Primary cutaneous diffuse large B-cell lymphoma, leg type

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Primary cutaneous diffuse large B-cell lymphoma, leg type
Other namesPCDLBCL-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]

Contents

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]

Presentation

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]

Pathophysiology

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]

Diagnosis

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]

Differential diagnosis

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]

Treatment

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]

Experimental treatments

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]

Related Research Articles

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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.

<span class="mw-page-title-main">Anaplastic large-cell lymphoma</span> Medical condition

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.

<span class="mw-page-title-main">Follicular lymphoma</span> Medical condition

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.

<span class="mw-page-title-main">MALT lymphoma</span> Medical condition

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.

<span class="mw-page-title-main">Primary effusion lymphoma</span> Medical condition

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.

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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.

<span class="mw-page-title-main">Intravascular lymphomas</span> Medical condition

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.

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<span class="mw-page-title-main">Marginal zone B-cell lymphoma</span> Group of lymphomas

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.

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<span class="mw-page-title-main">Lutzner cells</span>

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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.

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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.

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  17. ↑ "A Randomized Phase 2 Study of CDX-1127 (Varlilumab) in Combination with Nivolumab in Patients with Relapsed or Refractory Aggressive B-cell Lymphomas". 23 October 2021.
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