Immune Cells Show the Way in This Medical Mystery

A 54-year-old man presents to a foot and ankle clinic in Maryland with a diffuse, hard lesion in the middle of the arch of his left foot; it is tender to the touch and painful to walk on.

He explains that it began developing gradually about 3 years earlier as a dry, scaly spot, and that the skin later cracked but there was no pain. He says he had not been concerned, since he had a history of having severe eczema and dry patches of skin in the same spot on his foot.

However, his efforts to treat the eczema with topical cortisone cream and “over-the-counter acid” have been ineffective, he said, adding that he became concerned when the lesion slowly grew thicker and harder.

The patient’s surgical and medical histories include thyroidectomy (for thyroid cancer) at age 28, a diagnosis of bipolar disorder, headaches/migraines, and high blood pressure. His family history is unremarkable, and clinical assessment reveals no major abnormalities.

Dermatological Examination

Dermatological assessment shows a 3.0-cm, scaly, keratotic patch with slight erythema in the plantar central region of the left arch, which is notably tender to palpation. There is no evidence of skin atrophy or lymphadenopathy. Laboratory test results are within normal limits.

Clinicians perform a skin punch biopsy and send the sample for histological evaluation.

The report notes infiltration of atypical lymphocytes in the upper dermis. Most of the atypical lymphocytes are round or ovoid with a cerebriform nuclear contour but with no clear nuclear membrane or nucleoli.

Single units or small clusters of these have infiltrated up into the epithelial layers (epidermotropism), down into the eccrine sweat glands (syringotropism) and the walls of the blood vessels in the dermis.

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Histopathology and immunostaining profiles of mycosis fungoides palmaris et plantaris: (A) An infiltrate of the atypical lymphocytes in the upper dermis (hematoxylin and eosin [H&E], 40×1). (B) Round or ovoid atypical lymphocytes with cerebriform nuclear contour and no clear nuclear membrane or nucleoli (HE, 400×1). (C) Atypical lymphocytes infiltrating into the epidermis (epidermotropism) (HE, 100×1). (D) Atypical lymphocytes infiltrating into eccrine sweat glands (syringotropism) (HE, 100×1). (E) Perivascular infiltration of the atypical lymphocytes in the dermis (HE, 100×1). (F) Strong CD4 expression in atypical lymphocytes (3, 3 -diaminobenzidine [DAB], 100×1). (G) Reduced CD7 expression in atypical lymphocytes (DAB, 100×1). (H) Reduced CD8 expression in atypical lymphocytes (DAB, 100×1).

Immunostaining of the atypical lymphocytes shows almost uniformly strong positive staining for CD3, CD4 antibodies and about 30% positivity for CD7 and CD8; staining for CD20 was negative.

Clinicians note an approximately 3:1 ratio of CD4- to CD8-positive cells. Results of periodic acid-Schiff staining for fungal elements are negative for both spores and hyphae; yet the histomorphology and immunostaining profiles are judged to be consistent with mycosis fungoides palmaris et plantaris (MFPP).

The team discusses the treatment options with the patient, and he is referred to a dermatologist. The patient receives topical psoralen plus ultraviolet A (PUVA) photochemotherapy, which results in complete remission.

At 5-year follow-up, the patient is doing well, with no recurrence of MFPP.

Discussion

Clinicians reporting this case of MFPP in a middle-age patient note that they want to increase awareness of this rare variant of mycosis fungoides. While MF accounts for more than half the cases of cutaneous T cell lymphoma (CTCL), no more than 30 cases of this rare subtype have been reported in the English-language literature in the past 25 years.

As the name suggests, MFPP develops primarily on the palms and soles, manifesting variously as plaques, erythroderma, and tumors, among other presentations.

Histologically characterized by epidermotropism of atypical convoluted lymphocytes and infiltration of atypical lymphocytes in the upper dermis, MFPP typically has an indolent course. In contrast, advanced-stage MF (stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years.

A 2015 literature review identified the following 10 candidate markers for MF/SS:

  • Cutaneous histologic features of folliculotropism
  • Large-cell transformation
  • White blood cell/lymphocyte count
  • Serum lactate dehydrogenase
  • Identical T-cell clone in blood and skin

Of the 10 variables tested, four (stage IV, age over 60, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival.

MFPP, however, develops on the soles of the feet and the average age of patients is 52, although the range is approximately 11 to 83. Male patients are more than twice as likely as women to be affected, and the mean duration of lesions is approximately 4 years (range of 3 months to 25 years).

MFPP typically presents as psoriasiform, erythematous hyperkeratotic patches, blisters, or ulceration.

Clinical considerations for differential diagnosis include palmoplantar psoriasis vulgaris, dermatophytosis, secondary syphilis, eczema, hyperkeratotic lichen planus, contact dermatitis, and warts.

Histological assessment of biopsies that includes immunostaining profiling and genetic analysis of PCR-based monoclonal rearrangements of T cell receptors may be required for an accurate diagnosis, the case authors write, noting that with this patient, T cell receptor clonal analysis was necessary, and the morphological evaluation with immunostaining profiling confirmed the diagnosis.

Treatment Options

Treatment options for MFPP include topical or systemic chemotherapy, PUVA photochemotherapy, radiation therapy, and immunotherapy, and response (complete or partial) to any of these is excellent, with a response rate of 95%, the case authors write, adding that research suggests that radiation therapy and monotherapy with PUVA may be particularly effective.

As well, there is data to support efficacy of treatment with PUVA combined with:

  • Topical or systemic administration of corticosteroids
  • Gemcitabine and methotrexate
  • Carbon dioxide laser and excimer laser

In the event of a tumor relapse or recurrence, further treatment can often control progression of MFPP, the authors note. They cite the U.S. Cutaneous Lymphoma Consortium’s 2016 consensus guidelines for phototherapy of MF/SS, which state that ultraviolet (UV) light is well established for treatment of the diseases.

In addition to traditional treatments such as broadband, narrowband UVB light, and PUVA, newer options include UVA1 (which uses only the longer, non-erythemogenic UV wavelengths), and excimer laser.

According to the guidelines, UV light is used either as monotherapy or in addition to systemic therapy, demonstrating efficacy in many cases that equal or surpass systemic medications. “Despite its utility and duration of use, the current practice of using [ultraviolet light] guidelines for psoriasis to treat patients with MF/SS is problematic because the goals of prolonging survival and preventing disease progression are unique to CTCL compared to psoriasis,” the guidelines state.

The case authors also cite a recent case report in which treatment with brentuximab vedotin, an antibody that selectively targets tumor cells expressing the CD30 antigen, was associated with complete remission in a patient with MFPP with large cell transformation and partial CD30 expression. The clinicians involved said the patient had a complete remission, which persisted through 5-year follow-up with topical PUVA photochemotherapy.

The case authors write that in general, the factors to consider in choosing appropriate treatment for a patient with MFPP include the lesion’s location, size, and stage in the context of the patient’s overall health and available medical resources. Patient response and any adverse treatment effects will then help determine the need to modify treatment.

In addition, the case authors conclude, periodic follow-up visits are important due to the potential for recurrence or spread of MFPP to other areas of the body.

Disclosures

The case report authors noted no conflicts of interest.

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