Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous lymphoma in which clonal cytotoxic CD8-positive alpha/beta T cells infiltrate the subcutaneous fat lobule and rim individual adipocytes, producing nodules and plaques that mimic an inflammatory panniculitis. Since the 2008 EORTC classification study the term has been restricted to the alpha/beta phenotype; the gamma/delta counterpart is a separate, far more aggressive entity. SPTCL is unusual among lymphomas in having a defined germline predisposition: loss-of-function missense variants in HAVCR2, which encodes the inhibitory checkpoint receptor TIM-3, are found in a large fraction of cases and abolish TIM-3 surface expression, releasing a brake on innate immune activation. The resulting hyperinflammatory state explains the disease's defining complication, hemophagocytic lymphohistiocytosis (HLH), which is the dominant adverse prognostic factor. Outcome is otherwise good and immunosuppressive rather than cytotoxic therapy is now generally preferred first line, which - together with the striking responses to JAK inhibition seen in HAVCR2-mutant disease - has led several groups to question how much of the HAVCR2-mutant phenotype is neoplastic at all.
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Conditions with similar clinical presentations that must be differentiated from Subcutaneous Panniculitis-like T-cell Lymphoma:
name: Subcutaneous Panniculitis-like T-cell Lymphoma
creation_date: "2026-08-29T15:30:00Z"
category: Cancer
categories:
- Hematologic Malignancy
- T-cell Neoplasm
- Cutaneous Lymphoma
synonyms:
- SPTCL
- subcutaneous panniculitic T-cell lymphoma
- T-CELL LYMPHOMA, SUBCUTANEOUS PANNICULITIS-LIKE
- subcutaneous panniculitis-like T-cell lymphoma, Alpha/Beta type
- SPTL-AB
description: >-
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary
cutaneous lymphoma in which clonal cytotoxic CD8-positive alpha/beta T cells
infiltrate the subcutaneous fat lobule and rim individual adipocytes,
producing nodules and plaques that mimic an inflammatory panniculitis. Since
the 2008 EORTC classification study the term has been restricted to the
alpha/beta phenotype; the gamma/delta counterpart is a separate, far more
aggressive entity. SPTCL is unusual among lymphomas in having a defined
germline predisposition: loss-of-function missense variants in HAVCR2, which
encodes the inhibitory checkpoint receptor TIM-3, are found in a large
fraction of cases and abolish TIM-3 surface expression, releasing a brake on
innate immune activation. The resulting hyperinflammatory state explains the
disease's defining complication, hemophagocytic lymphohistiocytosis (HLH),
which is the dominant adverse prognostic factor. Outcome is otherwise good
and immunosuppressive rather than cytotoxic therapy is now generally
preferred first line, which - together with the striking responses to
JAK inhibition seen in HAVCR2-mutant disease - has led several groups to
question how much of the HAVCR2-mutant phenotype is neoplastic at all.
disease_term:
preferred_term: subcutaneous panniculitis-like T-cell lymphoma
term:
id: MONDO:0019475
label: subcutaneous panniculitis-like T-cell lymphoma
mappings:
mondo_mappings:
- term:
id: MONDO:0019475
label: subcutaneous panniculitis-like T-cell lymphoma
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: Primary MONDO disease identifier for this entry.
parents:
- Cutaneous T-cell lymphoma
- Peripheral T-cell lymphoma
classifications:
harrisons_chapter:
- classification_value: ONCOLOGY_HEMATOLOGY
notes: >-
A mature T-cell non-Hodgkin lymphoma; staging, prognosis and systemic
therapy follow lymphoma practice.
- classification_value: DERMATOLOGY
notes: >-
Disease is confined to the skin and subcutis in most patients and is
diagnosed on deep skin biopsy.
icdo_morphology:
classification_value: Lymphoma
evidence:
- reference: PMID:39538229
reference_title: "Characteristics and therapeutic outcomes of subcutaneous panniculitis-like T-cell lymphoma with and without germline HAVCR2 mutations in Thai children and adolescents."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a distinctive subtype of T-cell non-Hodgkin lymphoma (NHL), accounting for <1% of all NHL cases worldwide"
explanation: >-
Places SPTCL within the non-Hodgkin lymphoma family, supporting the
ICD-O lymphoma morphology bucket.
inheritance:
- name: Autosomal recessive predisposition via germline HAVCR2
description: >-
Most patients are clinically sporadic, but the HAVCR2 predisposition
behaves recessively: homozygous or compound heterozygous genotypes carry
the highest risk of the HLH-complicated phenotype, while heterozygous
carriage confers a smaller but measurable increase in risk. Genotype is
germline, so it is present in non-tumor tissue and is relevant to family
counselling and to donor selection for transplantation.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:30792187
reference_title: "Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In conclusion, individuals harboring biallelic HAVCR2 (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations."
explanation: >-
States the biallelic germline requirement for the predisposition while
noting that affected individuals are clinically sporadic.
- reference: PMID:37051767
reference_title: "Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively."
explanation: >-
Qualifies a strictly recessive model: heterozygous carriage also raises
HLH risk, though less than a biallelic genotype does.
prevalence:
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: ULTRA_RARE
notes: >-
No population-based incidence estimate exists. The only quantitative
anchor in the literature is SPTCL's share of non-Hodgkin lymphoma
diagnoses, which is consistently reported as under 1%.
evidence:
- reference: PMID:39538229
reference_title: "Characteristics and therapeutic outcomes of subcutaneous panniculitis-like T-cell lymphoma with and without germline HAVCR2 mutations in Thai children and adolescents."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a distinctive subtype of T-cell non-Hodgkin lymphoma (NHL), accounting for <1% of all NHL cases worldwide"
explanation: >-
Gives the only widely reported frequency figure, expressed as a fraction
of NHL rather than as a population rate.
epidemiology:
- name: Female predominance
description: >-
A consistent female excess across independent cohorts: a female-to-male
ratio of 1.7 in a European multicentre series and 69.8% women in a Korean
national cohort. Two unrelated populations agreeing on roughly 70% female
makes this a first-order feature of the disease rather than a cohort
artefact, and it is one of the things that distinguishes SPTCL from most
peripheral T-cell lymphomas.
evidence:
- reference: PMID:30126736
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: Clinical features, therapeutic approach, and outcome in a case series of 16 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The female-to-male ratio was 1.7. The median age at diagnosis was 46.5 years."
explanation: >-
Gives the sex ratio and median age in a European multicentre series.
- reference: PMID:34535012
reference_title: "Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The median age at diagnosis was 32 years (range, 8-74 years), and 37 (69.8%) patients were women."
explanation: >-
Independent confirmation of the female excess in a Korean national cohort,
with a younger median age.
- name: Age at diagnosis
description: >-
Median age at diagnosis differs markedly between cohorts - 46.5 years in a
European series against 32 years in a Korean national cohort. Two
explanations are available and this entry does not choose between them: the
p.Tyr82Cys allele is associated with younger onset, and it is also far
commoner in East Asian populations. They are confounded and cannot be
separated by these data, because the cohort with the younger median is the
one with the founder allele and neither series stratifies the other's
variable. The reported range spans childhood to old age.
minimum_value: 8.0
maximum_value: 74.0
mean_range: "median 32 years (Korean national cohort) to 46.5 years (European multicentre series)"
unit: years
notes: >-
The range recorded here is the Korean national cohort's, which is the only
one of the cited series to report one explicitly.
evidence:
- reference: PMID:34535012
reference_title: "Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The median age at diagnosis was 32 years (range, 8-74 years), and 37 (69.8%) patients were women."
explanation: >-
Gives the median and range recorded here.
- reference: PMID:34535012
reference_title: "Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HAVCR2Y82C was associated with younger age (P = .001), development of hemophagocytic lymphohistiocytosis or hemophagocytic lymphohistiocytosis-like systemic illness (P < .001), and short relapse-free survival (RFS) (P = .023)."
explanation: >-
Supports attributing the between-cohort age difference to genotype rather
than to geography alone.
progression:
- phase: Indolent relapsing cutaneous disease
notes: >-
Most patients follow a chronic, relapsing course confined to the subcutis
with an excellent survival. In the EORTC series the alpha/beta phenotype
was generally confined to the subcutis and had a 5-year overall survival of
82%.
evidence:
- reference: PMID:17934071
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SPTL-ABs were generally confined to the subcutis, had a CD4-, CD8+, CD56-, betaF1+ phenotype, were uncommonly associated with a hemophagocytic syndrome (HPS; 17%), and had a favorable prognosis (5-year overall survival [OS]: 82%)."
explanation: >-
Establishes both the indolent course and the baseline survival figure for
the alpha/beta entity.
- reference: PMID:30126736
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: Clinical features, therapeutic approach, and outcome in a case series of 16 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 5-year disease-specific survival rate was 85.7%."
explanation: >-
An independent multicentre series reporting concordant 5-year survival.
- phase: Hemophagocytic lymphohistiocytosis
notes: >-
A minority of patients develop HLH, either at presentation or during the
course of cutaneous disease. This is the single dominant adverse prognostic
event and drives most disease-related mortality.
evidence:
- reference: PMID:17934071
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SPTL-AB patients without HPS had a significantly better survival than patients with HPS (5-year OS: 91% vs 46%; P<.001)."
explanation: >-
Quantifies the survival penalty imposed by hemophagocytic syndrome.
- reference: PMID:15368328
reference_title: "Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The presence of HPS at diagnosis and expression of the gamma/delta T-cell receptor (TCR) by tumor cells were associated with poor survival, whereas age was not."
explanation: >-
Identifies hemophagocytic syndrome as an adverse prognostic factor
independent of age in a pooled literature analysis.
pathophysiology:
- name: Germline TIM-3 Loss of Function
biological_scale: MOLECULAR
description: >-
Germline missense variants in HAVCR2 substitute conserved residues in the
extracellular immunoglobulin variable-like domain of TIM-3. The variant
proteins misfold and never reach the plasma membrane, so the inhibitory
receptor is functionally absent from the surface of T cells and of the
myeloid cells that normally use it to damp innate activation. The
geographic split between the two commonest alleles - p.Tyr82Cys on an East
Asian and Polynesian founder haplotype, p.Ile97Met in European-ancestry
patients - is a strong argument that these are ancestral, not somatic,
lesions.
genes:
- preferred_term: HAVCR2
term:
id: hgnc:18437
label: HAVCR2
cell_types:
- preferred_term: CD8-positive, alpha-beta T cell
term:
id: CL:0000625
label: CD8-positive, alpha-beta T cell
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
- preferred_term: dendritic cell
term:
id: CL:0000451
label: dendritic cell
biological_processes:
- preferred_term: negative regulation of inflammatory response
modifier: LOSS_OF_FUNCTION
term:
id: GO:0050728
label: negative regulation of inflammatory response
genetic_context:
gene:
preferred_term: HAVCR2
term:
id: hgnc:18437
label: HAVCR2
allele_type: MISSENSE
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Homozygous or compound heterozygous germline missense alleles; the
commonest genotype reported is homozygous p.Tyr82Cys.
evidence:
- reference: PMID:30374066
reference_title: "Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution."
explanation: >-
The discovery cohort establishing germline loss-of-function HAVCR2
variants as a defining lesion in a majority of cases.
- reference: PMID:30374066
reference_title: "Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL."
explanation: >-
Functional work in the same paper showing the molecular consequence -
misfolding and loss of surface TIM-3 - that makes this a loss-of-function
node.
- reference: PMID:30792187
reference_title: "Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I)."
explanation: >-
Documents the biallelic genotypes that define this node's genetic
context.
downstream:
- target: Unrestrained Innate Immune Activation
description: >-
Absent surface TIM-3 removes an inhibitory input on macrophages and
dendritic cells, lowering the threshold for innate activation.
- name: Unrestrained Innate Immune Activation
biological_scale: CELLULAR
description: >-
With TIM-3 missing from the cell surface, myeloid cells sustain innate
signalling that would normally be terminated. The measured consequence in
patient material is persistent immune activation with excess production of
inflammatory cytokines, notably TNF and interleukin-1 beta. Inflammasome
assembly is the proposed proximal route to interleukin-1 family cytokine
release; that step is inferred from TIM-3 biology rather than demonstrated
directly in SPTCL tissue, and is recorded here at lower confidence than the
cytokine measurements themselves.
cell_types:
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
- preferred_term: dendritic cell
term:
id: CL:0000451
label: dendritic cell
biological_processes:
- preferred_term: activation of innate immune response
modifier: INCREASED
term:
id: GO:0002218
label: activation of innate immune response
- preferred_term: tumor necrosis factor production
modifier: INCREASED
term:
id: GO:0032640
label: tumor necrosis factor production
- preferred_term: interleukin-1 beta production
modifier: INCREASED
term:
id: GO:0032611
label: interleukin-1 beta production
- preferred_term: NLRP3 inflammasome complex assembly
modifier: INCREASED
term:
id: GO:0044546
label: NLRP3 inflammasome complex assembly
mechanism_confidence: PROVISIONAL
evidence:
- reference: PMID:30374066
reference_title: "Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL."
explanation: >-
Directly names persistent immune activation and the TNF and
interleukin-1 beta excess that define this node.
- reference: PMID:37051767
reference_title: "Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These mutations result in misfolding of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) protein, leading to persistent immune activation and cytokine release, which are responsible for the pathogenesis of HLH."
explanation: >-
An independent group stating the same causal link from TIM-3 misfolding
to sustained immune activation and cytokine release.
downstream:
- target: Macrophage Hyperactivation and Hemophagocytosis
description: >-
Sustained innate activation escalates into the systemic macrophage
activation syndrome recognised clinically as HLH.
- target: Clonal Cytotoxic Alpha-Beta T-cell Expansion
description: >-
The chronic inflammatory milieu is the proposed context in which a
cytotoxic T-cell clone emerges and is sustained.
- name: Clonal Cytotoxic Alpha-Beta T-cell Expansion
biological_scale: CELLULAR
description: >-
A clonal population of CD3-positive, CD4-negative, CD8-positive,
CD56-negative, betaF1-positive cytotoxic T cells expands and homes to
subcutaneous fat. Cooperating somatic mutations in epigenetic regulators
and signal transducers accompany the germline lesion. In HAVCR2 p.Tyr82Cys
tumours the transcriptional program is enriched for IL6-JAK-STAT3 and for
TNF signalling via NF-kappaB, which is the stated rationale for JAK
inhibition.
cell_types:
- preferred_term: CD8-positive, alpha-beta cytotoxic T cell
term:
id: CL:0000794
label: CD8-positive, alpha-beta cytotoxic T cell
biological_processes:
- preferred_term: cell surface receptor signaling pathway via JAK-STAT
modifier: INCREASED
term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
- preferred_term: canonical NF-kappaB signal transduction
modifier: INCREASED
term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
locations:
- preferred_term: subcutaneous adipose tissue
term:
id: UBERON:0002190
label: subcutaneous adipose tissue
evidence:
- reference: PMID:17934071
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SPTL-ABs were generally confined to the subcutis, had a CD4-, CD8+, CD56-, betaF1+ phenotype, were uncommonly associated with a hemophagocytic syndrome (HPS; 17%), and had a favorable prognosis (5-year overall survival [OS]: 82%)."
explanation: >-
Defines the immunophenotype and the subcutaneous localisation of the
expanding clone.
- reference: PMID:34535012
reference_title: "Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At the gene expression level, HAVCR2Y82C SPTCLs were enriched in genes involved in IL6-JAK-STAT3 signaling and in tumor necrosis factor-α signaling via NF-κB."
explanation: >-
Transcriptomic evidence for the two signalling programs annotated on this
node.
- reference: PMID:30792187
reference_title: "Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction."
explanation: >-
Establishes the cooperating somatic mutation burden in the neoplastic
clone.
downstream:
- target: Adipocyte Rimming and Lobular Panniculitis
description: >-
The expanded cytotoxic clone encircles and kills individual adipocytes
within the fat lobule.
- name: Adipocyte Rimming and Lobular Panniculitis
biological_scale: TISSUE
description: >-
The histologic hallmark of the disease: atypical cytotoxic lymphocytes
surround individual adipocytes in a lace-like pattern within a lobular
panniculitis, with karyorrhexis and fat necrosis and without epidermal
involvement. Adipocyte death is the direct tissue-level readout of
T-cell-mediated cytotoxicity in this compartment.
cell_types:
- preferred_term: adipocyte
term:
id: CL:0000136
label: adipocyte
- preferred_term: CD8-positive, alpha-beta cytotoxic T cell
term:
id: CL:0000794
label: CD8-positive, alpha-beta cytotoxic T cell
biological_processes:
- preferred_term: T cell mediated cytotoxicity
modifier: INCREASED
term:
id: GO:0001913
label: T cell mediated cytotoxicity
- preferred_term: apoptotic process
modifier: INCREASED
term:
id: GO:0006915
label: apoptotic process
locations:
- preferred_term: subcutaneous adipose tissue
term:
id: UBERON:0002190
label: subcutaneous adipose tissue
evidence:
- reference: PMID:34535012
reference_title: "Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Histopathologically, SPTCL is characterized by CD8-positive T cells infiltrating into subcutaneous adipose tissue, with rimmed individual fat cells in a lace-like pattern."
explanation: >-
States the rimming pattern and the tissue compartment this node
describes.
- reference: PMID:30126736
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: Clinical features, therapeutic approach, and outcome in a case series of 16 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Histopathology typically showed a lobular panniculitis with individual adipocytes surrounded by atypical lymphocytes, usually with a CD3+, CD4-, CD8+, CD56-, TIA1 cytotoxic granule associated RNA binding protein 1-positive phenotype and high proliferation rate."
explanation: >-
Independent confirmation of the lobular panniculitis pattern and the
cytotoxic phenotype of the rimming cells.
downstream:
- target: Subcutaneous Nodules and Plaques
description: >-
Destructive lobular panniculitis is what the patient feels and the
clinician sees as nodules and plaques.
- name: Macrophage Hyperactivation and Hemophagocytosis
biological_scale: ORGANISM
description: >-
In a substantial minority of patients the innate activation described above
escalates into full hemophagocytic lymphohistiocytosis, with activated
macrophages engulfing blood cells in marrow, spleen and liver and a
systemic cytokine excess producing fever, cytopenias, hyperferritinaemia,
hypertriglyceridaemia and hypofibrinogenaemia. HLH risk tracks HAVCR2
genotype dose and is higher in children and in males.
cell_types:
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
biological_processes:
- preferred_term: macrophage activation
modifier: INCREASED
term:
id: GO:0042116
label: macrophage activation
- preferred_term: inflammatory response
modifier: INCREASED
term:
id: GO:0006954
label: inflammatory response
evidence:
- reference: PMID:34535012
reference_title: "Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HAVCR2Y82C was associated with younger age (P = .001), development of hemophagocytic lymphohistiocytosis or hemophagocytic lymphohistiocytosis-like systemic illness (P < .001), and short relapse-free survival (RFS) (P = .023)."
explanation: >-
Links the germline genotype to the HLH endpoint in a nationwide cohort.
- reference: PMID:37051767
reference_title: "Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02)."
explanation: >-
Shows the genotype dose effect on HLH occurrence within an SPTCL cohort.
downstream:
- target: Hemophagocytic Lymphohistiocytosis
description: >-
Systemic macrophage activation is the mechanism behind the clinical HLH
syndrome.
phenotypes:
- category: Integument
name: Subcutaneous Nodules and Plaques
description: >-
Multiple, usually painless subcutaneous nodules and plaques, preferentially
on the legs and trunk. They are the presenting complaint in nearly all
patients and are routinely mistaken for a benign panniculitis, cellulitis
or erythema nodosum, which is the main source of diagnostic delay.
phenotype_term:
preferred_term: Subcutaneous nodule
term:
id: HP:0001482
label: Subcutaneous nodule
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:30126736
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: Clinical features, therapeutic approach, and outcome in a case series of 16 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients presented with multiple nodular or plaque-like lesions preferentially affecting the legs and/or trunk."
explanation: >-
Describes the lesion morphology and distribution recorded here.
- reference: PMID:35509196
reference_title: "The pathophysiology and current treatments for the subcutaneous panniculitis-like T cell lymphoma: An updated review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SPTCL is usually presented clinically as painless subcutaneous and erythematous nodules over the trunk or extremities."
explanation: >-
Confirms that the nodules are characteristically painless, which is part
of why they are initially dismissed.
- category: Integument
name: Lobular Panniculitis
description: >-
Inflammation of the subcutaneous fat lobule, which is simultaneously the
clinical presentation and the histologic substrate of the disease. In some
HAVCR2-mutant paediatric patients the biopsy shows panniculitis without
sufficient evidence of lymphoma.
phenotype_term:
preferred_term: Panniculitis
term:
id: HP:0012490
label: Panniculitis
frequency: VERY_FREQUENT
evidence:
- reference: PMID:37062931
reference_title: "Efficacy of ruxolitinib for HAVCR2 mutation-associated hemophagocytic lymphohistiocytosis and panniculitis manifestations in children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Histopathologically, only two patients were diagnosed with SPTCL and three were reported as panniculitis with no sufficient evidence of lymphoma."
explanation: >-
Documents panniculitis as the histologic finding, including cases where
it falls short of a lymphoma diagnosis.
- category: Neoplasm
name: Hemophagocytic Lymphohistiocytosis
description: >-
A systemic hyperinflammatory syndrome complicating a substantial minority
of cases, defined by the HLH-2004 criteria. It is the dominant adverse
prognostic factor and the main cause of disease-related death. Reported
frequency varies widely with the population studied - about 17% in the
adult-weighted EORTC series, about two thirds in a paediatric cohort
selected for HAVCR2 sequencing.
phenotype_term:
preferred_term: Hemophagocytosis
term:
id: HP:0012156
label: Hemophagocytosis
frequency: OCCASIONAL
evidence:
- reference: PMID:17934071
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SPTL-ABs were generally confined to the subcutis, had a CD4-, CD8+, CD56-, betaF1+ phenotype, were uncommonly associated with a hemophagocytic syndrome (HPS; 17%), and had a favorable prognosis (5-year overall survival [OS]: 82%)."
explanation: >-
Gives the 17% frequency underpinning the OCCASIONAL band for unselected
alpha/beta SPTCL.
- reference: PMID:39538229
reference_title: "Characteristics and therapeutic outcomes of subcutaneous panniculitis-like T-cell lymphoma with and without germline HAVCR2 mutations in Thai children and adolescents."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "86.4% harbored germline HAVCR2 mutation, either homozygous (77.3%) or heterozygous (9.1%) p.Y82C variant, while 68.2% developed HLH/HLH-like systemic illnesses."
explanation: >-
Shows that in a paediatric, HAVCR2-enriched cohort HLH is the majority
outcome, so the frequency band is population-dependent.
- category: Constitutional
name: Fever
description: >-
Constitutional fever, generally in the context of HLH or HLH-like systemic
illness rather than uncomplicated cutaneous disease.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:37051767
reference_title: "Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Those incompletely fulfilling the criteria but being clinically consistent with HLH (i.e., fever, cytopenias, serum ferritin ≥500 μg/L, and the presence of hemophagocytosis in BM) were accounted for ‘HLH-like systemic illnesses’."
explanation: >-
Names fever as a defining feature of the HLH-like systemic illness seen
in these patients.
- category: Blood
name: Cytopenias
description: >-
Peripheral cytopenias affecting two or more lineages are part of the HLH
definition applied in these cohorts and accompany the systemic phase of
disease.
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
evidence:
- reference: PMID:37051767
reference_title: "Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in clinical practice, patients with high-grade fever, cytopenias and presence of hemophagocytic activity in bone marrow (BM) can be presumptively diagnosed as having hemophagocytic syndrome (HPS)."
explanation: >-
Records cytopenias as a core clinical feature of the hemophagocytic
phase.
- category: Blood
name: Hyperferritinemia
description: >-
Marked elevation of serum ferritin, used both as an HLH-2004 criterion and
as a practical surveillance marker in patients with known HAVCR2 variants.
phenotype_term:
preferred_term: Increased circulating ferritin concentration
term:
id: HP:0003281
label: Increased circulating ferritin concentration
evidence:
- reference: PMID:37051767
reference_title: "Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Those incompletely fulfilling the criteria but being clinically consistent with HLH (i.e., fever, cytopenias, serum ferritin ≥500 μg/L, and the presence of hemophagocytosis in BM) were accounted for ‘HLH-like systemic illnesses’."
explanation: >-
Gives the explicit ferritin threshold used to define HLH-like systemic
illness in this disease.
genetic:
- name: HAVCR2
gene_term:
preferred_term: HAVCR2
term:
id: hgnc:18437
label: HAVCR2
relationship_type: SUSCEPTIBILITY
variant_origin: GERMLINE
frequency: >-
Reported in roughly 50% to 86% of patients depending on cohort ancestry and
on whether the series is enriched for paediatric or HLH-complicated
disease.
notes: >-
HAVCR2 encodes TIM-3, an inhibitory checkpoint receptor on T cells and
innate immune cells. Germline loss-of-function missense alleles are the
only recurrent genetic lesion established in SPTCL. Three recurrent
substitutions are reported - p.Tyr82Cys, p.Ile97Met and p.Thr101Ile - all
in the extracellular immunoglobulin variable-like domain.
case_fractions:
- population: Korean nationwide SPTCL cohort
case_fraction_percent: 51.0
cohort_size: 49
notes: >-
Numerator is p.Tyr82Cys specifically. That is comparable with the Thai
row, where every mutation detected was also p.Y82C, but not with the
integrated-reanalysis row, which counts any germline HAVCR2 mutation.
evidence:
- reference: PMID:34535012
reference_title: "Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of 49 patients with available HAVCR2 status, 25 (51.0%) were HAVCR2Y82C."
explanation: >-
Quantifies the p.Tyr82Cys share in an unselected Korean national
cohort.
- population: Integrated series of six Japanese patients plus 30 reanalysed public exomes
case_fraction_percent: 79.3
cohort_size: 29
notes: >-
Any germline HAVCR2 mutation, in 23 of the 29 patients with an evaluable
genotype. This is not an independent cohort and should not be counted as
one: only six patients are the authors' own series, and the other 30 are
public exome data whose SPTCL content overlaps the discovery cohorts
already cited in this block. It is recorded because the reanalysis is a
separate observation of the same axis, not because it adds 29 new
patients.
evidence:
- reference: PMID:39288772
reference_title: "Genetic profiles and clinical features in subcutaneous panniculitis-like T-cell lymphomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified 138 somatic mutations in skin tumors of 24 patients and HAVCR2 germline mutations in 23 of 29 patients."
explanation: >-
Gives the carrier fraction recorded here.
- reference: PMID:39288772
reference_title: "Genetic profiles and clinical features in subcutaneous panniculitis-like T-cell lymphomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we integrated whole-exome sequencing data from 60 samples collected from 36 SPTCL patients, encompassing six patients of our cohort and 30 patients of publicly available data."
explanation: >-
Establishes the composition of the series, which is why this row is
labelled as an integrated reanalysis rather than as an independent
cohort.
- reference: PMID:39288772
reference_title: "Genetic profiles and clinical features in subcutaneous panniculitis-like T-cell lymphomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HAVCR2 p.Tyr82Cys mutations were identified in four of six Japanese patients."
explanation: >-
Records the p.Tyr82Cys share in the study's own Japanese arm, which is
n=6 and correspondingly fragile.
- population: Thai SPTCL cohort aged 20 years or younger
case_fraction_percent: 86.4
cohort_size: 22
notes: >-
Numerator is any germline HAVCR2 mutation across the 22 patients aged 20
years or younger enrolled from six Thai centres. In this cohort the two
are the same set: every mutation detected was p.Y82C, homozygous in 77.3%
and heterozygous in 9.1%, which sums to the 86.4%. So this row is
comparable with the Korean p.Tyr82Cys row on numerator, and differs from
it on ascertainment - paediatric rather than unselected - which is the
likelier source of the gap between 51% and 86.4%.
evidence:
- reference: PMID:39538229
reference_title: "Characteristics and therapeutic outcomes of subcutaneous panniculitis-like T-cell lymphoma with and without germline HAVCR2 mutations in Thai children and adolescents."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "86.4% harbored germline HAVCR2 mutation, either homozygous (77.3%) or heterozygous (9.1%) p.Y82C variant, while 68.2% developed HLH/HLH-like systemic illnesses."
explanation: >-
Gives the much higher carrier fraction in a paediatric series, showing
the ascertainment dependence of this number.
- reference: PMID:39538229
reference_title: "Characteristics and therapeutic outcomes of subcutaneous panniculitis-like T-cell lymphoma with and without germline HAVCR2 mutations in Thai children and adolescents."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fifth, only HAVCR2 p.Y82C variant was identified in our study population of exclusively Thai pediatric patients with SPTCL."
explanation: >-
Confirms that every mutation detected in this cohort was p.Y82C, which
is what makes its 86.4% comparable on numerator with the Korean
p.Tyr82Cys row.
- reference: PMID:39538229
reference_title: "Characteristics and therapeutic outcomes of subcutaneous panniculitis-like T-cell lymphoma with and without germline HAVCR2 mutations in Thai children and adolescents."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Based on the Genome Aggregation Database (gnomAD), although HAVCR2 p.Y82C mutation in the general population is rare with a minor allele frequency (MAF) of 3.6 x 10-3, its ethnicity-specific MAFs are variable, ranging from 4.2 x 10-5 in Africans to 2.1 x 10-2 in East Asians"
explanation: >-
Evidences the ascertainment reading rather than leaving it asserted. The
same paper puts the Southeast Asian allele frequency an order of
magnitude below the East Asian one, yet this Southeast Asian cohort has
the higher carrier fraction of the two - so ancestry does not account
for the gap, and paediatric ascertainment is the remaining explanation.
evidence:
- reference: PMID:30792187
reference_title: "Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Consistent with a recent report, germline mutations in HAVCR2, encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases."
explanation: >-
Independent replication of the HAVCR2 association in an Asian cohort.
variants:
- name: HAVCR2 c.245A>G p.Tyr82Cys
description: >-
The commonest reported allele, carried on a probable founder chromosome
in patients of East Asian and Polynesian ancestry. Causes TIM-3
misfolding and loss of plasma membrane expression.
gene:
preferred_term: HAVCR2
term:
id: hgnc:18437
label: HAVCR2
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:30374066
reference_title: "Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry."
explanation: >-
Establishes the founder origin and ancestry distribution of this
allele.
- name: HAVCR2 c.291A>G p.Ile97Met
description: >-
The predominant allele in patients of European ancestry, with the same
misfolding and trafficking defect as p.Tyr82Cys.
gene:
preferred_term: HAVCR2
term:
id: hgnc:18437
label: HAVCR2
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:30374066
reference_title: "Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution."
explanation: >-
Names the coding change and its loss-of-function classification.
- name: HAVCR2 p.Thr101Ile
description: >-
A third recurrent allele, reported in compound heterozygosity with
p.Tyr82Cys.
gene:
preferred_term: HAVCR2
term:
id: hgnc:18437
label: HAVCR2
clinical_significance: LIKELY_PATHOGENIC
evidence:
- reference: PMID:30792187
reference_title: "Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I)."
explanation: >-
Documents p.Thr101Ile as the second allele in a compound heterozygous
patient.
histopathology:
- name: Adipocyte rimming by atypical lymphoid cells
description: >-
Atypical lymphoid cells encircling individual adipocytes within the
subcutaneous fat lobule. This is the defining diagnostic finding and is
assessed on a deep incisional or excisional biopsy rather than a
superficial punch.
diagnostic: true
evidence:
- reference: PMID:37051767
reference_title: "Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The pathological hallmark of SPTCL is an adipocyte rimming by atypical lymphoid cells expressing CD3, CD8, T-cell intracytoplasmic antigen 1 (TIA-1) and T-cell receptor β F1 (BF1)."
explanation: >-
States the hallmark finding and the accompanying immunophenotype.
- name: Ki-67 hotspots among rimming CD8-positive T cells
description: >-
Foci of high proliferative activity within the CD8-positive rimming
infiltrate. Their presence separates SPTCL from lupus erythematosus
panniculitis on a four-stain panel, and their absence argues against
lymphoma.
diagnostic: true
evidence:
- reference: PMID:26796503
reference_title: "Useful Parameters for Distinguishing Subcutaneous Panniculitis-like T-Cell Lymphoma From Lupus Erythematosus Panniculitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ki-67 hotspots were not identified in LEP, thus aiding the distinction of SPTCL from LEP."
explanation: >-
Establishes the discriminatory value of the finding against the principal
histologic mimic.
diagnosis:
- name: Deep skin biopsy with immunophenotyping
description: >-
Diagnosis rests on a deep biopsy showing lobular panniculitis with adipocyte
rimming, plus an immunohistochemical panel establishing the CD3-positive,
CD4-negative, CD8-positive, CD56-negative, betaF1-positive cytotoxic
phenotype. Demonstrating a clonal T-cell receptor rearrangement supports the
diagnosis.
evidence:
- reference: PMID:30126736
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: Clinical features, therapeutic approach, and outcome in a case series of 16 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Histopathology typically showed a lobular panniculitis with individual adipocytes surrounded by atypical lymphocytes, usually with a CD3+, CD4-, CD8+, CD56-, TIA1 cytotoxic granule associated RNA binding protein 1-positive phenotype and high proliferation rate."
explanation: >-
Sets out the histologic and immunophenotypic criteria used in practice.
- name: Germline HAVCR2 sequencing
description: >-
Sequencing of HAVCR2 exon 2 covers the three recurrent alleles and is
increasingly performed at diagnosis, particularly in children and in
patients with HLH, because a positive result changes surveillance, family
counselling and - if transplantation is considered - donor selection.
Reduced TIM-3 surface expression by flow cytometry has been proposed as a
screening test.
evidence:
- reference: PMID:37051767
reference_title: "Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The designed primer could cover pathogenic HAVCR2 variants of p.Y82C, p.I97M and p.T101I."
explanation: >-
Confirms that exon 2 sequencing captures all three recurrent alleles.
- reference: PMID:32285995
reference_title: "TIM-3 deficiency presenting with two clonally unrelated episodes of mesenteric and subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We show that mesenteric fatty tissue localization of SPTCL can be the presenting manifestation of TIM-3 deficiency, that this condition predisposes to recurrent lymphoma, and that flow cytometry is a possible screening tool."
explanation: >-
Supports flow cytometry as a screening approach and documents the
recurrence risk that motivates genotyping.
- name: FDG PET/CT for staging and response assessment
description: >-
Used to define the extent of subcutaneous disease, look for extracutaneous
involvement and follow treatment response.
evidence:
- reference: PMID:35509196
reference_title: "The pathophysiology and current treatments for the subcutaneous panniculitis-like T cell lymphoma: An updated review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Positron emission tomography scan is utilized for disease staging and treatment follow-up."
explanation: >-
States the role of PET in staging and follow-up for this disease.
differential_diagnoses:
- name: Lupus erythematosus panniculitis
description: >-
The principal histologic mimic. The two overlap clinically and
histologically and can coexist in the same patient, but SPTCL carries the
risk of HLH and so the distinction matters. Molecular profiling separates
them, and overlapping cases cluster with lupus panniculitis rather than
with SPTCL.
distinguishing_features:
- Ki-67 hotspots enriched in atypical CD8-positive T cells are present in SPTCL and absent in lupus panniculitis
- Clonal T-cell receptor rearrangement favours SPTCL
- Gene expression profiling separates the two entities, with overlap cases resembling lupus panniculitis
evidence:
- reference: PMID:26796503
reference_title: "Useful Parameters for Distinguishing Subcutaneous Panniculitis-like T-Cell Lymphoma From Lupus Erythematosus Panniculitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Lymphocyte atypia combined with adipocyte rimming of CD8+ T cells within Ki-67 hotspots was also highly specific for the diagnosis of SPTCL."
explanation: >-
Provides the specific histologic combination that discriminates the two.
- reference: PMID:33966586
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma, lupus erythematosus profundus, and overlapping cases: molecular characterization through the study of 208 genes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Gene expression unsupervised analysis of the samples differentiated SPTCL from LEP samples. Most overlapping cases were clustered with LEP cases."
explanation: >-
Molecular evidence that the entities are separable and that overlap cases
behave like lupus panniculitis.
- name: Primary cutaneous gamma-delta T-cell lymphoma
description: >-
Formerly grouped with SPTCL under a single label. It carries a gamma/delta
rather than alpha/beta receptor, frequently involves the epidermis and
ulcerates, and has a far worse outcome irrespective of treatment. Separating
the two on betaF1 and TCR-delta staining is the reason the term SPTCL is now
restricted to the alpha/beta entity.
distinguishing_features:
- CD4-negative, CD8-negative, CD56 variable, betaF1-negative phenotype
- Frequent epidermal or dermal involvement and ulceration rather than disease confined to the subcutis
- 5-year overall survival of 11% versus 82% for the alpha/beta entity
evidence:
- reference: PMID:17934071
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SPTL-GDs often showed (epi)dermal involvement and/or ulceration, a CD4-, CD8-, CD56+/-, betaF1- T-cell phenotype, and poor prognosis (5-year OS: 11%), irrespective of the presence of HPS or type of treatment."
explanation: >-
Gives the phenotype, distribution and outcome that separate the
gamma/delta entity.
- reference: PMID:17934071
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These results indicate that SPTL-AB and SPTL-GD are distinct entities, and justify that the term SPTL should further be used only for SPTL-AB."
explanation: >-
The nomenclature decision that makes this a differential rather than a
subtype.
treatments:
- name: Corticosteroid-based Immunosuppressive Therapy
description: >-
Systemic corticosteroids alone or combined with low-dose methotrexate or
cyclosporine A. This is now the usual first-line choice for uncomplicated
cutaneous disease, and gives high complete response rates without the
toxicity of anthracycline-based chemotherapy. Corticosteroid monotherapy
relapses more often than corticosteroids combined with another
immunoregulatory agent.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: prednisone
term:
id: CHEBI:8382
label: prednisone
- preferred_term: methotrexate
term:
id: CHEBI:44185
label: methotrexate
- preferred_term: cyclosporin A
term:
id: CHEBI:4031
label: cyclosporin A
target_mechanisms:
- target: Unrestrained Innate Immune Activation
description: >-
Broad suppression of cytokine production and lymphocyte activation, which
is why an immunosuppressive rather than cytotoxic strategy works in a
disease driven by loss of an inhibitory checkpoint.
evidence:
- reference: PMID:30126736
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma: Clinical features, therapeutic approach, and outcome in a case series of 16 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Oral steroids alone or in combination with low-dose methotrexate or cyclosporine A were the most common initial treatment, achieving a complete response in 85% of the treated patients."
explanation: >-
Gives the regimen and the complete response rate recorded here.
- reference: PMID:37840116
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma associated with hemophagocytic lymphohistiocytosis: a systematic review of 63 patients reported in the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The corticosteroid monotherapy experienced a higher recurrence rate than the corticosteroids plus other immunoregulatory agents therapy (66.7 vs. 0.0%, p = 0.029)."
explanation: >-
Supports combining corticosteroids with a second immunoregulatory agent
rather than using steroids alone.
- name: Multiagent Chemotherapy
description: >-
Anthracycline-based combination chemotherapy, historically the default and
now reserved for patients presenting with HLH or progressing on
immunosuppression. In a paediatric comparison it achieved a numerically
higher durable complete remission rate than immunosuppressive therapy but at
the cost of more adverse events, and the difference in remission rate was
not significant.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: chemotherapy
term:
id: NCIT:C15632
label: Chemotherapy
evidence:
- reference: PMID:39538229
reference_title: "Characteristics and therapeutic outcomes of subcutaneous panniculitis-like T-cell lymphoma with and without germline HAVCR2 mutations in Thai children and adolescents."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Durable complete remission (CR) was achieved in 71.4% and 50.0% after first-line chemotherapy and IST, respectively (P=0.45); however, chemotherapy tended to increase any AEs compared to IST (57.1% vs. 12.5%; P=0.07)."
explanation: >-
Reports the efficacy and toxicity trade-off between chemotherapy and
immunosuppression without establishing superiority of either.
- reference: PMID:15368328
reference_title: "Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Anthracycline-based chemotherapy regimens were the most commonly used and most effective systemic treatment options, producing long-term CR in approximately 30% of patients."
explanation: >-
Documents the historical role and the durable remission rate of
anthracycline-based regimens.
- name: Ruxolitinib
description: >-
A JAK1/JAK2 inhibitor. Its use follows directly from the mechanism: TIM-3
loss drives cytokine-mediated inflammation and HAVCR2-mutant tumours are
transcriptionally enriched for IL6-JAK-STAT3 signalling. Reported responses
in HAVCR2-mutant children have been rapid and durable after corticosteroids,
other immunosuppressants and chemotherapy had all failed.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ruxolitinib
term:
id: CHEBI:66919
label: ruxolitinib
target_mechanisms:
- target: Clonal Cytotoxic Alpha-Beta T-cell Expansion
description: >-
Blocks the JAK-STAT signalling program enriched in HAVCR2 p.Tyr82Cys
tumours.
- target: Macrophage Hyperactivation and Hemophagocytosis
description: >-
Suppresses the cytokine signalling that sustains the hemophagocytic
syndrome.
evidence:
- reference: PMID:37062931
reference_title: "Efficacy of ruxolitinib for HAVCR2 mutation-associated hemophagocytic lymphohistiocytosis and panniculitis manifestations in children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients initially received corticosteroids, immunosuppressants or chemotherapy, achieving unfavourable responses. Strikingly, they responded well to ruxolitinib targeting inflammatory cytokines, allowing rapid disease resolution and/or long-term maintenance of remission."
explanation: >-
Reports responses to ruxolitinib after failure of conventional therapy in
genotyped patients.
- reference: PMID:32271897
reference_title: "Efficacy of ruxolitinib in subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "First evidence of ruxolitinib efficacy for subcutaneous panniculitis-like T-cell lymphoma with hemophagocytic lymphohistiocytosis."
explanation: >-
The first report of ruxolitinib activity in this indication.
- name: Hematopoietic Stem Cell Transplantation
description: >-
Reserved for refractory or relapsed disease, particularly HLH-complicated
disease. Because the predisposing HAVCR2 variant is germline, donor genotype
matters: a relapse has been reported after a sibling-identical transplant
from a donor who turned out to carry the same homozygous HAVCR2 mutation.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: Hematopoietic Cell Transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
evidence:
- reference: PMID:37840116
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma associated with hemophagocytic lymphohistiocytosis: a systematic review of 63 patients reported in the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fifteen patients, including 5 with relapsed/refractory SPTCL-HLH, responded well and survived after receiving SCT."
explanation: >-
Supports transplantation as an effective option in refractory disease.
- reference: PMID:37840116
reference_title: "Subcutaneous panniculitis-like T-cell lymphoma associated with hemophagocytic lymphohistiocytosis: a systematic review of 63 patients reported in the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "One case who received a sibling-identical SCT relapsed. Further analysis revealed a homozygous HAVCR2 mutation with the donor."
explanation: >-
Documents the germline-genotype pitfall in related-donor selection.
- name: Radiation Therapy
description: >-
Skin-directed radiotherapy for localised or solitary lesions, avoiding
systemic exposure in patients whose disease is anatomically limited.
therapeutic_modality: RADIOTHERAPY
treatment_term:
preferred_term: Radiation Therapy
term:
id: NCIT:C15313
label: Radiation Therapy
evidence:
- reference: PMID:15368328
reference_title: "Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The authors performed a systematic analysis of all patients with SPTCL reported on in the English-language medical literature, with emphasis on specific clinical features, experiences involving the use of radiotherapy and systemic agents, and prognostic factors predictive of treatment response and clinical outcome."
explanation: >-
Establishes that radiotherapy is part of the reported treatment
repertoire; this pooled review does not isolate its efficacy.
discussions:
- discussion_id: sptcl_neoplastic_vs_inflammatory
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Is HAVCR2-mutant subcutaneous panniculitis-like T-cell lymphoma a lymphoma,
or an inherited autoinflammatory disease that produces a clonal
lymphocytic infiltrate?
attaches_to:
- pathophysiology#Clonal Cytotoxic Alpha-Beta T-cell Expansion
rationale: >-
Several observations sit uneasily with a neoplastic model. Immunosuppression
outperforms cytotoxic chemotherapy; JAK inhibition produces rapid remission
in genotyped patients who failed chemotherapy; some HAVCR2-mutant children
have panniculitis without histologic evidence of lymphoma at all; and a
patient has been described with two clonally unrelated episodes, which is
hard to reconcile with a single transformed clone. The authors of two of
these reports say the neoplastic nature of the condition is in question. The
KB models this as a lymphoma entry because that is its classification and
because clonal T-cell receptor rearrangement is a diagnostic criterion, but
the mechanism nodes here deliberately place the germline immune lesion
upstream of the clone rather than the reverse.
evidence:
- reference: PMID:32271897
reference_title: "Efficacy of ruxolitinib in subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Supporting rationale for ruxolitinib use, not more aggressive treatment, in this context, questioning this condition’s neoplastic nature."
explanation: >-
States the question explicitly on the basis of the treatment response.
- reference: PMID:37062931
reference_title: "Efficacy of ruxolitinib for HAVCR2 mutation-associated hemophagocytic lymphohistiocytosis and panniculitis manifestations in children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The excellent efficacy of ruxolitinib highlights this disease as an inflammatory condition instead of neoplastic nature and indicates novel agents targeting key inflammatory pathways as an encouraging approach for this disease entity."
explanation: >-
An independent group drawing the same inference from the ruxolitinib
response.
- reference: PMID:32285995
reference_title: "TIM-3 deficiency presenting with two clonally unrelated episodes of mesenteric and subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We show that mesenteric fatty tissue localization of SPTCL can be the presenting manifestation of TIM-3 deficiency, that this condition predisposes to recurrent lymphoma, and that flow cytometry is a possible screening tool."
explanation: >-
Two clonally unrelated episodes in one patient argue for a predisposing
immune defect rather than a single transformed clone.
- discussion_id: sptcl_havcr2_wildtype_mechanism
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
What drives the HAVCR2 wild-type cases, which are roughly half of an
unselected cohort?
attaches_to:
- pathophysiology#Germline TIM-3 Loss of Function
rationale: >-
The mechanism recorded in this entry starts from germline HAVCR2 loss of
function, but about half of patients in an unselected national cohort have
no HAVCR2 variant. Mutations in UNC13D, PIAS3 and KMT2D are reported more
often in those cases, and CCR4 is upregulated in them, but no unifying
mechanism has been established. The entry therefore has no upstream node
for the wild-type group.
evidence:
- reference: PMID:34535012
reference_title: "Genetic profiles of subcutaneous panniculitis-like T-cell lymphoma and clinicopathological impact of HAVCR2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations in UNC13D, PIAS3, and KMT2D were more frequent in HAVCR2WT SPTCLs."
explanation: >-
Names the candidate lesions that distinguish the wild-type group without
establishing a mechanism for it.
notes: >-
Entity scope: this entry covers the alpha/beta phenotype only, following the
2008 EORTC decision to restrict the term SPTCL to that entity. Primary
cutaneous gamma-delta T-cell lymphoma is recorded as a differential
diagnosis, not as a subtype.
Frequency figures in this entry are strongly ascertainment-dependent and the
cohorts are not interchangeable. HAVCR2 carrier fraction ranges from about
51% in an unselected Korean national cohort to about 86% in a Thai paediatric
series; HLH frequency ranges from 17% in the adult-weighted EORTC series to
68% in that same paediatric series. Both extremes are recorded with their
cohort so that neither is read as the disease-wide number.
No prevalence rate is recorded because none has been published; the only
quantitative anchor is SPTCL's share of non-Hodgkin lymphoma diagnoses.
review_notes: >-
Most of the reference cache committed alongside this entry comes from the
deep-research run's own citation-validation pass rather than from curation.
Those files are kept because the report that cites them is committed; they are
not evidence for anything in the entry. This is repository housekeeping rather
than disease content, which is why it sits here and not in `notes`.
Overview: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare, primary cutaneous peripheral T-cell lymphoma composed of clonal cytotoxic αβ CD8+ T cells that infiltrate subcutaneous adipose tissue, mimicking inflammatory panniculitis both clinically and histologically. It accounts for <1% of all non-Hodgkin lymphomas and <1% of peripheral T-cell lymphomas (StatPearls; Clinical Dermatology Review 2024). It was formally distinguished from the more aggressive primary cutaneous γδ T-cell lymphoma in the 2008 WHO-EORTC classification revision — the term SPTCL is now restricted to the αβ-phenotype entity, which carries a comparatively indolent course (StatPearls; PathologyOutlines).
Key identifiers: - OMIM: #618398 — "T-CELL LYMPHOMA, SUBCUTANEOUS PANNICULITIS-LIKE; SPTCL" (notably listed with a germline genetic basis via HAVCR2) - Orphanet: ORPHA:86884 - MONDO: MONDO:0019475 - ICD-10-CM: C86.3 — "Subcutaneous panniculitis-like T-cell lymphoma" - MeSH: Lymphoma, T-Cell, Cutaneous (subcutaneous panniculitis-like subtype)
Synonyms: SPTCL; subcutaneous panniculitic T-cell lymphoma; panniculitis-like T-cell lymphoma (older/broader usage, now split into SPTCL [αβ] and primary cutaneous γδ T-cell lymphoma).
Evidence basis: The literature is predominantly aggregated case series, retrospective cohorts (EORTC Cutaneous Lymphoma Group, French/Japanese/Korean/Chinese multicenter cohorts), and case reports; there is no large prospective trial or population-based registry (e.g., no dedicated SEER coding stratum), so most epidemiologic and outcome figures derive from pooled single- or multi-center series rather than individual EHR-level aggregation.
Disease causal factors: SPTCL arises from clonal expansion of cytotoxic αβ T cells homing to subcutaneous fat. A major mechanistic driver identified over the last decade is germline loss-of-function mutation in HAVCR2 (encoding the immune checkpoint receptor TIM-3), found in roughly half to 85% of cases depending on cohort/ancestry (Nat Genet 2018; Blood Adv 2019).
Genetic risk factors: - HAVCR2 (TIM-3) germline variants, most notably c.245A>G (p.Tyr82Cys) — enriched in patients of East Asian and Polynesian ancestry on a shared founder haplotype — and c.291A>G (p.Ile97Met), more common in European-ancestry patients. Both cause TIM-3 protein misfolding and loss of plasma-membrane expression (Nat Genet 2018). - A 2024 Japanese cohort (Okamura et al., Cancer Science) found HAVCR2^Y82C in 51.0% of patients, associated with younger age of onset, HLH development, and shorter relapse-free survival; TET2 recurrent mutations were also identified, while UNC13D, PIAS3, KMT2D mutations were enriched in HAVCR2-wild-type cases (Cancer Sci 2024; PMC11531942). - HAVCR2^Y82C tumors show transcriptional enrichment for IL6-JAK-STAT3 and TNF-α/NF-κB signaling. - Homozygous/biallelic HAVCR2 mutation has been documented even in pediatric sporadic (non-familial) SPTCL (PMID 34398459).
Environmental/associated risk factors: No specific infectious, occupational, or toxin exposure is established as causal. Autoimmune disease co-occurs in ~20% of cases, most notably systemic lupus erythematosus (SLE), at a rate exceeding background population prevalence — some patients present on a histologic/clinical continuum with lupus erythematosus panniculitis (LEP) (Clinical Dermatology Review 2024; molecular overlap study PMID 33966586).
Protective factors: None specifically established in the literature.
Gene-environment interaction: The prevailing model is that germline HAVCR2 loss-of-function lowers the threshold for macrophage/dendritic-cell inflammasome activation (see Mechanism, below); a superimposed trigger (infection, immune stimulation) is hypothesized to precipitate the hyperinflammatory/HLH phenotype, though a specific triggering exposure has not been consistently identified.
| Phenotype | Type | Frequency/Notes | Suggested HP term |
|---|---|---|---|
| Subcutaneous nodules/plaques | Physical sign | Cardinal finding; typically multiple, on extremities and trunk | HP:0031477 (Subcutaneous nodule) |
| Erythematous skin lesions | Sign | Common | HP:0010783 (Erythema) |
| Painless (or occasionally tender) lesions | Symptom | Variable; usually painless but can be tender/pruritic | — |
| Fever | Symptom | Common, especially with HLH | HP:0001945 (Fever) |
| Hepatosplenomegaly | Sign | Seen with HLH complication | HP:0001433 / HP:0001744 |
| Pancytopenia/bicytopenia | Lab abnormality | ~72.7% of HLH-complicated cases (general HLH cohort data) | HP:0001873 (Thrombocytopenia), HP:0001899 (Leukopenia), HP:0001903 (Anemia) |
| Hyperferritinemia | Lab abnormality | ~95% of HLH-complicated cases | HP:0012156 (Elevated serum ferritin, closest available; consider laboratory abnormality mapping) |
| Hypertriglyceridemia | Lab abnormality | ~52.5% of HLH cases | HP:0002155 (Hypertriglyceridemia) |
| Hypofibrinogenemia | Lab abnormality | ~30.8% of HLH cases | HP:0011900 (or related coagulation abnormality term) |
| Lymphadenopathy | Sign | Uncommon (helps distinguish from nodal PTCL) | HP:0002716 |
| Weight loss/B symptoms | Symptom | Variable | HP:0004325 |
| Hemophagocytic lymphohistiocytosis (HLH) | Complication/syndrome | 15–20% of cases; major prognostic determinant | HP:0005517 (Hemophagocytosis) |
Onset: Median age of presentation is reported variably across cohorts — roughly 30–46 years depending on series, with a female predominance; ~20% of cases occur in patients <20 years old, including infants (Dove Medical Press pediatric case series; PMC5660631 — 8-month-old infant case).
Progression/course: Classically indolent, relapsing-remitting cutaneous disease without extracutaneous spread in most cases; a minority develop HLH, which is associated with rapid deterioration and markedly worse prognosis. Upper-extremity involvement has been reported as an independent poor-prognostic clinical feature (EORTC study, Blood 2008;111:838).
Quality of life impact: Not systematically studied with validated instruments (EQ-5D/SF-36) in the literature reviewed; morbidity is driven primarily by recurrent cutaneous lesions and, in the HLH subset, systemic multi-organ dysfunction.
Causal/predisposition gene: - HAVCR2 (hgnc:18437; encodes TIM-3), 5q33.3. Germline biallelic (homozygous or compound heterozygous) or, in some series, monoallelic loss-of-function variants are strongly associated with SPTCL, particularly the HLH-complicated phenotype. OMIM entry #618398 frames SPTCL as having a defined germline genetic contribution via HAVCR2.
Key variants: - c.245A>G, p.Tyr82Cys (Y82C) — founder variant in East Asian/Polynesian populations; most frequently reported pathogenic allele (up to ~51% of an all-Japanese cohort) (Cancer Sci 2024). - c.291A>G, p.Ile97Met (I97M) — predominant in European-ancestry patients (Nat Genet 2018). - Both are missense, loss-of-function variants causing protein misfolding and failure of TIM-3 surface trafficking (functionally near-null alleles). - Zygosity: Homozygous or compound heterozygous germline genotypes correlate with more severe/HLH phenotypes; heterozygous carriage alone appears insufficient in some models, consistent with recessive inheritance for the HLH-prone phenotype, though case reports of a single confirmed homozygous 14-year-old female patient exist (PMID 34398459). - Somatic co-mutations: recurrent somatic TET2 mutations (epigenetic regulator); UNC13D, PIAS3, KMT2D mutations enriched in HAVCR2-wild-type tumors, suggesting at least partially distinct molecular subgroups (PMC11531942). - Enrichment of IL6-JAK-STAT3 and TNF-α/NF-κB transcriptional signatures in HAVCR2-mutant tumors provides rationale for JAK-inhibitor therapy (see Treatment).
Variant classification: HAVCR2 Y82C and I97M are generally reported as pathogenic/likely pathogenic loss-of-function alleles per functional (protein misfolding/trafficking) assays; population frequency in gnomAD is low but the Y82C founder allele shows regional enrichment in East Asian/Pacific populations.
Somatic vs. germline: The disease-defining HAVCR2 variants are germline (present in non-tumor tissue), distinguishing the genetic mechanism of SPTCL from typical somatically-driven lymphomas; additional somatic mutations (TET2, etc.) likely cooperate in clonal T-cell transformation.
Epigenetics: Limited direct data; TET2 (a DNA-demethylation enzyme) recurrent mutation implicates epigenetic dysregulation as a contributing somatic event, analogous to its role in other T-cell lymphomas (e.g., AITL, PTCL-NOS).
Chromosomal abnormalities: No recurrent SPTCL-specific translocation or aneuploidy has been established as a defining feature; TCR gene rearrangement (clonal) is used diagnostically rather than as a structural chromosomal marker.
Suggested gene/ontology terms: HGNC gene: hgnc:18437 (HAVCR2); GO biological process candidates: "negative regulation of inflammasome activation" (custom/at present no single precise GO ID exists but see GO:0043525-adjacent processes for regulation of neuron apoptosis is irrelevant — better: GO:0032621 "interleukin-18 production," GO:0032621/GO:0002218 "activation of innate immune response").
No specific toxin, occupational, radiation, dietary, or lifestyle exposure has been established as causally linked to SPTCL in the literature surveyed. No infectious agent (viral, bacterial, fungal, or parasitic) has been consistently implicated as an etiologic trigger, in contrast to some other T/NK-cell lymphomas (e.g., EBV in extranodal NK/T-cell lymphoma). One differential-diagnosis pitfall paper does note a peripheral T-cell lymphoma NOS case with HAVCR2 compound heterozygous mutation that was EBV-positive, but this represents a related/overlapping entity rather than an established SPTCL trigger (PMC9539911). No established gene-environment interaction data exist beyond the hypothesis that an unidentified inflammatory trigger unmasks HLH in HAVCR2-deficient hosts.
Causal chain (proposed model): 1. Germline HAVCR2 loss-of-function → TIM-3 protein misfolds and fails to reach the macrophage/dendritic-cell/T-cell plasma membrane. 2. Loss of TIM-3 inhibitory signaling on macrophages/dendritic cells removes a brake on the TLR–NF-κB pathway, ATP release, K+ efflux, and reactive oxygen species (ROS) production (Frontiers Immunology case report). 3. This lowers the threshold for NLRP3 inflammasome activation, driving excess IL-1β/IL-18 production and macrophage hyperactivation — mechanistically linking TIM-3 deficiency to both the panniculitic tissue infiltrate and, when uncontrolled, systemic hemophagocytic lymphohistiocytosis. 4. In parallel, clonal cytotoxic αβ CD8+ T cells (perforin/granzyme B/TIA-1–expressing) infiltrate and "rim" individual adipocytes within the subcutaneous fat lobule, driving adipocyte apoptosis, karyorrhexis, and fat necrosis — the histologic hallmark ("rimming"). 5. Somatic cooperating mutations (TET2 and others) and enrichment of IL-6/JAK/STAT3 and TNF-α/NF-κB signaling programs are proposed to support clonal T-cell survival/expansion.
Cellular processes: Cytotoxic T-cell–mediated apoptosis of adipocytes; macrophage/histiocyte hyperactivation and hemophagocytosis (engulfment of erythrocytes, leukocytes, platelets, and their precursors) in the HLH-complicated subset; chronic granulomatous-pattern fat necrosis.
Protein dysfunction: TIM-3 (HAVCR2 product) misfolding/loss of surface expression is the central molecular lesion identified to date; this is a loss-of-function immune-checkpoint defect rather than a classic oncogenic driver mutation.
Immune system involvement: Central to pathogenesis — SPTCL sits at the intersection of lymphomagenesis and autoinflammation/autoimmunity, given (a) the ~20% co-occurrence with autoimmune disease (especially SLE), (b) the checkpoint-deficiency mechanism causing innate immune hyperactivation, and (c) the frequent secondary HLH.
Tissue damage mechanisms: Direct cytotoxic T-cell killing of adipocytes; secondary necroinflammatory fat necrosis; in HLH, systemic cytokine-storm–mediated multi-organ injury (hepatic, marrow, splenic).
Suggested GO/CL terms: - GO:0097191 (extrinsic apoptotic signaling pathway) / GO:0001909 (leukocyte-mediated cytotoxicity) - GO:0002218 (activation of innate immune response); GO:0032621 (interleukin-18 production) - CL:0000625 (CD8-positive, alpha-beta T cell); CL:0000913 (effector memory CD8-positive, alpha-beta T cell); CL:0000439 (professional antigen-presenting cell) for macrophages/dendritic cells involved in NLRP3-driven hyperinflammation - CL:0000136 (fat cell/adipocyte) as the injured target cell population
Molecular profiling: RNA-sequencing/whole-exome sequencing studies (discovery cohorts of ~8 patients plus larger validation cohorts) have characterized the HAVCR2-mutant transcriptional signature (IL6-JAK-STAT3, TNF-NF-κB pathway enrichment) (PMC11531942; Blood Adv 2021, PMID 34535012). No large-scale single-cell, spatial transcriptomic, or proteomic datasets specific to SPTCL were identified in this search.
Epidemiology: SPTCL is exceedingly rare — accounting for <1% of all peripheral T-cell lymphomas and <1% of non-Hodgkin lymphomas overall. No dedicated national/SEER-level incidence figure specific to SPTCL was identified; it is generally described only through case-series aggregation.
Inheritance pattern (genetic subset): Where germline biallelic HAVCR2 loss-of-function is present, the pattern is consistent with autosomal recessive predisposition to the HLH-complicated phenotype (homozygous or compound heterozygous genotype associated with more severe disease); however, most reported cases are considered clinically sporadic even when the causal germline variant is identified (i.e., "sporadic" at the clinical-family level but molecularly germline/heritable) (Blood Adv 2019).
Penetrance/expressivity: Incompletely characterized; not all HAVCR2-mutant carriers develop SPTCL or HLH, implying incomplete penetrance and a likely requirement for additional somatic or environmental cooperating factors.
Founder effect: The HAVCR2 p.Tyr82Cys (Y82C) variant occurs on a shared founder haplotype in patients of East Asian and Polynesian ancestry; p.Ile97Met is more prevalent in patients of European ancestry — a clear population-genetic/geographic stratification (Nat Genet 2018).
Demographics: Reports consistently note a female predominance. Pediatric and adolescent presentation is well documented (~20% of cases <20 years).
Histopathology (gold standard): Deep incisional/excisional skin biopsy (not superficial punch) showing lobular panniculitis with atypical lymphocytes "rimming" individual adipocytes, karyorrhexis, fat necrosis, and cytophagic histiocytes (fat/lymphocyte engulfment by benign histiocytes — "beanbag cells") without epidermal involvement (PathologyOutlines; PMC2965923).
Immunohistochemistry: Neoplastic cells are CD3+, CD8+, βF1+ (αβ TCR), CD4−, CD56−, CD30−, with expression of cytotoxic markers TIA-1, granzyme B, perforin. An elevated Ki-67 proliferation index ("Ki-67 hotspots") among CD8+ rimming lymphocytes helps distinguish SPTCL from lupus panniculitis (PMID 26796503; PMID 29742552).
Molecular/genetic testing: Clonal TCR gene rearrangement (T-cell receptor gamma/beta) by PCR supports diagnosis. Germline HAVCR2 sequencing (Sanger or targeted NGS panel) is increasingly used, especially in cases with HLH or pediatric presentation, given the high mutation prevalence.
Differential diagnosis — SPTCL vs. lupus erythematosus panniculitis (LEP): LEP favors epidermal changes, reactive lymphoid follicles with germinal centers, mixed infiltrate with plasma cells, CD123+ plasmacytoid dendritic cell clusters, polyclonal TCR rearrangement, and low Ki-67; SPTCL favors monomorphous CD8+ rimming infiltrate, high Ki-67 "hotspots," and clonal TCR rearrangement. LEP and SPTCL can overlap and coexist in the same patient, and molecular studies of ~208 genes have shown genuine overlap cases exist on a disease spectrum (PMID 33966586; PMID 26796503).
Differential diagnosis — SPTCL vs. primary cutaneous γδ T-cell lymphoma: γδ phenotype (rather than αβ) predicts a much more aggressive course with frequent HLH, ulceration, and extracutaneous spread; distinguishing requires TCR-δ/βF1 immunostaining. Increased reactive γδ T cells within an otherwise αβ SPTCL is a described diagnostic pitfall (MD Anderson publication).
Imaging: ¹⁸F-FDG PET/CT is used for staging and to assess extracutaneous involvement/treatment response (Frontiers Oncology, 11 patients).
HLH work-up: When SPTCL is diagnosed, screen for HLH using the HLH-2004 criteria (≥5 of 8): fever, splenomegaly, cytopenia in ≥2 lineages, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis on marrow/spleen/node biopsy, low/absent NK-cell cytotoxicity, hyperferritinemia, elevated soluble CD25 (sIL-2R).
Staging: Cutaneous lymphoma TNMB (tumor, node, metastasis, blood) staging is applied per NCCN Cutaneous Lymphomas guidelines to define disease burden and guide skin-directed vs. systemic therapy selection.
Survival: Overall prognosis is favorable for the αβ (SPTCL proper) phenotype, with reported 5-year overall survival of 85–91% and 3-year OS around 85.2% in some cohorts (PMC8523605; EORTC study Blood 2008;111:838).
HLH impact: HLH complicates 15–20% of cases and is the single most important adverse prognostic factor, reducing 5-year OS to roughly 46%. HAVCR2-mutant (especially Y82C) cases show higher HLH incidence, greater HLH severity, and shorter relapse-free survival.
Other adverse prognostic factors: Upper-extremity lesion location has been associated with worse outcome (EORTC study).
Recurrence: Cutaneous relapse is common even after complete response to immunosuppressive therapy; ongoing surveillance is required.
Cause of death (when it occurs): Predominantly related to uncontrolled HLH/multi-organ failure or infection, rather than direct tumor-related organ failure from cutaneous disease itself.
First-line (non-HLH disease): Immunosuppressive therapy — systemic corticosteroids, alone or combined with low-dose methotrexate or cyclosporine A — is now generally preferred over cytotoxic polychemotherapy for uncomplicated disease, achieving complete response in up to 85% of treated patients in some cohorts. A French cohort found complete remission in 81.2% with immunosuppressive drugs vs. only 28.5% with polychemotherapy, and progression in 6.2% vs. 42.8% respectively (Acta Derm Venereol). Sustained CR rates were broadly comparable between chemotherapy (64%) and immunosuppressive therapy (55%) in another analysis.
therapeutic_agent bound to CHEBI terms for prednisone/prednisolone, methotrexate (CHEBI:44185), and ciclosporin (CHEBI:4031). Cyclosporine has also been proposed as upfront therapy even in aggressive-feature disease (PMC12778365).Radiotherapy: Used for localized/solitary lesions (NCIT:C15313, Radiation Therapy).
Chemotherapy: Multiagent regimens (e.g., CHOP-based) reserved for patients with HLH at presentation, or who progress on/are refractory to immunosuppressive therapy (NCIT:C15632, Chemotherapy). Pralatrexate has shown a significant response in a case of HLH-complicated SPTCL (PMC12593427).
HLH-directed therapy: Ruxolitinib (JAK1/2 inhibitor) has demonstrated efficacy in SPTCL-associated HLH, mechanistically rational given the IL6-JAK-STAT3 pathway enrichment in HAVCR2-mutant disease (Blood Adv 2020). Etoposide-containing HLH-directed regimens (e.g., HLH-94/HLH-2004-style, or CHOEP) have been used in severe/refractory HLH cases, sometimes bridging to autologous hematopoietic stem cell transplantation (PMID 23995110 — BFM-NHL/ALL-90 regimen plus autologous PBSCT).
Surgical/reconstructive: Dermal matrix (e.g., Integra®) reconstruction has been reported for extensive cutaneous defects in a multimodal management case (MDPI).
Experimental/novel: Emapalumab (anti-IFN-γ monoclonal antibody, approved for primary HLH) is mechanistically plausible for HLH-complicated SPTCL given interferon-driven macrophage activation, though this search did not surface SPTCL-specific published outcomes data for it.
Treatment algorithm summary: | Clinical scenario | Preferred approach | |---|---| | Uncomplicated cutaneous SPTCL | Corticosteroids ± methotrexate/cyclosporine (immunosuppressive-first) | | Localized/solitary lesion | Radiotherapy | | Refractory to immunosuppression | Multiagent chemotherapy | | SPTCL + HLH | Chemotherapy/HLH-directed regimen ± ruxolitinib; consider stem cell transplant in severe/refractory cases |
No established primary prevention strategy exists, as no modifiable environmental or infectious trigger has been identified. Secondary prevention/early detection centers on prompt deep biopsy of persistent subcutaneous nodules to avoid diagnostic delay (frequently misdiagnosed initially as benign panniculitis, cellulitis, or lupus panniculitis) and on proactive HLH surveillance (ferritin, triglycerides, fibrinogen, CBC) in confirmed SPTCL patients, particularly those with known HAVCR2 mutations, to enable rapid initiation of HLH-directed therapy. Genetic counseling may be considered for families with a germline HAVCR2 variant, given the (incompletely penetrant) autosomal-recessive-pattern association with HLH-complicated disease, though no formal cascade-screening guideline was identified in this search. No vaccine or prophylactic pharmacologic strategy is described.
No naturally occurring veterinary correlate of SPTCL specifically was identified in this search (unlike some other lymphoma subtypes with described companion-animal analogs in OMIA). TIM-3 (Havcr2) biology has been studied in mouse models: conditional deletion of TIM-3 in murine dendritic cells leads to ROS accumulation and NLRP3 inflammasome activation, and murine Tim-3-deficiency models have been used to demonstrate loss of the TLR–NF-κB inhibitory brake in macrophages, mechanistically recapitulating the human hyperinflammatory phenotype (Frontiers Immunology). These are gene-function models of the HAVCR2 pathway rather than spontaneous SPTCL-mimicking disease models. Orthologous gene: mouse Havcr2 (Tim-3), NCBI Gene.
| Domain | Suggested term |
|---|---|
| Disease | MONDO:0019475; OMIM:618398; ORPHA:86884; ICD-10: C86.3 |
| Causal gene | hgnc:18437 (HAVCR2) |
| Cell type | CL:0000625 (CD8+ αβ T cell); CL:0000136 (adipocyte); CL:0000235 (macrophage) |
| Anatomy | UBERON:0002190 (subcutaneous adipose tissue); UBERON:0002106 (spleen); UBERON:0002107 (liver) |
| Key phenotype | HP:0031477 (subcutaneous nodule); HP:0001945 (fever); HP:0005517 (hemophagocytosis); HP:0002155 (hypertriglyceridemia) |
| Treatment agent | CHEBI:4031 (ciclosporin); CHEBI:44185 (methotrexate); NCIT:C15986 (Pharmacotherapy); NCIT:C15632 (Chemotherapy); NCIT:C15313 (Radiation Therapy) |
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 25 |
| Resolved | 24 |
| Unresolved (possible confabulation) | 1 |
| Unverifiable | 0 |
| References weighed for topical relevance | 24 |
| On topic | 14 |
| Off topic | 0 |
These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:
DOI:10.1182/bloodadvances.2021004562/476947/Genetic-profiles-of-subcutaneous-panniculitis-like (2 mentions) - Identifier did not resolve to a recordChecked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 36 |
| Resolved | 33 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 2 |
| Terms whose name was checked | 20 |
| Terms named correctly | 13 |
| Terms named as a different term | 5 |
| Terms whose name is worth a second look | 2 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0031477 (2 mentions) - the report calls it "Subcutaneous nodule"; HP calls it obsolete Abnormal mitral valve morphologyHP:0012156 (1 mention) - the report calls it "Elevated serum ferritin, closest available; consider laboratory abnormality mapping"; HP calls it HemophagocytosisHP:0002716 (1 mention) - the report calls it "Uncommon (helps distinguish from nodal PTCL)"; HP calls it LymphadenopathyHP:0004325 (1 mention) - the report calls it "Variable"; HP calls it Decreased body weightHP:0005517 (2 mentions) - the report calls it "Hemophagocytosis"; HP calls it T-cell lymphoma/leukemiaThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
HP:0031477 (obsolete Abnormal mitral valve morphology) (2 mentions) - replaced by HP:0001633The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
CL:0000439 (1 mention) - the report calls it "professional antigen-presenting cell"; CL calls it prolactin secreting cellCL:0000136 (2 mentions) - the report calls it "fat cell/adipocyte"; CL calls it adipocyteTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM.