What is ALK Negative Anaplastic Large Cell Lymphoma?
ALK-negative anaplastic large cell lymphoma (ALK(-) ALCL) is a rare type of blood cancer called a CD30-positive T-cell lymphoma, which can be hard to diagnose. This disease can affect people of any age and can appear in several places within the body, both inside and outside of the lymph nodes. It can look a lot like many other types of cancers, both blood and non-blood related, which makes it especially difficult to identify.
Moreover, its ability to appear in different forms and its lack of typical T-cell markers can be misleading. However, recent studies have found that DUSP22 rearrangements (changes in a specific gene) are present in ALK(-) ALCL patients who generally have a better outlook. This summary provides a brief understanding of the challenges faced while diagnosing this rare form of cancer.
What Causes ALK Negative Anaplastic Large Cell Lymphoma?
No specific causes or risk factors have been found yet for Anaplastic Large Cell Lymphoma (ALCL), a type of cancer. Research has not found any strong proof that either the Epstein-Barr virus or the human T-cell leukemia virus are involved in causing this disease. Also, there’s no well-established link between ALCL and immune system disorders.
However, it’s important to note that a type of ALCL that’s clearly different from the rest has been linked with breast implants.
Risk Factors and Frequency for ALK Negative Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphoma (ALCL) is a type of cancer that mainly affects the body’s T-cells. These cancers share similar characteristics but may differ in genetic makeup and how they affect the body. According to the World Health Organization’s latest classification in 2017, there are three specific kinds of ALCL, namely: ALK-positive ALCL, ALK-negative ALCL, and breast implant-associated ALCL.
- ALK-positive ALCL involves changes to the ALK gene and usually carries a good prognosis.
- ALK-negative ALCL does not have these changes to the ALK gene and typically has less favorable outcomes.
- Primary cutaneous ALCL starts in the skin, might spread to nearby lymph nodes, but rarely spreads further and usually has a good prognosis. This type typically does not have changes to the ALK gene.
- There is also a variety linked to breast implants that typically has a good outcome, but it is not extensively covered in this article.
It’s important to note that about half of the ALCL cases are ALK-negative. This type typically impacts adults aged 40 to 65, with men being slightly more affected than women. Individuals often have swollen lymph nodes and symptoms like fever, night sweats, and weight loss. This form of ALCL usually affects lymph nodes initially but can also show up in different parts of the body such as the skin, brain, mouth, bladder, and liver. However, no particular risk factors for developing this type of ALCL have been identified to date.
Signs and Symptoms of ALK Negative Anaplastic Large Cell Lymphoma
Patients with advanced stage III to IV disease usually come in with certain symptoms, which are often referred to as B symptoms. They might also have lymph nodes that are swollen, either in the abdominal region or peripheral areas. While it is common to observe lymph node involvement, it’s less typical to find the disease spread beyond these nodes, especially in comparison to the ALK-positive variant of this disease.
When the disease does spread, it often reaches the skin, liver, and lungs. There is also a form of anaplastic large cell lymphoma that primarily affects the skin, and it may be challenging to tell the difference clinically between this and systemic ALCL affecting the skin. When it comes to skin manifestations, patients may present with single or localized skin abnormalities such as tumors, nodules, or papules.
Testing for ALK Negative Anaplastic Large Cell Lymphoma
In diagnosing a type of cancer known as ALK-negative ALCL, certain stains are key. One such is strong CD30 positivity, which means that the cells will show a high level of CD30 protein. This protein is usually found in the outer membrane and Golgi region of the cells, and also in the inner cell substance.
Typically, T-cell antigens such as CD2, CD3, CD5, and CD7 are present. If these are not present, CD43 can help identify the cancer as being of blood or lymph origin. CD4 protein is usually present, while CD8 is typically not seen. The cancer also often shows the presence of specific types of molecules including TIA-1, Granzyme-B, perforin, and clusterin. Vimentin might be seen, but its presence doesn’t indicate that the cancer originated in the connective tissue. Indicators of B-cell lineage are absent, including PAX5, CD19, CD20, and CD79a. Proteins such as EBV-latent membrane protein type 1 and EBER, which are related to the Epstein-Barr virus, are not seen in ALK-negative ALCL.
Only recently have we started getting an understanding of the genetics of ALK-negative ALCL. New research has shown around 30% of these cancer cases have chromosomal rearrangements of DUSP22 and around 8% have rearrangements of TP63. These rearrangements aren’t seen in ALK-positive ALCL cases. Notably, ALK-negative ALCL cases with DUSP22 rearrangements have better outcomes, similar to those of ALK-positive ALCL, while those with TP63 rearrangements tend to fare worse.
Comparison of gene expressions can help identify ALK-negative ALCL and distinguish it from other related diseases. A molecule called IRF4, for example, can help differentiate between a certain type of skin lymphoma and ALK-negative ALCL. A recent study has identified three genes – TNFRSF8, BATF3, and TMOD1 – whose co-expression may help correctly identify ALK-negative ALCL from other types of lymphomas with nearly 97% accuracy.
Treatment Options for ALK Negative Anaplastic Large Cell Lymphoma
Anaplastic lymphoma kinase-negative (ALK-negative) anaplastic large cell lymphoma (ALCL) is a rare type of lymphoma, a cancer affecting the lymphatic system. ALK(-) ALCL’s rarity has made it challenging to determine the best treatment approach. As ALK(-) ALCL often presents differently in different patients and there is a lack of trials focused solely on this lymphoma, it often gets grouped with other types of T-cell lymphomas when it comes to research and treatment. This disease generally responds to a chemotherapy protocol designed initially for aggressive B-cell lymphomas. Still, it is common for patients to experience a recurrence of the disease after treatment.
The typical first-line treatment for systemic ALCL, which means that the disease has spread throughout the body, is a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone, known as CHOP. However, the standard treatment for patients whose disease has returned or is not responding to the first-line treatment has not been defined yet.
More recently, targeted therapies have been introduced. One example is Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate used for systemic ALCL that has relapsed or is not responding to treatment. However, a recent case was reported where a patient with relapsed systemic ALK-negative ALCL showed a loss of CD30 expression after BV therapy. The loss of CD30, a protein typically found on the surface of cells affected by this lymphoma, suggests that the disease may change after BV treatment, which could affect future therapeutic options.
What else can ALK Negative Anaplastic Large Cell Lymphoma be?
When examining tissue samples of ALK(-) ALCL, a type of lymphoma, doctors need to take extra care because it can easily be mistaken for other diseases such as sarcomas, carcinomas, germ cell tumors, and melanomas. The resemblance can be quite strong, especially when looking at the shape and arrangement of cells. This is particularly tricky in small specimens, such as those gathered through a fine-needle aspiration biopsy. There have been cases where ALCL has even been confused with soft tissue sarcomas.
To correctly identify the disease, doctors often first try to broadly classify the condition as carcinoma (using a pancytokeratin cocktail), melanoma (using S100 or other specific markers), or lymphoma (using CD45). If the early tests come back negative or only show CD45, they’ll do a more directed test using CD30. However, it’s important not to use epithelial membrane antigen (EMA) staining to differentiate ALCL from metastatic carcinoma, as it may lead to false positives. Cytokeratins, markers of epithelial differentiation, are instead recommended.
High levels of CD30 expression can indicate ALCL, but note that many other lymphoid diseases may also show variable CD30 positivity. These include Hodgkin lymphoma, specific types of B-cell lymphoma, PTCL-NOS, certain T-cell lymphomas, and even non-cancerous immunoblast proliferations. However, these conditions usually do not show the same consistently strong and widespread CD30 pattern seen in ALCL.
It is not easy to tell the difference between ALK(-) ALCL and other CD30 positive T cell diseases because they often have similar features. Therefore, the pattern of CD30 expression is very important in distinguishing it from other peripheral T cell lymphomas that show varying levels of CD30. An exception would be ALK-positive ALCL which has a variable CD30 staining pattern. This can be distinguished from ALK(-) ALCL by looking for ALK staining using immunohistochemistry. To diagnose primary cutaneous ALCL, doctors should take into account the clinical signs along with the pathology to avoid falsely diagnosing secondary involvement systemic ALCL.
Immunohistochemistry (IHC) plays a critical role in distinguishing ALK(-) ALCL from classical Hodgkin lymphoma (CHL). This comes into play especially when the CHL case has a lot of malignant cells. CHL generally shows B-cell marker expression, with dim PAX-5 positivity, CD15, and occasionally EBER. On the other hand, only rare cases of ALCL express PAX-5. Notably, CHL can often express T-cell antigens, with CD4 and CD2 seen in over half of the cases and CD3, CD5, and/or CD7 seen in about a third. The T-cell attacking antigen TIA-1 is typically positive in ALK(-) ALCL and negative in CHL.
There are no specific characteristics that can define ALK(-) ALCL. The immune traits of primary cutaneous ALCL and systemic ALK(-) ALCL are largely the same and exhibit strong expression of CD30 along with the variable expression of T-cell antigens CD2, CD3, and CD5. While primary cutaneous ALCL and ALK(-) ALCL may show some recurrent gene alterations like DUSP22 rearrangements, the presence of this rearrangement alone does not distinguish between the two. Thus, clinical staging is needed to differentiate these conditions. ALK-positive ALCL, however, can just be identified with the highly specific combination of positive CD30 and ALK.
What to expect with ALK Negative Anaplastic Large Cell Lymphoma
Recent research has identified variations in survival outcomes among patients with a type of cancer known as ALK(-) ALCL. These differences are based on specific changes in the patient’s chromosomes. For example, about 30% of people with ALK(-) ALCL have what’s called the DUSP22 rearrangement. These patients have a 90% chance of surviving for at least five years, which is similar to those who have ALK-positive ALCL.
On the other hand, 8% of patients have the TP63 rearrangement, which results in a significantly reduced five-year survival rate of just 17%. Patients lacking ALK, DUSP22, or TP63 rearrangement have a five-year survival rate of around 42%, showing again how these chromosomal changes can affect prognosis.
When comparing the five-year survival rate of ALK(-) ALCL patients to other types of T-cell lymphoma, patients with this subtype fare better with a rate of 49%, compared to PTCL-NOS at 32%. However, ALK-positive ALCL patients still have the better prognosis, with a 70% five-year survival rate.
It’s important to note that this favorable prognosis may be because these patients are generally younger when diagnosed. In fact, one study found that there was no difference in survival rates when only considering ALCL patients who were 40 years of age and older.
On another note, primary cutaneous ALCL, a form of the disease that primarily affects the skin, seems to progress more slowly. It has a favorable five-year survival rate of 90%, but these patients have a higher chance of the disease returning, with a 55% chance of remaining disease-free for five years.
