We retrospectively analyzed eight cases of ITLPD-GI diagnosed between January 2018 and January 2024, including six in-house biopsy specimens and two consultation cases. All pathology slides were independently reviewed by two senior hematopathologists specializing in lymphoma, with the final diagnosis established according to the 2017 WHO classification criteria for hematopoietic and lymphoid neoplasms.

Histopathological examination: Tissue specimens were fixed in 10% neutral buffered formalin, routinely processed for paraffin embedding, and sectioned at 4 μm thickness for hematoxylin-eosin (HE) staining and light microscopic evaluation.

Immunohistochemistry (IHC): The EnVision two-step method was employed using primary antibodies against CD2, CD3, CD5, CD7, CD4, CD8, CD56, CD20, CD79α, TIA-1, granzyme B, and Ki-67 (all purchased from Zhongshan Golden Bridge Biotechnology, Beijing, China). Staining procedures followed the manufacturer’s protocols.

T-cell receptor (TCR) gene rearrangement analysis: Genomic DNA was analyzed using the BIOMED-2 multiplex PCR protocol (Europe) on an ABI 3500DX Genetic Analyzer. The assay covered TCRβ (Vβ-Jβ and Dβ-Jβ segments), TCRγ (Vγ1-11-Jγ segments), and TCRδ (Vδ-Dδ-Jδ segments). All procedures were performed in strict accordance with the manufacturer’s instructions.

The cohort comprised eight patients (five women, three men) with a mean age of 42 years (median: 45 years), demonstrating a female predominance (F:M ratio 1.7:1). All patients presented with chronic diarrhea and abdominal pain, while concurrent symptoms included fever (n=3), vomiting (n=2), and hematochezia (n=1). Notably, one patient was initially identified by laboratory findings of lymphocytosis (WBC 12-15×10⁹/L, lymphocyte percentage 80%) before developing diarrhea.

Endoscopic evaluations revealed erosive changes with multiple ulcers and mucosal hyperemia/edema (n=3); multiple small protrusions with diffuse villous shortening, flattening, and granular appearance (n=3); combined ulcerative and protrusive lesions (n=1); and normal endoscopic findings (n=1). All cases had multi-site gastrointestinal involvement, with six cases having small intestine involvement (n=6), including two cases with concurrent large intestine involvement and one with additional gastric involvement. Two cases had isolated large intestine involvement ( Figure 1 ).

Therapeutic interventions yielded variable responses:

Gross examination: All specimens consisted of 2–5 endoscopic biopsy fragments (diameter: 2–3 mm).

Microscopic findings: All eight cases exhibited identical histological features. Glandular architecture: Atrophy of gastric/intestinal mucosal glands. Infiltrate pattern: Dense, monotonous lymphoid infiltration confined to the lamina propria ( Figures 2A, B ). Cytomorphology: Small lymphocytes with scant cytoplasm; round to mildly irregular nuclei with condensed chromatin; inconspicuous nucleoli; rare mitotic figures or apoptosis. Key negative findings: No angioinvasion, necrosis, or lymphoepithelial lesions; infiltration strictly limited to the mucosal layer ( Figures 2C, D ). Additional observations: Mild scattered plasma cells and eosinophils in the superficial mucosa (six cases); prominent plasma cell infiltration in the superficial mucosa (two cases) ( Figure 3A ).

T-cell markers: Pan-T markers [CD2( Figure 2E ), CD3 ( Figure 2F ), CD5 ( Figure 2G ), CD7 ( Figure 2H )] were positive in five cases. One case with limited panel: CD3+ only. Two consultation cases: Case 1: CD3+/CD5+/CD7+; Case 2: CD3+/CD5+. CD4/CD8 subsets: CD4-/CD8+ (five cases, Figures 2I, J ): TIA1+ ( Figure 2M ) /Granzyme B- ( Figure 2N ) (three cases), TIA1+/Granzyme B+ (one case), not tested (one case); CD4+/CD8+ (two cases): TIA1+/Granzyme B- (one case), not tested (one case); CD4+/CD8- (one case, not tested). Aberrant markers: CD20+ (two cases, Figure 2K ), one co-expressed PAX5 (but CD79α-, Figure 2L ). CD56- in all cases. Proliferation index: Low Ki-67 (<15%, Figure 2O ). Plasma cell infiltration: CD138+ plasma cell clusters in the superficial mucosa (two cases, Figure 3B ). TCR gene rearrangement: Monoclonal TCR rearrangement confirmed in 4/4 tested cases; four cases not tested (see Table 1 ).

ITLPD-GI remains exceptionally rare, with less than 80 cases reported in the literature as of 2021, and a total of less than 90 documented cases (4–9). Our cohort of eight patients (F:M ratio 1.7:1, mean age 42 years) showed a slight female predominance compared to previous reports (M:F ≈1.5:1) (4), which may reflect the limited sample size.

The exact etiology is unknown, but persistent antigen stimulation—potentially driven by immune-mediated or infectious conditions (e.g., IBD, viral infections, autoimmune disorders, or Helicobacter pylori infection)—is hypothesized to play a role (1–3). In our series, three cases arose from long-standing inflammatory bowel disease (IBD; Crohn’s disease/ulcerative colitis), supporting the theory of chronic immune stimulation leading to monoclonal T-cell proliferation (9). Notably, TNF-α inhibitors have been implicated in triggering ITLPD-GI, with documented regression upon discontinuation (10).

Typical symptoms: Diarrhea, abdominal pain, fever, vomiting, and hematochezia, consistent with previous reports (4–9).

Novel findings: One case presented with peripheral lymphocytosis (WBC 12–15×10⁹/L, LY% 80%), possibly linked to sustained antigen exposure, although further studies are needed.

Other rare manifestations: Our cohort included tetany while the literature also describes refractory oral ulcers, anal fistulae (8, 9, 11), metabolic disturbances (hypocalcemia/hypokalemia/hypomagnesemia/hypozincemia), and neurological symptoms (paresthesia, confusion) (1). Asymptomatic cases are occasionally detected incidentally during endoscopy or lymph node biopsy (12).

Gastrointestinal involvement: All cases exhibited multi-site involvement (six cases: small intestine ± large intestine/stomach; two cases: large intestine only), aligning with published data (4–9, 13). Lesions predominantly affected the small bowel/colon, with sporadic gastric/esophageal involvement, typically showing discontinuous focal distribution.

Extraintestinal spread: In patients with this condition, rare cases involve the liver, bone marrow, peripheral blood, or lungs (4, 6, 9, 14, 15), with isolated reports of vitreoretinal infiltration (16).

None of the eight cases displayed pathognomonic endoscopic findings. Observations included erosions, shallow ulcers, mucosal hyperemia/edema, and villous shortening (one case appeared normal), mimicking IBD. Notably, mass formation or perforation is uncommon (4–9, 13).

Currently, there is no consensus on the treatment of ITLPD-GI, with “watchful waiting” being the primary recommended strategy (4, 9). Conventional chemotherapy typically shows limited efficacy (4), although some alternative therapies have demonstrated certain therapeutic effects. Low-dose radiotherapy (30 Gy/20 fractions) successfully treated a gastric case with 1-year recurrence-free survival (27). Furthermore, corticosteroids or anti-CD52 monoclonal antibodies can improve symptoms (3, 5). Metronomic chemotherapy (prednisone + cyclophosphamide + thalidomide) achieved 1-year clinical remission in patients with severe symptoms (5).

In our case series, of the two patients treated with prednisone plus thalidomide, one showed improvement after 9 months, while the other still experienced diarrhea and anxiety after 35 months, suggesting the need for psychological intervention. Of the five patients receiving symptomatic treatment, four showed varying degrees of symptom improvement (although with residual diarrhea, vomiting, or fever), while one achieved complete resolution. Notably, one CD20-positive patient with ITLPD-GI showed no response to rituximab after 14 months of treatment, indicating that its efficacy in T-cell lymphomas requires further validation (19).

Although ITLPD-GI typically follows an indolent course (median survival >10 years) (4), there is a risk of progression. ITLPD-GI can transform into aggressive T-cell lymphomas (e.g., ALCL), often with hepatic/bone marrow involvement and an extremely poor prognosis (2, 11, 20). The transformation mechanism may correlate with the CD4-positive phenotype (accounting for 60% of progressive cases) or genetic mutations, while CD8-positive cases may have a better prognosis (11, 13, 20). Additionally, ITLPD-GI may coexist with other lymphomas (e.g., diffuse large B-cell lymphoma, Hodgkin’s lymphoma) (28, 29) or autoimmune diseases (this series is the first to report co-occurrence with Castleman disease and celiac disease, the latter improved with a gluten-free diet). Notably, one case initially misdiagnosed as EATL showed a transient response to a PD-1 inhibitor before progressing to confirmed ITLPD-GI, highlighting the diagnostic complexity. However, this study has limitations. Given the rarity of ITLPD-GI, only eight cases were included. Future research should expand the cohort and investigate molecular mechanisms to refine treatment strategies.

In conclusion, ITLPD-GI is a rare indolent monoclonal T-cell proliferative disorder with non-specific clinical and endoscopic manifestations, requiring differentiation from aggressive T-cell lymphomas (e.g., MEITL, EATL) and IBD to avoid misdiagnosis and unnecessary treatment. Diagnosis primarily relies on histopathology (mucosa-limited small lymphocyte infiltration) and immunohistochemistry, while TCR gene monoclonal rearrangement testing is crucial for confirmation in cases with atypical immunophenotypes (e.g., aberrant CD20 expression). The disease typically follows an indolent course, potentially associated with chronic antigen stimulation (e.g., IBD, infection), with the majority of patients having a favorable prognosis, and “watchful waiting” being recommended. However, a minority of cases may progress to aggressive T-cell lymphoma with a significantly worse prognosis, although the exact transformation mechanisms remain unclear. Therefore, enhancing awareness among clinicians and pathologists is critical, and future research should further explore the molecular mechanisms to optimize treatment strategies.