A case of acanthosis nigricans–like mycosis fungoides

AN: acanthosis nigricans MF: mycosis fungoides INTRODUCTION Acanthosis nigricans (AN) is a common skin condition characterized by symmetric, hyperpigmented, velvety skin thickening most commonly involving the neck, axillae, and other intertriginous areas. AN can be acquired or inherited and is most often associated with obesity, insulin resistance, and other endocrinologic and metabolic disorders. Infrequently, AN may represent a paraneoplastic (or malignant) phenomenon, usually associated with underlying gastrointestinal malignancies, especially gastric adenocarcinomas. However, rare cases of AN secondary to underlying cutaneous T-cell lymphoma have been described. Complicating matters, an exceedingly rare, vegetating/papillomatous variant of mycosis fungoides (MF), referred to as ‘‘AN-like MF’’ has been reported. MF is the most common form of cutaneous T-cell lymphoma and the most prevalent form of primary cutaneous lymphoma overall. The clinical manifestations of MF have been well-documented and are heterogeneous, often mimicking other skin conditions. In addition to classical MF (Alibert-Bazin type), numerous other variants have been described. Herein, we present a case of AN-like MF with possible associated paraneoplastic AN.


INTRODUCTION
Acanthosis nigricans (AN) is a common skin condition characterized by symmetric, hyperpigmented, velvety skin thickening most commonly involving the neck, axillae, and other intertriginous areas. AN can be acquired or inherited and is most often associated with obesity, insulin resistance, and other endocrinologic and metabolic disorders. Infrequently, AN may represent a paraneoplastic (or malignant) phenomenon, usually associated with underlying gastrointestinal malignancies, especially gastric adenocarcinomas. However, rare cases of AN secondary to underlying cutaneous T-cell lymphoma have been described. [1][2][3][4] Complicating matters, an exceedingly rare, vegetating/papillomatous variant of mycosis fungoides (MF), referred to as ''AN-like MF'' has been reported. 2,[5][6][7] MF is the most common form of cutaneous T-cell lymphoma and the most prevalent form of primary cutaneous lymphoma overall. The clinical manifestations of MF have been well-documented and are heterogeneous, often mimicking other skin conditions. 8 In addition to classical MF (Alibert-Bazin type), numerous other variants have been described. 9,10 Herein, we present a case of AN-like MF with possible associated paraneoplastic AN.

CASE REPORT
A 35-year-old Asian woman presented with a pruritic rash of 2 years' duration that began a few weeks after delivery of her second child. The lesions started as skin-colored papules and plaques scattered on the trunk that coalesced and progressed to involve the neck and extremities. Over time, the lesions became increasingly raised, discolored, and coarse. The patient had gestational diabetes during her second pregnancy, which was well controlled with metformin and resolved promptly postpartum. She was otherwise healthy, with no history of persistent endocrinologic diseases, malignancies, chronic skin diseases, or other health conditions requiring long-term medications.
On examination, the patient had diffuse areas of thickened, velvety, hyperpigmented, and violaceous skin with exaggerated skin markings on the trunk, inguinal folds, and proximal aspect of thighs (Fig 1). Areas of sparing were admixed with scattered erythematous, hypopigmented and hyperpigmented patches that highlighted the color variegation of her disease process. No hepatosplenomegaly or lymphadenopathy was observed, and complete blood cell count, comprehensive metabolic panel, hemoglobin A1C, and thyroid function tests were normal. Computed tomography imaging of the neck, chest, abdomen, and pelvis was negative for lymphadenopathy and was otherwise unremarkable.
Multiple skin biopsies from different sites were performed. Shave biopsies from the left side of the  (Fig 2, A) and the left flank (not shown) revealed hyperkeratosis, papillomatosis with lacelike interdigitation, and pseudocystic invaginations into the stratum malpighii. The epidermis was notable for benign cellular hyperplasia with mildto-moderate spongiosis and epidermotropism of slightly enlarged, hyperchromatic lymphocytes with cerebriform nuclei forming variably-sized collections (Pautrier microabscesses) (Fig 2, B and C ). These atypical lymphocytes were also present along the basal layer (some surrounded by clear halos) and as dense lichenoid and superficial perivascular infiltrates housed by wiry fibrosis of the papillary dermis. Immunohistochemical studies demonstrated a CD3 1 /CD4 1 /CD8 À /CD7 À immunophenotype with markedly elevated CD4:CD8 ratio (Fig 3, A to  D). Additionally, immunohistochemical staining was Bcl-2 1 , CD2 1 , CD5 1 , CD43 1 , CD20 À , and CD30 À . T-cell receptor gene rearrangement studies showed a clonal T-cell receptor b/g gene rearrangement. Flow cytometry revealed no immunophenotypic abnormalities. A shave biopsy from the left axilla (Fig 4) showed hyperkeratosis, papillomatosis, and intervening ''valleys'' with underlying acanthosis and basilar hyperpigmentation, consistent with isolated AN.
The patient received a diagnosis of AN-like MF with concomitant non-MF AN and was started on topical clobetasol and twice weekly narrowband ultraviolet B phototherapy. Over a period of 6 years, the patient was transitioned from light therapy (partial response) to oral methotrexate titrated up to 22.5 mg weekly (partial response) to oral bexarotene titrated up to 375 mg/m 2 /d, eventually tapering off of methotrexate given clearance of AN and AN-like MF plaques on bexarotene (complete response). Although her AN-like MF lesions resolved, new, scattered, flesh-colored to pink nodules subsequently developed on her nose, axillae, and inner thighs, biopsies of which were consistent with tumor-stage MF (CD2 1 /CD3 1 /CD4 1 /CD5 1 /CD7 À admixed with reactive CD8 1 lymphocytes and CD30 highlighting only scattered large cells less than 25% of the population). She was restaged as stage IIB by Hematology/Oncology, and oral bexarotene was titrated up to 375 and 450 mg/m 2 on alternate days, in addition to topical corticosteroids and adjunctive intralesional triamcinolone injections (30-35 mg/mL), with partial response.

DISCUSSION
The vegetating/papillomatous variant of MF (''AN-like MF'') is a rare subset of the disease (Table I). 2,[5][6][7] In a limited number of cases, there does not appear to be any predilection for age, race, or sex. Flexural, umbilical, and areolar skin involvement predominates, representing a departure from the traditional buttocks and covered distribution of classical MF. Clinically, this subset of MF presents as velvety, hyperpigmented, polygonal plaques with variable patches of erythema interspersed between the lesions. Over time, some lesions may become more pronounced and even nodular. Pruritus may be a prominent feature. Histologic examination of lesional skin reveals features of both AN and MF. The treatment of ANlike MF is anecdotal, and topical corticosteroids, topical nitrogen mustard, psoralen plus ultraviolet A photochemotherapy, and electron beam therapy have been used successfully. Our patient improved with topical corticosteroids, narrowband ultraviolet B, oral methotrexate, oral bexarotene, and intralesional triamcinolone injections, further expanding the therapeutic ladder for AN-like MF.
Interestingly, AN has been described as a paraneoplastic phenomenon in cases of MF, in both the classical 1,3,4 and vegetating/papillomatous types. 2,7 The concomitant presentation of AN (benign or paraneoplastic) and AN-like MF makes diagnosis and distinction between the 2 entities difficult. A   complete evaluation for the other more common etiologies of AN must be performed. In cases of AN with negative preliminary workup and unknown etiology, a skin biopsy of an existing dermatosis may prove useful, as MF is a great imitator and early lesions are frequently misdiagnosed. 8 Furthermore, biopsy of a lesion itself may be considered, especially when the distribution is widespread or atypical, as this may in fact represent AN-like MF. This distinction is important, because the management of MF and AN is different. In our patient, the concomitant presentation of biopsy-proven AN in the setting of AN-like MF could represent idiopathic AN that arose incidentally with her AN-like MF, AN associated with her prior gestational diabetes and/or pregnancy, early stages of AN-like MF that had not yet fully evolved histologically, or malignant AN secondary to her underlying AN-like MF. We favored the latter, paraneoplastic phenomenon, given her negative systemic workup and resolution of AN lesions after treatment of her AN-like MF, although this hypothesis cannot be fully proven without serial, longitudinal biopsies, which proved burdensome for the patient. Our report is limited by the absence of T-cell receptor gene rearrangement studies on the left axillae biopsy specimen of isolated AN (Fig 4), which might have revealed an underlying AN-like MF that was not overtly evident on routine histopathology.