Primary cutaneous diffuse large B-cell lymphoma, leg type | |
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Other names | PCDLBCL-LT; PCDLBCL, leg type; primary cutaneous DLBCL, leg type |
Specialty | Dermatology, hematology, oncology |
Symptoms | One or more red/violaceous skin nodules/tumors on the legs and/or uncommonly elsewhere |
Complications | Spread to other tissues |
Diagnostic method | Skin biopsy |
Prognosis | guarded |
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) (also termed PCDLBCL, leg type or primary cutaneous DLBCL, leg type) is a cutaneous lymphoma skin disease that occurs mostly in elderly females. In this disease, B cells (a type of lymphocyte) become malignant, accumulate in the dermis (i.e. the layer under the epidermis) and subcutaneous tissue below the dermis to form red and violaceous skin nodules and tumors. These lesions typically occur on the lower extremities but in uncommon cases may develop on the skin at virtually any other site. [1] In ~10% of cases, the disease presents with one or more skin lesions none of which are on the lower extremities; the disease in these cases is sometimes regarded as a variant of PCDLBL, LT termed primary cutaneous diffuse large B-cell lymphoma, other (PCDLBC-O). [2] PCDLBCL, LT is a subtype of the diffuse large B-cell lymphomas (DLBCL) [3] and has been thought of as a cutaneous counterpart to them. [4] Like most variants and subtypes of the DLBCL, PCDLBCL, LT is an aggressive malignancy. It has a 5-year overall survival rate of 40–55%, although the PCDLBCL-O variant has a better prognosis than cases in which the legs are involved. [5]
Most lymphomas begin in a lymph node, mucosa-associated lymphoid tissue, the spleen, or another lymphoid tissue within the lymphatic system and then may spread to the skin. In these cases the skin is a secondarily site of involvement. PCDLBC, LT is a primary cutaneous lymphoma, i.e. it begins in the skin and then may spread to lymphoid and/or non-lymphoid tissues in virtually any other site. [6] A suspect PCDLBCL, LT that is not limited to the skin at the time of diagnosis should be regarded as some other variant or subtype of the diffuse large B-cell lymphomas. [7]
PCDLBC, LT represents 5–10% of all primary cutaneous lymphomas. [8] It is to be distinguished from two other primary cutaneous lymphomas that involve B-cells, primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL), [8] as well as from a B-cell lymphoma that at diagnosis may appear to be limited to the skin but often is a systemic disease affecting numerous organs and tissues viz., intravascular large B-cell lymphoma (IVLBCL). [7] These three B-cell lymphomas differ from PCDLBCL, LT in numerous ways but most importantly in their aggressiveness. [7] IVLEBC is, like PCDLBCL, LT, an aggressive disease with a guarded prognosis, but unlike the former disease, is often widely disseminated at presentation. [7] PCFCL and PCMZL, in contrast, are indolent lymphomas with a relatively good prognosis. [1] Distinguishing between these four cutaneous B-cell lymphomas at the time of diagnosis is critical for their appropriate treatment. [7]
Afflicted individuals (median age 76 years; range 49–92 years; more common in females [3] ) typically present with one or more rapidly growing red to bluish-red, firm tumors located on the leg(s) at some site(s) below the knees. [5] Occasionally the lesions are ulcerated. [3] About 10% of cases do not have lesions on the legs but rather present with one or more skin lesions outside of the legs; ~20% of individuals present with cutaneous lesion(s) but on further or later investigation are found to have disease in non-cutaneous sites such as the lymph nodes, visceral organs, [1] bone marrow, and/or, rarely, central nervous system. [5] Some individuals, particularly those with widespread disease, complain of having the B symptoms of fever, night sweats, and/or weight loss. [1] DLBCL cases that have cutaneous lesions in association with widespread disease may be advanced PCDLBCL, LT but without evidence that the disease began in the skin are diagnosed as having and treated for some other variant or subtype of the diffuse large B-cell lymphomas that has spread to the skin. [7]
The neoplastic cells in DLBCL are derived primarily from either germinal center B cells (i.e. GBC) or activated B cells (i.e. ABC) [9] with ABC-based DLBCL usually being a more aggressive disease than GBC-based DLBCL. [4] The neoplastic cells in PCDLBCL, LT are ABC, [6] bear gene abnormalities similar to those found in ABC-based DLBCL, [4] and as a likely result of this produce an aggressive disease. The potentially pathogenic gene abnormalities in the neoplastic cells of PCDLBCL, LT include:
These findings suggest that the development and/or progression of PCDLBCL, LT involves the step-wise acquisition by B-cells and/or their ABC descendants of gene abnormalities which promote the activation of NF-kappa B, B-cell receptor, JAK/STAT, and perhaps other signaling pathways. In consequence, these cells progressively acquire increased rates of proliferation, prolonged survival, the ability to spread to other tissues, the ability to avoid attack by the immune system, and other malignant behaviors that characterize this disease. [7]
The diagnosis of PCDLBCL, LT depends on analyzing skin biopsies of the involved sites microscopically. These sites show dense, diffuse sheets of infiltrating large-sized B-cells that resemble centroblasts and immunoblasts. [5] The infiltrates are located in the dermis and subcutaneous tissue but, unless there is ulceration, they are separated from the epidermis by the "grenz zone" i.e. a narrow area of the papillary dermis (i.e. the uppermost layer of the dermis that separates the dermis from the epidermis [13] ) that is not infiltrated by the disease. [5] In addition to the neoplastic B-cells, these infiltrates contain two types of cells that suppress immune reactions viz., M2 macrophages that express CD163 and myeloid-derived suppressor cells that express PD-L1 and CD33. [7] The sites may also contain poorly differentiated cells; [5] but rarely have T-cells, eosinophils, or plasma cells. [3] The lesion's neoplastic B-cells usually have a high proliferative index. [5] Immunostaining these tissues indicates that the neoplastic cells express B-cell marker proteins such as FOXP1 (90% of cases), (Bcl-2, (90% of cases), IRF4 (85% of cases), Bcl-6 (~60% of cases), [3] CD20, CD79a, PAX5, and cytoplasmic IgM. [5] The cells usually do not express CD5, CD10, CD30, or CD138. [5] The neoplastic cells are also usually characterized as being of the ABC phenotype as described in the section on the variants of DLBCL, NOS [6] and express the gene abnormalities indicated in the above Pathophysiology section. Patients should be evaluated for the involvement of non-cutaneous sites by CT scans of the chest, abdomen, and pelvis, a PET scan, and a bone marrow biopsy. [1] Individuals who present with an extra-cutaneous DLBCL-like disease should be diagnosed as having a variant or subtype of DLBCL other than PCDLBCL, LT unless in can be established that the disease began in the skin. [7]
Primary cutaneous follicular center lymphoma differs from PCDLBCL, LT in that its neoplastic B cells are germinal center B cells rather than activated B cells (see Pathophysiology section) that often infiltrate tissues in a follicular (i.e. small spherical groups of cells) rather than diffuse pattern. Primary cutaneous mantle cell lymphoma differs from PCDLBCL, LT in that is neoplastic B cells appear more like monocytes and/or plasma cells rather than centroblasts or immunoblasts. Intravascular large B-cell lymphoma differs from PCDLBCL, LT in that involved tissues contain large, neoplastic B-cells that are strictly confined within the lumen of small- to medium-sized dermal and subcutaneous blood vessels. [1]
Previously, most patients with PCDLBCL, LT were treated with the CHOP chemotherapy regimen of cycloheximide, hydroxydaunorubicin, oncovin, and prednisone. The more recent addition of the immunotherapy drug, rituximab, to this regimen has given better results. [14] Rituximab is a monoclonal antibody that kills cells which express high levels of CD20 by binding to this cell-surface protein and thereby targeting them for attack by the hosts immune system. [15] Accordingly, the addition of rituximab to CHOP, i.e. the R-CHOP chemoimmunotherapy regimen. with or without radiotherapy (used to treat symptoms resulting from specific localized lesions) is now recommended by the European Organisation for Research and Treatment of Cancer and the International Society for Cutaneous Lymphomas [16] as first line therapy for single, localized, and widespread diseases. Cases in which hydroxydaunorubicin is contraindicated because of, e.g. preexisting heart disease, may treated with the R-COP regiment (i.e. R-CHOP minus hydroxydaunorubicin). Patients who might be intolerant to R-CHO because of general health issues have been treated with just rituximab and radiotherapy [5] although more recent reports indicate that these patients may be successfully treated with a regimen that replaces hydroxydaunorubicin with PEGylated, liposome-encased doxorubicin in the R-CHOP regimen. [7]
A phase II clinical trial is recruiting individuals to study the efficacy and safety of nivolumab, a (monoclonal antibody that binds to programmed death-ligand 1 thereby blocking its ability to suppress immune responses) with or without varlilumab (a monoclonal antibody that binds to the CD27 protein expressed by cells and thereby promotes the anti-tumor activity of T cells) in treating patients with aggressive B-cell lymphomas, including PCDLBCL, LT that have relapsed after or do not respond to treatment. [17] Other agents are being evaluated in refractory or relapsed B-cell lymphoid malignancies but not PCDLBCL, NOS and ultimately may prove useful in PCDLBCL, LT. These include: ofatumumab, a monoclonal antibody that is stronger than rituximab in binding to CD20; two radioimmunotherapy monoclonal antibodies, Ibritumomab tiuxetan and Tositumomab that bind CD20 to deliver radiation from their attached radioactive isotopes to and kill CD20-bearing cells; lumiliximab, a monoclonal antibody that binds to CD23; dacetuzumab, a monoclonal antibody that binds CD40; Siglec-3 a monoclonal antibody that binds CD33; blinatumomab, a monoclonal antibody that binds both CD3 and CD19; chimeric antigen receptor T cell therapy using CD19-directed CAR-T cells; and lenalidomide, a drug with multiple anti-tumor actions. [7]
Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making aplasia, myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors, chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"), and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous"); these other blood conditions may also be managed by a hematologist.
Anaplastic large-cell lymphoma (ALCL) refers to a group of non-Hodgkin lymphomas in which aberrant T cells proliferate uncontrollably. Considered as a single entity, ALCL is the most common type of peripheral lymphoma and represents ~10% of all peripheral lymphomas in children. The incidence of ALCL is estimated to be 0.25 cases per 100,000 people in the United States of America. There are four distinct types of anaplastic large-cell lymphomas that on microscopic examination share certain key histopathological features and tumor marker proteins. However, the four types have very different clinical presentations, gene abnormalities, prognoses, and/or treatments.
Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normally occupy the follicles (nodular swirls of various types of lymphocytes) in the germinal centers of lymphoid tissues such as lymph nodes. The cancerous cells in FL typically form follicular or follicle-like structures (see adjacent Figure) in the tissues they invade. These structures are usually the dominant histological feature of this cancer.
MALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue (MALT), frequently of the stomach, but virtually any mucosal site can be affected. It is a cancer originating from B cells in the marginal zone of the MALT, and is also called extranodal marginal zone B cell lymphoma.
Primary effusion lymphoma (PEL) is classified as a diffuse large B cell lymphoma. It is a rare malignancy of plasmablastic cells that occurs in individuals that are infected with the Kaposi's sarcoma-associated herpesvirus. Plasmablasts are immature plasma cells, i.e. lymphocytes of the B-cell type that have differentiated into plasmablasts but because of their malignant nature do not differentiate into mature plasma cells but rather proliferate excessively and thereby cause life-threatening disease. In PEL, the proliferating plasmablastoid cells commonly accumulate within body cavities to produce effusions, primarily in the pleural, pericardial, or peritoneal cavities, without forming a contiguous tumor mass. In rare cases of these cavitary forms of PEL, the effusions develop in joints, the epidural space surrounding the brain and spinal cord, and underneath the capsule which forms around breast implants. Less frequently, individuals present with extracavitary primary effusion lymphomas, i.e., solid tumor masses not accompanied by effusions. The extracavitary tumors may develop in lymph nodes, bone, bone marrow, the gastrointestinal tract, skin, spleen, liver, lungs, central nervous system, testes, paranasal sinuses, muscle, and, rarely, inside the vasculature and sinuses of lymph nodes. As their disease progresses, however, individuals with the classical effusion-form of PEL may develop extracavitary tumors and individuals with extracavitary PEL may develop cavitary effusions.
The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals.
Intravascular lymphomas (IVL) are rare cancers in which malignant lymphocytes proliferate and accumulate within blood vessels. Almost all other types of lymphoma involve the proliferation and accumulation of malignant lymphocytes in lymph nodes, other parts of the lymphatic system, and various non-lymphatic organs but not in blood vessels.
Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.
Richter's transformation (RT), also known as Richter's syndrome, is the conversion of chronic lymphocytic leukemia (CLL) or its variant, small lymphocytic lymphoma (SLL), into a new and more aggressively malignant disease. CLL is the circulation of malignant B lymphocytes with or without the infiltration of these cells into lymphatic or other tissues while SLL is the infiltration of these malignant B lymphocytes into lymphatic and/or other tissues with little or no circulation of these cells in the blood. CLL along with its SLL variant are grouped together in the term CLL/SLL.
Marginal zone B-cell lymphomas, also known as marginal zone lymphomas (MZLs), are a heterogeneous group of lymphomas that derive from the malignant transformation of marginal zone B-cells. Marginal zone B cells are innate lymphoid cells that normally function by rapidly mounting IgM antibody immune responses to antigens such as those presented by infectious agents and damaged tissues. They are lymphocytes of the B-cell line that originate and mature in secondary lymphoid follicles and then move to the marginal zones of mucosa-associated lymphoid tissue, the spleen, or lymph nodes. Mucosa-associated lymphoid tissue is a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body such as the gastrointestinal tract, mouth, nasal cavity, pharynx, thyroid gland, breast, lung, salivary glands, eye, skin and the human spleen.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a slow-growing CD20 positive form of Hodgkin lymphoma, a cancer of the immune system's B cells.
Lutzner cells were discovered by Marvin A. Lutzner, Lucien-Marie Pautrier, and Albert Sézary. These cells are described as the smaller forms of Sézary cells, or Sézary-Lutzner cells, and the two variants are recognised as being morphologically different. Aggregates of these cells in mycosis fungoides are known as a Pautrier's microabscesses. They are a form of T-lymphocytes that has been mutated This atypical form of T-lymphocytes contains T-cell receptors on the surface and is found in both the dermis and epidermis layers of the skin. Since Lutzner cells are a mutated form of T-lymphocytes, they develop in bone marrow and are transported to the thymus is order to mature. The production and maturation stages occur before the cell has developed a mutation. Lutzner cells can form cutaneous T-cell lymphoma, which is a form of skin cancer.
Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.
Plasmablastic lymphoma (PBL) is a type of large B-cell lymphoma recognized by the World Health Organization (WHO) in 2017 as belonging to a subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation. The other lymphoid neoplasms within this subgroup are: plasmablastic plasma cell lymphoma ; primary effusion lymphoma that is Kaposi's sarcoma-associated herpesvirus positive or Kaposi's sarcoma-associated Herpesvirus negative; anaplastic lymphoma kinase-positive large B-cell lymphoma; and human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified. All of these lymphomas are malignancies of plasmablasts, i.e. B-cells that have differentiated into plasmablasts but because of their malignant nature: fail to differentiate further into mature plasma cells; proliferate excessively; and accumulate in and injure various tissues and organs.
Epstein–Barr virus–associated lymphoproliferative diseases are a group of disorders in which one or more types of lymphoid cells, i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells, are infected with the Epstein–Barr virus (EBV). This causes the infected cells to divide excessively, and is associated with the development of various non-cancerous, pre-cancerous, and cancerous lymphoproliferative disorders (LPDs). These LPDs include the well-known disorder occurring during the initial infection with the EBV, infectious mononucleosis, and the large number of subsequent disorders that may occur thereafter. The virus is usually involved in the development and/or progression of these LPDs although in some cases it may be an "innocent" bystander, i.e. present in, but not contributing to, the disease.
Duodenal-type follicular lymphoma (DFL) is a form of lymphoma in which certain lymphocyte types, the B-cell-derived centrocytes and centroblasts, form lymph node follicle-like structures principally in the duodenum and other parts of the small intestine. It is an indolent disease which on rare occasions progresses to a more aggressive lymphoma that spreads beyond these originally involved sites.
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a malignancy of B cells. B-cells are lymphocytes that normally function in the humoral immunity component of the adaptive immune system by secreting antibodies that, for example, bind to and neutralize invasive pathogens. Among the various forms of B-cell lymphomas, THRLBCL is a rarely occurring subtype of the diffuse large B-cell lymphomas (DLBCL). DLBCL are a large group of lymphomas that account for ~25% of all non-Hodgkin lymphomas worldwide. THRLBCL is distinguished from the other DLBCL subtypes by the predominance of non-malignant T-cell lymphocytes and histiocytes over malignant B-cells in its tumors and tissue infiltrates.
Primary testicular diffuse large B-cell lymphoma (PT-DLBCL), also termed testicular diffuse large B-cell lymphoma and diffuse large B-cell lymphoma of the testes, is a variant of the diffuse large B-cell lymphomas (DLBCL). DLBCL are a large and diverse group of B-cell malignancies with the great majority (-85%) being typed as diffuse large B-cell lymphoma, not otherwise specified. PT-DLBCL is a variant of DLBCL, NOS that involves one or, in uncommon cases, both testicles. Other variants and subtypes of DLBCL may involve the testes by spreading to them from their primary sites of origin in other tissues. PT-DLBCL differs from these other DLBCL in that it begins in the testes and then may spread to other sites.
Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is a subtype of the Diffuse large B-cell lymphomas and a rare form of the Epstein–Barr virus-associated lymphoproliferative diseases, i.e. conditions in which lymphocytes infected with the Epstein-Barr virus (EBV) proliferate excessively in one or more tissues. EBV infects ~95% of the world's population to cause no symptoms, minor non-specific symptoms, or infectious mononucleosis. The virus then enters a latency phase in which the infected individual becomes a lifetime asymptomatic carrier of the virus. Some weeks, months, years, or decades thereafter, a very small fraction of these carriers, particularly those with an immunodeficiency, develop any one of various EBV-associated benign or malignant diseases.
Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is an extremely rare form of the diffuse large B-cell lymphomas (DLBCL). DLBCL are lymphomas in which a particular type of lymphocyte, the B-cell, proliferates excessively, invades multiple tissues, and often causes life-threatening tissue damage. DLBCL have various forms as exemplified by one of its subtypes, diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI). DLBCL-CI is an aggressive malignancy that develops in sites of chronic inflammation that are walled off from the immune system. In this protected environment, the B-cells proliferate excessively, acquire malignant gene changes, form tumor masses, and often spread outside of the protected environment. In 2016, the World Health Organization provisionally classified FA-DLBCL as a DLBCL-CI. Similar to DLBCL-CI, FA-DLBCL involves the proliferation of EBV-infected large B-cells in restricted anatomical spaces that afford protection from an individual's immune system. However, FA-DLBCL differs from DLBCL-CI in many other ways, including, most importantly, its comparatively benign nature. Some researchers have suggested that this disease should be regarded as a non-malignant or pre-malignant lymphoproliferative disorder rather than a malignant DLBCL-CI.