Anaplastic Large Cell Lymphoma (ALCL)
- sunshine4cancerkid
- Aug 7
- 29 min read
Medha Kollepara | Writer/Researcher
Ishanth Shanthmoorthy | Writer/Researcher
Mahvish | Writer/Researcher
Batool Haider | Writer/Researcher
Table of Contents
Abstract...........................................................................................................................................2
Introduction................................................................................................................................ 3-4
Discussion....................................................................................................................................... 5
Diagnosis......................................................................................................................................6-7
......................................................................................................................................................
Medical Professions....................................................................................................................... 8
Treatments.................................................................................................................................9-14
Importance of Understanding Treatment Options..................................................................... 9
Prognostic Factors..........................................................................................................9
Metastatic Patterns.........................................................................................................9
Early Detection........................................................................................................................ 10
Use of Machine Learning in Histopathology Image Analysis.....................................10
Biomarkers as Indicators of Early Detection...............................................................10
Systemic ALCL (sALCL)........................................................................................................10
Chemotherapy.........................................................................................................10-11
Crizotinib..................................................................................................................... 11
Immunotherapy: Brentuximab Vedontin......................................................................12
Stem Cell Transplant....................................................................................................13
Differences in ALK-positive and ALK-negative Treatment....................................... 13
Primary Cutaneous ALCL (pcALCL)..................................................................................... 13
Local Excisions............................................................................................................13
Radiation Therapy........................................................................................................14
Low-Dose Methotrexate or Bexarotene.......................................................................14
Statistics...................................................................................................................................15-17
Impacts.................................................................................................................................... 18-20
ALK-positive ALCL................................................................................................................18
ALK-negative ALCL...............................................................................................................18
Primary Cutaneous Anaplastic Large Cell Lymphoma........................................................... 19
Breast-implant Associated ALCL............................................................................................19
Conclusion.................................................................................................................................... 21
Citations (MLA 8th Generation)...........................................................................................22-252
Abstract
Anaplastic Large Cell Lymphoma is a rare and heterogeneous subtype of non-Hodgkin
lymphoma (NHL) that originates from mature T-Cells and is marked by consistent expression of
the CD30 antigen. This study explores the diagnostic methods, treatment strategies, and
real-world impact of ALCL across its four major subtypes: systemic ALK-positive, systemic
ALK-negative, primary cutaneous ALCL, and breast implant-associated ALCL (BIA-ALCL). To
accurately distinguish between these types, diagnosis relies heavily on a combination of
histopathology, immunophenotyping, and molecular markers such as CD30, ALK, and EMA,
which are essential for distinguishing between subtypes and determining prognosis. Among these
subtypes, systemic ALK-positive ALCL is most common in children and young adults and
typically responds well to chemotherapy and ALK inhibitors, often resulting in favorable
outcomes, with an overall response rate of -90%, a 5-year relapse-free survival of -60%, and a 5
year overall survival of 70%. While, in contrast, systemic ALK-negative ALCL, which usually
affects older adults, tends to follow a more aggressive course and shows lower survival rates,
with a 5-year survival rate often below 50%, as it displays resistance to standard chemotherapy,
contributing to its poor prognosis. Meanwhile, primary cutaneous ALCL is confined to the skin
and often present as localized nodules on the trunk, and unlike systemic forms, it rarely spreads
to lymph nodes or other internal organs, with a 5-year survival rate exceeding 90%. Diagnosis is
often based on skin biopsy and CD30 gene positivity, with treatment commonly inducing local
excision or low-dose radiation on the nodules. Additionally, breast implant-associated ALCL
(BIA-ALCl) has emerged as a distinct clinicopathological entity linked to textured breast
implants. BIA-ALCL typically arises in the fibrous capsule surrounding the implant and presents
as a late-onset periprosthetic seroma, years after implantation. Overall, this study underscores the
essential role of immunohistochemical markers such as CD30 and ALK in accurately
distinguishing between ALCL subtypes and their clinical management. By exploring the unique
clinical presentations and pathological features of systemic, cutaneous, and breast
implant-associated forms, this study highlights the importance of integrating molecular
diagnostics and histological analysis, an approach that is essential for advancing personalized,
subtype-specific therapies that can improve prognostic predictions and develop more targeted
subtype-specific treatment for patients with ALCL.3
Introduction
Anaplastic Large Cell Lymphoma (ALCL) is a rare and clinically heterogeneous subtype of
non-Hodgkin lymphoma (NHL) that originates from mature T-cells and is consistently marked
by a strong CD30 expression. These lymphomas represent a distinct category within peripheral
T-cell lymphomas and encompass a wide range of clinical behaviors, genetic alterations, and
prognostic outcomes. ALCL is particularly significant in both clinical and research-based
contexts due to its uncommon presentations, the diversity among its subtypes, and its association
with both pediatric and adult populations.
Figure 1. Clinical Characteristics of Systemic ALK-Positive and ALK-Negative Anaplastic Large Cell
Lymphoma (ALCL).
This table summarizes key clinical and pathological differences between systemic ALK-positive and ALK-negative ALCL. Patients with ALK-positive ALCL are typically younger (25–35 years), whereas ALK-negative ALCL is more common in older adults (55–60 years). Both subtypes show a male predominance and are often present at advanced stages (Stage III–IV) with systemic B symptoms. Despite similar International Prognostic Index (IPI) scores and nodal involvement, ALK-positive ALCL shows a higher frequency of extranodal disease (60%) compared to ALK-negative ALCL (20%). The pattern of extranodal involvement also differs: ALK-positive cases
often affect bone, soft tissue, bone marrow, and spleen, while ALK-negative cases are more likely to involve the skin, liver, and gastrointestinal tract. Both subtypes rarely present with leukemic or central nervous system (CNS) involvement.
The classification of ALCL is primarily based on the presence or absence of the anaplastic
lymphoma kinase (ALK) gene rearrangements and its anatomical localization. Broadly, ALCL
subtypes include systemic ALK-positive, systemic ALK-negative, primary cutaneous ALCL4
(pcALCL), and breast implant-associated ALCL (BIA-ALCL). ALK-positive ALCL typically
affects children and tends to respond to chemotherapy and targeted ALK inhibitors. While
ALK-negative ALCL is more common in older adults, it generally displays a more aggressive
course, with reduced survival. Primary cutaneous ALCL remains confined to the skin and has a
favorable prognosis, while BIA-ALCL emerges as a rare implant-related lymphoma that arises
long after the insertion of textured prostheses in the breast region. Despite recent advances in the
classification of ALCL, accurate diagnosis continues to pose significant challenges. Mainly
because ALCL shares morphological and immunophenotypic features with other CD30-positive
lymphoproliferative disorders and reactive inflammatory conditions, which can lead to
diagnostic uncertainty. Additionally, rare molecular variants like DUSP22 and TP63
rearrangements add layers of complexity that demand precision and a multidisciplinary
diagnostic approach, similar to immunohistochemical tools such as CD30, ALK, and EMA, that
are essential for accurate subtype differentiation and prognostic assessments. This article
provides a comprehensive overview of anaplastic large cell lymphoma, as it examines current
insights into its classification, biological underpinnings, and diagnostic strategies, while also
highlighting recent progress in the development of targeted therapies. Ultimately, the goal is to
improve early recognition, enhance treatment precision, and contribute to more personalized
management strategies for patients with ALCL.5
Discussion
Choosing to research Anaplastic Large Cell Lymphoma (ALCL) was fueled by our curiosity
about the complexity of rare lymphomas and the pressing need for greater awareness and
improved treatment strategies. Among other diseases, ALCL stands out as a rare and aggressive
subtype of non-Hodgkin lymphoma, and its unpredictable nature forms different types of
ALK-positive and negative cases, making it a compelling topic for deeper investigation. What
made ALCL especially fascinating was the genetic and biological complexity behind the ALK
gene, as well as the immune system's role in disease progression, highlighted by how much is
still unknown about its behavior and treatment response to different mutations. By writing this
article, we hoped not only to dive deeper into the biology of ALCL but also to raise awareness
about its real-world implications, as learning about ALCL gave us a clearer picture of the
importance of early detection, potentially saving lives. Ultimately, through this paper, we aim to
shed light on the rare but impactful condition of ALCL to a broader audience, while contributing
to the understanding that one day might help improve outcomes for those affected by Anaplastic
Large Cell Lymphoma.6
Diagnosis
The diagnosing of Anaplastic Large Cell Lymphoma requires a proper, step-by-step approach
integrating clinical testing, advanced imaging, and histopathological analysis, which focuses on
the change of tissues caused by disease. Because ALCL’s signs and features are similar to those
in other lymphomas and ALK-positive diseases, an accurate diagnosis is needed to ensure the
correct course and treatment of the particular ALCL subtype and the molecular distinction of the
patient.
The way in which ALCL clinically represents itself heavily varies depending on subtype–
systemic ALK-positive, systemic ALK-negative, primary cutaneous ALCL, or breast
implant-associated ALCL. Common symptoms include the swelling of lymph nodes, which may
be present in the neck, armpits, or groin areas. Additionally, systemic “B symptoms’ are
common, such as night sweats or recurring fever, and inexplicable weight loss. Fatigue and skin
lesions are also seen in many patients with ALCL, especially those with primary cutaneous
ALCL. However, since these symptoms are vague in nature compared to other lymphomas and
ALK-positive diseases, a proper diagnosis from imaging software, laboratory tests, and biopsies
is required. Imaging, key to determining the location, size, and spread of lymphoma
involvement, is utilized in a multiplicity of forms. A useful example is the chest x-ray and
ultrasound, which checks for enlarged lymph nodes, masses, or fluid collections in the
mediastinal area, thus possibly classifying the patient’s illness as BIA-ALCL. Computed
tomography (CT) scans create multiple detailed images of the body using X-rays in order to
detect enlarged lymph nodes or organ involvement, thus possibly classifying the patient’s illness
as systemic ALCL. Blood tests, also assisting in the assessment of the patient’s overall health,
provide useful information on the patient’s condition, specifically that of the T-cells, since ALCL
is a cancer of the T-cells. An example of blood testing in the diagnosis stage of ALCL includes
enzyme testing and serum chemistry, which can detect abnormalities in the levels of certain
markers of lymphoma activity, such as LDH. A complete blood count (CBC) also helps to detect
lowered T-cell function in the immune and circulatory system.7
Figure 2. F-FDG PET maximum intensity projection (MIP) images of three patients with ALK-positive
ALCL
(a) and ALK-negative ALCL (b, c). a: Extensive involvement of systemic lymph nodes and extranodal organs of the nasopharynx and right parotid gland were found in a patient with ALK-positive ALCL. b: 18F-FDG-avid involvement was observed in the right localized cervical lymph nodes and extranodal organs of the stomach, small intestine and colon in a patient with ALK-negative ALCL. c: 18F-FDG-avid involvement of extranodal organs alone was detected in the bones of the left 6 lateral ribs, lumbar vertebra and right superior ramus of the pubis in a patient with ALK-negative ALCL
Although there are multiple ways to distinguish between the different types of ALCL, the only,
most common, absolute method is a biopsy. Biopsies involve taking samples of affected tissues
(specifically lymph nodes, skin lesions, or fluid collections) for microscopic examination.
Commonly used procedures include excisional or incisional biopsies, surgical removal of an
entire or a portion of a lymph mass or node. Core needle biopsies are less invasive, only taking a
small sample of tissue, and particularly used for diagnosing BIA-ALCL as tissue from the
breasts is sampled. Bone marrow biopsy, also using a needle, assesses bone marrow involvement
in the lymphoma. Following biopsies are the histopathological analyses, in which a pathologist
will examine the tissue samples. In the microscopic examination, ALCL will be characterized by
large, unusual lymphoid cells with horseshoe-shaped nuclei, often referred to as “hallmark cells.”
The utilization of immunohistochemistry (IHC) affirms the pathologist’s diagnosis by the
familiar protein markers of ALCL, primarily CD30, universal in all forms of ALCL, and ALK.
In terms of molecular testing, techniques such as FISH (Fluorescence In Situ Hybridization) are
used to find genetic rearrangements such as the NPM1-ALK fusion gene in ALK-positive
patients. Indefinitely, histopathology is key to distinguishing ALCL from other lymphomas and
inflammatory illnesses, and knowledge on the unique factors of the distinct subtypes of ALCL
continues to grow, bettering the prognosis and treatment course for all patients with the disease.8
Medical Professions
The diverse diagnosis, classifications, treatments and overall course of ALCL require a
comprehensive, multispecialty set of medical professionals, each of whom play crucial roles in
the ensuring of accurate diagnoses, staging, and treatment issuing.
Crucial and central to the diagnosis of ALCL stand pathologists, who study tissues and cell
samples in order to identify diseases via skin or lymph node biopsies, significantly searching for
signs of large cells with a strong CD30 expression. In order to tell apart Primary Cutaneous
ALCL from other CD30-positive illnesses, dermatopathologists, who examine cutaneous
diseases at microscopic levels and their causes in particular, ensure systemic extension is
eliminated as a possibility. Radiologists, key to the staging of ALCL, use computerized axial
tomography (CT) scans or positron emission tomography) scans to search for any signs of lymph
node or system involvement, and if positive, a bone marrow biopsy is performed. Nuclear
medicine physicians interpret these PET scans and issue radiotracers for a visual of the
lymphoma activity, working closely with radiologists and oncologists. It is important to note that
there is not a contemporary reliable means to tell apart PC-ALCL and Systemic ALCL based on
sole skin biopsies. For PC-ALCL, imaging studies and thorough examinations of the skin are
needed to verify that the cancerous cells are only present in the skin and not the lymph nodes or
other organs. Any diagnosis of skin lymphomas will be confirmed by a pathologist with
expertise on the diagnosis of cutaneous lymphomas. For diagnostic confirmation, cytogeneticists
or pathologists may perform tests to detect ALK rearrangements and fusions from chromosomal
translocations, and mutations of the ALK-negative genes DUSP22 and TP63. By closely
examining the genetic markers and molecular features associated with both ALK-positive and
ALK-negative ALCL, pathologists and other relevant professionals can accurately classify
patients into the subtypes of the lymphoma, predict prognosis and plan applicable treatments.
Once ALCL is confirmed, patients are then referred to hematologists or medical oncologists.
Hematologists study the physiology of the blood, and in the case of anaplastic large-cell
lymphoma, they perform blood tests such as CBC in the diagnosis stage and later on are present
during the treatment(chemotherapy, radiation, targeted therapies) as a part of a multidisciplinary
team. Medical oncologists and nurse practitioners are additionally present, supporting patients
during their treatment and monitoring and managing their side effects, simultaneously educating
the patient’s family on the lymphoma and the patient’s condition and progress. In specific cases
of Breast Implant-Associated ALCL, a surgical oncologist or plastic surgeon may have to
perform an extraction of the textured breast implant and a complete capsulectomy, which is the
surgical removal of scar tissue surrounding the implant followed by the replacement of the
implant. In summary, the multispecialty team, subspecialties included, is vital to improving
patient outcomes, adjusting therapies and treatment to the distinct biological and clinical features
of each case.9
Treatments
Importance of Understanding Treatment Options
A thorough understanding of different treatment options is essential for creating targeted and
effective plans to manage Anaplastic Large Cell Lymphoma (ALCL). Each subtype of ALCL,
including ALK- positive systemic ALCL (sALCL), ALK-negative systemic ALCL (sALCL),
and Primary Cutaneous ALCL (pcALCL), exhibit different biological behaviors, prognostic
outcomes, and metastatic patterns. Understanding these various aspects of each ALCL-subtype is
crucial in determining the appropriate treatment plan. Inadequate knowledge or a misapplication
of therapies could result in significant medical consequences for pediatric patients. (E.g. If
aggressive chemotherapy is unnecessarily used in more indolent forms of ALCL, such as
pcALCL, avoidable toxic reactions may occur. Conversely, if aggressive variants, such as
high-risk sALCL, are under-treated by omitting interventions like stem cell transplantation,
survival chances may be compromised.) Recognizing optimal treatment strategies for each
ALCL subtype is vital to improve patient outcomes, minimize treatment-related harm, and
ensure effective and personalized care.
Prognostic Factors
Prognostic outcomes refer to the progression and likely results of a disease. It includes, but is not
limited to, the seriosity of the disease, how effectively a patient responds to treatment, the life
expectancy with or without treatment, and the chances of recovery, remission, and survival.
These outcomes are based on prognostic factors such as the type and stage of a cancer, genetic or
molecular features of a tumor, a patient’s age and overall health, and how the disease has
responded to past treatments. In ALCL, prognostic outcomes guide doctors and medical
professionals in understanding the likely future of the cancer, to choose the most appropriate
treatment strategy.
Metastatic Patterns
Metastatic patterns refer to the specific ways or different pathways in which cancer cells spread
from their original location to secondary sites. These patterns vary based on the ALCL subtype,
aggressiveness of the cancer, and the routes of dissemination. Systemic ALCL (sALCL) spreads
from lymph nodes to extranodal sites such as the skin, bone, liver, and bone marrow. Primary
cutaneous ALCL (pcALCL) is usually limited to the skin, allowing for more localized treatment
plans. Breast-implant associated ALCL (BIA-ALCL) typically remains around the implant
capsule but may occasionally invade nearby tissues, requiring a more aggressive and multimodal
treatment plan. Understanding these patterns helps to avoid under-/over- treatment of ALCL
patients and provide more targeted and therapeutic responses.10
Early Detection
Early detection of ALCL can significantly improve the outcomes of tailored treatment,
increasing the curability of systemic ALCL, allowing for minimal interventions in localized
subtypes (like pcALCL or BIA-ALCL), and help prevent the spread of this cancer to high risk
organs such as the lungs or bone marrow. Early detection can allow for less toxic treatment
methods, reducing patient burden.
Use of Machine Learning in Histopathology image analysis
Machine Learning can enhance the diagnostic accuracy of histopathology image analysis,
especially in recognizing patterns of the CD30 biomarker. Histopathology image analysis is the
process of examining tissue samples to study the microscopic structure of cells and tissues. It is
used to identify abnormal cell patterns, structures, and markers that indicate ALCL. Machine
learning algorithms can be trained to detect and classify patterns such as cell morphology
(changes in size, shape, and arrangement), the presence of markers (e.g. how many cells at
CD-30 positive), and the spread of tumors. ML technology speeds up a pathologist’s cell analysis
by thousands of cells per second and assists in the early detection of markers to indicate ALCL
before a pathologist may spot it.
Biomarkers as Indicators of Early Detection
For Anaplastic Large Cell Lymphoma, biomarkers like CD30 and ALK fusion proteins are
valuable indicators for early detection. CD30 is a cell surface protein on ALCL tumor cells, and
is also a target for therapies like Brentuximab vedotin. In addition, the presence of an ALK gene
fusion is a strong indicator of ALK-positive ALCL, a subtype that commonly occurs in younger
patients. These biomarkers can be detected through tests on biopsy samples, and can appear
before a patient shows significant clinical symptoms. Biomarkers also predict how aggressive the
ALCL subtype will be, guiding physicians in personalized treatment planning. The presence of
biomarkers allows medical professionals to begin cancer treatment before the disease even
presents a visible impact on the body. This early detection enhances the treatment process,
allowing for faster and stronger recovery.
Systemic ALCL (sALCL) Treatment
Chemotherapy
Chemotherapy is the standard treatment for sALCL, as it rapidly destroys dividing cancer cells in
the body and is effective in inducing remission. The abbreviation CHOP is used at the standard11
first line of treatment. CHOP includes the drugs Cyclophosphamide, Doxorubicin, Vincristine,
and Prednisone. Cyclophosphamide is an agent that damages DNA and prevents cancer cell
replication. Hydroxydaunorubicin is an antibiotic that intercalates DNA and inhibits
topoisomerase II, leading to DNA breaks and cell death. Oncovin is a mitotic inhibitor that
prevents microtubule formation, inhibiting the cancer cells to grow past metaphase. Prednisone is
a corticosteroid that induces apoptosis (cell death) in lymphoid cells and reduces inflammation.
Together, these drugs work to interfere with the cancer cells’ ability to grow and divide, reducing
the growth of ALCL tumors. Chemotherapy is most often given in cycles over several months,
but may be altered based on a patient’s response.
Crizotinib
Figure 3. Longitudinal Treatment Response in a Patient Receiving Crizotinib
(A) Radiographic imaging over time illustrates the response to treatment. CT scans from January 2020 (01/20), March 2020 (03/20), and April 2021 (04/21) show the evolution of tumor burden. Arrows indicate hepatic lesions that decrease significantly over time, suggesting a strong therapeutic response.(B) Treatment regimen and molecular findings. The patient was initially diagnosed with a ROS1-positive non-small cell lung cancer (NSCLC) with CD74-ROS1 fusion, as confirmed by FoundationOne CDx and other molecular assays. After initiating Crizotinib 250 mg BID, further testing in April 2021 revealed additional mutations, including TP53 and PIK3CA, and a fusion
involving the TPM3 gene. The patient continued targeted therapy with noted benefit. (C)Timeline of treatment and imaging assessments. Crizotinib treatment began in March 2020 and continued through April 2021. Follow-up imaging (labeled "F/U") was conducted periodically to assess response. Molecular testing Figure 2. using FoundationOne and liquid biopsy panels (Guardant360) was performed at key points, showing evolving tumor genomics under treatment pressure.
Targeted therapies like Crizotinib may be used to inhibit ALCL growth. Crizotinib is an ALK
(Anaplastic Lymphoma Kinase) inhibitor. It is a targeted drug, used especially when sALCL
returns after treatment (relapsed) or doesn’t respond at all (refractory). ALK-positive ALCL has
a specific gene mutation, most often a fusion between the NPM and ALK genes, which creates12
an abnormal ALK protein. This ALK protein is always active, continuously sending signals for
ALCL cancer cells to divide uncontrollably. Crizotinib specifically blocks this
abnormal ALK protein by shutting down those growth signals. As a result, cancer cells stop
growing and dividing, undergoing apoptosis and dying naturally. However, this drug only targets
the faulty protein and not all multiplying cells like traditional chemotherapy would, presenting
fewer side effects.
Crizotinib is taken as a pill, usually once or twice a day, and is often well tolerated. It can lead to
strong responses in patients, shrinking tumors and controlling disease even after other treatments
have failed. In some cases, it’s used temporarily to stabilize the patient before moving to more
long-term options like stem cell transplantation.
Immunotherapy: Brentuximab Vedotin
Figure 4. Proposed Mechanism of Action of Brentuximab Vedotin (an Antibody-Drug Conjugate Directed to
CD30).
This figure illustrates the step-by-step intracellular mechanism by which Brentuximab Vedotin targets and eliminates CD30-expressing tumor cells. First, the monoclonal antibody (Brentuximab) specifically binds to the CD30 antigen present on the surface of tumor cells. Upon binding, the entire antibody-drug conjugate is internalized into the cell via endocytosis (Step 2), forming an endosome. Within the lysosome, the protease-sensitive linker is cleaved (Step 3), releasing the cytotoxic payload monomethyl auristatin E (MMAE) into the cytoplasm (Step 4). MMAE disrupts the microtubule network (Step 5), inhibiting cell division and eventually triggering apoptotic cell death (Step 6). The process also facilitates antibody-dependent cellular phagocytosis (ADCP), contributing to the antitumor immune response. This multi-step mechanism underpins the drug's therapeutic effect in conditions like Hodgkin lymphoma and systemic anaplastic large cell lymphoma.
Brentuximab vedotin is considered an ADC, an antibody-drug conjugate. This is a specialized
type of cancer treatment designed to attack ALCL cells by targeting the CD30 protein. The drug
is made up of two parts: a monoclonal antibody that specifically binds to the CD30 protein on
the surface of ALCL cells, and an apoptosis-inducing drug called monomethyl auristatin E
(MMAE) attached to that antibody. When brentuximab vedotin binds to the CD30 biomarker on
ALCL cancer cells, ALCL cells engulf the whole drug complex. Once inside, the brentuximab
vedotin drug releases MMAE which disrupts the cell’s internal skeleton (microtubules). This13
prevents the cancer cell from dividing further and induces apoptosis. The approach kills cancer
cells while limiting damage to healthy cells.
Brentuximab vedotin is approved to treat lymphomas that have CD30 on their cells, including
ALK-positive ALCL. It is often used together with chemotherapy drugs, commonly in a
combination known as “BV plus CHP.” Brentuximab vedotin replaces the chemotherapy drug
vincristine because both vincristine and brentuximab vedotin can cause nerve damage if used
together. This drug is used both as a first treatment option and for cases where the lymphoma has
returned.
Stem Cell Transplant
Stem cell transplant is a treatment option for systemic ALCL. It can involve either the patient’s
own stem cells (autologous transplant) or donor stem cells (allogeneic transplant). Allogeneic
transplants are more commonly used in aggressive or high-risk cases. SCT is typically
considered for patients who experience a relapse after initial treatment or those who do not fully
respond to first-line chemotherapy.
Stem cell transplants aim to eliminate any remaining cancer cells and to rebuild healthy blood
and immune systems. It begins by giving the patient very high doses of chemotherapy,
sometimes combined with total body irradiation, to destroy both the cancer and the bone marrow
where blood cells are made. After this, stem cells are infused back into the patient’s bloodstream
to restore the bone marrow’s ability to produce healthy blood cells and support the immune
system.
Differences in ALK-positive and ALK-negative Treatment
To treat ALK-positive sALCL, professionals may use CHOP chemotherapy, Crizotinib targeted
therapy, Brentuximab vedotin, and (if the situation calls for it) stem cell transplants. Conversely,
ALK-negative sALCL is treated through CHOEP chemotherapy, with the addition of the
Etoposide drug for younger patients. However, ALK-positive treatment, ALK-negative treatment
may also call for Brentuximab vedotin and stem cell transplants.
Primary Cutaneous ALCL (pcALCL)
Local Excisions
Local excisions are common treatments for primary cutaneous ALCL (pcALCL), where
professionals surgically remove the lymphoma lesion by cutting out the affected area of skin
where the tumor is located. This method is typically used when the ALCL is limited to only a14
few isolated skin tumors and is not widespread across the body. This treatment aims to
completely remove the visible tumor, controlling cancer growth in that specific area and
potentially cure it. Because pcALCL often remains confined to the skin, physically removing the
lesion can be very effective. In many cases, surgery alone can cure the disease when the
lymphoma is localized. However, this treatment is not effective if there are multiple lesions or
the pcALCL is extensive across great regions of the skin.
Radiation Therapy
Radiation therapy is an effective option when the pcALCL lymphoma is only confined to the
skin. Using ionizing radiation, this targeted therapy destroys cancer cells in localized skin
lesions. This approach is helpful for patients who cannot undergo surgery to get local excisions.
pcALCL tumors usually require only low to moderate doses of radiation to achieve strong results
(24 to 36 Gy). External Beam Radiation Therapy (EBRT) is the standard method for radiation
therapy. Advanced radiation techniques like proton therapy are usually used for deep tumors,
making it unnecessary since pcALCL lesions are not usually localized at the skin’s dermis.
Radiation therapy effectively stops ALCL from returning to a treated area, and tends to have
minimal side effects.
Low-Dose Methotrexate or Bexarotene
Methotrexate and bexarotene are treatment options for patients with pcALCL that has
widespread skin involvement or recurring lesions that cannot be controlled with excision or
radiation.
Methotrexate is a chemotherapy drug that blocks DNA synthesis in dividing cancerous
lymphoma cells. For pcALCL, it is given in low doses once a week to reduce its side effects,
while still controlling the ALCL. Bexarotene is a retinoid (a Vitamin A derivative) that helps
regulate how cells grow. It is typically used as a topical cream or taken by the mouth.15
Statistics
While anaplastic large cell lymphoma is considered an uncommon subtype within the broader
category of non-Hodgkin lymphomas, its clinical relevance is underscored by the distinct
biological and epidemiological features observed across its subtypes. Although it accounts for
less than 3% of all NHL cases, ALCL has significant clinical importance due to its variable
presentation, age distribution, and the aggressive nature of several subtypes. Among peripheral
T-cell lymphomas, ALCL represents approximately 10-15% of cases, with the ALK-positive
subtype of ALCL typically affecting adolescent patients, while the ALK-negative form is most
often seen in adults over the age of 50. Additionally, According to data from the Surveillance,
Epidemiology, and End Results (SEER) program and other international registries, systemic
ALK-positive ALCL occurs most frequently in patients between the ages of 10 and 30, with a
individuals over the age of 50, is also mostly common in men. ALK-positive subtypes are
associated with more favorable outcomes, as they have a 50-year overall survival rate
approaching 70-90%, and ALK-negative cases often lead to a more aggressive course, with an
estimated 5-year survival ranging from 30 to 50%.
Figure 5. National Cancer Statistics for Lymphoid Malignancies in the United States (2025 Estimates and
Trends from 1992–2023).
This figure summarizes projected statistics and historical trends for lymphoid cancers, including estimated16 incidence, mortality, and 5-year relative survival. In 2025, approximately 80,350 new cases are expected, representing 3.9% of all new cancer diagnoses. An estimated 19,390 deaths are projected, accounting for 3.1% of all cancer-related deaths. The 5-year relative survival rate between 2015 and 2021 is reported at 74.2%, reflecting improvements in early detection and treatment. The accompanying line graph illustrates trends in the rate of new cases (light green squares) and death rate (dark green triangles) per 100,000 persons from 1992 to 2023. While
incidence has remained relatively stable over time, the mortality rate has steadily declined, indicating progress in disease management and outcomes over the past three decades.
Primary cutaneous ALCL (pcALCL), although rarer than systemic forms, contributes
significantly to the spectrum of CD30-positive lymphoproliferative disorders. It approximately
accounts for 9% of all cutaneous T-cell lymphomas and presents most often in adults ages 50 or
older. The prognosis with this subtype is generally excellent, with the 5-year survival rate
exceeding 90%, with many therapy-related cases responding well to the treatment.
Figure 6. Comparison of Treatment Outcomes in ALK+ vs. ALK-ALCL
This figure compares treatment outcomes between ALK-positive (ALK+) and ALK-negative (ALK−) anaplastic
large cell lymphoma (ALCL), highlighting differences in clinical response and long-term prognosis. Both subtypes
are typically treated with front-line chemotherapy regimens such as CHOP, CHOEP, or (BV)-CHP. ALK+ ALCL demonstrates superior outcomes across all metrics, with a complete remission (CR) rate of 85%, 5-year progression-free survival (PFS) of 69%, and a median survival exceeding 10 years. In contrast, ALK− ALCL shows a lower CR rate (63%), reduced 5-year PFS (43%), and a median survival of only 4.5 years. The 5-year overall survival rate ranges from 70–90% in ALK+ cases compared to 40–60% in ALK− cases, underscoring the prognostic significance of ALK status in treatment planning and disease trajectory.
Breast implant-associated ALCL (BIA-ALCL) has emerged more recently as a recognized
subtype and is not included in many general lymphoma registries due to its distinct etiology and
presentation. Though rare, it has an estimated lifetime risk ranging from 1 in 3,000 to 1 in
30,000, depending on implant type and manufacturer. Most cases are diagnosed by a median of
7-10 years after textured breast implants are placed, with early-stage disease confined to the
capsule carrying a favorable prognosis when treated with surgery.17
Figure 7. Epidemiologic and Clinical Characteristics of Aggressive PTCL Subtypes
This figure outlines the demographic and clinical characteristics of aggressive peripheral T-cell lymphoma (PTCL) subtypes commonly seen in North America and Europe. PTCL not otherwise specified (PTCL-NOS) accounts for the largest proportion (25.9%) of cases, followed by angioimmunoblastic T-cell lymphoma (AITL, 18.5%) and ALK+ ALCL (6.6%). Most subtypes present at advanced stages (stage III/IV), with AITL showing the highest rate (89%). ALK+ ALCL primarily affects younger males (median age 34, 63% male), whereas ALK− ALCL tends to present later in life (median age 58). CD30 expression is universal in both ALK+ and ALK− ALCL (100%), which is relevant for targeted therapies. Bone marrow involvement varies widely, from 3% in enteropathy-associated PTCL to 74% in hepatosplenic lymphoma. These findings emphasize the heterogeneity of PTCL subtypes and the importance of individualized diagnostic and therapeutic approaches
The pediatric adolescent population is also affected by ALCL, with ALK-positive ALCL
comprising up to 30% of non-Hodgkin lymphomas in children and adolescents, making it one of
the most common T-cell lymphomas in patients under 20. The ALCL99 trial and subsequent
pediatric protocols have already reported promising remission and survival rates in this group,
especially with the integration of ALK inhibitors into frontline therapy. With an estimated global
incidence exceeding 10,000 cases annually and survival outcomes that vary widely based on
subtypes, ALCL remains a significant and evolving challenge for both clinicians and researchers.
In addition, geographic disparities in diagnosis, treatment availability, and awareness in relation
to BIA-ALCL further emphasize the need for coordinated international efforts in disease
monitoring, molecular profiling, and therapeutic development. In response to these disparities
and the expanding recognition of ALCL subtypes, there is a growing imperative to deepen
research into the molecular mechanisms that drive disease progression, as advancements in early
diagnostic tools and individual treatment strategies will be essential as our understanding of
ALCL continues to develop. Ultimately, improving clinical outcomes and quality of life for
patients across all age groups and disease subtypes will depend on a multifaceted approach that
integrates precision medicine and global collaboration in creating treatments with increased
survival rates.18
Impacts
Anaplastic large cell lymphoma (ALCL) is a clinically and molecularly heterogeneous type of
peripheral T-cell lymphoma (PTCL) and rare non-Hodgkin's lymphoma (NHL), accounting for
1-3% and constituting 15% of T-cell lymphoma cases. Although it reports a small percentage of
the total lymphomas, it has a serious impact on patients and their families. WHO's classification
in 2016 identified 4 subtypes of ALCL differentiated on the basis of clinical symptoms, gene
changes, prognoses, and therapy: ALK-positive ALCL (ALK+ ALCL), ALK-negative ALCL
(ALK- ALCL), primary cutaneous ALCL (pcALCL), and breast-implant-associated ALCL
(BIA-ALCL).
ALK-positive ALCL (ALK+ ALCL) accounts for 1–3% of non-Hodgkin’s lymphomas in adults
and between 10–20% in children and adolescents. It typically affects younger people and is seen
to be more common in males (sex-linked). Systemic "B symptoms,” including fevers, excessive
sweating, and weight loss, develop quickly along with swollen lymph nodes. It's often diagnosed
when it reaches an advanced stage. It’s also common for the cancer to spread beyond the lymph
nodes, with many patients showing involvement in other areas such as the skin (26%), bones
(14%), soft tissue (15%), lungs (12%), and liver (8%), while central nervous system or leukemic
presentations remain rare.Parents and guardians of paediatric patients go through a really tough
and incredibly emotional situation, where they need to quit their job or extend their leave to take
care of the suffering child which causes financial burden and also emotional exhaustion. There is
often little time to adjust between diagnosis and aggressive treatment. Pediatric patients are often
treated under protocols such as ALCL99 or BFM-based regimens. Studies have shown that
ALK+ ALCL patients achieve high complete remission rates following first-line therapy, with
overall survival (OS) rates ranging from 70% to 90% at five years. Immunohistochemical
markers such as high CD30 expression and ALK nuclear/cytoplasmic staining patterns also carry
diagnostic and prognostic implications. ALK inhibitors such as crizotinib and brentuximab
vedotin are improving outcomes in children and generally adding few toxicities to treatment.
Awareness of this rare disease among the public is really low which often leads to delayed
diagnosis. Targeted drug therapies can be used to treat this disease. A huge number of ALK-1
inhibitors such as crizotinib, ceritinib and alectinib are used in clinical practice, which inhibits
the activity of ALK protein that plays a key role in cell division and survival.
ALK-negative ALCL (ALK- ALCL) is a rare aggressive form of non-Hodgkin’s lymphoma that
more often occurs in persons over the age of 50. The ALK- ALCL, rare CD30-positive T-cell
lymphoma, lacks the ALK gene arrangement with the lower survival rate (around 30–49%) of 5
years old and unfortunately relapse and refractory disease are common. The mutations in
Oncogene TP63, STAT3, JAK1, and DNMT3A genes, suggesting that disturbs JAK-STAT
signaling and epigenetic dysregulation may contribute significantly to disease development.
There is no reported optimal therapy due to disease rarity, heterogeneity, and lack of randomized19
trials on this lymphoma. The therapeutic backbone similar to other aggressive lymphomas has
been CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) with suboptimal
results. Being aggressive in nature, a high rate of relapse has been noticed and limited targeted
therapies have been reported which leads to emotional and psychological burden among patients
and caregivers. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, is a current
approach used in case of relapsed/refractory lymphomas. Agents targeting the JAK-STAT
pathway, epigenetic modulators like HDAC inhibitors, and immune checkpoint inhibitors are
currently under investigation. Since it's less responsive to chemotherapy regimen, it demands
oncology service that integrates palliative care, salvage therapies, and potentially stem cell
transplants. Especially in the hematology oncology unit in clinics and hospital services.
Primary Cutaneous Anaplastic large cell lymphoma (pcALCL), is a new CD30+
lymphoproliferative disorder (LPD) of the skin constituting 25-30% of the primary cutaneous
lymphomas and the second most common clonal T-cell neoplasm of the skin behind mycosis
fungoides. It comprises about 9% of all cutaneous T-cell lymphomas. Major cases have been
reported positive for CD45, CD43, MUM1/IRF4, and CD4 with variable expression of CD2,
CD5, CD7, and CD45RO. Five-year survival for early stage PC-ALCL ranges between 90% and
97.5% for T1 disease, 93% for T1 and T2 combined and 77% for T3. pcALCL remains confined
to the skin at the time of diagnosis and is not associated with ALK gene rearrangements. It must
be distinguished from other CD30+ cutaneous disorders, particularly lymphomatoid papulosis
(LyP) and secondary skin involvement from systemic ALCL which is crucial for treatment
decisions and prognostic expectations vary significantly between these conditions. As
misdiagnosis can lead to over or under treatment. Although the prognosis for patients with
pcALCL is highly favorable, with a 5-year survival rate often exceeding 90%, the patient
endured psychological breakdown if the lesion occurs at the visible area of the skin like face.
The development of non-invasive monitoring tools, such as liquid biopsy for circulating tumor
DNA (ctDNA), holds promise for tracking disease progression and early relapse. In immuno
suppressed individuals, Morphologic Variants of Primary Cutaneous ALCL such as
Neutrophil/eosinophil-rich variant commonly known as “pyogenic cutaneous lymphoma” were
reported. “Epidermotropic” variant (DUPS22-rearranged) nurturing translocation involving the
DUSP22-IRF4 gene (located at 6p25.3).
Breast-implant Associated ALCL (BIA-ALCL), a non-Hodgkin’s T-cell lymphoma typically
CD30+
, ALK- that develops near breast implant, years after surgery. The major risk factor is the
use of textured implantation as it triggers local inflammation and stimulates the immune system
leading to lymphoproliferation. It seems to be underestimated in many countries with primary
symptoms- seroma might be overlooked or misdiagnosed. In 2011, FDA’s MDR (Medical
Device Reports) Review reported a pattern demonstrating a clear and concerning link between
textured implants and the development of BIA-ALCL, upon which certain regulation step were
taken. The 2023 FDA Medical Device Reports on BIA-ALCL points to a more frequent20
occurrence when textured (73% of cases) and silicone-filled (66% of cases) devices were used. It
has led to increased attention on post marketed surveillance of the medical devices and breast
implants affecting the public trust on administrations and manufacturer and individual surgeons.
Renowned companies like Allergan, whose Biocell textured implants were linked to the majority
of cases. The FDA required Allergan to recall these implants in 2019. Most patients have
undergone emotional distress not only from the cancer diagnosis but also from the betrayal of a
medical device they believed to be safe. Especially breast cancer survivors who received
implants following mastectomy, BIA-ALCL can feel like a second trauma. It leaves a lifetime
impact on the quality of life of the patient left dealing with visible physical changes and
emotional struggles. On early diagnosis of BIA-ALCL, treatment prognosis is effective, so the
awareness among public and healthcare professionals is crucial. If the disease is found at a later
stage and has spread, harsher treatments like chemotherapy or radiation may be needed, which
can make the physical and emotional burden even heavier. We also found that > 75% of the
oncologists were seen not to inform about the risk of BIA-ALCL during pre-surgery
consultation. It's really painful to even imagine the emotional distress a woman undergoes to
know about it after a reconstruction procedure. The process of decision making should put more
emphasis on collaborative discussions.21
Conclusion
In this study, we reported a rare but clinically significant subtype of non-Hodgkin lymphoma that
poses diagnostic, therapeutic and psychosocial challenges i.e., Anaplastic Large Cell Lymphoma
(ALCL) , a heterogeneous group of disorders. We explored the biological complexity and clinical
heterogeneity of ALCL and its subtypes in terms of distinct mechanisms, treatment, and
prognosis., including its systemic forms (ALK-positive and ALK-negative), primary cutaneous
variant (pcALCL), and the emerging breast implant-associated subtype (BIA-ALCL). Although
of the advances in molecular diagnostics, particularly immunohistochemistry and gene
rearrangement studies, such as the use of CD30 immunostaining, ALK gene rearrangement
detection, and advanced imaging have revolutionized the ability to detect ALCL subtypes
accurately, the risk of misdiagnosed or overlooked still remains. There is a critical need for
public awareness to avoid misdiagnosis or underestimation which might lead to under or over
treatments.
Conventional first-line treatment with multi-agent chemotherapy regimens, such as CHOP
(cyclophosphamide, doxorubicin, vincristine, and prednisone), remains a mainstay, particularly
for systemic ALCL. For localized primary cutaneous ALCL, radiation therapy or surgical
excision can be highly effective. ALK inhibitors have played a key role in achieving response
rates exceeding 80%, especially in younger populations with relapsed/refractory disease for
ALK+ ALCL. For ALK- ALCL, the treatment remains challenging but the establishment of
brentuximab vedotin, an anti-CD30 antibody-drug conjugate incorporated with chemotherapy
has led to improved outcomes. Primary cutaneous and implant-associated variants call for
balanced treatment that preserves both life and quality of life.
It demands continued research, clinical trials and access to equipped advances of treatment. And
above all campaigns and surveys could help in creating awareness among the public, patients,
caregivers and healthcare professionals. Regardless of the subtype, age, or socioeconomic status,
it's essential that all the patients receive access and awareness of the risks, and emerging
therapies for the best possible outcome.22
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