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Lymphoma & related disorders

Mature T/NK cell disorders

Cutaneous / soft tissue involvement

Primary cutaneous gamma delta


Editor-in-Chief: Debra L. Zynger, M.D.
Robert E. LeBlanc, M.D.

Last author update: 1 April 2018
Last staff update: 8 March 2023 (update in progress)

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PubMed search: Primary cutaneous gamma delta T cell lymphoma


Robert E. LeBlanc, M.D.
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Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Clinical images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: LeBlanc R. Primary cutaneous gamma delta. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBcutangammadelta.html. Accessed March 25th, 2023.
Definition / general
  • Peripheral T cell lymphoma derived from mature, postthymic cytotoxic γδ (gamma delta) T cells
  • Most have an aggressive clinical course with poor overall survival; these cases tend to involve the dermis and subcutis, similar to subcutaneous panniculitis-like T cell lymphoma
  • Subset shows a prolonged indolent phase before progressing to aggressive disease; a smaller subset shows indolent behavior with reports of self resolving lesions
  • Cases at ends of this disease spectrum exhibit significant clinical, histologic and immunophenotypic overlap with mycosis fungoides and extranodal NK / T cell lymphoma, nasal type
Essential features
  • Aggressive peripheral γδ T cell lymphoma that can present as patches, plaques and nodules with frequent mucosal and extracutaneous dissemination and risk of hemophagocytic lymphohistiocytosis
  • Epidermotropism, dermal infiltration and panniculitis-like subcutaneous involvement in variable proportions; cases at ends of the spectrum mimic mycosis fungoides and subcutaneous panniculitis-like T cell lymphoma
  • Some cases show a prolonged, indolent phase or spontaneous resolution of lesions before progression; however, there are rare reports of cases that remain indolent with clinical behavior more suggestive of mycosis fungoides, lymphomatoid papulosis and subcutaneous panniculitis-like T cell lymphoma
ICD coding
  • C84.A: cutaneous T cell lymphoma, unspecified
    • C84.A9: cutaneous T cell lymphoma, unspecified, extranodal and solid organ sites
Epidemiology
Sites
  • Buttocks, thighs and legs most often involved
  • Can arise in any part of the body
Etiology
  • Etiology of this rare disease is not well understood
  • Some cases seem to evolve in the setting of precursor T cell dyscracias with prolonged indolent phases reminiscent of mycosis fungoides or inflammatory panniculitides preceding clinical progression of disease (J Cutan Pathol 2008;35:1063, Am J Clin Pathol 2012;138:50)
Clinical features
  • Patches, plaques and subcutaneous nodules
  • Nodules are red to violaceous and can ulcerate
  • Mucosal involvement, salivary gland involvement and neurotropism well documented
  • Involvement of lymph nodes, bone marrow and spleen is rare
  • Patients often develop fever, night sweats, weight loss, lymphadenopathy and splenomegaly which can sometimes suggest a diagnosis of autoimmune panniculitis (Clin Rheumatol 2013;32:1169)
  • Subset of patients has an antecedent autoimmune disease (Am J Surg Pathol 2012;36:1656)
  • High risk of hemophagocytic lymphohistiocytosis relative to subcutaneous panniculitis-like T cell lymphoma
  • Poor median survival of 15 months (J Dtsch Dermatol Ges 2009;7:1065); 5 year overall survival is 11% - 33%, as compared with 82% in subcutaneous panniculitis-like T cell lymphoma (Blood 2008;111:838, Blood 2003;101:3407, Am J Surg Pathol 2012;36:1656)
  • Some cases begin with a prolonged, indolent or waxing and waning course
Diagnosis
  • Requires strong clinical and pathologic correlation to exclude skin involvement by an extracutaneous γδ T cell lymphoma and to help exclude mycosis fungoides
  • Multiple biopsies may help in establishing the diagnosis because histomorphologic findings can change with progression from an indolent to aggressive phenotype and synchronous lesions can appear histologically heterogeneous
Laboratory
  • Hemophagocytic Lymphohistiocytosis Study Group 2004 diagnostic criteria for hemophagocytic lymphohistiocytosis
    • Fever
    • Splenomegaly
    • Cytopenias affecting ≥ 2 lineages
    • Hypertriglyceridemia or hypofibrinogenemia
    • Low or absent NK cell activity
    • Ferritin ≥ 500 µg/L
    • Soluble CD25 ≥ 2,400 U/mL
    • Evidence of hemophagocytosis in the bone marrow, spleen or lymph node
  • 5 of the criteria are necessary to establish the diagnosis in the absence of a hemophagocytic lymphohistiocytosis causing mutation (Pediatr Blood Cancer 2007;48:124)
Prognostic factors
  • Epidermotropic cases that begin with a patch stage reminiscent of mycosis fungoides can demonstrate an indolent course relative to those that present with plaques and nodules; however, some of these cases progress to an aggressive phenotype (Am J Surg Pathol 2017;41:204)
  • While most cases follow an aggressive course, there are no histologic features to entirely predict which rare patients will experience a completely indolent course
  • There are also no features to predict which patients are at risk of developing hemophagocytic lymphohistiocytosis, although overall survival is equally unfavorable for patients who do not develop the sequela (Blood 2008;111:838)
Case reports
Treatment
Clinical images

Images hosted on other servers:

Multiple erythematous tumors

Dermatologic and histologic features

Microscopic (histologic) description
  • Can show epidermotropism, diffuse dermal involvement and involvement of subcutis in variable proportions
  • Epidermotropism is variable but can mimic either pagetoid reticulosis or mycosis fungoides replete with Pautrier microabscesses (Ann Dermatol 2017;29:229)
  • Nodular diffuse dermal infiltrate often extends between Grenz zone and subcutis
  • Subcutaneous involvement is variable and often extensive: lymphoma cells splay intralobular adipocyte lobules but can also show internalization within adipocytes reminiscent of rimming encountered in subcutaneous panniculitis-like T cell lymphoma
  • Early lesions can show abundant interstitial mucin deposition causing diagnostic confusion with lupus erythematosus panniculitis (J Am Acad Dermatol 2007;56:643, Acta Derm Venereol 2017;97:665)
  • Necrosis, debris laden macrophages and hemophagocytosis are common
  • Angiotropism and vascular injury are common
  • Adnexotropism is common
  • Lymphoma cells are medium sized with increased pale, eosinophilic cytoplasm and elongated, irregular nuclei with conspicuous nucleoli
Microscopic (histologic) images

Contributed by Robert E. LeBlanc, M.D.
 

Prominent epidermotropism

   

Cytologic atypia with more conspicuous nucleoli


Angiodestruction and fibrinoid necrosis

 

TCR gamma

TIA1

Positive stains
  • TCR gamma
  • Variable CD56 expression
  • Often expresses cytotoxic markers granzyme B, TIA1, perforin
  • Often CD4- / CD8- but can occasionally express CD8
  • Variable CD30 expression
Negative stains
Molecular / cytogenetics description
  • Clonal rearrangement of the T cell receptor gamma chain
    • Can be a helpful clue to the diagnosis whenever the histologic findings are nonspecific and there is strong clinical consideration for a diagnosis of lymphoma
    • Identification of a single biopsy is considerably less specific for the diagnosis of lymphoma than identification of the same clone in multiple biopsies taken at different times or from different sites
    • Clones can persist in atypical lymphocytic lobular panniculitis and other T cell dyscrasias that do not behave as lymphoma
  • Complex karyotype can be identified by SNP array CGH with gains and losses in regions associated with RAS and PI3K / AKT / MTOR pathways, as well as MYC and PT53 signaling (Cancer Genet 2012;205:459)
Differential diagnosis
  • Atypical lymphocytic lobular panniculitis (ALLP)
    • Indolent
    • Clonal T cell dyscrasia with relatively subtle lymphoid atypia and inconspicuous erythrocyte phagocytosis by histiocytes
    • Absence of distinct adipocyte rimming
    • Less extensive fat necrosis
    • Propensity for spontaneous clinical resolution and recurrence
    • However, a subset of ALLP cases with γδ T cells showed morphologic and clinical progression to lymphoma (J Cutan Pathol 2008;35:947, Am J Clin Pathol 2012;138:50)
      • Features described are distinct from lupus erythematosus panniculitis and lymphoma yet this diagnosis is somewhat controversial
  • Extranodal NK / T cell lymphoma, nasal type
    • Distinction can be impossible when the lymphoma is comprised of γδ T cells with T cell receptor gene rearrangement and EBER expression
    • WHO classification suggests that γδ lymphomas should not be associated with evidence of EBV infection although classification with EBER ISH reactivity may be too rigid as a sole criterion given the clinical and immunophenotypic heterogeneity of these lymphomas (Am J Surg Pathol 2012;36:481, Hum Pathol 2017;68:61)
  • Hepatosplenic T cell lymphoma
    • Clinical correlation is required to exclude this lymphoma, which can rarely mimic primary cutaneous γδ (gamma delta) T cell lymphoma when it involves the skin (Virchows Arch 2016;469:591)
    • Isochromosome 7q is not specific for hepatosplenic T cell lymphoma but has not been reported in primary cutaneous γδ T cell lymphomas (Virchows Arch 2016;469:591)
    • These lymphomas use Vδ1 chain whereas primary cutaneous γδ T cell lymphomas use Vδ2 (J Mol Diagn 2000;2:11)
  • Hydroa vacciniforme-like lymphoproliferative disorder
    • TCR gamma negative; EBER positive
  • Lupus erythematosus panniculitis
    • TCR gamma negative
    • Ubiquitously low Ki67 expression without hotspots
    • No lymphoid cytologic atypia
    • No distinct rimming (the infiltrate splays adipocyte lobules)
    • No T cell clonality
    • Multiple biopsies may be necessary as early lymphoma can closely mimic this entity
  • Lymphomatoid papulosis (LyP)
    • Strong communication with referring clinicians and great caution should be taken when contemplating LyP in the differential diagnosis of a γδ T cell infiltrate as some aggressive γδ lymphomas begin with a relatively indolent period
    • Papulonodular eruption followed by necrosis and spontaneous resolution with scar formation
    • Type D has cytotoxic marker expression but should have strong, diffuse CD8 and CD30 expression, along with expression of TCR Beta F1 (Am J Dermatopathol 2015;37:822)
    • There are rare reports of LyP exhibiting a γδ phenotype; (Br J Dermatol 2015;172:372); however, followup data are limited for most cases
  • Monomorphic epitheliotropic intestinal lymphoma
    • Clinical correlation would be required to resolve this unlikely differential diagnosis
    • Formerly known as enteropathy associated T cell lymphoma
    • Associated with celiac disease
    • Accompanying eosinophilia
  • Mycosis fungoides (MF)
    • Some clinically annotated cases of MF appear to have a γδ immunophenotype; however, there are other reports of aggressive γδ lymphomas following a protracted, indolent course mimicking MF
    • Therefore, a diagnosis of γδ MF should be made with caution and close communication with the referring clinicians
      • MF occasionally expresses cytotoxic markers; however, it is more likely to have a CD4+ / CD8- immunophenotype which is not characteristic of γδ lymphoma
  • Pagetoid reticulosis
    • TCR gamma negative
    • Usually solitary
  • Peripheral T cell lymphoma, NOS
    • TCR gamma negative
    • Diseases comprising this category are often either CD4+ / CD8- or CD4- / CD8-
  • Pityriasis lichenoides
    • Can occasionally show increased γδ T cells
    • Clinical correlation is required to confirm this impression
  • Primary cutaneous acral CD8+ T cell lymphoma
    • TCR gamma negative
    • Usually solitary or localized lesions on the acral surface, ear or face
  • Primary cutaneous anaplastic large cell lymphoma
    • TCR gamma negative
    • Usually larger cells with greater pleomorphism TCR Beta F1 and CD30 expression in ≥ 75% of cells
    • Infiltrate is not confined to fat lobules
    • No rimming
  • Primary cutaneous CD4 positive small / medium sized pleomorphic T cell lymphoproliferative disorder
    • TCR gamma negative
  • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma
    • TCR gamma negative
    • Pronounced and often confluent epidermotropism with necrotic intraepidermal keratinocytes and no Pautrier microabscesses
    • Less commonly involves dermis and subcutis
  • Subcutaneous panniculitis like T cell lymphoma
    • TCR gamma negative
Board review style question #1
Which of the following features is common in primary cutaneous γδ T cell lymphoma and generally not associated with subcutaneous panniculitis like T cell lymphoma?

  1. Absence of epidermotropism
  2. Adipocyte rimming
  3. Cytotoxic marker expression
  4. Mucosal involvement
Board review style answer #1
D. Mucosal involvement is common in classic γδ T cell lymphoma but is generally not associated with subcutaneous panniculitis like T cell lymphoma (SPTCL). Both diseases can show cytotoxic marker expression. Adipocyte rimming in γδ lymphoma can be histologically identical to that of SPTCL. There are reports of both γδ T cell lymphoma and SPTCL exhibiting epidermotropism, albeit epidermotropism in SPTCL is highly unusual and of a limited distribution without Pautrier type microabscesses. An absence of epidermotropism (option A) is associated with most cases of SPTCL.

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Reference: Primary cutaneous gamma delta T cell lymphoma
Board review style question #2
Expression of which of the following stains would argue against a diagnosis of primary cutaneous γδ T cell lymphoma?

  1. CD3
  2. CD4
  3. CD5
  4. CD8
Board review style answer #2
B. CD4 expression in primary cutaneous γδ T cell lymphoma is limited to exceedingly rare reports. Most cases show a double negative CD4- / CD8- immunophenotype. CD8 expression is present in a subset of cases. CD5 is often lost along with other mature T cell markers; however, the diagnosis is not predicated on this finding. CD3 expression is often retained and can be helpful in confirming T cell lineage when other T cell markers are deleted.

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Reference: Primary cutaneous gamma delta T cell lymphoma
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