Lymphomas: Pathology review

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Case Study0:00–0:41

At the family medicine center, there is a 25 year old male, named Hogan, who came in because of a painless non-erythematous mass on his neck.
Next to Hogan, there is a 30 year old male immigrant from Africa, named Burak, who has noticed a painless mass on his jaw.
He also complains of drenching night sweats, and unexplained weight loss over the last few months. Biopsy is ordered for both people.
In Hogan’s there’s binucleated B cells surrounded by mainly lymphocytes. Burak’s biopsy showed numerous lymphocytes with some tingible-body macrophages.
CBC is normal for both. Both Hogan and Burak have lymphoma.

Pathology0:41–1:17

Lymphomas are tumors derived from lymphocytes, which are B and T cells. They can be broadly grouped into two categories; Hodgkin and non-Hodgkin lymphomas.
In contrast, non-Hodgkin lymphomas don’t have Reed-Sternberg cells can sometimes spread non-contiguously, and can involve extranodal sites like the skin, gastrointestinal tract, and brain.
Non-Hodgkin’s lymphomas can occur in both children and adults. Finally, overall prognosis is better with Hodgkin lymphomas.Let’s start by looking at Hodgkin lymphoma.

Hodgkin Lymphoma1:17–4:30

This type of lymphoma typically arise from B-cells and spread in a contiguous manner, meaning it spreads to nearby lymph nodes, and rarely involve extranodal sites.
It has a bimodal age distribution, affecting young adults in their 20s and adults older than 60 years of age. Histologically, it’s characterized by the presence of Reed-Sternberg cells and for your exams, remember that these are binucleated, neoplastic B cells that look kind of like owl eyes.
The large mononuclear version of Reed-Sternberg cells are called Hodgkin cells. These abnormal, neoplastic cells are usually surrounded by non-neoplastic inflammatory cells, mostly T cells, and sometimes eosinophils.
They can also activate fibroblasts, which secrete collagen. Okay, now Hodgkin lymphoma includes two major subgroups, the first and more common is classical Hodgkin lymphoma, or cHL.
In classical Hodgkin lymphoma, neoplastic cells don’t express CD45 or CD20, which are seen on normal B-cells, but they do express CD15 and CD30.
Classical Hodgkin lymphoma can be further divided into four histologic subtypes based on the type of inflammatory cells and whether fibrosis is present.
Nodular sclerosis is the most common subtype and the neoplastic cells are surrounded by collagen that create nodules. Also, a unique Reed-Sternberg cell, called a lacunar cell can be seen.
When the tissue is fixed in formalin, the cytoplasm shrinks and it makes the nucleus look like it’s sitting in the middle of a lake, or lacunae.
Now, the second most common subtype is mixed cellularity Hodgkin lymphoma and the neoplasm is mixed with many different types of immune cells like eosinophils, neutrophils, lymphocytes, plasma cells, and histiocytes.
The third subtype is lymphocyte-rich Hodgkin lymphoma, and it’s named for having mostly lymphocytes surround the Reed-Sternberg cells.
It generally has the best prognosis of all of the classical Hodgkin lymphoma subtypes. The fourth type is lymphocyte-depleted Hodgkin lymphoma, and it’s the least common type.
It’s named for the lack of normal lymphocytes and the abundance of Hodgkin and Reed-Sternberg cells. Mixed cellularity and lymphocyte-depleted Hodgkin lymphoma are seen more commonly in immunocompromised patients.
The other major subgroup of Hodgkin lymphoma is nodular lymphocyte predominant Hodgkin lymphoma. In contrast to classical Hodgkin lymphoma the abnormal B cells express CD20 and CD45 on their surface, but don’t have CD15 and CD30.
They have a variant of Reed-Sternberg cells called lymphocyte predominant cells. The lymphocyte predominant cells have a lobulated nucleus that looks like popcorn, so they're called “popcorn cells.” It’s also called nodular because a large number of lymphocytes cluster around the popcorn cells, forming nodules.
Alright, now let’s switch gears and talk about non-Hodgkin lymphomas, which can be further subdivided in two main groups, B cell and T cell lymphomas.

Non-Hodgkin Lymphoma4:30–4:59

B cell lymphomas are more common and the neoplastic B cells usually express CD20 on their surface. And there are various types of non-Hodgkin B cell lymphomas and an important feature is how quickly each one grows.
They can be indolent, aggressive, or highly aggressive. Let’s start with B cell lymphomas, and the first one is follicular lymphoma, and it’s usually indolent.

Follicular Lymphoma4:59–6:02

The main concept you’ll need to know for the exams is that follicular lymphoma can develop from a chromosomal translocation between chromosome 14 and chromosome 18.
In the translocation, the two chromosomes swap large pieces of chromosome with each other. As a result, the BCL2 gene from chromosome 18 is placed on chromosome 14, and this causes an overexpression of bcl-2.
Bcl-2 normally blocks cell death, or apoptosis, so overexpression of the bcl-2 gene prevents abnormal cell death. Okay, now, another high yield fact is that, under the microscope, follicular lymphoma is characterized by clusters of packed follicles composed primarily of centrocytes, which are small cleaved cells, and a few centroblasts which are large non-cleaved cells.
A helpful clue is that this type of lymphoma often cause waxing and waning painless lymphadenopathy. The second type of B cell lymphoma is diffuse large B cell lymphoma which shows aggressive growth.

DL B-Cell Lymph.6:02–6:18

This is the most common type of non-Hodgkin B-cell lymphoma in adults and it’s linked with BCL-6 and BCL-2 mutations. A third type of B cell lymphoma is Burkitt lymphoma, and it’s a highly aggressive lymphoma.

Burkitt Lymphoma6:18–7:53

Burkitt lymphoma can also result from a chromosomal translocation. In this case, the Myc gene is translocated from chromosome 8 where it ends up on chromosome 14 and again that upregulates its expression.
The Myc gene stimulates cell growth and metabolism, so the translocation results in increased cell division. Now, high yield fact that is frequently tested is that Burkitt lymphoma is often associated with Epstein Barr virus, or EBV, infection.
EBV infects lymphocytes and can incorporate its DNA into a host cell’s DNA, but exactly how that leads to lymphoma is still unclear.
For the exams, you also have to remember that in Burkitt’s lymphoma there is extranodal involvement. In individuals from Africa, Burkitt lymphoma classically causes extranodal involvement of the jaw, while in individuals outside Africa, Burkitt lymphoma classically causes extranodal involvement of the abdomen, most often at the ileocecal junction..
Another high yield fact is that under the microscope, Burkitt lymphoma is said to have a "starry sky” appearance. The “sky” is composed of a large number of medium sized neoplastic B-cells with very little cytoplasm, so their prominent nucleus gives them a dark appearance.
The “stars” are tingible-body macrophages that contains bits and pieces of dead neoplastic cells. And these are scattered among the neoplastic lymphocytes.
The fourth type of B cell lymphoma is mantle cell lymphoma, and this one’s an aggressive lymphoma that’s more common in males.

Mantle Cell Lymphoma7:53–8:25

Mantle cell lymphoma can also result from a chromosomal translocation. In this case, the BCL1 gene from chromosome 11 ends up on chromosome 14, which again upregulates its expression.
The BCL1 gene encodes the protein cyclin D1, which stimulates cell growth, so once again the translocation results in increased cell division.
The fifth type of B cell lymphoma is marginal zone lymphoma, and it’s an indolent lymphoma more common in older people. The most common type is marginal zone lymphoma of mucosa-associated lymphoid tissue, or MALT.

Marginal Zone Lymphoma8:25–9:08

This type is extranodal, mostly arising in the lymphoid tissue in organs that contains mucosa like the GI tract, thyroid, eyes, and lungs.
In the stomach, a risk factor is chronic inflammation, like those with Helicobacter pylori infection that causes chronic gastritis.
There’s also nodal marginal zone lymphoma, which happens within lymph nodes, and splenic marginal zone lymphoma which happens in the spleen and is linked with Hepatitis C.
The sixth type of B cell lymphoma is lymphoplasmacytic lymphoma, and this one’s also an indolent lymphoma. This form of lymphoma often involves the bone marrow, lymph nodes, and spleen, and the neoplastic cells sometimes produces immunoglobulins, called “M proteins,” that can reach high levels in the blood.

LPL9:08–9:34

When this happens, the blood becomes more viscous and the condition is called Waldenstrom macroglobulinemia.The other group of non-Hodgkin lymphomas are the T cell lymphomas.

T-cell Lymphoma9:34–10:32

The first T cell lymphoma is adult T-cell lymphoma, but it’s sometimes referred to as leukemia because the abnormal white blood cells, or leukocytes, often get into the bloodstream.
Adult T-cell lymphoma is often aggressive and it is thought to be caused by the human T-lymphotropic virus or HTLV. This virus spreads through body fluids so breast feeding infants and IV drug users that share needles are at risk.
Once inside the T cell, HTLV turns its RNA into DNA, which then incorporates into T cell DNA and causes a genetic mutation in the process, and that leads to adult T-cell lymphoma.
For unknown reasons, this type of lymphoma also causes increased bone resorption, resulting in severe hypercalcemia and bone lesions.
The second T cell lymphoma is mycosis fungoides which is a T cell lymphoma of the skin that causes patch or plaque like lesions on the skin that looks a bit like a fungal infection.

Mycosis Fungoides10:32–11:24

Eventually these will transform into tumors. On biopsy, a classic sign is Pautrier microabscesses in the epidermis.
These are filled with neoplastic lymphocytes instead of the normal neutrophils and macrophages. The neoplastic cells in mycosis fungoides are CD4+ helper T-cell in the epidermis, and under a microscope it has a distinctive “cerebriform” nucleus because the nuclear membrane has many folds, so it looks like a brain.
If these neoplastic helper T-cells start to circulate in the blood, they can cause Sezary syndrome, which is when there’s a generalized red, itchy rash called erythroderma.
Okay, as far as symptoms go, both Hodgkin and non-Hodgkin lymphomas typically present with lymphadenopathy. Remember that the enlarged lymph nodes are painless, rubbery, nonerythematous and nontender.

Symptoms11:24–12:46

Now, with Hodgkin lymphoma, lymphadenopathy is localized and most commonly involves cervical, supraclavicular, and axillary lymph nodes.
With nodular sclerosis Hodgkin lymphoma subtype, mediastinal lymphadenopathy is also common. However, non-Hodgkin lymphoma is localized only 10 to 20 percent of the time and it’s more likely to involve extranodal sites.
If there’s involvement of the gastrointestinal tract, it can cause bowel obstruction. If there’s involvement of the bone marrow, neoplastic cells can crowd out normal bone marrow progenitor cells and decrease the number of healthy RBCs, WBCs and platelets, causing symptoms like fatigue, recurrent infections, or easy bruising.
And if there’s extranodal involvement of the spinal cord, it can cause weakness and a loss of sensation usually in the legs.
Another high yield fact is that lymphomas can also present with constitutional symptoms such as low grade fever, drenching night sweats, and 10 per cent weight loss.
These are also referred to as B symptoms and is common in lymphomas and leukemias. Alright, now, let’s talk about diagnosis.

Diagnosis12:46–13:25

For your exams, it’s important to know that an excisional lymph node biopsy is the essential first step to diagnose lymphoma.
After this, imaging studies like chest CT and abdominal CT, can help determine staging of the disease. But the most important thing to do is a marrow biopsy because this is the strongest predictor of prognosis.
CBC is typically normal but sometimes lymphocyte levels in the blood can be increased when lymphomas transform into leukemias.
Other lab tests that are useful prognostically include elevated LDH and ESR levels. Alright, as a quick recap!

Review13:25–14:28

Lymphomas can be broadly classified to Hodgkin and non-Hodgkin lymphomas. Hodgkin lymphomas mainly affect B-cells and have the characteristic Reed-Sternberg cells.
They tend to spread in a contiguous manner, rarely involve extranodal sites, and usually affect adults in their 20s and 60s.
Non-Hodgkin lymphomas can be either B cell or T cell lymphomas. B-cell lymphomas include diffuse large B cell lymphoma, follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma.
Now, T cell lymphomas include adult T cell lymphoma, and mycosis fungoides. Lymphomas can present with non-tender, non-erythematous lymphadenopathy, and B symptoms, which include low grade fever, drenching night sweats and 10 percent weight loss.
Diagnosis is made with excisional lymph node biopsy and imaging studies are done to establish the stage. Now, back to the patients!
Hogan has non-tender, non-erythematous lymphadenopathy which is typical for lymphoma. Due to his age and the presence of Reed-Sternberg cells in the biopsy, Hogan most probably has Hodgkin lymphoma.

Summary14:28–15:02

Now, Burak also has lymphoma but it’s found in the jaw, and this is the common extranodal site for Burkitt lymphoma in individuals from Africa.
The “starry sky” appearance in biopsy confirms the diagnosis of Burkitt lymphoma. Imaging studies have to be done for both people to establish staging before treatment can begin.