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JAMA Dermatology Clinicopathological Challenge
February 19, 2020

Rapidly Evolving Necrotic Plaques and Nodules in a Middle-aged Woman

Author Affiliations
  • 1Department of Dermatology, University of Minnesota, Minneapolis
JAMA Dermatol. Published online February 19, 2020. doi:10.1001/jamadermatol.2019.4992

Case

A woman in her 50s presented to a tertiary dermatology referral center with scaly erythematous patches and plaques covering 10% of her total body surface area without clinically appreciable lymphadenopathy. Histopathological testing demonstrated an epidermotropic infiltrate of hyperchromatic, convoluted, atypical CD3+, CD4, and CD8+ lymphocytes with haloed nuclei with basilar tagging and papillary dermal fibrosis. Studies of T-cell gene rearrangements identified a clonal population. Blood-flow cytometry did not reveal aberrant T-cell immunophenotypes. She was treated initially with topical and intralesional corticosteroids and narrow band UV B phototherapy. Oral bexarotene was subsequently added for recalcitrant disease. Within 2 months, she developed isolated, painful tumors. A second biopsy was performed, which was notable for an epidermotropic infiltrate of CD3+, CD4, and CD8 weak lymphocytes, which were positive for TIA-1, granzymes, and B factor (Bf) 1 and negative for CD30 and CD56. The results of flow cytometry and imaging were unremarkable. After an initial favorable response with chlorambucil, she developed expanding ulcerated tumors complicated by a polymicrobial superinfection. Chlorambucil was discontinued in favor of antimicrobial treatment. She then received liposomal doxorubicin, although skin involvement continued to progress rapidly, with ulcerating tumors making up as much as 80% of her total body surface area. She was hospitalized for worsening disease and pain (Figure, A). Repeated histopathologic analysis was done (Figure, B, C, and D).

Figure.  
A, Clinical image. B, Original magnification ×50. C, Considerable lymphocytic epidermotropism in a pagetoid reticulosis–like pattern without striking Pautrier microabscesses (original magnification ×230). D, Original magnification ×50.

A, Clinical image. B, Original magnification ×50. C, Considerable lymphocytic epidermotropism in a pagetoid reticulosis–like pattern without striking Pautrier microabscesses (original magnification ×230). D, Original magnification ×50.

Box Section Ref ID

What Is Your Diagnosis?

  1. CD8+ mycosis fungoides

  2. Lymphomatoid papulosis, type D

  3. Primary cutaneous aggressive epidermotropic cytotoxic CD8+ T-cell lymphoma

  4. Natural killer/T-cell lymphoma

Discussion

Diagnosis

C. Primary cutaneous aggressive epidermotropic cytotoxic CD8+ T-cell lymphoma

Discussion

The repeated histopathologic analysis revealed atypical, strikingly epidermotropic lymphocytes positive for CD3, CD8, TIA1, granzymes, and Bf1 and negative for CD4, CD30, CD56, and Epstein-Barr virus–encoded RNA, with enlarged, misfolded nuclei throughout the spinous layer (Figure, C and D). Histological testing and clinical presentation supported a diagnosis of primary cutaneous aggressive epidermotropic cytotoxic CD8+ T-cell lymphoma (PCECTCL).

This condition is recognized as a distinct diagnosis in current World Health Organization and European Organization for Research and Treatment of Cancer guidelines and represents less than 1% of all cutaneous T-cell lymphomas.1-3 It is characterized by the abrupt onset of widespread, ulcerating papules, plaques, or tumors with or without mucosal and/or visceral involvement.1,3-6 While this disease entity is generally described as strikingly and rapidly progressive, in several case reports, patients presented initially with patch/plaque-stage CD8+ mycosis fungoides (MF), which slowly progressed to recalcitrant, ulcerating tumors over months to years after the initial diagnosis.6 On histopathologic examination, marked epidermotropism in a pagetoid reticulosis–like pattern may be appreciated, generally in the absence of significant Pautrier microabscesses.1,6 Angiocentricity and destruction are not uncommon and likely contribute to the ulceration perceived on clinical examination.1,6 A characteristic cytotoxic phenotype is present with lymphocytes expressing Bf1, TIA1, and granzyme B to a marked degree.1,3,6 Expression of CD2 and CD5 is typically not present, and lymphocytes rarely express CD30 or CD56.1,3,6 In addition, high proliferative fractions may be present, as evidenced by high KI-67 fractions.1

Suggested systemic evaluation for patients suspected to have PCECTCL includes laboratory and imaging studies (a complete blood cell count, complete metabolic panel, lactic dehydrogenase level test, and HIV serology test and computed tomography with contrast or positron emission tomography–computed tomography of the chest, abdomen, and/or pelvis).3 Therapeutic management consists of multiagent chemotherapy and immunotherapy regimens, in addition to consideration of hematopoietic stem-cell transplant and total skin electron-beam therapy.2-4 Prognosis is poor, and few studies report a successful, durable response to therapy.4,7 Median survival time is estimated to be 12 to 32 months from the time of diagnosis.1,3 The present case reveals a clinicopathologic correlation between the rapidly evolving ulcerating tumors noted in this patient and markedly epidermotropic, atypical cytotoxic lymphocytes positive for CD3, CD8, TIA1, granzymes, and Bf1 and negative for CD4, CD30, CD56, and Epstein-Barr virus–encoded RNA.

A benign, protracted clinical course distinguishes CD8+ MF from PCECTCL. Strong CD8 expression does not necessarily portend a poor prognosis in all patients, given the largely favorable prognosis in patients diagnosed with CD8+ MF compared with those with PCECTCL.1 Distinctive features of CD8+ MF, such as hypopigmentation, poikiloderma, or follicular mucinosis, may aid in distinguishing CD8+ MF from PCECTCL, as they may be more prominent in CD8+ MF.1,6 Also, Pautrier microabscesses as scattered microaggregates are more closely associated with MF.6 Type D lymphomatoid papulosis commonly manifests a pagetoid reticulosis–like pattern of epidermotropic CD8+ and wedge-shaped CD30+ atypical lymphocytes on histopathological testing, although patients present clinically with a history of papules and nodules that wax and wane over time.1,6,8 Natural killer/T-cell lymphoma may also present with multiple ulcerating plaques and tumors.1 Although this clinical entity is readily distinguished by immunophenotype and rarely occurs in the absence of Epstein-Barr virus expression and Epstein-Barr virus–induced lymphoproliferation, PCECTCL has been reported as a mimicker.9

Patient Outcome

In the hospital, the patient received 2 cycles of romidepsin, with slight improvement in ulceration and pain. She was eventually discharged to a long-term care facility for continued wound care and pain management; she died shortly thereafter from pneumonia.

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Article Information

Corresponding Author: Laurel L. Wessman, MD, Department of Dermatology, University of Minnesota, 516 Delaware St SE, Mail Code 98, Phillips-Wangensteen Building, Ste 4-240, Minneapolis, MN 55455 (wessm018@umn.edu).

Published Online: February 19, 2020. doi:10.1001/jamadermatol.2019.4992

Conflict of Interest Disclosures: None reported.

Disclaimer: Dr Gaddis is associate editor of JAMA Dermatology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Additional Contributions: We thank the patient’s daughter for granting permission to publish this information.

Self-assessment Credit: This article is eligible for journal-based self-assessment (1 credit) for Maintenance of Certification (MOC) from the American Board of Dermatology (ABD). After completion of an activity, please log on to the ABD website at www.abderm.org to register your credits. This may be done after each exercise or after accumulating many credits.
References
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Robson  A, Assaf  C, Bagot  M,  et al.  Aggressive epidermotropic cutaneous CD8+ lymphoma.  Histopathology. 2015;67(4):425-441. doi:10.1111/his.12371PubMedGoogle ScholarCrossref
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Kempf  W, Zimmermann  AK, Mitteldorf  C.  Cutaneous lymphomas—an update 2019.  Hematol Oncol. 2019;37(suppl 1):43-47. doi:10.1002/hon.2584PubMedGoogle ScholarCrossref
3.
Geller  S, Myskowski  PL, Pulitzer  M, Horwitz  SM, Moskowitz  AJ.  Cutaneous T-cell lymphoma (CTCL), rare subtypes.  Chin Clin Oncol. 2019;8(1):5. doi:10.21037/cco.2018.11.01PubMedGoogle ScholarCrossref
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Al Aoun  SM, Iqbal  S, AlHalouli  TM, Zaidi  SZ, Motabi  IH.  Durable remission of a patient with primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma.  Hematol Oncol Stem Cell Ther. 2018;S1658-3876(18)30096-7. doi:10.1016/j.hemonc.2018.09.004PubMedGoogle Scholar
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Tomasini  C, Novelli  M, Fanoni  D, Berti  EF.  Erythema multiforme-like lesions in primary cutaneous aggressive cytotoxic epidermotropic CD8+ T-cell lymphoma.  J Cutan Pathol. 2017;44(10):867-873. doi:10.1111/cup.12995PubMedGoogle ScholarCrossref
6.
Guitart  J, Martinez-Escala  ME, Subtil  A,  et al.  Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas.  Mod Pathol. 2017;30(5):761-772. doi:10.1038/modpathol.2016.240PubMedGoogle ScholarCrossref
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Cyrenne  BM, Subtil  A, Girardi  M, Foss  F.  Primary cutaneous aggressive epidermotropic cytotoxic CD8+ T-cell lymphoma.  Int J Dermatol. 2017;56(12):1448-1450. doi:10.1111/ijd.13792PubMedGoogle ScholarCrossref
8.
Berti  E, Tomasini  D, Vermeer  MH, Meijer  CJ, Alessi  E, Willemze  R.  Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas.  Am J Pathol. 1999;155(2):483-492. doi:10.1016/S0002-9440(10)65144-9PubMedGoogle ScholarCrossref
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Pan  ST, Chang  WS, Murphy  M, Martinez  A, Chuang  SS.  Cutaneous peripheral T-cell lymphoma of cytotoxic phenotype mimicking extranodal NK/T-cell lymphoma.  Am J Dermatopathol. 2011;33(2):e17-e20. doi:10.1097/DAD.0b013e3181ea6571PubMedGoogle ScholarCrossref
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