Marianna Shvartsbeyn, MD; Department of Pathology, New York University, School of Medicine, New York, New York; Shaily Pandey, BA; Stephen E. Mercer, MD, PhD; and Gary Goldenberg, MD, Division of Dermatopathology, Department of Dermatology, Mount Sinai School of Medicine, New York, New York
Disclosure: The authors report no relevant conflicts of interest.
Leukemia cutis (LC) is rarely encountered in general practice and is often a harbinger of advanced disease with impending blast crisis. The clinical findings can be quite variable. Nodules and plaques are most common, but the lesions may present as ulcerations or vesicular eruptions. LC as the presenting sign of unrecognized advanced disease is exceedingly rare. Only one prior case has been reported of acute promyelocytic leukemia (APL) initially presenting with LC. The authors report an additional patient who presented with cutaneous infiltrates of advanced APL mimicking disseminated herpes zoster.
Myeloid LC is indicative of transformation to acute leukemia; it is regarded as a manifestation of a disseminated aggressive systemic leukemia that has spread to the skin. Typically, LC is concurrent with or signals relapse in myeloid tumors. In the aleukemic form of LC, the infiltration of the skin by leukemic cells precedes their appearance in the bone marrow or peripheral blood.[3–5] LC is often associated with immunosuppression, chemotherapy, and infectious diseases. The prognosis of patients with acute myelocytic leukemia (AML) with LC is very grave. Most patients, as was the case in this patient, die within a few months from the time of histological diagnosis.[6,7]
A 46-year-old man with a history of hypertension, hyperlipidemia, and depression presented with a two-week history of fatigue, fevers, night sweats, and bruising. The patient also complained of diffuse aching pains. Physical exam revealed multiple 3 to 4cm ulcers over the left lateral abdomen, one partially crusted with a thick eschar. This eruption was mildly tender to palpation. The patient also had numerous nontender purpuric macules, patches, and resolving ecchymoses over his arms and legs. Another hyperpigmented patch was present on the left medial back surrounded by re-epithelialized erosions. He had no active vesicles or bullae. Initially, the skin eruption was interpreted to be herpes zoster, and the patient was treated with oral acyclovir. After a dermatology consultation, treatment was changed to intravenous (IV) acyclovir.
A punch biopsy was taken from the border of the ulcer with the eschar. Hematoxylin-eosin stained sections revealed massive papillary dermal edema and a superficial and deep perivascular and periadnexal infiltrate with a sparse interstitial component. No viral cytopathic changes were identified. The infiltrate included a mixed population of atypical mononuclear cells, including cells with very large nuclei (up to 15µm) and binucleated cells. The myeloid nature of these cells was demonstrated by immunohistochemical staining for KP-1 and myeloperoxidase (Figure 1, Figure 2, and Figure 3).
Serological analysis revealed a white blood count of 35×109 cells/L, hemoglobin of 6.2g/dL, and a platelet count of 7×109/L. The patient was admitted for further work up and treatment of a presumed leukemia. A peripheral blood smear demonstrated 65 percent blasts with Auer rods. A bone marrow biopsy showed a hypercellular bone marrow (~95% cellularity) replaced by large myeloid blasts, some binucleated with a few eosinophilic granules in the cytoplasm, consistent with APL. Flow cytometry showed a blast population expressing CD13, CD33, CD15, CD117, and myeloperoxidase (MPO), which comprised 82 percent of the total cells. Cytogenetic analysis revealed a reciprocal translocation between the long (q) arms of chromosome 15 and 17 in 4 out of 9 of the metaphase cells. Fluorescence in situ hybridization (FISH) detected a t(15;17) rearrangement involving the promyelocytic leukemia (PML) and retinoic acid receptor a (RARa) genes in 81 percent of 200 interphase cells examined, confirming the diagnosis of M3 ANLL/APL.8
Treatment with all-trans retinoic acid (ATRA), idarubicin, and dexamethazone was initiated. On hospital Day 2, the patient developed hypoxia with rapidly progressing infiltrates and ultimately required intubation. His course was further complicated by febrile neutropenia with temperatures up to 103.5°F and an absolute neutrophil count of <100mm3. Over the next two weeks, he developed multiorgan failure in a setting of overwhelming refractory gram-negative sepsis with Klebsiella pneumonia and fungemia and passed away.
The initial clinical impression was that this patient had disseminated herpes zoster and he was treated empirically without a biopsy. It was only after he failed to respond to antiviral therapy that a biopsy was performed leading to the unexpected diagnosis of APL. As shown in this case, the clinical findings of myeloid LC are nonspecific and can include macules, papules, plaques, nodules, ecchymoses, palpable purpura, or ulcers. Lesions can be erythematous or purpuric, and no clear site predilection has been seen.[9,10] LC can masquerade as a viral exanthema, vitiligo, psoriasis, or seborrheic dermatitis.[11–14] The diagnosis is further compounded by the fact that a spectrum of other skin eruptions can be associated with acute leukemia without leukemic involvement of the skin. These include viral infections, such as herpes simplex, herpes zoster, erythema multiforme, and erythema nodosum.
The diagnosis of LC can be challenging as well because of the great variability in the histopathological features. The neoplastic cells can form nodular infiltrates within the dermis or be present as diffuse or scant perivascular or adnexal infiltrates. The infiltrate is usually composed of medium-sized, immature myeloid cells with blastic chromatin. The immunostain for CD68, which was positive in this case, has been reported to be the most sensitive marker for the detection of myeloid LC.
The exact incidence of myeloid LC is unknown. In an early study, leukemic infiltration of the skin was seen in 11 percent of patients with AML. Later studies reported a varied incidence from 2 to 20 percent.[18–21] The occurrence of LC in APL is very rare. Only 24 patients with APL have been reported to have developed LC.[22–26] Interestingly, in all of these cases, the rash appeared to be induced by treatment with ATRA.[22–26] ATRA treatment is associated with an increased incidence of extramedullary disease at the time of relapse, possibly mediated through an increase in expression of adhesion molecules. In addition, two patients in a series of six patients who presented with granulocytic leukemia of the skin were found to have Auer rods in their peripheral blood or bone marrow. Prior to this patient, only a single case of APL presenting initially as LC had been reported. These two patients are unique in that they are also the only two cases of cutaneous APL that arose in the absence of treatment with ATRA.
The biopsy was also unusual for the extent of the dermal edema, which was highly reminiscent of a Sweet’s like syndrome. There was, however, no neutrophilic infiltrate, which is the definitive diagnostic feature of Sweet’s syndrome. Sweet’s syndrome (the eponym for acute febrile neutrophilic dermatosis) is characterized by a constellation of clinical signs and symptoms that include fever, neutrophilia, tender erythematous skin lesions (papules, nodules, and plaques), and histopathological findings of papillary dermal edema, swollen endothelial cells, and a diffuse infiltrate of mature neutrophils in the upper dermis. Sweet’s syndrome can be associated with malignancy, and it is most commonly related to AML.[30–33] Of note, there are several reports of concomitant Sweet’s syndrome and LC.[34–36]
Extramedullary leukemic cells are extremely uncommon in acute promyelocytic leukemia. The authors present a unique case of a patient with APL who developed LC that clinically mimicked a disseminated herpes zoster infection. This is only the second reported case of LC as the presenting sign of APL. Another salient histopathological feature was Sweet’s-like massive dermal edema. The authors postulate that the myeloid leukemic cells may be creating a process in dermis in the spectrum between leukemia cutis and histiocytoid Sweet’s syndrome.
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