—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 4 - Cutaneous Gamma-delta T cell Lymphomas

Joan Guitart, Northwestern University, Chicago, IL





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Clinical History
This 74 year old male had a long history of mycosis fungoides and now presents with oral erosive lesions and an ulcerated tumor in the upper gingival mucosa. The patient also complaint of recent onset of daily fevers, asthenia and anorexia. Past medical history is significant for peptic ulcer disease and hyperlipidemia.

On examination multiple erythematous papulosquamous patches and plaques were noted mostly involving the extremities and face. The oral mucosa showed extensive erosive patches with an ulcerated tumor on the gingival mucosa. There was no evidence of lymphadenopathy or organomegaly.

A biopsy of the oral mucosa showed a tumor composed of intermediate size uniform mononuclear cells with cytoplasmic TIA-1 expression.


Case 4 - Figure 1
Case 4 - Figure 2
Case 4 - Figure 3

Cutaneous gamma-delta (γδ) T cell Lymphoma (CGDTL) is a rare condition which is still considered a "provisional entity" in the latest WHO-EORTC classification of cutaneous lymphomas [3] . CGDTL have been poorly characterized to date due to the lack of reliable immunomarkers. Historically, the diagnosis of CGDTL from paraffin embedded material was basically a presumptive diagnosis, relying on the absence of αβ T cell receptor (TCR) heterodimer expression on the tumor cells. The diagnosis of a CGDTL could only be established with certainty by flow cytometry of tissue samples or on frozen sections by immunohistochemistry. Recently, a new method to identify the gamma chain of the γδ TCR heterodimer in paraffin-embedded tissue was reported [17]. We recently analyzed the clinical, pathological and immunophenotypic features of a cohort of CGDTL using this method. The diagnosis of CGDTL was based on expression of the γδ heterodimer on the tumor cells by immunohistochemisty or flow cytometry. In most cases, the monoclonal antibody gamma M1 (clone γ3.20, Thermo/Fisher Scientific, Waltham, MA) was used according to the retrieval method described by Roullet et al [17].

Fifty-four patients (30 male, 22 female, 2 unknown) with a median age of 60 years (range 7-91 years) were diagnosed with CGDTL. Most subjects were Caucasian (39) with 3 Hispanics, 2 blacks, 1 Asian and 9 subjects of unknown or unreported race. The median duration of the lesions at the time of presentation was 2 years ranging from 1 month to 20 years. In 23 subjects the onset of symptoms was within one year at the time of presentation. Multifocal or generalized (T3) skin involvement without anatomic preference at presentation was reported in 38 patients [11]. Thirteen patients presented with a solitary lesion (T1) or localized involvement in one anatomic region (T2). These localized lesions often presented clinically as unilesional with a clinical impression of cellulitis, hematoma, pyoderma or an arthropod bite reaction (Figure 1a). Some of these lesions were deep involving the subcutaneous soft tissue or underlying structures like salivary glands. The most common site of involvement at presentation was the legs (37) followed by the torso (28) and arms (25). The head and neck region was affected less frequently (15), but in some patients the lesions were exclusive confined to this region. Mucosal lesions were rare (2). Most patients presented with large and deep indurated plaques with a panniculitic appearance (38). The plaques were eroded at presentation or eventually became ulcerated with a hemorrhagic and necrotic appearance in 60% (27/45) of the patients. Ten patients presented with chronic scaly erythematous patches resembling psoriasis or mycosis fungoides often with superimposed superficial erosive features. Constitutional symptoms were reported in 54% (25/46) of the patients at the time of presentation, including some patients with limited skin involvement.

Co-morbidities at the time of presentation were common including 5 patients with other lymphoproliferative disorders, 4 patients had carcinoma (2 prostate, 1 thyroid and 1 pharyngeal) and 2 patients had hepatitis C. Concurrent illness associated with immune dysregulation was also noted in several patients including hypothyroidism secondary to Hashimoto's thyroiditis (3S) and one patient each with Crohn's disease, temporal arteritis, alopecia areata, celiac disease/uveitis/arthritis, and sarcoidosis. Four patients carried the diagnosis of "lupus panniculitis", which for the most part was directly related to the lesions eventually diagnosed as CGDTL with a panniculitic pattern. None of the patients had a history of immunesuppression from either HIV infection, post-organ-transplant or other causes. Lymphadenopathy was noted in 3 of 38 patients at presentation, but biopsies were not obtained. Serum lactose dehydrogenase levels (LDH) were increased at the time of presentation (>200 U/L) in 55% (22/39) of the patients with a median LDH level of 273 U/L and ranging from 91-2800 U/L. . Bone marrow biopsies were mostly negative, with 21% (6/29) reported as positive including 4 patients with signs of hemophagocytosis.

Results from imaging studies at presentation were available for 36 patients and were reported positive in 20 patients, most commonly demonstrating PET avid subcutaneous tumors with only one patient with nodal involvement and one patient with pleural/lung uptake. One patient progressed with tumor involvement in the testes and three patient developed mental status changes with confirmation of tumor by brain imaging (3/3) and cerebrospinal fluid involvement by flow cytometry (2/3). Three patients had lymphomatous involvement of the gastrointestinal tract concurrently or after the skin lymphoma was diagnosed. A prominent pagetoid pattern was noted in the skin biopsies of 2 of these 3 patients.

Follow up information was available on 47 patients with a median follow-up time of 18 months (range 1-107 months). Twenty-six patients (57%) died of disease or complications of treatment, including 4 patients with hemophagocytic syndrome (HPS) and complications of central nervous system (CNS) involvement in 3 patients. The 5-year overall survival rate is 21.3%. All 4 patients with HPS died of disease, but this finding was not statistically significant (p=0.10). All 6 patients presenting with mycosis fungoides-like lesions survived, which was statistically significant, although the number of patients was small. No other factor was found to be prognostic of survival, including single anatomical site at presentation, panniculitis-like presentation, ulceration of the lesions or pathological evidence of vasculitis (Table 1).

We reviewed a total of 61 skin biopsies from 54 patients. The pattern of the lymphoid infiltrate was variable ranging from a pagetoid pattern to cases with exclusive subcutaneous tissue involvement. In some patients diverse patterns were noted in biopsies obtained simultaneously or at different times.

Most cases had a dense infiltrate with partial involvement of epidermal, dermal and subcutaneous compartments. The epidermal component was predominantly a junctional lymphoid infiltrate often accompanied by superficial hemorrhage and subtle exocytosis of erythrocytes. Fourteen cases had an initial presentation resembling mycosis fungoides with an interface lymphoid infiltrate involving the lower epidermal layers, occasionally with vacuolar degeneration of the basal cell layer and scattered necrotic keratinocytes. Variable acanthosis and hyperkeratosis was noted, but Pautrier microabscesses were not observed in any cases. Three cases had significant pagetoid features with atypical lymphocytes involving the entire epidermal thickness. We also noted adnexotropism in 2 of these pagetoid cases.

A dermal lymphoid infiltrate was a common feature with the density ranging from a mild perivascular to confluent and deep nodular infiltrates. A dermal epicenter of the infiltrate was noted in 58% (34/59) of the biopsies. Involvement of the subcutaneous tissue was noted in 24 of 40 biopsies with subcutaneous tissue available for evaluation. However the subcutaneous tissue was absent in 18 biopsies. A predominantly panniculitic pattern was identified in 18 biopsies (Twelve of these cases were also associated with extensive necrosis and karyorrhexis. Cytotoxic features included hemorrhage (35) or rarely a vasculitic pattern with fibrinoid necrosis. Subcutaneous fat necrosis with karyorrhexis was noted in 11 cases and hemophagocytosis in 4 cases. A histocytic-rich infiltrate was noted in 8 cases including 4 cases with granulomatous. The cytological detail of these lymphomas was rather monomorphous and consisted predominantly of medium-sized lymphocytes with a few case characterized by a predominantly large cell infiltrate (7 cases).

All cases analyzed by immunohistochemistry were CD3 positive and βF1 negative. The null phenotype CD4-/CD8- seen in 29 cases was more common than CD8+ (20) or CD4+ (5). CD30 was mostly negative. Gamma/delta T –cell phenotype was inferred in all cases by the absence of βF-1 expression and/or by the expression of gamma M1. In addition γδ markers were also positive by flow cytometry in 4 cases including samples from skin, CNS or bone marrow. The 3 gamma M1 negative cases were also negative for βF1 and CD5. Gamma M1 was not detected in 11 cases due to insufficient material or technical difficulties with the sections. CD56 was positive in 35% (18 cases) of the cases and CD5 was only positive in 12% (6) of the cases. CD45RA was expressed in 35% (12) of the cases and CD7 was positive in 28% (13) of the cases.

Based on our experience, CGDTL tends to present with extensive and deep indurated plaques on the extremities, which may resemble inflammatory panniculitis. However, unlike inflammatory panniculitis the process is usually more extensive with a tendency to ulcerate during the course of the disease. Our data did not confirm a worse prognosis for patients with a subcutaneous presentation as compared to more superficial variants as reported by others [21]. Another subset of cases was characterized by a solitary or multiple lesions confined to one anatomic region. Clinically, this presentation resembled other conditions like pyoderma, cellulitis, hematoma or arthropod bite reaction, but was associated with constitutional symptoms, high LDH levels and carried an equally poor prognosis. Therefore unlike other cutaneous lymphomas, the skin tumor burden does not appear to correlate with prognosis. This observation was also noted in a recent report of a patient with a single lesion on the left foot who died of CNS involvement six months after presentation [24]. We identified a third subset of patients presenting with chronic erythematous and scaly patches resembling mycosis fungoides (MF) or psoriasis. While some of these patients evolved into a more aggressive phase with extensive ulceration of the patches and tumor formation, the overall survival of this group was significantly better and some patients have remained with indolent patch lesions for several years of follow up. With the exception of a few cases presenting with a pagetoid pattern, these patches differ from MF by the absence of Pautrier microabscesses and the frequent association with scattered necrotic keratinocytes. During the indolent patch phase, γδ cells are not activated lacking TIA-1 and granzyme B expression. Conversely, cytotoxic molecules are almost invariably expressed during tumor progression when the lesions become ulcerated. An activated cytotoxic phenotype with expression of granzyme B was associated with a poor prognosis (p=0.017). Unlike previous reports [1], we did not find mucosal lesions to be particularly prevalent among our cohort. Only one patient with a long history of patches developed tumor lesions in the oral mucosa and gastric mucosa and another patient also with patch lesions developed oral apthous ulcers and necrotic papules in the extremities with the biopsies showing infiltrates composed primarily of γδ T cells. Furthermore, we have followed other patients not included in this study presenting with waxing and waning papules composed of atypical γδ T cells with CD30 expression. In our experience this rare variant of lymphomatoid papulosis behaves in an indolent fashion similar to conventional lymphomatoid papulosis (JG personal observation).

The myriad of clinical and pathological presentations of these cutaneous γδ T cell proliferations challenges the concept of CGDTL as a distinct entity. For instance, some cases were purely subcutaneous (panniculitis-like) while others presented with a predominantly epidermotropic pattern corresponding to the now obsolete diagnosis of "generalized pagetoid reticulosis" or "Kettron-Goodman's disease". Two of the pagetoid cases in our cohort had evidence of lymphoma in the GI tract. Similar CGDTCL cases presenting with a pagetoid pattern and associated with hepatosplenic or GI tract γδ T-cell lymphoma have been reported [1, 9, 15]. These pagetoid CGDTCL cases also seem to overlap with PCAECTCL, another rare and aggressive skin lymphoma. For example, two of these pagetoid cases expressed CD8, one was adnexotropic with tumor cells infiltrating eccrine glands and pilosebaceous units and one of these cases also expressed CD45RA, a marker of naïve T-cells also expressed by PCAECTCL and intestinal γδ T-cell lymphomas. We also noted in some cases extensive histiocytic infiltrates with or without granuloma formation. Histiocytic-rich infiltrates in γδ lymphomas have been observed by others and may represent an intrinsic component of the tumor or could be a consequence of tumor necrosis [5].

Several of our patients had co-morbidities associated with immune-suppression including other lymphoproliferative conditions, immune dysregulation, other malignancies and pregnancy. Chronic antigenic stimulation has been hypothesized to play a role in the pathogenesis of CGDTCL [22]. This premise is supported by the clonal expansion of γδ T cells which has been observed in patients with celiac disease, Crohn's disease, renal allografts, lupus erythematosus, rheumatoid arthritis, multiple sclerosis and Hodgkin lymphoma [2, 10, 23]. There are also reports of γδ T-cell lymphomas associated with opportunistic infections occurring in patients in congenital and acquired immune-suppression and autoimmunity [1, 10, 13, 20]. Several of our patients had other lymphoproliferative disorders or clonal B cell populations in the blood. This association of CGDTCL with B cell clonality was also noted by Toro et al [20], who favored lineage infidelity with dual rearrangements bigenotypic tumor cells, a finding common in HIV and other immune-suppressive states. We also noted co-morbidity with lupus erythematosus, an association that has also been reported in patients with αβ subcutaneous panniculitis-like T cell lymphoma (αβ-SCPLTCL) [16]. Some of these initial skin biopsies in our cases showed dermal mucin deposits and an interface vacuolar reaction. An interface pattern in CGDTCL resembling lupus erythematosus was also noted by Massone et al [14]. The pathomechanistic connection between these precursor biopsies resembling lupus and CGDTCL has not been elucidated. Likewise, a panniculitic precursor resembling lupus profundus was observed in one of our patients. Another case report of a patient with an atypical lymphocytic lobular panniculitis for 15 years with eventual progression into an aggressive CGDTCL emphasizes the disparity of presentations and the fact that while many patients have a rapid aggressive course, others may have a prolonged cutaneous lymphoid process that is difficult to categorize [8]. As previously noted, an atypical lymphoid infiltrate involving the dermis and subcutaneous tissue is an important clue for the diagnosis of CGDTCL [19, 21]. A pure panniculitic pattern, as seen in αβ-SCPLTCL, was rarely observed in our cohort. We observed variable patterns of the lymphoma infiltrate (i.e. superficial vs. deep subcutaneous) even when simultaneous biopsies where obtained from different anatomic sites of the same patient. This inconsistency of histopathological patterns noted in CGDTCL suggests that multiple skin biopsies may be required for proper evaluation.

Chronic EBV infection and viral integration may play an etiologic role in a subset of CGDTCL cases. The first case of EBV-induced GDTCL was recently reported by Caudron et al [4]. Five of our cases showed strong EBV expression in the tumor cells, including a child with hydroa vacciniforme- like lymphoproliferative disorder and two adults; one of whom had an angiotropic lymphoma and another patient who developed nasopharynx involvement upon follow up. Similar cases overlapping with NK/T cell lymphoma have been reported. Occasionally GDTCL can express one or more NK cell markers (CD16, CD56, CD57) and there is evidence that normal NK/T cells comprise subsets of γδ T cells. Therefore clinical and pathological overlap with NK/T cell lymphomas may be observed in exceptional cases [1, 2, 22].

In our experience, the lack of CD5 expression is associated with the γδ phenotype, but CD56 expression was often negative and hence not reliable to define γδ T- cells. Three skin biopsies specimens were negative with both the γδ and for the αβ TCR heterodimer antibodies, but γδ expression was detected by flow cytometry in one of them. This lack of TCR expression may reflect persistent limitations of the present immunohistochemistry techniques on paraffin tissue or could be consistent with the recently introduced concept of "TCR silent" lymphomas [6]. While CD4/CD8 double negative was the most common immunophenotype, we observed numerous CD8 positive and rare CD4 positive cases, as previously reported [4, 18] . This immunophenotypic model may replicate the distribution of normal human γδ T cells which are mostly double negative with fewer cells expressing CD8 and only rare cells expressing CD4 [7]. We also noted a switch of phenotype from CD4 to CD8 at the time of tumor progression in one of our patients.

For the most part all therapies have shown modest effectiveness. Neither radiation, immune therapy nor multiagent chemotherapy has resulted in sustained remissions. Only one of four patients treated with myeloablative AHSCT was alive with a partial remission at the end of the study. However, a case with complete remission for 23 months following AHSCT was recently reported [12]. Cytarabine combined with platinum-containing dose-intensive chemotherapy consolidated with AHSCT has been suggested as the best therapeutic option for eligible patients [22].

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