
with varying results. In most studies, IFN-α was associated with a prolongation of
remission, but not overall survival.
A notable exception was the GELF86 trial, in which overall survival was prolonged.
The Southwest Oncology Group (SWOG) reported results of a large phase III trial in
which patients with indolent lymphomas were randomized to receive IFN-α or
observation following induction with an intensive anthracycline-containing regimen
and in some cases radiotherapy. Post-remission therapy did not prolong
progression-free survival or overall survival.
90. Stem Cell Transplantation and High-Dose Chemotherapy
• There has been a great interest in the application of HDC with stem cell rescue in the
treatment of malignant lymphomas, both for relapsed disease following initial treatment
and for those patients deemed to be at high risk for relapse at diagnosis.
• The underlying concept is that larger doses of conventional chemotherapy will result in
greater tumor cell kill and increased cure rates.
• The doses involved are so large that they would be lethal because of hematopoietic
toxicity without a rescue strategy.
• Accordingly, hematopoietic progenitor cells are harvested from the patient before the
HDC, either from the bone marrow itself or more often mobilized from the patient’s
peripheral blood and then reinfused to re- establish marrow function (autologous stem
cell transplantation [ASCT]).
• The high frequency of bone marrow involvement in certain types of NHL limits this
strategy, as well as chemotherapy resistance.
91. • Alternatively, an allogeneic transplant may be carried out in individuals with a
suitable matched donor in which the stem cells are harvested from the donor.
• In this procedure, it is hoped that the infused donor stem cells will additionally
mount an immunologic attack on the tumor.
• Allogeneic transplantation may be preceded by full-dose (myeloablative)
chemotherapy designed to have not only an antitumor effect, but also to condition
the patient for the infusion of the donor cells, or it may be preceded by a
nonmyeloablative or reduced intensity conditioning (RIC) program designed
primarily to enable the recipient to accept the donor stem cells.
• In this latter situation the major antitumor effect is postulated to derive from the
infused donor stem cells. RIC allogeneic transplants are associated with a much
lower treatment-related mortality (10% to 20%) compared with myeloablative
allogeneic transplants (40% to 50%). TBI is often a component of the conditioning
program, with doses varying quite widely from 2 to 13.5 Gy
92. In general, ASCT has been investigated in three types of situations:
(a) patients who have been treated with conventional chemotherapy and then relapsed
(b) patients who fail conventional chemotherapy from the onset (so-called primary
refractory disease)
(c) patients who have responded well to primary chemotherapy but are considered at
high risk for relapse.
The most widely accepted use is for the treatment of patients with DLBCL who have
relapsed following initial CHOP or R-CHOP chemotherapy.
.
93. • In a phase III trial from the Parma group, patients with DLBCL who had
relapsed following initial CHOP chemotherapy and who were responsive to a
salvage program (dexamethasone, cisplatin, cytarabine [DHAP]) were then
randomly assigned to receive either four additional cycles of DHAP or a high-
dose chemotherapy program.
• Those receiving the HDC program had a markedly improved FFS and OS
compared with those getting conventional chemotherapy (46% FFS vs. 12%,
53% OS vs. 32%).
• Note that in both arms of this trial, IFRT to original bulky sites of disease (≥5
cm) was utilized, with a dose of 35 Gy in 20 fractions in the conventional
chemotherapy arm and 26 Gy in 1.3 Gy fractions twice a day in the HDC arm.
• All patients in the Parma trial were <60 years of age. Patients with a favorable
IPI score of 0 did not benefit. Those with a short remission after initial
chemotherapy had a worse outcome
94. • The Parma trial and associated phase II studies have led to the adaptation of ASCT as
standard of care for patients <60 years of age with DLBCL relapsing after initial
chemotherapy, although the Parma trial is the only phase III investigation of relapsed
DLBCL patients ever done.
• HDC and ASCT have generally not been successful in improving survival and curing
patients with indolent disease (e.g., FL). These data have also been comprehensively
reviewed recently.
• In brief, OS for indolent lymphomas does not appear to be improved with HDC/ASCT for
relapsed disease. Late consequences, particularly the development of myelodysplasia or
acute leukemia, are a real concern. The data on the use of allogeneic SCT are all from
phase II trials, and, while promising, this procedure is still inhibited by the substantial
treatment-related mortality, about 20% at 3 years for RIC transplants and 40% for
myeloablative transplants. Thus, allogeneic SCT remains investigational.
95. • The role of radiotherapy in patients undergoing HDC with SCT, either autologous or
allogeneic, is undefined. The rationale for RT lies in the observation that most treatment
failures after HDC SCT occur at sites of initial involvement.
• As mentioned above, consolidation RT was employed in the landmark Parma trial. It is
also commonly used at a number of institutions, usually directed at bulk disease sites
present before the start of salvage chemotherapy, but with considerable interinstitutional
variation and without a clear definition of what constitutes bulk disease.
• There are a number of phase II trials but no phase III trials addressing this issue. The
majority of phase II trials do suggest benefit. The authors recommend doses of 20 to 30
Gy for those patients who have not received prior RT, depending on clinical
circumstances and also dependent on whether or not TBI is planned as part of the
conditioning regimen. Generally, it is preferable to irradiate prior to reinfusion of stem
cells.
96.
97. HIGHLY AGGRESSIVE LYMPHOMA
Burkitt Lymphoma- Burkitt lymphoma is named after Denis Parsons Burkitt, 1958,who
mapped its peculiar geographic distribution across Africa. This aggressive B-cell subtype
represents about 2.5 percent of NHL cases, composed of Small non-cleaved cell lymphoma,
exclusively of B-cell origin usually appears as abdominal masses of lymphoma cells and is
uniformly associated with the Epstein-Barr virus. The characteristic histological features of
BL is the so-called “Starry Sky” appearance. imparted by scattered macrophages with
phagocytes cell debris. It may involve the marrow, blood, CNS and other organs. More than
half of those treated can be cured with current therapies.
Mainly chemotherapy is used to treat this type of NHL. Combination chemotherapy is used:
1st line (COM): • Cyclophosphamide • Oncovin (Vincristine) • Methotrexate (MTX)
Prophylactic x 3 courses(for low risk= Extra-abdominal tumor <10 cm)
Therapeutic x 6 courses(for high risk= All, other than above, eg CNS, intra- abdominal, extra-abdominal tumour >10cm)
Course repeated every 2 weeks x 6 courses. Commonly used agents include prednisone, cyclophosphamide, vincristine,
cytarabine, doxorubicin and methotrexate.
98. Precursor B- and T-Cell Lymphoma/Leukemia.
Precursor B- and T-cell lymphoblastic lymphoma or leukemia are rare, aggressive diseases
that can develop in either B cells or T cells. Disease that is predominantly in the marrow is
described as “leukemia,” whereas disease that is predominantly in tissue outside of the
marrow is described as “lymphoma.”
Treatment for newly diagnosed patients with precursor T-cell lymphoblastic
lymphoma or leukemia is aggressive chemotherapy and radiation. Nelarabine is
FDA-approved for the treatment of patients with T-cell lymphoblastic lymphoma or
T-cell lymphoblastic leukemia whose disease has not responded to or has
relapsed following treatment with at least two chemotherapy regimens.
99. AGGRESSIVE TYPE
Diffuse Large B-Cell Lymphoma
This is the most common NHL subtype and represents about 30 percent of cases of
NHL diagnosed in the United States. With DLBCL, the lymphoma cells are spread
diffusely throughout the lymph node, disrupting normal lymph node structure in a
uniform pattern.
DLBCL development usually starts in lymph nodes in the neck or abdomen and is
characterized by masses of large B cells (lymphocytes). It is often widespread in the
body and includes
• Tumor masses composed of large B lymphocytes
Extranodal involvement (tumor masses outside the lymph nodes in other sites of
• the body)
• Fever, weight loss and drenching night sweats.
100. To date, gene expression profiling studies have distinguished three molecular
subtypes of DLBCL called “germinal center B-cell-like” (GCB), “activated B-cell-like”
(ABC), and “primary mediastinal B-cell lymphoma” (PMBL). These distinct DLBCL
subtypes arise due to specific genetic changes.
The WHO recognizes several distinct variants of DLBCL. The most notable include
primary mediastinal DLBCL, T-cell/histiocyte-rich large B-cell lymphoma, and primary
DLBCL of the CNS
DLBCL is frequently treated with chemotherapy made up of four or more drugs. A
common combination is cyclophosphamide, doxorubicin, vincristine and prednisone
with rituximab (R-CHOP). Rituximab is indicated for previously untreated diffuse large
B-cell, CD20-positive NHL in combination with CHOP or other anthracycline- based
chemotherapy regimens.
101. Five randomized studies were subsequently conducted comparing chemotherapy
with a combined modality program. The South West Oncology Group (SWOG) study
demonstrated that brief CHOP chemotherapy (3 cycles) plus RT was superior to a
more extended CHOP regimen (8 cycles). Both PFS and OS were improved in the
combined modality arm with less toxicity
102.
103. The Eastern Cooperative Oncology Group study demonstrated that consolidation RT reduced
the risk of relapse even with extended chemotherapy (8 cycles of CHOP in this case).
Disease-free survival at 6 years was 73% with consolidation RT versus 56% with observation
104. . Disease-free survival for complete remission patients in the Eastern Cooperative Oncology Group randomized
trial. Observation (solid line) and consolidation radiotherapy (dotted line) are shown.
105. Diffuse Large B-Cell Lymphoma, Stage III or IV
The mainstay of treatment of disseminated DLBCL is clearly systemic chemotherapy. RT has
been thought to play little, if any, role. A recently published overview of chemotherapy for
“aggressive” NHL histologic type reviewed 111 scientific reports including 35 randomized
trials with a total of approximately 22,000 patients. The overview concluded that in
unselected patients with advanced-stage disease, CHOP was curative in approximately one-
third.
A European cooperative trial compared R-CHOP and CHOP in 824 patients aged 18 to 60
with stages II to IV DLBCL. Three-year FFS was 79% in the R-CHOP group compared with
59% in the CHOP group. Three-year OS was 93% and 84%, respectively. These studies
have led to the rapid adaptation of R-CHOP as standard initial therapy of DLBCL for all
stages of disease.
A comparatively unexplored approach is the use of consolidation RT in combination with
chemotherapy for advanced DLBCL. One rationale for the use of such RT is the tendency of
patients with advanced lymphoma to relapse at sites of disease present at diagnosis and, in
particular, sites of bulky disease present at diagnosis.
106. Follicular Lymphoma, Stages I and II
In follicular lymphoma the abnormal smaller B-cell lymphoma cells are grouped in
clusters or follicles throughout the lymph node. This is the second most frequent type
of lymphoma, accounting for about 20 percent of cases of NHL. FL cells often have a
specific chromosome abnormality (a translocation between parts of chromosomes 14
and 18) that causes the overexpression of a gene, BCL-2, and makes the cells
resistant to therapy.
However, treatment may keep the disease in check for many years, even when tests
show that disease remains in some parts of the body. FL has a relatively high rate of
transforming into a more aggressive disease.(follicular lymphoma stage 3).
The treatment historically for stage I or II FL has been RT alone.
107. TABLE 78.8 RADIATION THERAPY OF STAGE I/II FOLLICULAR LYMPHOMA SELECTED PHASE II TRIALS
108. The predominant pattern of failure for patients with stage I or II disease treated with RT
alone is distant. Local failure of any type, either alone or combined with distant failure,
occurs in <10% of patients. Nodal extension is an uncommon pattern of failure, seen in
perhaps 20% of patients.
Follicular Lymphoma, Stages III and IV
FL is quite responsive to a variety of systemic agents, including alkylating agents,
anthracyclines, purine analogs, vinca alkaloids, corticosteroids, and monoclonal antibodies.
• Immunotherapy: Rituximab produces responses in about 50% of relapsed FL patients as a
single agent. As first-line therapy, the response rate is about 70%. More often, however,
rituximab has been combined with chemotherapy.
• Radioimmunotherapy: This has also been extensively investigated in FL, both for the
treatment of relapsed disease as well as an initial therapy. The two agents in wide use are
90Y ibritumomab tiuxetan and 131I-tositumomab. Both agents demonstrate comparable
activity with response rates of 60% to 80% in relapsed FL
109. • Interferon: A recent meta-analysis concluded that when given in the context of relatively
intensive initial chemotherapy interferon-alfa prolongs both remission duration and
survival
• Stem cell transplantation: A number of studies have examined the role of autologous and
allogeneic transplantation in FL, for both relapsed disease and FL in first remission
following induction chemotherapy.
Role of RT: RT has also been advocated as consolidation therapy after chemotherapy in
patients with advanced stage FL. A phase III trial by Aviles et al. randomized 118 untreated
patients with stage III or IV FL to receive CVP chemotherapy alone or the same
chemotherapy followed by IFRT to initially involved nodal sites, at doses of 35 to 45 Gy. The
7-year FFS was 33% in the group treated by chemotherapy alone and 66% in those receiving
CMT. The 7-year OS was also doubled from approximately 40% to 80%. The improvement in
FFS was highly significant, and the survival showed improvement of borderline statistical
significance
110. Follicular Lymphoma, Grade 3
Grade 3 FL comprises cases where there are >15 centroblasts per high-power field. In
the current WHO classification, patients with FL who have diffuse areas in the
pathological specimen comprised predominantly or entirely of large blastic cells are
also reported to have DLBCL. FL grade 3 is an uncommon variety of FL, comprising
approximately 15% of all cases of FL.
The University of Nebraska group and MD Anderson Cancer Center group patients received
anthracycline-containing combination chemotherapy, with the patients with earlier-stage
disease receiving IFRT as well in varying dosages. The aforementioned as well as other series
have led to a consensus that patients with FL grade 3 should be treated similarly to patients
with DLBCL in terms of chemotherapy. The prognosis, in general, is better than for DLBCL
but median survivals are shorter than for FL.
111. Mantle cell lymphoma
Mantle cell lymphoma represents about 6 percent of NHL cases. The malignant cells originate
from a lymphocyte in the mantle zone of a lymph node.
This subtype usually occurs in people over 50 years of age and is found four times more
frequently in men than it is in women. The disease is usually already widespread at diagnosis,
involving lymph nodes, the marrow and sometimes the liver, intestines and spleen.
Chemotherapy programs can be generally grouped as CHOP-like, now usually including
rituximab, which does have activity in MCL, purine analog containing programs (e.g., R-FCM
[fludarabine, cyclophosphamide, mitoxantrone]) or more intensive programs such as
hyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytarabine, and
methotrexate). High response rates are seen (80% to 90%), but relapse usually occurs with no
plateauing of FFS. There is no clear evidence for superiority of one regimen over another. The
addition of rituximab to chemotherapy does seem beneficial.
112. HDC and SCT have also been employed, both autologous as well as allogeneic, both
in first remission and for relapse. One phase III trial did demonstrate improved FFS
for SCT in first remission, but no survival benefit as yet.
Patients with localized MCL (stage I or II) are seldom encountered.
One small series from British Columbia has been reported, however Seventeen
patients treated with RT (30 to 35 Gy) with or without chemotherapy had a 5-year FFS
of 68% and OS of 71%.
Adjuvant chemotherapy did not seem to influence the outcome. Thus, RT appears to
have an important role for those few patients with limited stage MCL. RT is also very
effective palliation for patients with advanced disease. Clinically the disease is quite
sensitive to radiation, and low doses (<20 Gy) may suffice.
113. Peripheral T-Cell Lymphoma
The International Peripheral T-Cell Lymphoma Project recognized 12 varieties of PTCL,
accounting for 5% to 10% of NHL in Western countries but 5% to 20% of NHL in Asia where
NK/T-cell lymphoma and adult T-cell leukemia/lymphoma are far more common.
ALCL is another T-cell lymphoma. Two forms may be distinguished: a systemic illness with
widespread involvement of lymph nodes and extranodal sites and a type primarily limited to
the skin. The systemic type may in turn be separated into those patients who are ALK positive
and those who do not overexpress this protein.
The clinical features and prognosis differ widely among these two categories. Patients with
ALK-positive ALCL are predominantly young men and, despite advanced- stage disease,
respond well to combination chemotherapy, with survival rates in the range of 75% to 90%.
114. Patients who are ALK negative, in contrast, tend to be older with a more nearly equal
male to female ratio. Their response to chemotherapy is much worse, with survival
rates reported in the 20% range.
Cutaneous ALCL constitutes a special situation. It is almost invariably ALK negative
but carries an excellent prognosis. It is often difficult to distinguish from benign
lymphomatoid papulosis (LyP). The latter may spontaneously remit and tends to run
a benign clinical course over many years. ALCL of the skin is quite responsive to
localized radiotherapy. PTCL is less responsive to radiotherapy then DLBCL, a dose
of approximately 40 Gy in 2 Gy fractions is recommended.
Overall ALCL has one of the best survival rates of any lymphoma, approximately
75% at 5 years in the ILSG study, despite its aggressive appearance under the
microscope.
115. INDOLENT SUBTYPES
Small Lymphocytic Lymphoma
SLL is morphologically and immunotypically identical to CLL; the two are classified as
one entity by the WHO.
Of combined cases, about 85% are CLL and 15% SLL. Clinically, SLL is distinguished
from CLL by the absence of peripheral blood involvement and <30% infiltration of the
bone marrow. SLL is generally manifest by widespread nodal involvement with or
without hepatosplenomegaly. CLL is primarily a disease of the blood and marrow, but
CLL cells may travel to the lymph nodes.
Bendamustine is a chemotherapy agent that was approved by the FDA for the
treatment of patients with CLL and for patients with indolent B-cell NHL who have
progressed during or within six months of treatment with rituximab or a Rituximab
containing regimen.
116. Lymphoplasmacytic Lymphoma and Waldenström Macroglobulinemia.
Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia are closely related,
slow-growing types of lymphoma that originate in a B-lymphocyte precursor.
In lymphoplasmacytic lymphoma, the lymph nodes are more involved than in Waldenström
macroglobulinemia.
Both disorders show malignant lymphoplasmacytic cells in the marrow and spleen.
Lymphoplasmacytic lymphoma is usually diagnosed by lymph node biopsy, while
Waldenström macroglobulinemia is diagnosed by marrow examination. These two types of
lymphoma account for less than 2 percent of NHL cases.
117. The malignant lymphoplasmacytic cells in both disorders secrete an monoclonal
immunoglobulin M (IgM). If the monoclonal IgM levels in the blood become elevated
enough, patients experience increased blood viscosity, inadequate blood flow, and symptoms
and signs of limited blood flow . This is referred to as “hyperviscosity syndrome,” which
may require urgent intervention.
Hyperviscosity syndrome can be treated by plasmapheresis to reverse acute symptoms and
signs, but long-term control requires a multidrug chemotherapy and a monoclonal antibody,
if indicated. If the disease appears to be progressive, therapy may be administered at the time
of diagnosis. Progressed disease may also involve the lungs, the gastrointestinal tract and
other organs.
118. MARGINAL ZONE LYMPHOMA
This indolent B-cell lymphoma subtype may be extranodal or nodal. The disease
tends to remain localized.
Marginal zone lymphomas include
Mucosa-associated lymphoid tissue (MALT) lymphoma, which affects sites outside
the lymph nodes such as the gastrointestinal tract, eyes, thyroid gland, salivary
glands, lungs or skin, and represents about 7.5 percent of NHL cases.
Transformed MALT lymphoma is an aggressive lymphoma and is uncommon. For
this small subset of patients, MALT lymphoma can transform into diffuse large B-cell
lymphoma (DLBCL). These patients have shown to benefit from treatments used for
DLBCL.
Nodal marginal zone B-cell lymphomas, also known as “monocytoid B-cell
lymphomas,” which may be found in the spleen and blood. This form of NHL is
uncommon, accounting for less than 2 percent of NHL cases, and is generally
treated like follicular lymphoma.
119. Splenic marginal zone lymphoma (SMZL), an indolent lymphoma, is
diagnosed in less than 1 percent of all NHL patients.
Splenic MZL patients usually present with splenomegaly. Almost all have
stage IV disease, principally because of bone marrow involvement.
The disease is relatively indolent, with three-quarters of patients alive at 5
years, but a aggressive subset does exist.
The most effective therapy appears to be splenectomy. Radiotherapy to the
spleen has infrequently been used.
120. MALT lymphoma is responsive to chemotherapy in a high percentage of patients.
With single-agent chlorambucil, a 75% CR rate was observed in one series. A large
SWOG analysis, however, indicated that FFS and OS rates were similar to those
observed in FL, with no plateauing of the survival curve. Thus, chemotherapy is
palliative and reserved for patients with generalized disease who are symptomatic.
Asymptomatic individuals with generalized disease should be considered for
observation, similar to patients with generalized FL because the course is so often
indolent.
121. PRIMARY EXTRANODAL LYMPHOMAS
Extranodal disease accounts for approximately 35% to 40% of all patients with NHL
and approximately half of those with stage I and II NHL.
The most common sites of involvement are the GI tract, accounting for approximately
25% to 35% of all ENL, the head and neck region, which accounts for approximately
20% to 30% (including Waldeyer’s ring and other head and neck sites, but excluding
brain), and skin, with a variety of miscellaneous sites accounting for the rest.
Gastrointestinal Lymphoma
The stomach is the most common site of involvement (50% to 80% of all cases of GI
lymphoma). The remaining GI lymphomas occur in the small and large intestines,
primarily ileum, followed by colon and rectum, but lymphomas may arise in any of the
GI tissues. Histopathologically, 90% to 95% of gastric lymphomas are MALT or
DLBCL, the two being approximately equal in frequency.
Surgical resection has traditionally been the cornerstone of treatment, followed by
adjuvant RT or chemotherapy
122. Gastric Diffuse Large B-Cell Lymphoma
The use of systemic chemotherapy has resulted in considerable improvement. Multiple
centers now report 5-year OS in the range of 70% to 80% for patients with localized disease
treated with chemotherapy with or without RT.
Excellent results have been reported in patients treated with 25 Gy after surgical
resection.For patients treated without resection, a wide variety of radiation doses have
been reported, ranging from 30 to 50 Gy, similar to what has been described for the
treatment of nodal DLBCL.
123. • The radiation field should probably encompass the entire stomach and perigastric
lymph nodes along the greater and lesser curvature of the stomach as well as any
other involved nodal areas with an appropriate margin.
• Patients should be fasting for several hours prior to simulation and treatment. CT-
based planning is preferred.
• Respiratory-induced motion should be assessed and accounted for using
fluoroscopy or four-dimensional CT.
• The typical field arrangement is parallel-opposed anterior and posterior fields.
More complex field arrangements may be necessary depending on the position of
the kidneys in relation to the target volume.
• In the event the patient has responded completely to chemotherapy by negative
endoscopic examination and biopsy, a dose of 30 Gy is appropriate. If there is
persistent biopsy-documented disease after chemotherapy, other systemic
therapy should be considered or higher doses of radiation must be used, in the
range of 40 Gy.
124. Gastric Lymphoma, Mucosa-Associated Lymphoid Tissue Type
MALT lymphoma is a distinct clinical-pathologic entity first described by Isaacson
and Wright and occurring most often in the stomach. A unique feature of gastric
MALT is the association with H. pylori infection. H. pylori can be identified in up to
92% of patients.
Accordingly, first-line treatment for patients who are H. pylori positive is
appropriate antibiotics. A frequently recommended combination is omeprazole,
metronidazole, and clarithromycin.
The complete remission rate is approximately 75%.
Several factors have been associated with resistance to antibiotics, including deep
invasion of the gastric wall and the (11:18) translocation. Additionally, some
patients in CR will have persistent B cell monoclonality on PCR analysis and are
at higher risk of relapse.
RT is reserved for patients who are H. pylori negative or who fail antibiotic therapy.
The same techniques utilized for gastric DLBCL apply. Doses of 25 to 30 Gy are
adequate.
There is no apparent role for adjuvant chemotherapy in localized gastric MALT
125. Intestinal Lymphomas
Small intestinal lymphomas may comprise 20% to 30% of all GI lymphomas. The majority are
B-cell lymphomas, predominantly DLBCL.
Because of the frequent presentation with obstructive signs and symptoms, along with the
complexity of establishing a diagnosis endoscopically, surgery is more commonly used, both
for diagnosis and for therapy, than it is for gastric lymphoma.
For surgically resected, localized intestinal lymphoma of the DLBCL type, anthracycline-
based chemotherapy with rituximab should be given after surgery, as for localized DLBCL of
other sites.
For completely resected disease, adjuvant RT is probably not necessary. In the case of
localized disease incompletely resected, some authorities recommend the addition of WAI
although more conformal fields may be used if the target region can be appropriately
demarcated.
126. T-cell lymphomas account for approximately 10% to 20% of all intestinal
lymphomas, and multiple subtypes have been known to arise in the bowel,
including extranodal NK/T-cell lymphoma, anaplastic
large cell lymphoma.
A distinct intestinal lymphoma entity in the WHO classification is enteropathy-
associated T-cell lymphoma, which occurs primarily in the presence of celiac
disease. This has also been described as malignant histiocytosis of the intestine,
but it is now known to represent a T-cell lymphoma.
127. The diagnosis is usually established with laparotomy. After surgical resection,
treatment has usually consisted of anthracycline-based chemotherapy. The outcome,
however, has been poor, with 5-year survivals of 20% to 25%.
These patients usually have a worse performance status and tolerate chemotherapy
poorly. Intestinal perforation after chemotherapy is not unusual.
There are no reported results for RT. For patients with residual disease after surgery, it
is possible that a protracted course of RT with small fractions followed by
chemotherapy might reduce the frequency of intestinal perforation reported after
conventional doses of CHOP.
128. Head and Neck Lymphomas
Head and neck lymphomas are the second most frequent variant of ENL after
those of the GI tract, representing approximately 20% of all ENL.
They occur in a variety of sites, including Waldeyer’s ring, the thyroid, salivary
glands, nasal cavity, paranasal sinuses, and orbit, with differing histologic types
and clinical characteristics depending on the site of origin.
Most appear to be of B-cell origin and most of those are DLBCL. MZL is less
common but constitutes a majority of salivary gland lymphomas. A special entity
is that of nasal NK/T-cell lymphoma.
The pathologic type is usually DLBCL. The treatment guidelines are those for
nodal stage I and II DLBCL.
129. • Most paranasal sinus tumors are B cell in origin and usually present in men in
the sixth or seventh decade. The outlook when treated with RT alone seems
to be particularly poor for both stage I and II disease, with 12% long-term
survival in the Stanford University series and approximately 30% in an MD
Anderson Cancer Center report.
• Nasal cavity lymphomas, on the other hand, appear to be of predominantly T-
cell origin and fall into the category of NK/T-cell lymphomas.
• The disease affects primarily men, mostly in the fifth decade. It often presents
as a destructive necrotizing process. Because of this, histologic diagnosis
may be difficult.
• The disease appears to progress primarily locally with only a small
predilection for regional or systemic failure. Treatment approaches have
consisted of RT alone, chemotherapy alone, and the two combined. With RT
alone, approximately two- thirds of patients achieved CR, but half of those
relapsed. The prognosis appears somewhat worse for stage II than stage I.
130. Salivary gland lymphomas are frequently of a more indolent histologic type
Treatment usually consists of RT alone.
The prognosis is excellent, with survival >90%. One small randomized trial
explored the use of chemotherapy in addition to RT.
In this trial, 5-year survival rates of 90% were achieved with RT alone or with CMT
DOSES
For NK/T-cell tumors, few data are available. Recommended dose of 40 to 50 Gy
in combination with chemotherapy. The NCCN guidelines recommend a dose of at
least 50 Gy. Indolent histologies involving the head and neck should be treated
with RT alone to a maximum of 30 Gy.
132. Cutaneous Lymphomas
The term primary cutaneous lymphoma (PCL) is used to define those lymphomas
that present in and are confined to the skin without evidence of extracutaneous
disease. PCL is the third most common ENL, closely following GI and head and
neck lymphomas. About 75% of all PCL is of T-cell origin and 25% of B-cell origin. Most
cutaneous T-cell lymphomas are mycosis fungoides.
The treatment of choice for cutaneous ALCL is local radiotherapy. A dose of 40 Gy
is generally recommended. About 40% of patients will relapse elsewhere in the skin
but may often still be sufficiently localized so they can be treated again with
radiation. As stated above, death from lymphoma is infrequent. LyP, if it can be
distinguished from cutaneous ALCL, should be left untreated as spontaneous
regression is a characteristic feature. There is generally no role for chemotherapy
for cutaneous ALCL
133. Orbital Lymphomas
Lymphomas of the eye may involve either the extraocular orbital tissues such as the
conjunctiva, retrobulbar region, or lacrimal gland, or may involve the globe itself.
The latter condition is referred to as primary intraocular lymphoma and is, in
essence, a subset of PCNSL in which lymphoma cells are initially present only in the
eyes, without evidence of disease in the brain or other CNS tissues. Orbital
lymphomas comprise approximately 4% of all ENL.
They typically arise in superficial tissues such as conjunctiva and eyelids and are most
commonly seen in an older population, with a median age of approximately 60 years.
Histopathologically, approximately two-thirds of these tumors are MZL. Most of the
remainder are DLBCL
134. Patients typically present with mass lesions in the conjunctivae or lids, described in the
literature as “salmon pink” in color. Tumors of the retrobulbar region may present with
swelling and proptosis and associated disturbances in function of the extraocular
muscles
the treatment principles for lymphomas generally apply. MZL is treated with RT alone. No
more than 30 Gy is required for local control. Doses of 20 to 30 Gy have been reported as
equally effective.
Orbital MZL has recently joined the group of MZL’s associated with infectious agents, in this
instance C. psittaci.
A trial of antibiotic therapy has been suggested for patients in whom this organism is
identified, but a meta-analysis has shown highly variable results of antibiotic therapy, with an
overall incidence of C. psittaci of 23%.
It has also been suggested that observation only is a reasonable strategy.
135. A much smaller percentage of patients (10% to 30%) presents with orbital disease
that is DLBCL. The treatment of choice is CMT, R-CHOP followed by IFRT.
After CR to chemotherapy, the appropriate dose of RT is no more than 30 Gy. It is
particularly important to minimize dose to the eye to avoid late complications. With
this program, cure rates of 80% would be expected and have been reported.
136. Extranodal Lymphomas of Other Sites
In addition to the areas previously described, NHL may arise in almost any organ or
tissue of the body, including but not limited to bone, testis, ovary, kidney, bladder,
female genital tract, breasts, and lung.
Lymphoma in any of these sites is quite uncommon.
Testicular lymphoma is rare, accounting for approximately 2% to 3% of all ENL and <1% of all
NHL.
It presents typically in elderly men in their seventh and eighth decades. Most patients have
stage I or II disease. The histologic type is typically DLBCL.
Approximately one-fourth of patients have stage IV disease at presentation, with a
predilection for unusual sites of involvement such as CNS, skin, and lung.
137. Treatment programs of surgery, CHOP, and RT have still resulted in only an
approximately 30% long-term survival. There is a high predilection for both
contralateral testis relapse as well as CNS relapse, with some 30% to 40% of
patients failing in these sites as well as other generalized sites.
ENL of bone is another uncommon entity, representing <5% of all. The disease is
managed similarly to stage I or II NHL of other sites. therapy is initiated with R-CHOP
followed by involved field RT. Although a dose of 30 Gy is appropriate for patients
achieving CR, that determination may be difficult in bone disease.
138. Another quite uncommon variety of ENL is that arising in the lung.
Although secondary involvement in the lung in NHL is common, primary involvement
in the lung represents approximately 1% of all ENL presentations.
The prognosis of primary lung lymphoma is good, because these are primarily MZL.
They are known as BALT tumors because they arise from bronchus-associated
lymphoid tissue.
139. There are very few patients reported treated with radiation, either alone or in
combination with surgery and chemotherapy. Excellent local tumor control would be
predicted for RT, however, in modest doses typical for MZL.
It is therefore the treatment of choice in unresectable BALT lymphoma or where the
extent of pulmonary resection would significantly compromise lung function. If only a
small amount of lung needs to be surgically removed to encompass the tumor,
surgical resection may carry less morbidity than RT.
A small percentage of pulmonary lymphomas are DLBCL. These should be managed
in accordance with the accepted principles of management of DLBCL, namely, R-
CHOP.
140. Primary Central Nervous System Lymphoma
PCNSL is a rare form of extranodal NHL, often associated with HIV. In addition, the
tumor is virtually always associated with EBV in immunocompromised.
Neurologic symptoms are usually of brief duration, 3 months or less. Specific neurologic
deficits depend on tumor location.
Generalized symptomatology such as altered mental status, seizures, and symptoms of
increased intracranial pressure such as headache, nausea, and vomiting may occur.
The role of surgery in the management of PCNSL is limited to establishing the diagnosis,
preferably by stereotactic biopsy.
Corticosteroids, commonly used to alleviate symptoms including intracranial pressure, have a
direct antitumor effect. Tumor regression may lead to difficulties in establishing diagnosis.
Accordingly, steroids should be withheld, if possible, until after biopsy, if the diagnosis of
lymphoma is suspected.
141. PCNSL is usually not amenable to surgical resection due to deep location and involvement of
critical structures.
Occasionally, surgical decompression and shunt placement is necessary for relief of increased
intracranial pressure. Cerebrospinal fluid (CSF) analysis, including immunoglobulin gene
rearrangement studies, can identify clonal populations to establish the diagnosis.
Almost all studies reveal age and performance status to be important independent prognostic
factors.
Historically, the treatment was whole-brain radiotherapy (WBRT) alone to address the
disease’s multifocal nature. Results were poor, however, despite the known radiosensitivity of
NHL outside the CNS. Two representative series from the Radiation Therapy Oncology Group
(RTOG) and Princess Margaret Hospital report median survivals of 12.2 months and 17
months, respectively, and 5-year survivals of 10% to 20%
A randomized trial by the Medical Research Council showed no benefit for CHOP added to RT.
142. The phase II RTOG- 9310 study treated patients with combination chemotherapy,
including high-dose MTX, and WBRT. The 5-year OS was 32% and the FFS 25%,
results better than historically obtained with RT alone. Neurologic complications can
arise as early as 3 months posttreatment with symptoms of attention deficit, memory
impairment, ataxia, and urinary incontinence and could ultimately lead to dementia.
In an effort to reduce neurologic complications, radiation dose reduction has been
investigated. Bessell et al. reduced RT dose to 30 Gy in 26 patients who had achieved CR to
chemotherapy. The 3-year overall survival was 92% versus 60% for a retrospective
comparison group receiving 45 Gy plus a 10 Gy boost.
the Memorial Sloan-Kettering Cancer Center group has reduced the dose to 23.4 Gy for
patients achieving CR to rituximab and MTX-based chemotherapy with promising short-term
results. Two-year OS and PFS were 67% and 57%, respectively. With a median follow-up of
37 months, no treatment-related neurotoxicity was observed.
143. Future areas of research include additional chemotherapeutic drugs in combination with
high-dose MTX. Regimens including cytarabine and rituximab have been reported
HDC with ASCT has also been evaluated.
High-dose MTX, >3 g/m2 every 2 to 4 weeks, is the cornerstone of therapy.
The addition of other drugs and the role of stem cell transplant remain controversial.
The role of WBRT after high-dose MTX is especially controversial, particularly in
patients achieving a CR and in those >60 years old. It seems clear that 45 Gy WBRT
results in unacceptable toxicity in older patients and perhaps in younger ones as well.
Given the overall unsatisfactory results of therapy, the addition of low-dose RT (24
Gy) to chemotherapy for patients achieving a CR is a promising approach.
Editor's Notes
Patients with gastric lymphoma usually present with symptoms of abdominal pain (~80%).320 Other common complaints are loss of appetite (~50%), weight loss (25%), and bleeding (20%). B symptomatology is uncommon (10% of patients). In this regard, only fever and night sweats are significant because weight loss is so often a function of direct effects on the stomach. Perforation as an initial symptom is very uncommon, occurring in <2% of patients. Many cases of gastric MZL are detected incidentally during endoscopic examinations.
The diagnosis of gastric lymphoma is usually established endoscopically, although in past years laparotomy was often necessary.323 Surgical resection has traditionally been the cornerstone of treatment, followed by adjuvant RT or chemotherapy
DLBCL of the intestine is seen primarily in Western countries and resembles primary DLBCL of the stomach. The clinical presentation is usually with abdominal pain, anorexia, and weight loss. However, ileus or perforation is much more common than in gastric lymphoma, occurring in approximately 40% of the patients in the German series.320 Most patients have localized disease at onset, but the usual staging workup is appropriate. PET-CT should be performed, primarily for delineation of disease outside the intestinal tract and determination of the size of mass lesions in the intestinal tract. Intraluminal disease is probably better visualized with conventional barium studies.
The clinical presentation is similar to that described for B-cell intestinal lymphomas. Diarrhea is prominent, reported in approximately 40% of patients. Presentation with perforation or obstruction occurs in approximately 40% of patients.353 There is a greater tendency for these patients to have widespread bowel involvement.
Immunoproliferative small intestinal disease (IPSID), also referred to as Mediterranean lymphoma, occurs mainly in young adults in the Middle East and North Africa.
PSID is a B-cell lymphoma, believed to arise from the clonal proliferation of B lymphocytes that produce immunoglobulin-A (IgA heavy chain). C. jejuni has recently been shown to have an etiologic role. In its early stages, the disease responds to antibiotic therapy. The disease frequently affects the entire small intestine. Symptoms of malabsorption predominate. Treatment has usually consisted of chemotherapy.354,355 The prognosis has been poor, with survival rates not exceeding 20%. WAI has been reported to be useful in selected patients.
Lymphomas presenting in Waldeyer’s ring typically involve the tonsil, base of tongue, or nasopharynx. The clinical symptoms are those associated with epithelial tumors in those sites, such as dysphagia, sore throat, nasal congestion, and eustachian tube blockage. The lesions are frequently clinically apparent on thorough head and neck examination. Neck adenopathy is common.
The usual lymphoma staging studies are appropriate, including CT or PET-CT scans of head and neck, chest, and abdomen and bone marrow examination. MRI may be necessary for precise anatomic delineation. There is a predilection for Waldeyer’s ring lymphomas to have GI tract involvement as well, so direct imaging (i.e., upper GI series or endoscopy) is indicated. Most cases are stage I or II after full staging evaluation
These patients usually present with painless enlargement of the parotid gland. There is an association with Sjögren syndrome.
