Are You Confident of the Diagnosis?

Five distinct cutaneous T-cell lymphoma variants (ATLL, LyP, ALCL, SPTL, and CGD-TCL) are presented with how best to identify them based on their clinical presentation, physical findings, and diagnostic studies.

Each of the five variants of cutaneous T-cell lymphoma has its own clinical presentation. ATLL can present with erythroderma, infiltrated plaques, papules, patches nodules and even tumors. ALCL predominantly presents as violaceous to red brown solitary nodules or tumors. They can also present in a localized fashion and in some cases may have ulceration present. LyP will present with reddish-brown necrotic papules and/or nodules of the skin. These are typically in varying stages at clinical presentation. SPTL will present with a solitary nodule or plaque that typically is located on the lower extremity. These nodules may become numerous and generalize over time. The last form CGD-TCL presents with disseminated plaques with or without ulceronecrotic nodules and tumors.

In Adult T-cell leukemia/lymphoma (ATLL) there are four clinically distinct entities: acute, chronic, smoldering and lymphomatous:

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Acute ATLL is characterized by the presence of leukemia, lymphadenopathy, organomegaly, hypercalcemia and skin lesions (in approximately 50%).

The lymphomatous type is characterized by lymphadenopathy without extranodal lesions, lymphomatosis or hypercalcemia, and with sporadic leukemic cells in less than 1%.

The chronic type is characterized by lymphocytosis, elevated LDH, and no hypercalcemia with 5% or more of atypical lymphocytes in the blood.

The smoldering variant of ATLL is characterized primarily by skin lesions, which closely resemble mycosis fungoides in presentation and bears a more favorable prognosis than the other variants.

Cutaneous manifestations are generally a presentation of disseminated disease and can occur in 43-72% of cases. ATLL can appear on the skin as erythroderma, infiltrated plaques, localized or generalized macules, papules, patches, nodules, or tumors.

Expected results of diagnostic studies

The gold standard for the diagnosis of ATLL is a positive HTLV-1 serology. Other findings include cytologic or histopathologic evidence of leukemia or T-cell lymphoma, presence of abnormal T-lymphocytes in blood smears, and demonstration of monoclonal HTLV-1 proviral integration. Histopathological findings may simulate mycosis fungoides with a superficial lymphocytic infiltrate with epidermotropism, but can also have a dense infiltration of medium-sized to large pleomorphic and epidermotropic T-cells. Skin lesions in the smoldering type may have sparse dermal infiltrates with only slightly atypical cells.

Most cells exhibit a CD3+, CD4+, CD25+ and CD8- phenotype. HTLV-1 preferentially infects and transforms CD4+ T-cells, but may also infect CD8+ T-cells, and, thus, occasionally, ATLL may have a CD8+ phenotype. Tumor cells are commonly positive for Fox-P3. It may be difficult to distinguish the chronic and smoldering variants of ATLL from mycosis fungoides (MF). A true distinction can only be made by positive HTLV-1 serology or by demonstration of clonally integrated HTLV-1 and an abnormal population of CD25 expressing cells on flow cytometry for those with systemic involvement.

ATLL immunophenotyping shows the tumor to be CD3+, 4+, 25+, CD8-, and FoxP3 +/-.

Primary cutaneous CD30+ disorders account for approximately 30% of all CTCLs. Two of its subtypes are lymphomatoid papulosis (LyP) and anaplastic large cell lymphoma (ALCL). (Figure 1, Figure 2). The diagnosis of primary cutaneous ALCL versus LyP is based on clinical presentation and disease course. LyP is classically defined as a chronic, recurrent and self-healing process even though its histologic features may be suggestive of a malignant lymphoma. Though lesions in primary cutaneous ALCL frequently spontaneously resolve, resolution may be prolonged without therapy and typically occurs with scarring, and, thus the course is more often altered by initiation of a therapeutic regimen.

Figure 1.

Lymphomatoid papulosis.

Figure 2.

Anaplastic large cell lymphoma.

Primary cutaneous ALCL occurs mainly in adults with a higher prevalence in men than women. Its presentation is characterized by solitary or localized violaceous to reddish-brown nodules or tumors, and sometimes papules that can show ulceration. Multifocal lesions are seen in 20%. Like LyP, skin lesions can regress, but more often result in a partial rather than complete resolution.

On histopathology, there is evidence of a diffuse, nonepidermotropic infiltrate with cohesive sheets of large CD30+ tumor cells that are mostly anaplastic cells on morphology (round, oval or irregularly shaped nuclei). Less commonly tumor cells have a Reed-Sternberg like appearance. Reactive lymphocytes can be seen along the periphery of the lesion, while those with ulceration may have an abdundant inflammatory infiltrate of reactive lymphocytes as in LyP. The neoplastic cells are mostly CD4+ (though less than 5% may have CD8+ expression) and CD30+ (by definition more than 75%), and express cytotoxic proteins such as granzyme B, TIA-1 and perforin. Most lesions demonstrate a clonal rearrangement of the T-cell receptor.

The distinction of primary cutaneous ALCL from systemic ALCL is imperative given that skin is the most common extranodal site of disease. In contrast to a systemic CD30+ lymphoma, the cutaneous variant expresses cutaneous lymphocyte antigen (CLA), while epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK) are absent. ALK is commonly positive in patients with systemic disease and in those with evidence of secondary cutaneous manifestations. The (2;5)(p23;q35) translocation is rarely seen in cutaneous ALCL.

LyP occurs mostly in young adults as violaceous to reddish-brown papular, papulonecrotic, and/or nodular skin lesions at different stages of development. They are commonly initially misdiagnosed as insect, spider or mosquito bites. They occur mostly on the trunk and proximal extremities. They are usually less than 1cm in size, self healing, and may disappear within 3-12 weeks leaving behind superifical scars. Larger tumors may occur implying a morphological variant rather than transformation into an aggressive lymphoma. The time interval between eruptions is variable from patient to patient, ranging from weeks to several years.

The histology is divided into three different subtypes (types A, B and C). Type A lesions are wedge-shaped and have evidence of scattered or small clusters of large CD30+ cells mixed with histiocytes, small lymphocytes, neutrophils, and/or eosinophils. Type B lesions are uncommon (less than 10%) and are characterized by a wedge-shaped or sometimes band-like infiltrate of epidermotropic small atypical cells with cerebriform nuclei, similar to the histopathology observed in MF. Unlike the other types, these cells do not express the CD30 antigen. Type C lesions have a nodular infiltrate of sheets of large CD30+ T-cells with few inflammatory cells. 60-70% of patients have a clonally rearranged T-cell receptor. However, despite its clonality, it does not necessarily behave like a malignant disorder.

Histologically, the distinction between ALCL and LyP is based on the density of CD30+ tumor cells and the extent of dermal and subcutaneous involvement. In LyP, cells are scattered and found in the upper dermis. In ALCL, the cells are in sheets and extend from the D-E junction down to subcutaneous fatty tissue. However, at times these entities may histologically overlap, which then requires us to rely on clinical history for an accurate diagnosis.

The clinical differential diagnosis for LyP is broad, but commonly includes pityriasis lichenoides et varioliformis (PLEVA), CD30+ pseudolymphomas, and insults by an arthropod. In PLEVA the skin lesions can be hemorrhagic papules. Necrosis of individual keratinocytes is common in PLEVA, but lacking in LyP. LyP is mostly CD4+ CD30+, whereas PLEVA is mostly CD8+. LyP may also be confused with CD30+ pseudolymphomas. Gene rearrangement studies reveal a polyclonal population in those patients, in contrast to LyP. Nodular scabies may also clinically resemble LyP. In scabies, though the cells are CD30+, they express B-cell antigens, in contrast to T-cell antigens in LyP.

The immunophenotype of ALCL is CD2+, CD3+, CD4+, CD5+, CD30+, CD8 -(+), TIA-1 +, CD56 – (+), and MUM-1 +.

The immunophenotype of LyP is CD2+, CD3+, CD4+, CD5+, CD30+, CD15 -, CD8 – , TIA-1 – (+), CD56 – (+), and MUM-1 +

When comparing and contrasting ALCL and LyP there are clinical and histological differences, ALCL presents with localized nodules that will occasionally self heal. ALCL can on occasion show systemic spread. LyP presents with a few to multiple papules. These papules will almost always ulcerate and self heal. There is rarely systemic spread with LyP. Histology in ALCL will show clusters of CD30+ cells in a mixed background that can appear like Hodgkin’s disease. Many mitoses are present. This is in contrast with LyP where there are few to many Cd30+ cells, many inflammatory cells, a variable amount of cerebriform T-cells, and multiple mitosis.

Subcutaneous panniculiti-like T-cell lymphoma (SPTL) alpha/beta (AB type) occurs in both young children as well as adults, and affects both sexes equally. Patients present with solitary or multiple erythematous nodules or plaques which mainly involve the legs, but can become more generalized involving the arms, trunk, and very rarely the face in areas of adipose tissue. Ulceration is rarely present.

The disease may be preceded for many years by what appears to be a benign panniculitis since skin lesions may simulate erythema nodosum, lupus panniculitis, or other panniculitic diseases. Once lesions resolve, they may result in lipoatrophy. Patients may also present with systemic symptoms including fevers, chills, night sweats, fatigue and weight loss.

SPTL-AB is defined as a cytotoxic lymphoma characterized by a subcutaneous, nodular or diffuse, atypical lymphoid infiltrate mimicking a lobular panniculitis with small, medium-sized, or sometimes large pleomorphic T-cells with hyperchromatic nuclei. Rimming of fat cells by neoplastic T-cells is a helpful, but non specific diagnostic sign. Septal involvement is generally absent. Necrosis, karyorrhexis, and cytophagocytosis are common findings. The overlying dermis is occasionally involved while the epidermis is usually not involved. The neoplastic cells demonstrate clonal rearrangment and by immunophenotyping are alpha/beta+ (betaF1 positive), CD3+, CD4-, and CD8+. They also strongly express cytotoxic proteins including granzyme B, TIA-1, and perforin.

Patients are commonly misdiagnosed as having lupus erythematosus panniculitis (lupus profundus) since their clinical features may overlap, and, a portion of patients with SPTL have autoimmune syndromes. These include a positive antinuclear antibody, hematologic changes (anemia, neutropenia), renal changes, and a positive immunoflourescence test on lesional skin. Usfeul histopathologic criteria to distinguish SPTL from lupus (favoring a diagnosis of lupus erythematosus) include epidermal involvement, mucin deposition, the presence of reactive germinal centers, clusters of B cells, and a polyclonal TCR gene rearrangement. An extranodal NK/T-cell lymphoma is also included in the differential. Features that favor NK/T-cell lymphoma are involvement of the dermis, positivity for CD56, positive EBV antigens, and lack of monoclonal rearrangement of TCR genes.

The Immunophenotype of SPTL-AB is CD2+, CD3+, CD5+, CD8+, betaF1 +, CD4 -, CD30 -, CD56 -, and TIA-1 +.

Cutaneous gamma/delta T-cell lymphoma (CGD-TCL), (Figure 3) previously described as an SPTL with a gamma/delta phenotype, is now identified as its own clinical entity. It generally occurs in adults affecting both sexes equally. Patients present with rapidly growing disseminated plaques and/or as ulceronecrotic nodules or tumors that occur mostly, but are not limited to, the extremities. Patients can present with systemic symptoms including lymphadenpathy, hepatosplenomegaly, cytopenias, and/or elevated liver function tests. Constitutional symptoms of fever, night sweats and fatigue are common.

Figure 3.

Subtle cutaneous Gamma/Delta lesion.

There are three histologic patterns of involvement: epidermotropic, dermal and subcutaneous. More than one histologic pattern can be seen within a given specimen. The neoplastic cells are medium to large sized with coarsely clumped chromatin. Apotosis and necrosis can be seen, often with angioinvasion. Infiltration of the epidermis can vary from few scattered cells in the basal layer to a marked lichenoid infiltrate with extensive necrosis of keratinocytes and ulceration. Those with subcutaneous involvement may show rimming of fat cells as in SPTL-AB. However, in comparison to SPTL-AB, the subcutaneous infiltrates tend to be more monotonous and diffuse.

The tumor cells are betaF1-, CD3+, CD2+, CD5-, CD7+/-, and CD56+ with strong expression of cytotoxic proteins (granzyme B, TIA-1, perforin). Most cases lack both CD4 and CD8, though some may show rare CD8 positivity. In frozen section, the cells are strongly TCR-delta positive. If only paraffin sections are available, betaF1 negativity may be used to infer the diagnosis. Bone marrow examination may show histiocytic hyperplasia, hemophagocytosis or decreased cellularity, but previous cases have not demonstrated evidence of lymphoma.

The comprehensive criteria for diagnosis of CGD-TCL includes (1) prominent involvement of the dermis and epidermotropism, (2) CD4-/CD8- phenotype, (3) aberrant expression of CD56, (4) TCR gamma gene rearrangement, and (5) unresponsiveness to chemotherapy with an extremely poor prognosis.

The Immunophenotype of CGD-TCL is CD3 +, CD5 +, gamma1(frozen) +, betaF1 -, CD4 -, CD30 -, CD8-(+), and TIA-1 +.

If one were to compare SPTL-AB and CGD-TCL a few features can be used. The hemophagocytic syndrome (HPS) is uncommonly seen in SPTL-AB and is commonly seen in CGD-TCL. Ulceration and nodularity of disease is almost exclusively seen in CGD-TCL. Autoimmune diseases and connective tissue diseases can often be seen in conjunction with SPTL-AB, and are exceedingly rare with CGD-TCL. CGD-TCL tends to involve the epidermis and dermis much more frequently than SPTL-AB. The 5-year survival rate of SPTL-AB is 82%(in those without HPS), and 42% (with HPS). The prognosis is worse for CGD-TCl, where the 5-year survival is around 10%.

Who is at Risk for Developing this Disease?

ATLL is prevalent in areas such as southwest Japan, the Caribbean islands, South America, and parts of Central Africa that have a high prevalence of HTLV-1. In addition, an increased prevalence is identified in Jewish ancestry from Mashad, Iran. Infective dermatitis associated with HTLV-1 (IDH) may also act as a risk factor for the development of ATLL.

Early identification of IDH in patients from certain prevalent areas may serve as an early clinical marker. Given poor diagnostic tools in these areas, it is highly underdiagnosed and may not be accurately identified until patients show progression of disease. Children are most commonly affected and present with an elevated proviral load, strongly predisposing them to ATLL. However, only 1-2% of seropositive individuals with actually develop ATLL.

In up to 20% of patients with LyP, the disease may be preceded by, associated with, or followed by another type of lymphoma, either MF, ALCL, or Hodgkin’s Lymphoma. In some patients, the same neoplastic T-cell clone has been identified in the second lymphoma.

What is the Cause of the Disease?

ATLL is most commonly a neoplasm of CD3+CD4+CD25+ T-cells etiologically associated with the human T-cell leukemia virus (HTLV-1). It is most often transmitted from an infected mother to an infant via breast milk, or during pregnancy, and less commonly by sexual contacts, blood transfusions, or IV drug use. Most people with HTLV-1 infection never develop the disease.

After several decades only 2.1% of females and 6.6% of males actually progress to ATLL. The reason for this still remains unknown. It is postulated that the continuous replication of provirus carrying lymphocytes via HTLV-1 driven regulatory proteins leads to genomic instability and chromosomal abnormalities that eventually yield unchecked proliferation of infected cells.

CD30 signaling affects the growth and survival of lymphoid cells. Studies have shown that allelic specific differences in the transcription control of CD30 may affect the development of CD30+ lymphoproliferative disorders and may contribute to the self-healing properties in LyP. It has also been shown that the CD30+ tumor cells are unresponsive to the inhibitory effects of TGF-beta due to a mutation in the TGF-beta type I receptor on those cells, allowing for tumor progression.

Cutaneous ALCL has been observed in immunocompromised patients. An association with HHV-8 has been identified in patients with HIV.

For a more comprehensive description of the pathogenesis of cutaneous T-cell lymphomas, please refer to the chapter on MF/SS.

Systemic Implications and Complications

Given that skin lesions are commonly secondary in ATLL, it is important to rule out systemic involvement. Moreover, a significant proportion of patients will have hypercalcemia.

In primary cutaneous ALCL, 10% of patients will have extracutaneous dissemination that will mainly involve lymph nodes. Patients with multifocal skin lesions and those with only involvement of regional lymph nodes have a similar prognosis to those with skin lesions only.

LyP generally has an excellent prognosis. However, a rare subset of patients (20%) may develop a preceding, concurrent or following malignant lymphoma. It is uncertain if the degree of control of LyP lesions alters the risk of developing a second lymphoma. If LyP-like lesions develop in a patient with mycosis fungoides, it is crucial to rule out large cell transformation, as both are CD30+.

SPTL may be complicated by a hemophagocytic syndrome that is characterized by a rapidly progressive course. Dissemination to extracutaneous sites is rare.

CGD-TCL may frequenly develop visceral involvement of the liver, lungs, kidney, CNS and oral mucosa. However, the involvement of lymph nodes, spleen or bone marrow is uncommon. A hemophagocytic syndrome may occur in patients with panniculitis-like tumors. The distinction between a primary versus secondary CGD-TCL is not useful in this patient population given that the prognosis is very grim for both.

Treatment Options

Treatment for ATLL

  • For the smoldering variant, skin-targeted therapies similar to those recommended for mycosis fungoides may be used

  • systemic chemotherapy

  • Interferon with or without Systemic retinoids (Bexarotene) with or without azidothymidine (AZT)

Treatment for ALCL:

  • Surgical excision

  • Methotrexate (most cases are highly sensitive)

  • Bexarotene

  • Radiotherapy – electron beam irradiation (4-10 million eV) with a total radiation dose of 40 Gy

  • Combination surgical excision and radiotherapy

  • Systemic chemotherapy – with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens

  • Pentostatin

  • Interferon gamma

  • Aldara

  • SGN-35 (Brentuximab Vedotin): an antibody-drug conjugate of an antitubulin agent monomethyl auristatin E (MMAE) and a CD30-specific monoclonal antibody in trial as a therapy for relapsed ALCL

Treatment for LyP:

  • Low dose oral Methotrexate (5-30mg/week) – most cases are quite sensitive

  • PUVA

  • Topical chemotherapeutics (Nitrogen Mustard, Carmustine) – apply nightly

  • Systemic steroids

  • Interferon alpha2b

  • Interferon gamma

  • Targretin – optimal dose of 300mg/m2/d (approximately 10mg/kg)

  • Topical Targretin 1.0% gel

  • Tetracyclines

  • Observation only for mild cases

Treatment for SPTL:

  • Radiotherapy

  • Systemic steroids

  • Methotrexate

  • Thalidomide

  • Hydroxychloroquine

  • Denileukin diftitox (Ontak) (highly effective)

  • Cyclosporine

  • Surgical excision

  • CHOP (cycophosphamide, doxorubicin, vincristine, prednisone)

  • A-CHOP – addition of alemtuzumab

  • Stem cell transplant (autologous or allogeneic) Combinations of: prednisone, cyclosporine, chlorambucil, methotrexate, cyclophosphamide, interferon alpha, and gemcitabine

  • Observation only for mild cases

Treatment for CGD-TCL:

  • CHOP or CHOP-like regimens preceded by short courses of prednisone with stem cell transplant afterwards

  • HyperCVAD (Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone plus Methotrexate and Cytarabin) followed by stem cell transplant

  • Stem cell transplant

Optimal Therapeutic Approach for this Disease

In ATLL, patients with evidence of systemic disease should be referred to oncology for initiation of systemic chemotherapy. Those with cutaneous disease only may benefit from the same skin directed therapies offered to patients with mycosis fungoides. Both cutaneous disease and systemic disease may respond to biologic response modifiers including interferon alpha, retinoids, particularly bexarotene orally and anti-retrovirals, including azidothymidine. It therefore may be beneficial to attempt this latter approach initially in an effort to preserve the host immune response. Denileukin diftitox (Ontak) has also been used successfully for ATLL.

In ALCL, given that 25% of primary lesions may spontaneously recur, it is reasonable to first have expectant follow-up over 6-8 weeks. A small subset will have regression of their disease without recurrence. For those whose disease persists or recurs and have evidence of solitary lesions or a few localized nodules or tumors, radiation therapy or surgical excision is first choice. They may also benefit from low-dose methotrexate therapy as in LyP.

Those with extracutaneous disease or rapidly progressive skin disease require referral to oncology and therapy with doxorubicin based multiagent chemotherapy. However, it is recommended that methotrexate in low to moderate doses represent first-line drug therapy for this condition as even those with nodal involvement have been observed to respond readily to methotrexate.

For LyP, there is no proven curative therapy, however, there are therapeutic modalities that may control the course of the disease leading to a shorter time to resolution or a decreased frequency of eruptions. Given that LyP has an excellent prognosis and that treatment modalities may not alter the natural course of the disease, one must weigh the risks and benefits when deciding on a suitable course of therapy for a patient. Approximately one third to one half of patients have their disease recur after discontinuation of treatment. Therefore, patients with few, non-scarring lesions should undergo long-term observation.

For patients with numerous or scarring lesions, low-dose methotrexate may be the most effective therapy. However, it is not indicated in women of child-bearing age, patients with a history of liver disease, or patients with blood dyscrasias. PUVA , low dose prednisone, and topical chemotherapy (nitrogen mustard and carmustine) have also been used with some success. Carmustine is not advised for use on the face given its potential side effect of permanent telangiectasias. Low-dose oral bexarotene can also suppress new lesion development.

Patients with solitary or localized lesions with SPTL-AB may show success with radiotherapy or surgical excision. For more extensive disease, some reports have shown success with systemic steroids in combination with an immunosuppressive agent, instead of full CHOP therapy. Reports of major responses to denileukin diftitox (Ontak) among patients with extensive disease have been published. It is recommended that overly aggressive chemotherapeutic regimens not be initially administered in this patient population.

Previously, when the cases of hemophagocytic syndrome and the gamma/delta subtype were included within the prognostic evaluation, this disease was noted to have a very poor 5-year survival rate implying the need for more aggressive chemotherapeutics. However, after separating the alpha/beta subtype from the gamma/delta subtype, the prognosis of SPTL-AB is much better than once thought. Therefore, it is recommended that non-chemotherapeutic approaches be tried first in this patient population.

For CGD-TCL, greatest success has been demonstrated in patients responsive to chemotherapy followed by an allogeneic stem cell transplant. As a result, these patients will need immediate referral to oncology for co-management. However, the prognosis is generally very poor. These patients will require symptomatic relief from their painful ulcerative lesions, which can be achieved by response to chemotherapy, total skin electrom beam therapy (TSEB) (will need referrral to radiation oncology), or topical or systemic steroids.

Patient Management

For smoldering ATLL, patients can be managed similarly to those with mycosis fungoides. A biopsy should be sent for H+E as well as immunostaining. Blood should be sent for a complete blood count, comprehensive metabolic profile with liver function tests, a lactate dehydrogenase, HTLV1+2, and flow cytometry for assessment of the CD4+CD25+ population. Serum calcium should be closely monitored. They should follow up regularly for repeat clinical history and physical exam.

However, given the common presentation of systemic ATLL with associated skin findings, patients should undergo a full staging workup including a PET/CT, and, as mentioned above, a lymphoma panel for flow cytometry. Those with evidence of systemic involvement may need referral to oncology for initiation of systemic chemotherapy. Immunomodulatory therapy with interferon, oral targretin, and, possibly, azidothymidine may be attempted initially to preserve the immune response, as ATLL patients can be quite immunosuppressed due to factors produced by the transformed T-cells.

For patients with ALCL, those who present with primary cutaneous disease usually have a more favorable prognosis with a 10 year survival rate greater than 85%. However, for appropriate patient care and follow-up, it is crucial to distinguish primary vs secondary ALCL. Tissue should be sent for H+E as well as immunostains including CD30, CLA, EMA and ALK. Regardless of associated B-symptoms, patients should undergo a complete staging workup including a complete blood count, complete metabolic profile including liver function tests, a lactate dehydrogenase and a PET/CT scan. Bone marrow involvement is rare, and as a result, a biopsy is not indicated.

If patients have evidence of solitary or localized cutaneous disease, they may have success with excision, radiotherapy or a combination of both. They should follow-up regularly for evaluation. Those with disseminated skin disease are at greater risk of developing extracutaneous involvement. As a result, patients with more generalized disease or evidence of a secondary cutaneous process should be referred to oncology for consideration of systemic polychemotherapy. Most cases will respond to low to modest doses of methotrexate (10 to 30mg weekly).

Patients can become very disconcerted by the diagnosis of LyP given its association with mycosis fungoides or Hodgkin’s disease in 10-15% of cases. Patients may undergo therapy, but it is likely not curative. They have an increased risk of a secondary lymphoma (in 10-15% of patients) that may not be diminished by initiation of therapy. As a result, patients may become easily concerned about any changes in their signs or symptoms.

In the absence of any B-symptoms (including fevers, chills, night sweats, fatigue or unintentional weight loss) a complete staging workup is not necessary. A thorough clinical history is needed to determine if lesions are self-healing. Many patients are misdiagnosed as having ALCL given that the histology may not always be clear. Distinction can be based upon the clinical nature of the lesions which tend to be larger and typically nodular in ALCL as opposed to being papular in LYP. Patients should have a thorough physical exam including assessment of lymphadenopathy. A biopsy should be sent for H+E and immunostains, including CD30. Baseline labs including a complete blood count, complete metabolic profile including liver function tests, and a lactate dehydrogenase should be sent.

Patients should understand that therapy will help reduce the number of lesions and frequency of recurrence. However, therapy is likely not curative, and its discontinuation will frequently lead to recurrence. As a result, patients with few, non-scarring or non painful lesions isolated to areas not of cosmetic importance to the patient should be treated with observational therapy first. Have the patient monitor their affected area and return in several months for follow-up evaluation. Patients may then follow-up on a regular basis if their disease remains stable and they do not develop any associated B symptoms.

For patients whose lesions are more widespread or symptomatic, suppressive therapies can be tried. Though low-dose methotrexate has been used with success, it cannot be used in a woman of childbearing age given its teratogenic effects, patients will have to present for serial blood tests, and they cannot drink alcohol while on the medication. It is recommended to start at 5mg weekly and then titrate up to 30mg, as needed to obtain control of patient’s flares. PUVA twice weekly has also shown success. Psoralen may cause GI discomfort, but overall is well tolerated. PUVA is relatively contraindicated in patients with a history of melanoma or non melanoma skin cancers. Oral Targretin (bexarotene) in low to modest doses can also exert a suppressive effect on LYP expression.

For SPTL-AB, explain to the patient that this diagnosis confers a better prognosis than a gamma/delta subtype, but that they will need to be followed by an oncologist as well. Their 5-year survival is about 82-85%, however, it can be as high as 91% without the occurrence of hemophagocytic syndrome. Evidence of B-symptoms can be predictive of impending hemophagocytic syndrome.

Patients will require a thorough physical assessment for extent of cutaneous involvement and evidence of lymphadenopathy. A biopsy should be sent for H+E and immunostainings including CD2, CD3, CD4, CD5, CD7, CD8, CD30, CD56, betaF1, TCRgamma-1, B-cell antigens (CD20, CD79a), cytotoxic proteins (granzyme B, TIA-1, perforin), histiocytes (CD68), and the proliferation marker Mib-1. A complete staging work-up including a complete blood count, complete metabolic profile including liver function tests, and a lactate dehydrogenase is necessary, as well as a PET/CT scan. A bone marrow biopsy may reveal evidence of HPS when performed.

Patients should understand that without the occurrence of HPS, their disease may be well controlled without aggressive chemotherapeutics. They must discuss with oncology the therapy related side effects and risk of disease to come to a decision as to how they would tailor their treatment course. For patients with progression, initial therapy with an anti-inflammatory (prednisone, thalidomide, cyclosporine, hydroxychloroquine) with denileukin diftitox (Ontak) should be considered.

For CGD-TCL, explain to the patient that unfortunately this diagnosis can be associated with a very poor prognosis with very low 2-year and 5-year survival rates irrespective of the presence of HPS. These patients require an expedited referral to oncology for initiation of chemotherapy. The workup is the same as for a patient with SPTL-AB. The revelation of a gamma/delta process will warrant more aggressive therapy, however, will still be associated with a very poor 5-year survival rate (11%). An allogeneic stem cell transplant may control the process.

Unusual Clinical Scenarios to Consider in Patient Management

In ATLL, extreme levels of hypercalcemia may occur. Patients should be monitored closely. ATLL patients are also susceptible to opportunistic infections due to soluble factors produced by the malignant T-cells which can suppress the immune response. The authors have observed dramatic clinical responses to biologic response modifiers (interferon, oral retinoids, anti-retrovirals, Ontak), and, thus, it is recommended that this approach be tried initially. We observed a dramatic response in the clinical disease itself to the biologic response modifiers.

In both ALCL and LyP, rarely, a few neoplastic cells can be detected in the peripheral blood with unknown significance. It is recommended that methotrexate be utilized first in the treatment of these conditions if systemic therapy is to be selected.

For panniculitic lymphoma, should the hemophagocytic syndrome be detected, high dose steroids and Ontak should be considered as initial therapy followed by chemotherapy, and possibly, stem cell transplant.

What is the Evidence?

Willemze, R, Jaffe, ES, Burg, G, Cerroni, L, Berti, E, Swerdlow, SH. “WHO-EORTC classification for cutaneous lymphomas”. Blood. vol. 105. 2005. pp. 3768-85. (An outstanding review and classification of all cutaneous lymphomas detailing their clinical features, histopathology, immunophenotype, genetic features, prognosis, and therapies.)

Cerroni, L, Gatter, K, Kerl, H. Skin lymphoma. 2009. pp. 66-79. (A comprehensive yet concise review of all skin lymphomas.)

Willemze, R, Bolognia, JL, Jorizzo, JL, Rapini, RP. “Cutaneous T-cell lymphoma”. Dermatology. 2008. (A concise review of all cutaneous T-cell lymphomas.)

Boxus, M, Willems, L. “Mechanism of HTLV-1 persistence and transformation”. Br J of Cancer. vol. 101. 2009. pp. 1497-1501. (An overview of the presumed mechanism of the role of HTLV-1 in the development of ATLL.)

Bittencourt, AL, de Fatima Paim de Oliveira, M. “Cutaneous manifestations associated with HTLV-1 infection”. Int J Dermatol. vol. 49. 2010. pp. 1099-1110. (A more detailed description of the skin findings in patients with HTLV-1 infection, not limited to the development of ATLL.)

Kadin, ME. “Current management of primary cutaneous CD30+ T-cell lymphoproliferative disorders”. Oncology. vol. 23(13). 2009. pp. 1158-64. (A comprehensive and practical review of the clinical presentation, diagnosis, histology, and treatment of LyP and ALCL.)

Willemze, R, Jansen, PM, Cerroni, L, Berti, E, Santucci, M, Assaf, C. “Subcutaneous panniculitic-like T-cell lymphoma: definition, classification, and prognostic factors: and EORTC cutaneous lymphoma group study of 83 cases”. Blood. vol. 111. 2008. pp. 838-45. (A well-written review of SPTL-AB and CGD-TCL and their differentiating features.)

Stein, H, Foss, H, Durkop, H, Marafioti, T, Delsol, G, Pulford, K. “CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic and clinical features”. Blood. vol. 96. 2000. pp. 3681-95. (A review of the systemic findings of ALCL and its implications for patient care.)

Kao, GF, Resh, B, McMahon, C, Gojo, I, Sun, C, Phillips, D. “Fatal subcutaneous panniculitis-like T-cell lymphoma gamma/delta subtype (cutaneous gamma/delta T-cell lymphoma): report of a case and review of the literature”. Am J Dermatopathol. vol. 30. 2008. pp. 593-9. (A representative case report and review of CGD-TCLs.)

Younes, A, Bartlett, N, Leonard, J, Kennedy, D, Lynch, C, Sievers, E. “Brentuximab vedotin (SGN-35) for relapsed CD30 positive lymphomas”. NEJM. vol. 363. 2010. pp. 1812-21. (Discussion of a phase I trial with promise for patients with CD30 positive lymphomas refractory to current therapeutic modalities.)

Here Lee, R, Schwartz, RA. “HTLV1 associated infective dermatitis: a comprehensive review”. JAAD. vol. 64. 2011. pp. 152-160. A comprehensive review of HTLV1 associated infective dermatitis and its associated risks.)

Here Lee, R, Schwartz, RA. “HTLV1 associated infective dermatitis: a comprehensive review”. JAAD. vol. 64. 2011. pp. 152-60. (A comprehensive review of HTLV1 associated infective dermatitis and its associated risks.)