|Year : 2020 | Volume
| Issue : 2 | Page : 105-109
Extranodal natural killer/T-cell lymphoma, nasal type, presenting with acneiform eruptions: A previously undescribed variant
Chen-Pu Yeh1, Yun-Wen Chiu2, Chih-Chaung Chen1, Han-Nan Liu3
1 Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
2 Department of Dermatology, Taipei Medical University – Shuang Ho Hospital, New Taipei City, Taiwan
3 Department of Dermatology, Taipei Veterans General Hospital; Department of Dermatology, Taipei Medical University – Shuang Ho Hospital, New Taipei City, Taiwan
|Date of Submission||04-Jan-2019|
|Date of Decision||27-Aug-2019|
|Date of Acceptance||13-Sep-2019|
|Date of Web Publication||24-Apr-2020|
Dr. Han-Nan Liu
Department of Dermatology, Taipei Medical University – Shuang Ho Hospital, No. 291, Zhongzheng Road, Zhonghe District, New Taipei City 23561
Source of Support: None, Conflict of Interest: None
Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is an Epstein–Barr virus (EBV)-associated aggressive form of lymphoma that primarily involves areas outside the nasal cavity. Skin is also commonly involved resulting in a variety of skin manifestations. Here, we report an ENKTL, nasal type, in a 29-year-old male with a previously undescribed acneiform presentation. Skin biopsy revealed an angiodestructive, perivascular lymphocytic infiltration, which stained positive for CD3, CD56, and TIA-1 in various proportions. Scattered EBV-infected cells were demonstrated by in situ hybridization. The patient received chemotherapy with almost complete resolution of the skin lesions initially but later experienced flare-ups.
Keywords: Acneiform eruption, Epstein–Barr virus, extranodal natural killer/T-cell lymphoma
|How to cite this article:|
Yeh CP, Chiu YW, Chen CC, Liu HN. Extranodal natural killer/T-cell lymphoma, nasal type, presenting with acneiform eruptions: A previously undescribed variant. Dermatol Sin 2020;38:105-9
|How to cite this URL:|
Yeh CP, Chiu YW, Chen CC, Liu HN. Extranodal natural killer/T-cell lymphoma, nasal type, presenting with acneiform eruptions: A previously undescribed variant. Dermatol Sin [serial online] 2020 [cited 2021 Sep 28];38:105-9. Available from: https://www.dermsinica.org/text.asp?2020/38/2/105/283210
| Introduction|| |
Extranodal natural killer/T-cell lymphoma (ENKTL) is an Epstein–Barr virus (EBV)-associated aggressive lymphoma that is more prevalent in Asia and Central and South America. It primarily affects adults, with a male predominance. It is further categorized into nasal ENKTL and extranasal ENKTL, depending on the primary site of involvement. The extranodal ENKTL, also termed "nasal type," involves not only the upper digestive tract but also tissues outside the upper digestive tract, including the skin and the gastrointestinal tract.,,, The cutaneous presentation of ENKTL, nasal type, is commonly reported as cellulitis or abscess-like lesions and erythematous plaques, nodules, or ulcerations. However, various cutaneous manifestations can be present. In this article, we report a rare case of ENKTL presenting with acneiform eruption that was initially diagnosed as acne vulgaris.
| Case Report|| |
A 29-year-old Asian male presented with multiple nonitching acneiform eruptions over the face and the trunk with intermittent fever for >1 year. He had a medical history of allergic rhinitis and smoked 0.5 pack/day for 9 years. He described the fever pattern as 38°C–40°C every 1–2 weeks, lasting for 1–2 days. Except for mild general malaise, he did not have chills, a sore throat, cough, abdominal discomfort, dysuria, or joint pain. Initially, he visited a rheumatologist and an infectologist regarding his intermittent fever. The results were unremarkable, except his antinuclear antibodies (ANAs), which were 1:160. He was also HIV negative. Six months later, a whole-body magnetic resonance imaging (MRI) performed during a physical checkup found multiple variable-sized lymph nodes in the bilateral submandibular region. Secondary hyperplasia was suspected. Based on the MRI findings, an otolaryngologist performed an endoscopic examination but did not note any abnormality. He was referred to a dermatologist who diagnosed him with acne vulgaris; oral tetracycline and topical adapalene were prescribed. However, the patient responded to the treatments poorly, with further progression of skin lesions. One and a half years after the disease onset, an acute nasal obstruction developed. This time, a second nasopharyngoscopy examination revealed a septal perforation with crust and necrotic tissue in the bilateral nasal cavities. A biopsy taken from the nasal cavity was interpreted as "inflammation and necrosis." He was admitted 2 weeks later for further investigation. Upon dermatologic examination, numerous various-sized erythematous papules and pustules and inflammatory nodules were noted over his face, back, and chest wall, extending to the middle abdomen in a way similar to the distribution of typical acne. Many papules were folliculocentric with some comedone-like lesions. Most of the lesions were surrounded by peripheral erythema and some papules ruptured spontaneously, leaving tiny depressed necrotic centers [Figure 1]a and [Figure 1]c. An oval-shaped oral ulcer was observed over the tip of the tongue. No palpable lymph node was detected. Laboratory examination showed mild anemia (hemoglobin 11.8 g/dl) without leukocytosis (white blood cell count 9800/mm); slightly elevated lactate dehydrogenase (243 IU/L); and normal renal function, liver function, and uric acid levels. An autoimmune profile was negative for anti-dsDNA, anti-SSA/SSB, anti-extractable nuclear antigen, human leukocyte antigen-B27, and anti-neutrophil cytoplasmic antibody. An atypical infection survey was negative for the syphilis rapid plasma reagin test, Toxoplasma immunoglobulin (Ig) IgM, Chlamydophila IgM, and Legionella urine antigen. Metabolic profile indicated that free thyroxine, thyroid-stimulating hormone, and cortisol were within the normal limits. Tumor markers, including carcinoembryonic antigen, CA125, CA199, and prostate-specific antigen, were also not significant.
|Figure 1: Multiple papulopustular lesions resemble acneiform eruption over (a) the face and (c) the trunk before treatment. The skin biopsy was taken from the area marked in white rectangle with higher magnification (e). After treatment, resolution of acneiform eruption is noted (b and d). (f) Six months after peripheral blood stem cell transplantation, he has a tumor recurrence presenting as a solitary ulcerative nodule over the right forearm|
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Skin biopsy on one of the acneiform papules over the abdominal wall was performed [Figure 1]e. Pathologically, small lymphocytes infiltrating the superficial and deep perivascular area with prominent angiodestruction were most noticeable [Figure 2]a and b]. In situ hybridization for EBV-encoded small RNA also detected many EBV-encoded mRNA (EBER)-positive cells [Figure 2]c. Various portions of perivascular cells also stained positive for cytoplasmic CD3, CD56 [Figure 2]d, and TIA-1. CD4 staining was only partially positive, whereas CD8 staining was negative for these neoplastic cells. Besides, the serum EBV viral load levels detected by polymerase chain reaction were extraordinarily high (15,174 copies/ml). On the basis of morphology, immunohistochemical staining, laboratory results, and clinical manifestations, a diagnosis of ENKTL, nasal type, was established. Following this diagnosis, the preceding nasal septum biopsy, reported as "inflammation and necrosis," was re-examined, and immunochemical patterns similar to those in skin biopsy were identified. Moreover, the specimen from bone marrow biopsy also revealed similar findings. Whole-body positron emission tomography with18 F-labeled fluoro-2-deoxyglucose and computed tomography (FDG-PET/CT) reported nasal cavity lymphoma with lymphadenopathy in the bilateral neck levels I and II and bilateral axillary regions. As no biopsy was performed from the nasal mucosa during the first nasolaryngoscopy examination, we cannot completely exclude the possibility of very early ENKTL that was undetectable by either MRI or nasopharyngoscopy. However, given the clinical history of intermittent fever and extensive involvement of acneiform eruptions 6 months prior to the diagnosis, we are confident in characterizing this patient as a case of Stage IVB ENKTL nasal type, with skin involvement and B symptoms (presence of fever).
|Figure 2: (a) Histological examination reveals superficial-to-deep perivascular infiltrate (H and E, ×40). (b) The perivascular infiltrates are composed of small lymphocytes with angiodestruction (H and E × 200). (c) Epstein–Barr virus positivity is demonstrated by in situ hybridization (×200). (d) Some perivascular small lymphocytes stain positive for CD56 (immunohistochemical, ×200)|
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In the subsequent 6 months, he underwent several cycles of chemotherapy with the SMILE regimen (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide), followed by pralatrexate. The EBV viral load dropped to <1000 copies/ml initially but rebounded to 1486 copies/ml 1 month later. A follow-up FDG-PET/CT still revealed some remaining metabolic uptake. Due to the partial response to treatment, an allogenic peripheral blood stem cell transplantation (PBSCT) was performed 7 months after the initial diagnosis. Before PBSCT, most of the skin lesions turned brownish, flattened, and partially healed with scarring without the appearance of new active lesions [Figure 1]b and [Figure 1]d. His EBV viral load decreased to an undetectable level successfully 2 weeks after the PBSCT. Unfortunately, this EBV viral load rose up again to 7154 copies/ml 3 months later. Tumor recurrence was also documented by another skin biopsy on a solitary ulcerative nodule on his right forearm 6 months after the PBSCT [Figure 1]f. He is now undergoing another cycle of tumor treatment.
| Discussion|| |
EBV has been linked to various lymphoproliferative diseases of B-, T-, or natural killer (NK)-cell lineages. Among them, EBV-associated lymphoproliferative disease of T- and NK-cell lineages is more prevalent in Asia, Mexico, Central America, and South America. According to the most recent World Health Organization classification of Tumours of Haematopoietic and Lymphoid Tissues, the entities of EBV-positive mature T/NK neoplasm include ENKTL, aggressive NK-cell leukemia, node-based EBV + peripheral T-cell lymphoma, chronic active EBV infection, and systemic EBV + T-cell lymphoma of childhood. The frequency of ENKTL among all malignant lymphoma is estimated to be approximately 3% in Japan, 6% in Hong Kong, 7% in Taiwan, and 9% in Korea., Typically, the upper aerodigestive tract, especially the nasal cavity and nasal pharynx, is the primary site of involvement. However, there are tumors that primarily involve extranasal sites, including skin, gastrointestinal tract, bone marrow, lung, testis, central nervous system, and adrenal gland, and are termed "nasal type" or "extranasal." Among them, skin is the most frequent site of involvement outside the aerodigestive tract. The two subgroups of "nasal" and "nasal type" are defined clinically on the primary site of involvement. The skin lesions may be due to "nasal" ENKTL, with secondary spread to the skin or "nasal-type" ENKTL that presented initially in the skin. In our case, skin eruption accompanied with fever came first. Thus, it is better to classify our case as "nasal-type" ENKTL, with initial presentation in the skin. The involvement of the nasal cavity leads to nasal obstruction, sinusitis, and epistaxis. In contrast, the cutaneous presentation of ENKTL, nasal type, has great variety.
Common skin manifestations of ENKTL include cellulitis or abscess-like lesions, subcutaneous nodules, and ulceration, which made up 46%, 43%, and 21%, respectively, of the clinical features in a 45-case study. This study also revealed that there was no significant difference in cutaneous manifestations between cutaneous ENKTL and nasal ENKTL with secondary skin metastasis. Other frequently reported cutaneous manifestations also include erythematous patches or plaques and vasculitis/panniculitis-like lesions. Kim et al. reported a case of ENKTL presenting as pruritic erythematous papules and plaques on the trunk and limbs, which was initially misdiagnosed and treated as eczema. Another study demonstrated genital ulcers as the only clinical presentation of nasal-type ENKTL. Although a variety of cutaneous presentations of ENKTL have been demonstrated, to our knowledge, acneiform eruptions have never been reported before.
Although acne vulgaris is quite common in adolescent male individuals, the presentation of our case is not typical of acne vulgaris. The involvement of the back and the abdomen in our patient was beyond the traditional seborrheic area. Several medications have been implicated to induce acneiform eruptions, such as corticosteroids, anabolic steroids, testosterone, isoniazid, halogenated compounds, EGFR inhibitors, and lithium. However, our patient did not report using any of the suspected medications prior to the skin eruptions. Our patient's skin lesions did not fall into the category of occupational acne, radiation acne, mechanic acne, or Gram-negative acne. The fact that our case did not have incidentally concurrent acne vulgaris is supported by the lack of response to acne vulgaris treatment and the resolution of the acneiform skin eruption after treatment for ENKTL. Therefore, it could be concluded that the acneiform eruption in our case is directly caused by ENKTL.
Several types of cutaneous lymphomas are reported to have acneiform presentation. Primary cutaneous follicle center lymphoma presented as multiple 1–3-mm erythematous papules on the forehead, cheeks, and chin in a 29-year-old woman, or as multiple erythematous, firm papules arranged in a millet seed-like manner or in small clusters in another 18-case study. Primary cutaneous marginal zone lymphoma can present with unusual facial "acne" lesions. Other than B-cell neoplasms, follicular mycosis fungoides can present with acneiform eruption due to folliculocentric involvement. Other lymphomas with acneiform presentation include primary cutaneous CD4-positive small/medium pleomorphic T-cell lymphoma and systemic mantle cell lymphoma involving the skin.
The histopathological features of cutaneous ENKTL include an angiocentric or angiodestructive growth pattern and tumor necrosis. The angiocentricity was reported to range from 31% to 78%,, and is not specific for cutaneous ENKTL. The size of the infiltrate cell varies from small to large lymphocytes and may also present as a mixed pattern. Our case showed a perivascular infiltration pattern with angiodestruction. Geographic tumor necrosis was not identified in our case. Immunohistochemical studies indicate that ENKTL mostly expresses the NK-cell marker and is positive for CD2, CD56, and cytoplasmic CD3. A minority of ENKTL may originate from cytotoxic T-cell lineage, showing clonal TCR gene rearrangement and expression of TCR protein αβ, or γδ. A study of 73 cases of ENKTL, nasal type, in Taiwan revealed a higher portion of T-cell lineages (46%) than the previous report. Nevertheless, the immunophenotype in our case was compatible with a typical NK-cell lineage, evidenced by the positivity of CD3, CD56, and the cytotoxic molecule of TIA-1. In situ hybridization for EBER also demonstrated the presence of EBV in our case.
ENKTL is an aggressive lymphoma. The current main treatment for Stage III/IV is L-asparaginase-based chemotherapy with or without radiotherapy. Regardless of whether the ENKTL is of the "nasal" or "nasal type," the prognosis is poor. The previously reported median survival time was between 13 and 42 months, and the 5-year overall survival rate ranges from 20% to 65%.,,, The median overall survival was better in nasal than in nasal-type ENKTL in one study. However, if cutaneous involvement is focused, the prognosis is better in nasal-type ENKTL in several previous research studies., This may be because cutaneous involvement in nasal ENKTL is representative of a more generalized disease condition. Our patient initially received a SMILE regimen, which was an L-asparaginase-based chemotherapy, followed by an allogeneic hematopoietic stem cell transplantation later due to poor response to first-line treatment. However, he eventually relapsed despite all treatments.
We presented a case of nasal-type ENKTL with a rare presentation of acneiform eruption. Although ENKTL is extremely rare, dermatologists still need to be alert when the treatment directed to the initial diagnosis fails. Then, a skin biopsy is justified especially when the patient presents with other symptoms such as fever in our case. As the prognosis of ENKTL is relatively poor, early diagnosis and early treatment are crucial.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This study was funded by the Ministry of Science and Technology, R.O.C. under Grant (MOST 105-2628-B-010-016-MY3, MOST 107-2314-B-075-032-MY3-1) and Taipei Veterans General Hospital under Grant (VN107-10, V107C-124).
Conflicts of interest
There are no conflicts of interest.
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