The Future of Continuing Education in Diagnostic Imaging

Lymphoma Imaging

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 Author: Tom Iarocci, MS, MD

Abstract: In recent decades, therapeutic advances and advances in medical imaging have fueled improvements in survival in a variety of hematologic malignancies, including various types of leukemia, lymphoma and myeloma. In concert with these advances, knowledge of lymphoma types and subtypes has exploded, and differing classification systems are in use. While detailed knowledge of lymphoma is, of necessity, mostly the jurisdiction of specialists, there are several key definitions, concepts and distinctions which have emerged that are of great relevance to medical imaging. These include defining characteristics of Hodgkin’s and non-Hodgkin’s lymphoma, patterns of lymph node involvement, and the role of PET/CT and other imaging modalities in diagnosis, staging, and assessment of treatment response.

Introduction

Medical imaging, along with the availability of better therapies, has played a huge role in improving outcomes for many patients with lymphoma in recent decades. Some types of lymphoma are now highly curable. Successful treatment can mean patients live full lives, with the same life expectancy as those who have never had cancer. Still, other types of lymphoma have no cure, and the focus becomes managing life with cancer, and keeping the malignancy at bay for as long as possible. Prognosis and survival times vary widely. With some aggressive lymphoma types, survival may be measured in months, while in other cases, people routinely live a decade or more following diagnosis and treatment.

Part of the challenge with lymphoma is all of the complexity: there are more than 60 different types of lymphoma.1,2 This tends to cause confusion -- not only for patients and their loved ones, but also for the entire health care team. This includes most physicians who do not specialize in this area. Differing classification systems are currently in use, adding to potential confusion. Finally, with the added layer of molecular medicine, genetic mutations in the tumor cells can come into play so that even patients with the same lymphoma subtype may have very different prognoses.

Despite this complexity, knowledge of just a few key definitions can go a long way, as can familiarity with a few differing patterns of presentation and spread. The present review aims to cover key concepts that have the most relevance to medical imaging.

 

Lymphoma Overview

Today, lymphoma is considered one of the hematologic malignancies, along with leukemia and multiple myeloma. Overall, there are more cases of lymphoma than either leukemia or myeloma. According to the American Cancer Society, estimates for new cases in 2015 are as follows:3 

Lymphoma - 80,900 people:

 

  • 71,850 non-Hodgkin’s lymphoma
  • 9,050 Hodgkin’s lymphoma

 

Leukemia - 54,270 people

Myeloma - 26,850 people

Initial diagnosis of lymphoma depends on certain aspects that need to be gleaned from a sample of the tissue itself, including cellular appearance, immune markers, and other laboratory tests, potentially including molecular studies to accurately categorize the lymphoma.4

 

Lymphomas Usually Start in the Lymph Nodes

While it is true that lymphomas usually start in the lymph nodes, it is possible for a lymphoma to start virtually anywhere in the body. Lymphoma is defined today as any malignancy of the lymphoid tissue, which includes cells in the lymph nodes; however, it also includes diffusely scattered tissues and other discrete organs composed of lymphoid tissue -- the thymus, bone marrow, lymph nodes and spleen. The most common cell type in the lymphoid tissue is, of course, the lymphocyte -- hence, the potential for B-cell lymphomas and T-cell lymphomas (and even Natural Killer T-cell lymphomas). But lymphoid tissue is also scattered throughout the body, often at strategic sites for interfacing with pathogens and other immune cells. These sites occur in the respiratory tract and gastrointestinal tract, for instance, and beneath the mucous membranes. Lymphoid tissue in these areas can give rise to malignancies known as MALT lymphomas. MALT is short for mucosa-associated lymphoid tissue, and the most common place to find a MALT lymphoma is actually in the stomach.5,6 MALT lymphoma is an excellent example of what is considered an extranodal lymphoma.

 

Extranodal Lymphoma vs. Extranodal Involvement

 

Extranodal Lymphoma

When a lymphoma is believed to have originated outside the lymph nodes -- meaning the cancerous cells developed in lymphoid tissue elsewhere in the body -- it’s called an extranodal lymphoma, or more precisely, a primary extranodal lymphoma. The most frequent site of extranodal lymphoma is in the GI tract. The next most frequent site after the GI tract is the skin; however, when a lymphoma starts only in the skin, it is usually referred to as a cutaneous lymphoma. The fact that a lymphoma is considered a primary extranodal lymphoma may or may not be key to treatment and prognosis. The lymphoma subtype, the B-cell or T-cell type, the histology and the primary organ or tissue of origin can be prognostic factors of equal or greater importance.5,6 And, incidentally, even though it’s modern times, on occasion it can still be difficult for doctors to tell whether a particular lymphoma began in a lymph node or not. In these cases, some may take a shortcut to make their call: if the lymphoma at one time had its major tumor mass -- its most obvious bulk – outside the lymph nodes, then it may be considered an extranodal lymphoma. Nevertheless, the concept of a primary extranodal lymphoma a crucial one. Extranodal lymphomas are commonplace among non-Hodgkin’s lymphomas.

 

Extranodal Involvement

Lymphomas that start in the lymph nodes, or the so-called nodal lymphomas, almost all of them can have extranodal involvement -- that is, they can spread to extranodal sites. A lymphoma that spreads to other organs from the lymph nodes is not considered a primary extranodal lymphoma. In order to be primary extranodal, the lymphoma has to have originated outside the lymph nodes.5,6

Hodgkin’s vs. Non-Hodgkin’s Lymphoma

Hodgkin’s lymphoma, or HL, and non-Hodgkin’s lymphoma, or NHL, are the two main categories of lymphoma. The difference between the two was originally historical, but today differing characteristics also help to shape the current understanding of how HL and NHL differ.

HL is historical. Also called Hodgkin’s disease, Hodgkin’s lymphoma refers specifically to the kind of lymphoma first described by Thomas Hodgkin, a doctor who lived in the early 1800s. In 1826, Hodgkin was appointed “first lecturer in morbid anatomy” and museum curator at the new Guy's Hospital Medical School in London. Early on, he was actually responsible for bringing the first stethoscope back from Paris to Guy’s Hospital, helping to introduce the newfangled device to Britain. Apparently, the older physicians did not care for the new invention and, as it was quite a bit larger at the time, used it as a flowerpot. When the more established physicians left the room, however, the students removed the flowers and started using it to examine each other.7

Hodgkin spent 12 years at Guy’s Hospital, where he performed hundreds of autopsies and cataloged over 3000 specimens. He had many contributions other than Hodgkin’s disease, but in one report, he described clinical histories and postmortem findings of seven patients who had enlarged lymph nodes and spleen but no inflammation or other significant pathology. Hodgkin noted that tuberculosis coexisted in some of these patients, but said that the firmness and size of the nodes indicated this was something different.7 He pointed out that the disease spread to contiguous lymph node groups in an orderly manner and that splenic involvement was a late.7,8 This was controversial at the time, but his paper from 1822 was later rediscovered, and he was properly credited for the discovery.8 Abdominal lymph nodes (Hodgkin's original case), still survive today at the Gordon Museum of Pathology in King's College, London.7

NHL Cases are numerous and Diverse. Non-Hodgkin’s lymphoma essentially refers to a huge variety of lymphomas that, quite literally, are not Hodgkin’s lymphoma. More than 60 different types of lymphoma have been described that are distinct from Hodgkin’s lymphoma. NHL is far more common overall, accounting for up to 90% of all lymphomas today.

HL vs. NHL: Which one is a Younger Person’s Disease?
Without further qualification, this is a question that has no good answer. First, it depends on how young that younger person is. Hodgkin’s lymphoma is rare in children under 5 years of age, but it’s common in the 15 to 40 year-old age group, and it hits a peak in young adults in their twenties.3  So, in a way, HL might be considered a younger person’s disease. But there’s a catch -- HL has another peak later in life, after age 55.

Second, the answer can change if you go to specific subtypes. Overall, NHL can occur at any age, but about half of patients are older than 66, and the risk of developing NHL increases throughout life. More than 95 percent of cases occur in adults, so in some ways, NHL might be considered an older person’s disease. However, there is a catch again -- some of the NHL types are among the more common childhood cancers.3

 HL vs. NHL: Basic Anatomic Differences

The majority of both NHL and HL are nodal lymphomas, originating within the lymph nodes. However, NHL is the type that is much more likely to be extranodal. Some 33% of NHL cases are considered primary extranodal lymphomas. The most frequent site of primary extranodal lymphoma is in the gastrointestinal tract -- and almost all of these are NHL. Extranodal lymphomas are rare in HL. In the chest, typical patterns of lymph node involvement can be another point of difference between HL and NHL, as shown in Table 1. Hodgkin’s lymphoma is more likely to involve the thorax, and when it does it almost always involves the mediastinal lymph nodes. What is more, HL tends to progress from lymph node group to lymph node group in a relatively ordered way, while NHL often skips lymph node groups.


Anatomical staging is a stronger indicator of prognosis in HL. In addition to finding the anatomical sites of the cancer, imaging studies can help to define disease bulk, which can also impact the prognosis.

 

Hodgkin’s Disease Essentials

Cell Type

HL is characterized by the presence of Reed-Sternberg cells – those large, often multinucleated cells that microscopically resemble owls, with big eyes, as shown in figure 1.

 

Reed-Sternberg cells don’t seem much like T-lymphocytes or B-lymphocytes, so it took investigators many years to figure out what cell type or lineage they arise from. Today, it is generally believed that they are derived from B-cells. These lymphoma cells are actually the minority of cells in HL tumors because many other cells infiltrate the site. 

Types: Far fewer than in NHL
Classical Hodgkin's Lymphoma refers to only four different types (nodular sclerosing HL, mixed cellularity HL, lymphocyte rich classical HL, and lymphocyte depleted HL). Non-classical HL includes uncommon subtypes and comprises a smaller percentage of all HL cases.

Clinical Presentation

Clinical presentation can vary, but the most common symptom is enlarged lymph node and nothing else. Lymph nodes may be enlarged in the neck, armpits, or groin, or within the chest. Less commonly, those with HL may have weight loss, fever, itching or drenching sweats at night – collectively called B symptoms. The presence of just one of these symptoms qualifies as having B symptoms.

Prognosis

Hodgkin’s lymphoma is one of several lymphoma types that are considered the most curable. Adult patients with early-stage disease (stage I–IIA) have an overall survival exceeding 90% in many trials. In advanced-stage disease, overall survival is 75–90%. In both early-stage and advanced-stage disease, further grouping according to risk factors is often done.9

 

Non-Hodgkin’s Disease Essentials

Cell Types

Non-Hodgkin’s lymphomas arise from the immune cells of the lymphoid lineage, the lymphocytes, or B cells, T cells and natural killer cells.. 

More and More Types and Subtypes

With NHL, the list of types and subtypes is very long. Even restricting the list to just one cell type -- the B-cell lymphomas, for instance – leaves more than a dozen B-cell lymphoma types and subtypes.

A Diverse Group of Malignancies

NHLs are a diverse group of malignancies that vary in their radiologic findings, course and prognoses. In most of the cases, the cancer cells are located in the lymph nodes or in other lymphoid tissues – in organs such as the spleen and bone marrow -- but they may also invade other organs such as the small bowel and kidney.

Clinical Presentation

The clinical presentation of NHL is extremely variable depending on the type of lymphoma. Some NHLs are slowly growing, or indolent, with lymph node enlargement that flares up and settles down, over years. Other NHLs are highly aggressive, resulting in death within weeks if left untreated. Aggressive lymphomas typically involve a rapidly growing mass and the systemic or so-called B symptoms of fever, night sweats and weight loss. Diffuse large B cell lymphoma, or DLBCL is an example of a lymphoma that can have an aggressive presentation. In contrast, indolent lymphomas typically develop more slowly, with gradual lymphadenopathy, hepatomegaly, splenomegaly or cytopenias. Follicular lymphoma is an example of a lymphoma that can have a more indolent presentation.

Prognosis

In part because NHL is such a diverse collection of diseases, prognosis is highly variable and depends on many different factors such as the cell type of origin, the histology or microscopic appearance of the cancer, the aggressiveness of the malignancy and the availability of effective therapy -- not to mention patient factors separate from the lymphoma. Different types of NHL have different courses and are associated with different survival rates. While some of the more difficult-to-treat malignancies fall in this category, so do some of the more easily cured.

The following list illustrates the diversity of NHL and shows one of several ways in which NHLs are classified. The current World Health Organization Classification of Lymphoid Neoplasms is more robust, with recognition of additional subtypes of clinical importance.2

 

List of NHLs, Organized by Cell Type 

B-cell Lymphomas

Burkitt lymphoma

Burkitt-like lymphoma

Diffuse large B-cell lymphoma, or DLBCL

-- Primary mediastinal B-cell lymphoma, or PMBL

            -- Intravascular large B-cell lymphoma, or IVL

Follicular lymphoma

Hairy cell leukemia -- sometimes considered a lymphoma

Lymphoplasmacytic lymphoma aka Waldenström’s macroglobulinemia

Mantle cell lymphoma

Marginal zone B-cell lymphomas

-- Extranodal marginal zone B-cell lymphomas, also known as mucosa-associated lymphoid tissue lymphomas, or MALT lymphomas

            -- Nodal marginal zone B-cell lymphoma

            -- Splenic marginal zone B-cell lymphoma

Primary central nervous system (CNS) lymphoma

Small lymphocytic lymphoma, or SLL aka chronic lymphocytic leukemia, or CLL

T-cell Lymphomas

Precursor T-lymphoblastic lymphoma/leukemia

Peripheral T-cell lymphomas:

Cutaneous T-cell lymphomas

    -- Mycosis fungoides                                

    -- Sezary syndrome

    -- Others

Adult T-cell leukemia/lymphomas

    -- Smoldering subtype

    -- Chronic subtype

    -- Acute subtype

    -- Lymphoma subtype

Angioimmunoblastic T-cell lymphoma

Extranodal natural killer/T-cell lymphoma, nasal type

Enteropathy-associated intestinal T-cell lymphoma – EATL

    -- Type 1 EATL

    -- Type 2 EATL

Anaplastic large cell lymphoma

   -- Primary cutaneous

   -- Systemic

Peripheral T-cell lymphoma, unspecified

 

Other Lymphoma Adjectives and Descriptors

Cutaneous refers to the skin, and several T-cell lymphomas fall in this category (e.g. mycosis fungoides and Sezary syndrome). Anaplastic refers to a cellular appearance with characteristics differing from those expected of mature cells -- sometimes described as primitive or lacking differentiation. Enteropathy is a disease of the intestines, and especially the small intestines; however, as relates to lymphoma, certain types of enteropathy are associated with malignancy. Type 1 enteropathy-associated intestinal T-cell lymphoma, or Type 1 EATL, is linked to gluten-sensitive enteropathy, or celiac disease. Celiac disease is an autoimmune disease in which gluten, a wheat protein, results in the gluten-sensitive person making antibodies that attack their own intestinal lining, as well as other tissues.1

 

Positron Emission Tomography (PET)/Computed Tomography (CT) Essentials

About PET/CT

PET uses radioactive sugar, or fluorodeoxyglucose (FDG), which is generally taken up by lymphoma cells quite well, or with high avidity. FDG-PET is generally more sensitive than CT as it can detect disease in normal-sized lymph nodes and help to evaluate extranodal disease. PET is often combined with CT to allow comparison of areas of higher radioactivity on the PET scan with the more detailed appearance of that area on the CT. Compared with conventional imaging, the use of PET/CT at baseline caninfluence staging and lead to a different therapeutic strategy in a substantial number of cases.4,10-11

Which Lymphomas Avidly Take up FDG?

Some of the most common lymphomas are avid in their uptake of FDG, including HL, diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma -- these malignancies are almost always FDG-avid at presentation.4,10-11  Routinely FDG-avid lymphomas also include other types of NHL, such as other aggressive B-cell malignancies, Burkitt lymphoma, follicular lymphoma, mantel cell lymphoma and aggressive T-cell lymphomas.11-13

When is PET/CT recommended?

PET/CT has an established role in the staging and evaluation of HL and is now recommended for staging and post-treatment response assessment of all FDG-avid NHLs as well.4,11 For HL and FDG-avid NHL subtypes, PET and PET-CT improve the accuracy of staging compared with CT scans for nodal and extranodal sites.4 PET/CT can help identify extranodal involvement and detect primary extranodal disease. According to the International Conference on Malignant Lymphomas Imaging Working Group, focal FDG uptake within the bone or bone marrow, liver, and spleen is highly sensitive for involvement in HL and aggressive NHL.14 This general preference for PET/CT for routine staging has some exceptions, however, and the suitability of PET/CT may be assessed on a case-by-case basis.

What is Interim PET (iPET)?     

iPET is interim imaging to get a look at how the tumor is responding to the chosen therapy. It’s done after staging, but before the end of treatment. iPET is increasingly used today, especially with so many patients participating in clinical trials to assess new therapies. For many malignancies, it is not known whether interim imaging improves outcomes, so clinical trials are attempting to answer this question.11 According to the International Working Group, the evidence is good that iPET for HL, usually done after two cycles of treatment, is good at predicting response to therapy. At present, the working group recommends that if interim imaging is done, PET-CT is superior to CT alone to assess an early response.11

Pre- and Post-Treatment PET/CT

An example of the role of PET/CT in evaluation of treatment response is shown in figure 2. This is a case of anaplastic large cell lymphoma -- a non-Hodgkin’s lymphoma and a T-cell lymphoma. On the left side of figure 2, FDG avidity is seen in the mediastinum upon staging in a coronal view. Moving toward the right coronal view in figure 2, a much milder avidity is seen after chemotherapy. Moving to the transaxial views on the right side of the figure, the area of FDG avidity is shown in transaxial view, again before chemotherapy (top right) and after chemotherapy (bottom right). In this case, the patient had a partial response to therapy, and 4 months after the post therapy scan, progression had occurred, so the patient was given salvage chemotherapy.15

 


Hodgkin’s Lymphoma Case:
Eric Berry, a 25 year-old male with chest discomfort

History

All of the Kansas City Chiefs had undergone a full physical in June 2014, which included routine blood work. However, routine blood tests were normal for Chiefs Safety Eric Berry. According to ESPN, there had been no signs that anything was wrong with Berry until the Oakland game in the fall of 2014. Berry, in peak physical condition, reported absolutely no symptoms prior to this point.16,17

Presentation and Imaging

According to the Kansas City Star, Berry had some pain in his chest one Friday afternoon. Everyone assumed it was a football related injury at first, and the team physicians got a chest x-ray, but it didn’t reveal anything unusual. The team's orthopedic physician, Cris Barnthouse, examined him, however, and things did not seem to make sense to him from the musculoskeletal perspective – the physical findings did not add up. As reported in the Star, “Berry experienced pain when he moved his arm but was not sensitive to touch, nor was his strength affected. If he had bruised his chest, he would have experienced pain in all three cases.” Barnthouse recommended Berry get an MRI, and when the radiologists and doctors at the University of Kansas Hospital read the MRI, they discovered that Eric Berry had a mass on the right side of his chest. The next day they did other tests, including CT scans, some blood work and a PET scan. At that point, the Berry family, along with the Chiefs medical crew, opted for further evaluation in Atlanta, at the Emory University Hospital, in the care of Dr. Christopher Flowers, a specialist in lymphoma. With the announcement that Eric Berry had Hodgkin’s Lymphoma, Dr. Flowers gave the following statement: "This is a diagnosis that is very treatable and potentially curable with standard chemotherapy approaches. The goal of Mr. Berry’s treatment is to cure his lymphoma and we are beginning that treatment now.” 16,17

 

Medical Imaging of Hodgkin’s Lymphoma

Thoracic Imaging

As was the case with Eric Berry, conventional chest radiography still often leads the way, whether HL is suspected or not. And according to Gaubert and colleagues, chest plain film is still needed as the first line examination for mediastinal masses in order to carefully select the acquisition protocol for CT. However, current guidelines emphasize that the chest x-ray is no longer required in lymphoma staging because it is less accurate than CT.4 In HL, the lymph nodes in the superior mediastinum are often affected – the paratracheal and pre-vascular nodes in particular. When the chest radiograph is normal, it is uncommon for a CT to show abnormal mediastinal nodes in a person with HL; however, CT often reveals additional nodal involvement in the chest not seen on radiographs, and such findings change the treatment plan in some patients. Furthermore, PET/CT can help distinguish between nonmalignant nodal enlargement and active disease.4,18

Mediastinal Lymph Nodes -- Up Close

Even though HL is less common than NHL, it may not seem that way from the perspective of someone who performs thoracic imaging all day. Some 85% of people with HL have thoracic involvement at the time of diagnosis, and of these, nearly 100% have mediastinal lymph node involvement. HL most often involves the lymph nodes of the superior mediastinum -- that is, the prevascular, paratracheal and aortopulmonary lymph nodes.19-22

On plain radiographs, anterior mediastinal lymph node enlargement can appear as either a unilateral or bilateral mediastinal abnormality. With a Hodgkin’s-type pattern of nodal involvement, multiple involved lymph nodes seen together can look like an elongated or lobulated mass. When the mass does not have a clearly defined border, this can indicate invasion or extension into adjacent lung tissue.18-21

The appearance of involved lymph nodes on CT can be variable – from well-defined and discrete to a more matted together appearance, with the intervening fat planes hard to see; versus a diffuse infiltration in the mediastinum in which individual nodes cannot be discerned. Typical mediastinal masses with HL are homogeneous soft-tissue anteriorly mediastinal with mild to moderate contrast enhancement, irregular contours, surface lobulation and absence of vascular involvement. 19, 21-22

Enlarged lymph nodes are typically homogeneous and have the attenuation of soft tissue, but they can have areas of necrosis and low attenuation following contrast enhancement. Some calcification is possible, however this is much more common following treatment – especially following radiation therapy.18

Other Involved Structures

In the chest, in association with mediastinal lymph node enlargement, the thymus may also be involved. Patients with HL may also have pleural effusion, pericardial effusion and chest wall involvement. When the chest wall is involved, the tumor may affect the ribs sternum or vertebral bodies and typically has lytic bone destruction. Lytic bone destruction is characterized by light areas in otherwise dense bone, as if something destroyed or replaced and area of healthy bone. In contrast, a sclerotic lesion is characterized by thickening or calcification.
HL within the thorax is usually associated with disease elsewhere, and the cervical lymph nodes are commonly involved. Hepatosplenomegaly may be present, and the most common site of extranodal HL is the spleen, but primary disease in the spleen is very rare.23 HL may rarely involve other structures. Abdominal and pelvic manifestations of lymphoma are covered in greater depth in the NHL section.

As seen in Figure 3, PET can detect uptake in areas not thought involved with disease.24


 

Staging of Hodgkin’s Lymphoma

The staging system for HL is known as the Cotswold system, which is a modification of the older Ann Arbor system. Though modified, it is still anatomically based. The precise staging based on the anatomy of involved sites is considered important in HL because anatomical stage correlates strongly with prognosis and helps determine treatment. With NHL, it is not that anatomical staging is unimportant, but rather that the histology and grade are more strongly predictive of prognosis and more influential in the treatment decision. In HL, stages I and II have typically been treated with radiation therapy, while a combination of radiation and chemotherapy or chemotherapy alone may be offered to patients in stages III and IV.25

Cotswold Staging System

 

This modified Ann Arbor Staging Classification, Courtesy of the American Cancer Society, is described as follows:26

If HL affects an organ outside of the lymph system, the letter E is added to the stage (for example, stage IE or IIE). If it involves the spleen, the letter S is added.

Stage I: Either of the following means that the disease is stage I:

  • Hodgkin disease is found in only 1 lymph node area or lymphoid organ such as the thymus (I).
  • The cancer is found only in 1 area of a single organ outside the lymph system (IE).

Stage II: Either of the following means that the disease is stage II:

  • Hodgkin disease is found in 2 or more lymph node areas on the same side of (above or below) the diaphragm (II).
  • The cancer extends locally from one lymph node area into a nearby organ (IIE).

Stage III: Either of the following means that the disease is stage III:

  • Hodgkin disease is found in lymph node areas on both sides of (above and below) the diaphragm (III).
  • Hodgkin disease is in lymph nodes above and below the diaphragm, and has also spread to a nearby organ (IIIE), to the spleen (IIIS), or to both (IIIES).

Stage IV: Any of the following means that the disease is stage IV:

  • Hodgkin disease has spread widely through 1 or more organs outside of the lymph system. Cancer cells may or may not be found in nearby lymph nodes.
  • Hodgkin disease is found in organs in 2 distant parts of the body (and not in nearby lymph nodes).
  • Hodgkin disease is in the liver, bone marrow, lungs (other than by growing there directly from another site), or cerebrospinal fluid (the liquid that surrounds the brain and spinal cord).

Other Descriptors Used in HL Staging:

Bulky disease, or “X”

Bulky disease may be recorded by adding the letter X to the stage. In the chest, bulky disease refers to tumors that are at least one-third as wide as the chest. In other areas, it refers to tumors that are at least 10 centimeters across. Bulky disease might need more intensive treatment.

“A” versus “B”

The so-called B symptoms that a patient with lymphoma may or may not experience include the following:

  • Unintentional loss of more than 10% of body weight over the previous six months
  • Unexplained fever of at least 101.5°F
  • Drenching night sweats

When B symptoms are present, “B” is be added to the stage. These symptoms usually mean the disease is more advanced. If a person has any of these, then more intensive treatment is usually recommended. If no B symptoms are present, the letter A is added to the stage.

Treatment Response and Relapse of HL

PET imaging is rapidly becoming the method of choice post treatment for many different lymphomas.4 Patients with HL always see a reduction in tumor bulk with adequate treatment. There can be some normal enlargement persisting in cured patients following treatment for HL, referred to as a residual mediastinal mass. This is seen by many patients with HL and a good proportion of patients with NHL (Weihrauch 2001). PET imaging can help discern active tumor from residual benign or fibrous masses. 12,19,27

Common sites for recurrent HL include the upper mediastinum and lung. When recurrence occurs in the lungs, it is not commonly seen on chest radiographs, but can be seen on CT in about half of cases. On MRI, a high relative intensity with T2 weighting indicates the need for biopsy, follow-up or further imaging.22

Non-Hodgkin’s Lymphoma Case -- DLBCL:
Gov. Larry Hogan, a 59 year-old male with a painless lump on the neck

History

The Governor of Maryland is no stranger to fighting uphill battles. In the fall of 2014, news networks reported that Larry Hogan, a Republican, had scored a stunning upset to become only the second Republican Governor to be elected in Maryland, a deeply blue state, since the 1960s. Months later, he was in Asia on a trade mission for the state when he noticed something. His own account of his history of present illness follows, courtesy of the Baltimore Sun:28

“I had no symptoms whatsoever. We were on a trade mission. We did 50 or 60 meetings in three countries in 12 days. I was working 15 hours a day. We were on a 12-hour flight, on a 12-hour time difference. People couldn't believe the energy I had. I didn't feel sick at all. But the day before we left, I was shaving and I felt a big lump in my neck, didn't hurt at all. It was like a golf ball here…and I'm like, that's a very strange thing, some kind of a cyst or bump or something. So I went to go see my primary care physician when I got back.”

Presentation and Imaging

Hogan continued to relate the story of his evaluation and workup:28

“[My] primary care physician sent me to go get an ultrasound, then [they] sent me to an ENT guy — ear, nose, and throat guy — who then said ‘I want you to get some MRIs and some CAT scans,’ which they did. Then they found 12 more of these things in my neck and chest, and said, ‘We want to do a full MRI.’ They found 20 or 30 more in my core area and groin area. It was one test after another after another. It was like peeling an onion. ‘Let's send you for this test. Oh, that's bad. Let's send you for this test. That doesn't look so good. Let's send you for [a] test. It's even worse than we thought.’ But I didn't really have any symptoms. I saw one thing pop out. I had a little bit of pain in my back, which I thought was a pulled muscle. Turns out it was a tumor pressing up against my — well, it still is — pressing up against my nerves, and that was what was causing the pain. But I still feel good. I've got energy, other than that I don't have much of an appetite. I'm not tired, and I'm not in terrible pain. 28

Maryland’s Governor Larry Hogan has the most common kind of lymphoma -- NHL. He also has the most common type of NHL -- diffuse large B-cell lymphoma, or DLBCL. Hogan announced the plan was to stay in office. Some patients in his situation are not able to work full time, although some are able to keep up with their schedules, and Hogan has staff that can assist during this process. The 59-year-old governor began a six-month course of therapy with both chemotherapy and immunotherapy drugs. This regimen often causes fatigue, hair loss and increased risk of infection.

 

Medical Imaging of Non-Hodgkin’s Lymphoma

While PET/CT is generally the imaging method of choice for initial staging and evaluation of NHL, and other exams often precede the PET /CT.

Thoracic Imaging

NHL is similar to HL in that mediastinal lymph node involvement is the most common abnormality in the chest and CT is more sensitive than chest radiographs in detecting lymph node enlargement. Overall, the patterns of mediastinal lymph node involvement with NHL tend to differ from those of HL, however.

Involvement of only a single lymph node group is much more common in NHL. Some 40% of people with NHL and thoracic involvement have only a single node group, while the same is true for only 15% of those with HL. Enlarged lymph nodes may have low attenuation on CT due to necrosis or may have a cystic appearance, and calcification is rare. 18-19,22,29

Abdominal/Pelvic Disease
NHL may involve virtually any organ, including bowel, pancreas, kidneys, bone marrow, pelvic organs and skin.30 Involvement of the spleen, liver, kidneys, pancreas, adrenal glands and testes is relatively common while involvement of the uterus, ovaries and prostate is rare by comparison.31 When lymphoma involves solid organs it can be focal, multifocal or diffuse. In focal and multifocal disease, there are discrete nodules of lymphoma present, while in diffuse disease, the lymphoma cells infiltrate the involved site.

On CT scans, nodules of lymphoma tend to have a lower attenuation than that of surrounding organs, but lymphoma has a higher attenuation than that of water, as shown in Figure 4.

 

 

Paraaortic adenopathy is detected in about 50% of patients with NHL. Non-Hodgkin’s lymphoma often appears as bulky retroperitoneal and mesenteric lymphadenopathy on abdominal CT. 30, 32-33. Some 40% have involvement of the spleen, and the liver is involved in about 15%. While lymphoma is the most common malignant tumor involving the spleen, this is usually nodal lymphoma that has spread to the spleen, although primary splenic lymphomas are possible.

The pancreas is involved secondarily in more than 30% of patients with NHL. The stomach is the part of the GI tract most frequently involved in lymphoma. Lymphoma can have a variety of appearances on CT including diffuse gastric wall thickening.

As shown in figure 5, In this case of fistulating gastric B cell lymphoma, there was thickening of the gastric wall, a left upper quadrant mass involving the spleen, and a secondary splenic metastasis.

Lymphomas are also among a number of malignancies that can form annular masses or masses that involve the bowel circumferentially. Luminal constriction, dilation or cavitation are also possible. The small bowel is the second most common site of gastrointestinal lymphoma34, and approximately 20% of all malignant tumors of the small bowel are lymphomas. Bulky, diffuse regional or mesenteric lymph node enlargement is typical, which helps differentiate lymphoma from other GI lesions. Involvement of the gastrointestinal tract can be nodular, polypoid, infiltrative, cavitary, ulcerative, and mixed. Lymphomas involving the kidney can mirror the infiltrative appearance of pyelonephritis on CT. Diffuse infiltration can occur in patients with renal lymphoma and infiltration of the kidneys may be bilateral.30, 32-33, 35-36 Overall, lymphoma is not a common testicular tumor, yet it is the most common testicular tumor in patients older than 60 years.14 

Disease Extent and Staging of NHL

PET/CT is recommended for staging and post-treatment response assessment for all FDG-avid NHLs.4,11 The list of FDG-avid NHLs includes DLBCL and follicular lymphoma -- the two most common types of NHL.

Unlike HL, which tends to spread in a fairly orderly way, NHL is assumed to be in multiple sites, and there is no similar assumption about the sequence of progression. Scans of the abdomen, pelvis and neck are performed in patients with NHL. When people have intermediate- or high-grade disease or stage III or IV aggressive NHL, they usually receive chemotherapy regardless of the anatomical stage. Many people with low grade NHL also receive chemotherapy, while primary radiotherapy is usually limited to those with low-grade lymphoma at stage I or II at diagnosis. The most common type of low grade NHL is follicular lymphoma, for which radiotherapy to the affected lymph nodes may control the disease for some time. Though indolent or slow growing lymphomas such as follicular lymphoma do not advance rapidly, they can be more difficult to treat for a cure.  In contrast, the most common aggressive NHL is diffuse large B-cell lymphoma – and though it is aggressive or fast growing, it tends to respond well to intensive chemotherapy, which is able to target these rapidly dividing cells. 4,11

DLBCL – The Most Common NHL

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL. It is considered an aggressive B-cell lymphoma. DLBCL involves the bone marrow in a substantial number of cases. Staging by PET-CT identifies all clinically relevant marrow involvement by DLBCL.13

In DLBCL, interim PET/CT, or iPET, is predictive of the outcome after R-CHOP or similar immunochemotherapy.  R-CHOP refers to rituximab, a monoclonal antibody, plus chemotherapy with cyclophosphamide, hydroxydaunorubicin, oncovin, etoposide and prednisolone. The role of interim PET/CT scans is being researched for a variety of lymphoma types and treatments. Determining the need for additional treatment is especially significant for curable lymphomas like HL and DLBCL.4,11

Summary

Patients with lymphoma are living longer than ever before, and medical imaging has played a crucial role in these advances. Basic patterns of emergence and spread can be readily appreciated from modern scans, which combine CT and PET technology to identify active disease – both within lymph nodes and at extranodal sites.

Anatomical staging is especially important in Hodgkin’s lymphoma, and PET/CT has an established role in staging and evaluation. Non-Hodgkin’s lymphomas -- which are more common overall and more likely to be primary extranodal lymphomas -- also benefit from staging with PET/CT, which can detect active disease in normal sized nodes and help differentiate between residual masses and active disease after treatment. Though most NHLs are FDG-avid, some typically are not, and therefore the utility of FDG PET may differ across malignancies. The role of interim PET/CT, or iPET, in the management of various lymphoma types is the subject of many current research efforts.

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