Primary cutaneous T cell lymphomas, rare subtypes

Author:: Rein Willemze, MD
Section Editor:: John A Zic, MD
Deputy Editor:: Rosamaria Corona, MD, DSc

Literature review current through: Jan 2024.

This topic last updated: May 18, 2022.

INTRODUCTION — The term "primary cutaneous T cell lymphoma" (CTCL) refers to T cell lymphomas that present primarily in the skin without evidence of extracutaneous disease at the time of diagnosis. The group of classical CTCLs (mycosis fungoides, variants of mycosis fungoides, and Sézary syndrome) and the group of primary cutaneous CD30⁺ lymphoproliferative disorders (anaplastic large cell lymphoma and lymphomatoid papulosis) encompass the most common forms of CTCLs, accounting for approximately 90 percent of CTCLs in the Western world [1]. However, different distributions have been observed in other parts of the world [2,3].

Other types of CTCLs recognized in the 2018 update of the World Health Organization (WHO)-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas [1] and in the 2016 revision of the WHO classification of tumors of hematopoietic and lymphoid tissue [4] include uncommon entities, such as subcutaneous panniculitis-like T cell lymphoma; extranodal natural killer/T cell lymphoma, nasal type; primary cutaneous peripheral T cell lymphoma (PTCL), not otherwise specified; and rare subtypes of PTCL [1,4].

This topic will focus on rare subtypes of primary cutaneous PTCL, which include:

●Primary cutaneous gamma-delta T cell lymphoma

●Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T cell lymphoma

●Primary cutaneous acral CD8⁺ T cell lymphoma

●Primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder

Mycosis fungoides, Sézary syndrome, primary cutaneous CD30⁺ lymphoproliferative disorders, and other uncommon types of CTCL are discussed separately.

●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

●(See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

●(See "Primary cutaneous anaplastic large cell lymphoma".)

●(See "Lymphomatoid papulosis".)

●(See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

●(See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

PRIMARY CUTANEOUS GAMMA-DELTA T CELL LYMPHOMA — Primary cutaneous gamma-delta T cell lymphoma (PCGD-TCL) is a rare lymphoma composed of a clonal proliferation of mature, activated gamma-delta T cells with a cytotoxic phenotype and characterized by rapid progression and poor prognosis [1,4]. This group includes cases previously known as subcutaneous panniculitis-like T cell lymphoma (SPTCL) with a gamma-delta phenotype.

Epidemiology — PCGD-TCL is rare, representing less than 1 percent of all cutaneous T cell lymphomas (CTCLs) and with a cumulative incidence of 0.4 per 10 million individuals [1,5]. Most patients are adults, with a median age of approximately 60 years (range 25 to 91) [6].

Pathogenesis — Studies suggest a relationship between clinicopathologic presentation and cell of origin [7]. Superficial epitheliotropic lymphomas are derived from V-delta-1 cells, the predominant gamma-delta T cell in the epidermis and dermis, while panniculitic cases arise from V-delta-2 cells, the predominant gamma-delta T cell in the fat. V-delta-2 lymphomas are associated with inflammatory gene signatures that may contribute to the development of a hemophagocytic syndrome [7].

Clinical features — PCGD-TCL usually presents with disseminated, rapidly progressing plaques and/or ulceronecrotic nodules or tumors, preferentially located on the extremities (picture 1) [8,9]. Mucosal and other extranodal sites are frequently involved, but involvement of lymph nodes, spleen, or bone marrow is uncommon. PCGD-TCL may be associated with a hemophagocytic syndrome, particularly in patients with panniculitis-like tumors [8,9]. B symptoms, including fever, night sweats, and weight loss, are seen in most patients. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Pathology

Morphology — In contrast with SPTCL, the neoplastic infiltrates of PCGD-TCL are not confined to the subcutaneous tissue but generally involve the epidermis and/or dermis as well [8-10]. Epidermal infiltration may occur as mild epidermotropism to marked pagetoid reticulosis-like infiltrates, which may be associated with intraepidermal vesiculation and necrosis. Angiocentricity, angiodestruction, and tissue necrosis are common. The neoplastic cells are generally medium to large in size with coarsely clumped chromatin (picture 2).

Immunophenotype — The neoplastic cells of PCGD-TCL characteristically have a T cell receptor (TCR)-gamma/delta⁺, beta-F1^-, CD3⁺, CD2⁺, CD5^-, CD4^-, CD8^-, CD56⁺ phenotype with strong expression of cytotoxic proteins (picture 3) [8,9,11,12]. CD30 may be expressed by a subset of patients [13]. Coexpression of TCR-gamma/delta and beta-F1 has been reported in some cases [14]. Epstein-Barr virus is negative.

Genetics — Most cases of PCGD-TCL show clonally rearranged TCR-gamma and TCR-delta genes. No other genetic features have been reported.

Diagnosis — The diagnosis of PCGD-TCL requires the integration of clinical, histologic, phenotypic, and molecular genetic data. Deep punch biopsies (≥4 mm) or incisional biopsies can be performed for routine histopathology, immunophenotyping, and molecular analysis. A new commercially available TCR-delta antibody has been extremely helpful in differentiating between PCGD-TCL and other aggressive primary CTCLs with a cytotoxic T cell phenotype [15]. However, it should be noted that TCR-gamma/delta expression is found not only in PCGD-TCL but also in other types of CTCLs, including rare cases of otherwise classical mycosis fungoides (MF) and lymphomatoid papulosis type D [14,16,17].

Differential diagnosis — The differential diagnosis of PCGD-TCL includes SPTCL and MF.

Subcutaneous panniculitis-like T cell lymphoma — Both PCGD-TCL and SPTCL may present on histopathologic examination as nodular lesions with panniculitis-like features with rimming of fat cells (picture 4A-B). In contrast to SPTCL, PCGD-TCL commonly involves not only the subcutis but also the dermis and/or epidermis, either in the same biopsy or in different biopsies of lesional skin, and may show ulceration.

While SPTCL has an alpha-beta T cell phenotype, PCGD-TCL has a gamma-delta T cell phenotype, is generally negative for both CD4 and CD8, and commonly expresses CD56 (table 1). The differentiation of these two entities is important, since PCGD-TCL with panniculitis-like features generally has a poor prognosis and requires systemic combination chemotherapy [8,9]. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

Mycosis fungoides — The histopathologic differentiation of PCGD-TCL from tumor-stage MF and, uncommonly, plaque-stage MF may be difficult. Clinicopathologic correlation is essential. While the neoplastic T cells in MF have TCR-gamma/delta^-, beta-F1⁺, CD4⁺, or, less commonly, a CD8⁺ T cell phenotype, the T cells in PCGD-TCL have a TCR-gamma/delta⁺, beta-F1^-, CD4^-, CD8^- T cell phenotype. However, rare cases of otherwise classical MF expressing TCR-gamma have been reported [14,16]. Documentation of previous or concurrent presence of patch or plaque-like lesions strongly suggests a diagnosis of MF. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Treatment and prognosis — Because of its rarity, there are no randomized trials addressing the treatment of PCGD-TCL. These patients should be treated with combination chemotherapy using the regimens suggested for peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). Pretreatment evaluation, initial treatment, and treatment of PTCL, NOS are presented elsewhere. (See "Initial treatment of peripheral T cell lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma".)

PCGD-TCL usually has an aggressive clinical course, is resistant to multiagent chemotherapy, and has a poor prognosis, with a median survival of approximately 15 months [8,9]. Patients with subcutaneous fat involvement tend to have a poorer prognosis than patients with epidermal or dermal disease only [9,10]. Rare cases of PCGD-TCL following a more indolent clinical course have been reported [6,18,19].

PRIMARY CUTANEOUS CD8+ AGGRESSIVE EPIDERMOTROPIC CYTOTOXIC T CELL LYMPHOMA — Primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T cell lymphoma (AECTCL) is a rare cutaneous lymphoma characterized by a proliferation of epidermotropic CD8⁺ cytotoxic T cells, an aggressive clinical behavior, and poor prognosis [20]. CD8⁺ AECTCL is included as a provisional entity in the 2018 update of the World Health Organization (WHO)-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas and in the 2016 revision of the WHO classification of hematopoietic neoplasms [1,4].

Epidemiology — CD8⁺ AECTCL is rare, representing less than 1 percent of all cutaneous T cell lymphomas (CTCL) [1]. Most patients are adults.

Clinical features — Patients with CD8⁺ AECTCL present with localized or disseminated eruptive papules, nodules, and tumors showing central ulceration and necrosis (picture 5) or with superficial, hyperkeratotic patches and plaques [20-22]. CD8⁺ AECTCL progresses rapidly over weeks to months and shows a propensity to disseminate to visceral sites such as the lung, testis, central nervous system, and oral mucosa, but lymph nodes are often spared [20,22]. Some patients may have a prodrome of chronic patches prior to the development of aggressive ulcerative lesions [23].

Pathology

Morphology — The histopathologic appearance of CD8⁺ AECTCL is variable, ranging from a lichenoid pattern with marked, pagetoid epidermotropism and subepidermal edema in early patch-like lesions to diffuse dermal infiltrates in nodular and tumor-like lesions (picture 6). Epidermal necrosis and ulceration as well as invasion and destruction of adnexal skin structures are commonly found [20-22,24]. Angiocentricity and angioinvasion may be present. Tumor cells are small-medium or medium-large with pleomorphic or blastic nuclei.

Immunophenotype — The neoplastic T cells of CD8⁺ AECTCL have a beta-F1⁺, CD3⁺, CD8⁺, granzyme B⁺, perforin⁺, TIA-1⁺, CD45RA^+/-, CD45RO^-, CD2^-/+, CD4^-, CD5^-, CD7^+/- phenotype (picture 7) [20-22]. CD30 is rarely expressed [22,25]. Epstein-Barr virus is negative [22,26].

Genetics — The neoplastic T cells of CD8⁺ AECTCL show clonal T cell receptor gene rearrangements. Overactivation of Janus kinase 2 (JAK2) signaling is common, which makes AECTCL susceptible to JAK2 inhibitors [27,28].

Diagnosis — The diagnosis of CD8⁺ AECTCL is based upon the combination of the clinical, histopathologic, and immunophenotypic findings described above. Deep punch biopsies (≥4 mm) or incisional biopsies can be performed for routine histopathology, immunophenotyping, and molecular analysis. Since several types of primary CTCLs express a CD8⁺ cytotoxic T cell phenotype (table 2), a careful clinicopathologic correlation is key to the correct diagnosis [25,29].

Differential diagnosis — The differential diagnosis of CD8⁺ AECTCL includes several subtypes of CTCL that show infiltration of CD8⁺ neoplastic T cells (table 2).

Lymphomatoid papulosis — Lymphomatoid papulosis (LyP) type D is a newly described histologic subtype of LyP that shows the same histologic and immunophenotypic characteristics as CD8⁺ AECTCL [30]. However, in contrast with CD8⁺ AECTCL, LyP type D has a clinical indolent behavior characterized by the recurrence of self-healing papulonecrotic lesions limited to the skin, without involvement of extracutaneous sites. (See "Lymphomatoid papulosis".)

Primary cutaneous anaplastic large cell lymphoma — Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) usually shows a CD4⁺ CD30⁺ T cell phenotype, but in rare instances it may express CD8 [31]. In contrast with CD8⁺ AECTCL, which in most cases presents with multiple disseminated lesions, PC-ALCL usually presents with a solitary or a few clustered skin lesions. Rare cases of CTCL showing coexpression of CD8 and CD30 most likely belong to the spectrum of primary cutaneous CD30⁺ lymphoproliferative disorders, although CD8⁺ AECTCL may occasionally also express CD30 [22,25]. (See "Primary cutaneous anaplastic large cell lymphoma".)

Mycosis fungoides — Early lesions of CD8⁺ AECTCL should be differentiated from patch- or plaque-stage mycosis fungoides (MF). Although in most cases MF has a CD4⁺, CD8^- T cell phenotype, approximately 15 percent of cases of early-patch/plaque-stage MF show a CD4^-, CD8⁺ T cell phenotype with strong expression of cytotoxic proteins [32]. Differentiating CD8⁺ AECTCL from rare cases of CD8⁺ tumor-stage MF, which may also present with ulcerating tumors, is much more difficult. Clinical and histopathologic documentation of previous or concurrent patch or plaque lesions is essential for a correct diagnosis. Strong expression of CD30 in such cases argues against a diagnosis of CD8⁺ AECTCL [25]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Pagetoid reticulosis — On histology, early lesions of CD8⁺ AECTCL that show marked pagetoid epidermotropism of neoplastic CD8⁺ cytotoxic T cells may closely resemble pagetoid reticulosis, a rare variant of MF characterized by intraepidermal proliferation of neoplastic T cells. Pagetoid reticulosis typically presents with a solitary, slowly progressive, psoriasiform or hyperkeratotic patch or plaque or with a solitary, hyperkeratotic, wart-like lesion at the distal extremities. Unlike CD8⁺ AECTCL, the neoplastic T cells in pagetoid reticulosis may have either a CD4⁺, CD8^- or a CD4^-, CD8⁺ T cell phenotype and often express CD30 [33,34].

Subcutaneous panniculitis-like T cell lymphoma — Subcutaneous panniculitis-like T cell lymphoma (SPTCL) presents with nodular skin lesions most often located on the legs. The neoplastic T cells express CD8 and the cytotoxic proteins TIA-1, granzyme B, and perforin. However, in contrast with CD8⁺ AECTCL, the infiltrates of SPTCL are restricted to the subcutis, and epidermotropism is absent [8]. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

Primary cutaneous acral CD8+ T cell lymphoma — The main differences between primary cutaneous acral CD8⁺ T cell lymphoma and tumor-like lesions of CD8⁺ AECTCL include the presence of a solitary lesion at acral sites (particularly the ears), an indolent clinical behavior, lack of epidermotropism, negative staining for granzyme B, and low proliferation rate. (See 'Primary cutaneous acral CD8+ T cell lymphoma' below.)

Treatment and prognosis — Because of its rarity, there are no randomized trials addressing the treatment of CD8⁺ AECTCL. Patients are usually treated with combination chemotherapy, using the regimens for peripheral T cell lymphoma (PTCL), not otherwise specified. Pretreatment evaluation, initial treatment, and treatment of relapsed or refractory PTCL are presented elsewhere. Complete and durable remissions after allogeneic stem cell transplantation have been reported in selected cases [23,35,36]. (See "Initial treatment of peripheral T cell lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma".)

The clinical course of CD8⁺ AECTCL is aggressive, and the response to chemotherapy is often disappointing. The reported median survival is less than two years [20-23].

PRIMARY CUTANEOUS ACRAL CD8+ T CELL LYMPHOMA — Primary cutaneous acral CD8⁺ T cell lymphoma is a newly described entity histologically characterized by a diffuse infiltrate of medium-sized CD8⁺ cytotoxic T cells suggesting a high-grade malignant lymphoma and an indolent clinical behavior [37]. This condition, initially designated "indolent CD8-positive lymphoid proliferation of the ear," has been included as a provisional entity in the 2018 update of the World Health Organization (WHO)-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas and in the 2016 revision of the WHO classification [1,4].

Epidemiology — Primary cutaneous acral CD8⁺ T cell lymphoma is rare. It has been reported only in adults and shows a male predominance.

Clinical features — Patients with primary cutaneous acral CD8⁺ T cell lymphoma typically present with a solitary, slowly progressive papule or nodule, most commonly located on the ear (picture 8). Similar lesions may occur at other acral sites including the nose and the foot [37-41]. In rare cases, both ears or feet may be affected [37,40-43]. One report describes a patient with recurrent and multifocal lesions on several acral sites [41].

Pathology

Morphology — The lesions of primary cutaneous acral CD8⁺ T cell lymphoma show a diffuse proliferation of monomorphous, medium-sized blast cells throughout the dermis and subcutis, separated from the epidermis by a clear grenz zone (picture 9) [37].

Immunophenotype — The tumor cells have a CD3⁺, CD4^-, CD8⁺, TIA-1⁺, granzyme B^-, CD30^- T cell phenotype (picture 9) [37,40]. CD68 often shows a positive Golgi dot-like staining [43]. Loss of pan-T cell antigens (CD2, CD5, CD7) may occur. In almost all cases, the proliferation rate is very low (<10 percent). Epstein-Barr virus is negative.

Genetics — The neoplastic T cells of primary cutaneous acral CD8⁺ T cell lymphoma show clonal T cell receptor gene rearrangements. Specific genetic abnormalities have not been described.

Diagnosis — The diagnosis of primary cutaneous acral CD8⁺ T cell lymphoma is based upon the finding of a solitary, slowly growing papule or nodule on the ear or other acral site that demonstrates on histopathologic examination a diffuse proliferation of monomorphous CD8⁺ medium-sized blast cells. An excisional biopsy can be performed for lesions that are small (<2 cm) and well demarcated. For larger lesions, deep punch biopsies (≥4 mm) or incisional biopsies are appropriate for diagnosis. In contrast with aggressive CD8⁺ primary cutaneous T cell lymphoma, the proliferation rate is typically low.

Differential diagnosis — The differential diagnosis of primary cutaneous acral CD8⁺ T cell lymphoma includes benign and malignant lesions that may also present with a solitary papule or nodule on the ears, nose, or other acral sites. These include, among others, primary cutaneous follicle center lymphoma, folliculotropic mycosis fungoides, and, in particular, cutaneous B cell pseudolymphomas (picture 10). However, the demonstration of a diffuse proliferation of CD8⁺ T cells on histopathologic examination suggests the correct diagnosis. (See "Cutaneous B cell pseudolymphoma".)

Treatment and prognosis — Surgical excision or radiotherapy usually results in complete remission. Relapses may occur and are often localized at the same acral site [40]. However, dissemination to extracutaneous sites is exceptional [44]. The recognition that these lesions have an indolent clinical behavior, despite an aggressive histology, is important to prevent unnecessarily aggressive treatment. The prognosis of primary cutaneous acral CD8⁺ T cell lymphoma is excellent, and in typical cases, staging is not recommended [37,40].

PRIMARY CUTANEOUS CD4+ SMALL/MEDIUM T CELL LYMPHOPROLIFERATIVE DISORDER — In the 2018 update of the World Health Organization (WHO)-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas and in the 2016 revision of the WHO classification, primary cutaneous CD4⁺ small/medium T cell lymphoma was included as a provisional type of primary cutaneous T cell lymphoma (CTCL), defined by a predominance of small- to medium-sized CD4⁺ pleomorphic T cells without prior or concurrent patches and plaques typical of mycosis fungoides (MF) [1,4]. It has been recognized that cases presenting with a solitary plaque or tumor have the same clinicopathologic and immunophenotypic features and the same benign clinical course as cutaneous T cell pseudolymphomas with a nodular growth pattern [45-47] (see "Cutaneous T cell pseudolymphomas", section on 'Idiopathic (solitary) T cell pseudolymphoma'). In the 2018 update of the WHO-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas and in the 2016 revision of the WHO classification, the term "primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder" is, therefore, preferred [1,4].

Epidemiology — Primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder is increasingly recognized and is more common than the other rare subtypes of PTCL, accounting for 6 percent of all CTCL [1].

Clinical features — Most patients with primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder typically present with a solitary plaque or tumor, generally on the face, the neck, or the upper trunk (picture 11) [45,46,48-51]. Generalized skin lesions are a much less common presentation [45,46].

Rare cases presenting with generalized skin lesions and large, rapidly growing tumors showing on histopathology more than 30 percent large pleomorphic T cells and/or a high proliferative fraction do not belong to this group [48,49]. Such cases usually have a more aggressive clinical behavior and should be classified as peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified".)

Pathologic features

Morphology — On histopathologic examination, primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder is identical to idiopathic (solitary) T cell pseudolymphoma with a nodular growth pattern (picture 12) [45-47]. (See "Cutaneous T cell pseudolymphomas", section on 'Idiopathic (solitary) T cell pseudolymphoma'.)

These lesions show dense, nodular to diffuse infiltrates within the dermis, with a tendency to infiltrate the subcutis. There is a predominance of small-/medium-sized pleomorphic T cells; epidermotropism is generally mild or absent [45,46,48-50]. A small proportion (<30 percent) of large pleomorphic cells may be present [26]. In almost all cases, there is a considerable admixture with small reactive CD8⁺ T cells, B cells, plasma cells, and histiocytes, including multinucleated giant cells [45,46,50]. Eosinophils are generally few or absent.

Immunophenotype — By definition, primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder has a CD3⁺, CD4⁺, CD8^-, CD30^- phenotype, similar to idiopathic T cell pseudolymphoma (nodular/diffuse type). Loss of pan-T cell markers is uncommon, and cytotoxic proteins are not expressed [45,46,48,50]. Several studies showed that the medium-sized to large atypical CD4⁺ T cells consistently express the follicular helper T cell markers PD-1, BCL6, and CXCL13 but (unlike angioimmunoblastic T cell lymphoma) not CD10 (picture 13) [46,50]. The proliferation rate is low, varying between less than 5 percent and at most 20 percent. In some cases with plasma cells showing monotypic immunoglobulin light chain expression, differentiation from primary marginal zone lymphomas may be difficult [52]. Epstein-Barr virus is negative.

Genetics — Clonal T cell receptor gene rearrangements are detected in most cases [46,50]. Specific genetic abnormalities have not been described.

Diagnosis — The diagnosis of primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder is based upon the clinical finding of a solitary plaque or nodule on the face or trunk that demonstrates the histopathologic and immunophenotypic features described above. An excisional biopsy can be performed for lesions that are small (<2 cm) and well demarcated. For larger lesions, deep punch biopsies (≥4 mm) or incisional biopsies are appropriate for diagnosis. A careful clinicopathologic correlation is necessary for a correct diagnosis.

Differential diagnosis — The differential diagnosis of primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder includes tumor stage MF and primary cutaneous PTCL, NOS.

Presentation with a solitary skin lesion; the presence of scattered, medium-sized to large CD4⁺ T cells expressing PD-1; many admixed B cells, CD8⁺ T cells, and histiocytes; and the low proliferation rate are useful criteria to differentiate this condition from MF and primary cutaneous PTCL, NOS [46,53]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Morphology' and "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified", section on 'Pathology'.)

Treatment and prognosis — Primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder lesions may resolve spontaneously after skin biopsy [46,50]. Persistent lesions can be treated with intralesional steroids, surgical excision, or, in rare instances, with radiotherapy [45,46,48].

Local recurrences after initial treatment are rarely observed. Patients have an excellent long-term prognosis and do not require further examinations or staging [45,46,48].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Definition – Primary cutaneous T cell lymphomas, rare subtypes, are a heterogeneous group of extremely rare T cell lymphomas that present primarily in the skin without evidence of extracutaneous involvement. A careful clinicopathologic correlation is the key to a correct diagnosis. (See 'Introduction' above.)

●Primary cutaneous gamma-delta T cell lymphoma – Primary cutaneous gamma-delta T cell lymphoma (PCGD-TCL) is a rare lymphoma composed of a clonal proliferation of mature, activated gamma-delta T cells with a cytotoxic phenotype. It presents with disseminated plaques and/or ulceronecrotic nodules or tumors preferentially located on the extremities (picture 1). The neoplastic cells of PCGD-TCL characteristically have a T cell receptor-gamma/delta⁺, beta-F1^-, CD3⁺, CD2⁺, CD5^-, CD4^-, CD8^-, CD56⁺ phenotype with strong expression of cytotoxic proteins (picture 3). PCGD-TCL has usually an aggressive clinical course, is resistant to multiagent chemotherapy, and has a poor prognosis. (See 'Primary cutaneous gamma-delta T cell lymphoma' above.)

●Primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T cell lymphoma – Primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T cell lymphoma (AECTCL) is a rare cutaneous lymphoma characterized by a proliferation of epidermotropic CD8⁺ cytotoxic T cells, an aggressive clinical behavior, and poor prognosis. It typically presents with localized or disseminated eruptive papules, nodules, and tumors showing central ulceration and necrosis (picture 5). The neoplastic T cells show a beta-F1⁺, CD3⁺, CD8⁺, granzyme B⁺, perforin⁺, TIA-1⁺, CD45RA^+/-, CD45RO^-, CD2^-/+, CD4^-, CD5^-, CD7^+/- phenotype (picture 7). The clinical course is aggressive, and the response to chemotherapy is often disappointing. (See 'Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma' above.)

●Primary cutaneous acral CD8⁺ T cell lymphoma – Primary cutaneous acral CD8⁺ T cell lymphoma is a newly described entity histologically characterized by a diffuse infiltrate of medium-sized CD8⁺ cytotoxic T cells suggesting a high-grade malignant lymphoma and an indolent clinical behavior. The tumor cells have a CD3⁺, CD4^-, CD8⁺, TIA-1⁺, granzyme B^-, CD30^- T cell phenotype (picture 9). Surgical excision or radiotherapy usually result in complete remission. (See 'Primary cutaneous acral CD8+ T cell lymphoma' above.)

●Primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder – Primary cutaneous CD4⁺ small/medium T cell lymphoproliferative disorder is included as a provisional entity in the 2018 update of the World Health Organization (WHO)-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas and in the 2016 revision of the WHO classification of tumors of hematopoietic and lymphoid tissue. It includes or is a new term for:

•Primary cutaneous CD4⁺ small/medium T cell lymphoma – Presents with a solitary lesion (from the 2005 WHO-European Organization for Research and Treatment of Cancer and 2008 WHO classifications).

•Idiopathic cutaneous T cell pseudolymphoma with a nodular growth pattern – Presents with a solitary plaque or tumor, generally on the face, the neck, or the upper trunk (picture 11). It is histologically characterized by a predominance of small to medium-sized CD3⁺, CD4⁺, and CD8^- T cells; the presence of scattered, large CD3⁺, CD4⁺, PD-1⁺ T cells; and an abundant inflammatory infiltrate of small reactive CD8⁺ T cells, B cells, and histiocytes.

Lesions may resolve spontaneously. Persistent lesions can be treated with intralesional corticosteroids or surgical excision. (See 'Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder' above.)

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Agnarsson BA, Vonderheid EC, Kadin ME. Cutaneous T cell lymphoma with suppressor/cytotoxic (CD8) phenotype: identification of rapidly progressive and chronic subtypes. J Am Acad Dermatol 1990; 22:569.
Quintanilla-Martinez L, Jansen PM, Kinney MC, et al. Non-mycosis fungoides cutaneous T-cell lymphomas: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop. Am J Clin Pathol 2013; 139:491.
Bekkenk MW, Vermeer MH, Jansen PM, et al. Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood 2003; 102:2213.
Bastidas Torres AN, Cats D, Out-Luiting JJ, et al. Deregulation of JAK2 signaling underlies primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. Haematologica 2022; 107:702.
Lee K, Evans MG, Yang L, et al. Primary cytotoxic T-cell lymphomas harbor recurrent targetable alterations in the JAK-STAT pathway. Blood 2021; 138:2435.
Willemze R. CD30-Negative Cutaneous T-Cell Lymphomas Other than Mycosis Fungoides. Surg Pathol Clin 2014; 7:229.
Saggini A, Gulia A, Argenyi Z, et al. A variant of lymphomatoid papulosis simulating primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Description of 9 cases. Am J Surg Pathol 2010; 34:1168.
Bekkenk MW, Geelen FA, van Voorst Vader PC, et al. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 2000; 95:3653.
Massone C, Crisman G, Kerl H, Cerroni L. The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality. Br J Dermatol 2008; 159:881.
Haghighi B, Smoller BR, LeBoit PE, et al. Pagetoid reticulosis (Woringer-Kolopp disease): an immunophenotypic, molecular, and clinicopathologic study. Mod Pathol 2000; 13:502.
Mourtzinos N, Puri PK, Wang G, Liu ML. CD4/CD8 double negative pagetoid reticulosis: a case report and literature review. J Cutan Pathol 2010; 37:491.
Plachouri KM, Weishaupt C, Metze D, et al. Complete durable remission of a fulminant primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma after autologous and allogeneic hematopoietic stem cell transplantation. JAAD Case Rep 2017; 3:196.
Cyrenne BM, Gibson JF, Subtil A, et al. Transplantation in the Treatment of Primary Cutaneous Aggressive Epidermotropic Cytotoxic CD8-Positive T-Cell Lymphoma. Clin Lymphoma Myeloma Leuk 2018; 18:e85.
Petrella T, Maubec E, Cornillet-Lefebvre P, et al. Indolent CD8-positive lymphoid proliferation of the ear: a distinct primary cutaneous T-cell lymphoma? Am J Surg Pathol 2007; 31:1887.
Swick BL, Baum CL, Venkat AP, Liu V. Indolent CD8+ lymphoid proliferation of the ear: report of two cases and review of the literature. J Cutan Pathol 2011; 38:209.
Li JY, Guitart J, Pulitzer MP, et al. Multicenter case series of indolent small/medium-sized CD8+ lymphoid proliferations with predilection for the ear and face. Am J Dermatopathol 2014; 36:402.
Greenblatt D, Ally M, Child F, et al. Indolent CD8(+) lymphoid proliferation of acral sites: a clinicopathologic study of six patients with some atypical features. J Cutan Pathol 2013; 40:248.
Kluk J, Kai A, Koch D, et al. Indolent CD8-positive lymphoid proliferation of acral sites: three further cases of a rare entity and an update on a unique patient. J Cutan Pathol 2016; 43:125.
Beltraminelli H, Müllegger R, Cerroni L. Indolent CD8+ lymphoid proliferation of the ear: a phenotypic variant of the small-medium pleomorphic cutaneous T-cell lymphoma? J Cutan Pathol 2010; 37:81.
Wobser M, Roth S, Reinartz T, et al. CD68 expression is a discriminative feature of indolent cutaneous CD8-positive lymphoid proliferation and distinguishes this lymphoma subtype from other CD8-positive cutaneous lymphomas. Br J Dermatol 2015; 172:1573.
Alberti-Violetti S, Fanoni D, Provasi M, et al. Primary cutaneous acral CD8 positive T-cell lymphoma with extra-cutaneous involvement: A long-standing case with an unexpected progression. J Cutan Pathol 2017; 44:964.
Beltraminelli H, Leinweber B, Kerl H, Cerroni L. Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases. Am J Dermatopathol 2009; 31:317.
Cetinözman F, Jansen PM, Willemze R. Expression of programmed death-1 in primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma, cutaneous pseudo-T-cell lymphoma, and other types of cutaneous T-cell lymphoma. Am J Surg Pathol 2012; 36:109.
Rijlaarsdam JU, Scheffer E, Meijer CJ, Willemze R. Cutaneous pseudo-T-cell lymphomas. A clinicopathologic study of 20 patients. Cancer 1992; 69:717.
Grogg KL, Jung S, Erickson LA, et al. Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma: a clonal T-cell lymphoproliferative disorder with indolent behavior. Mod Pathol 2008; 21:708.
Garcia-Herrera A, Colomo L, Camós M, et al. Primary cutaneous small/medium CD4+ T-cell lymphomas: a heterogeneous group of tumors with different clinicopathologic features and outcome. J Clin Oncol 2008; 26:3364.
Rodríguez Pinilla SM, Roncador G, Rodríguez-Peralto JL, et al. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers. Am J Surg Pathol 2009; 33:81.
James E, Sokhn JG, Gibson JF, et al. CD4 + primary cutaneous small/medium-sized pleomorphic T-cell lymphoma: a retrospective case series and review of literature. Leuk Lymphoma 2015; 56:951.
Bakr F, Wain EM, Barlow R, Robson A. Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder or Primary Cutaneous Marginal Zone B-Cell Lymphoma? Two Distinct Entities With Overlapping Histopathological Features. Am J Dermatopathol 2021; 43:e204.
Bakels V, van Oostveen JW, van der Putte SC, et al. Immunophenotyping and gene rearrangement analysis provide additional criteria to differentiate between cutaneous T-cell lymphomas and pseudo-T-cell lymphomas. Am J Pathol 1997; 150:1941.

Topic 103306 Version 10.0

References

1 : The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.

2 : Cutaneous lymphomas other than mycosis fungoides in Singapore: a clinicopathological analysis using recent classification systems.

3 : World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous lymphoma in Korea: a retrospective study at a single tertiary institution.

4 : The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

5 : Epidemiology of primary cutaneousγδT-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma in the U.S.A. from 2006 to 2015: a Surveillance, Epidemiology, and End Results-18 analysis.

6 : CutaneousγδT-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas.

7 : Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas.

8 : Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases.

9 : Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma.

10 : Primary Cutaneous T-Cell Lymphomas Showing Gamma-Delta (γδ) Phenotype and Predominantly Epidermotropic Pattern are Clinicopathologically Distinct From Classic Primary CutaneousγδT-Cell Lymphomas.

11 : Cytotoxic T-cell and NK-cell lymphomas: current questions and controversies.

12 : NonhepatosplenicγδT-cell lymphomas represent a spectrum of aggressive cytotoxic T-cell lymphomas with a mainly extranodal presentation.

13 : Primary cutaneousγδT-cell lymphoma with unusual immunophenotype: A case report and review of published work.

14 : TCR-γexpression in primary cutaneous T-cell lymphomas.

15 : T-cell receptor-δexpression andγδ+ T-cell infiltrates in primary cutaneousγδT-cell lymphoma and other cutaneous T-cell lymphoproliferative disorders.

16 : Mycosis fungoides expressing gamma/delta T-cell receptors.

17 : γδlymphomatoid papulosis type D: A histologic mimic of primary cutaneousγδT-cell lymphoma.

18 : Indolent primary cutaneousγ/δT-cell lymphoma localized to the subcutaneous panniculus and its association with atypical lymphocytic lobular panniculitis.

19 : Indolent course of cutaneous gamma-delta T-cell lymphoma.

20 : Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior.

21 : Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop.

22 : Aggressive epidermotropic cutaneous CD8+ lymphoma: a cutaneous lymphoma with distinct clinical and pathological features. Report of an EORTC Cutaneous Lymphoma Task Force Workshop.

23 : Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas.

24 : Cutaneous T cell lymphoma with suppressor/cytotoxic (CD8) phenotype: identification of rapidly progressive and chronic subtypes.

25 : Non-mycosis fungoides cutaneous T-cell lymphomas: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop.

26 : Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients.

27 : Deregulation of JAK2 signaling underlies primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma.

28 : Primary cytotoxic T-cell lymphomas harbor recurrent targetable alterations in the JAK-STAT pathway.

29 : CD30-Negative Cutaneous T-Cell Lymphomas Other than Mycosis Fungoides.

30 : A variant of lymphomatoid papulosis simulating primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Description of 9 cases.

31 : Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.

32 : The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality.

33 : Pagetoid reticulosis (Woringer-Kolopp disease): an immunophenotypic, molecular, and clinicopathologic study.

34 : CD4/CD8 double negative pagetoid reticulosis: a case report and literature review.

35 : Complete durable remission of a fulminant primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma after autologous and allogeneic hematopoietic stem cell transplantation.

36 : Transplantation in the Treatment of Primary Cutaneous Aggressive Epidermotropic Cytotoxic CD8-Positive T-Cell Lymphoma.

37 : Indolent CD8-positive lymphoid proliferation of the ear: a distinct primary cutaneous T-cell lymphoma?

38 : Indolent CD8+ lymphoid proliferation of the ear: report of two cases and review of the literature.

39 : Multicenter case series of indolent small/medium-sized CD8+ lymphoid proliferations with predilection for the ear and face.

40 : Indolent CD8(+) lymphoid proliferation of acral sites: a clinicopathologic study of six patients with some atypical features.

41 : Indolent CD8-positive lymphoid proliferation of acral sites: three further cases of a rare entity and an update on a unique patient.

42 : Indolent CD8+ lymphoid proliferation of the ear: a phenotypic variant of the small-medium pleomorphic cutaneous T-cell lymphoma?

43 : CD68 expression is a discriminative feature of indolent cutaneous CD8-positive lymphoid proliferation and distinguishes this lymphoma subtype from other CD8-positive cutaneous lymphomas.

44 : Primary cutaneous acral CD8 positive T-cell lymphoma with extra-cutaneous involvement: A long-standing case with an unexpected progression.

45 : Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases.

46 : Expression of programmed death-1 in primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma, cutaneous pseudo-T-cell lymphoma, and other types of cutaneous T-cell lymphoma.

47 : Cutaneous pseudo-T-cell lymphomas. A clinicopathologic study of 20 patients.

48 : Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma: a clonal T-cell lymphoproliferative disorder with indolent behavior.

49 : Primary cutaneous small/medium CD4+ T-cell lymphomas: a heterogeneous group of tumors with different clinicopathologic features and outcome.

50 : Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers.

51 : CD4 + primary cutaneous small/medium-sized pleomorphic T-cell lymphoma: a retrospective case series and review of literature.

52 : Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder or Primary Cutaneous Marginal Zone B-Cell Lymphoma? Two Distinct Entities With Overlapping Histopathological Features.

53 : Immunophenotyping and gene rearrangement analysis provide additional criteria to differentiate between cutaneous T-cell lymphomas and pseudo-T-cell lymphomas.

خرید پکیج

Primary cutaneous T cell lymphomas, rare subtypes

References