Primary Cutaneous Acral [CD8.sup.+] T-Cell Lymphoma.
Primary cutaneous acral [CD8.sup.+] T-cell lymphoma typically occurs in adults older than 50 years, with a slight male predominance. (4) Most cases are characterized by a solitary, slow-growing nodule (7,8) without preceding patches or plaques, (5,9) but bilateral, symmetrical disease and recurrent disease have been reported. (2,4) Although most cases arise on the ear, other peripheral locations, particularly the nose, hands, and feet, have also been described as sites of involvement. (2-5,8,10) These findings suggest that a local, antigenic stimulus specific to the ear is unlikely. (9) Because of the invariably indolent clinical course, there has also been speculation that primary cutaneous acral [CD8.sup.+] T-cell lymphoma may represent a reactive process; however, the frequent monoclonality and aberrant loss of T-cell antigens supports these lesions being a true lymphoproliferative disorder. (9)
The original series described by Petrella and colleagues (1) showed a diffuse proliferation of monomorphic, intermediate-sized [CD8.sup.+] T-cells (Figure 1, A and B) involving the dermis and subcutis. Each case exhibited a well-defined grenz zone without epidermotropism. The neoplastic cells had irregular, lymphoblast-like nuclei (Figure 1, C). Immunoperoxidase studies showed expression of CD3, CD8, T-cell receptor-[beta]F1 (Figure 1, D) and T-cell intracytoplasmic antigen-1 (TIA-1; Figure 2, A) with a low proliferation index (<10%) (Figure 2, B). (1) CD4, CD30, CD56, granzyme B, and Epstein-Barr virus-encoded small RNA were negative with variable loss of other T-cell antigens. (1) Of the 3 cases examined by molecular analysis, all patients demonstrated a monoclonal T-cell [gamma]-gene rearrangement. (1)
Using the Petrella et al (1) series as the prototype, additional cases have amassed in the literature, and it is apparent that the morphologic and immunophenotypic features for the entity indolent [CD8.sup.+] lymphoid proliferation of acral sites are reproducible. (2,4,7,8,11) Additional features identified in later case studies include the absence of necrosis, ulceration, and angiocentricity. (2,12) Although most cases exhibit similar morphology to those originally described, variant features including a moderate proliferation index (30%-40%), focal epidermotropism, Pautrier collections, and granzyme B expression have been reported. (2) Also, although most cases exhibit a monoclonal T-cell [gamma]-gene rearrangement, rare negative cases have been observed. (1,2,4,5,7,9,13)
Recently, CD68 was described as a possible discriminatory marker in distinguishing primary cutaneous acral [CD8.sup.+] T-cell lymphoma from aggressive T-cell lymphomas with a cytotoxic [CD8.sup.+] phenotype. (3) Wobser and colleagues (3) investigated 44 cases of [CD8.sup.+] cutaneous T-cell lymphomas and identified 5 cases of primary cutaneous acral [CD8.sup.+] T-cell lymphoma. During immunohistochemical workup, all 5 cases of primary cutaneous acral [CD8.sup.+] T-cell lymphoma demonstrated unusual, dotlike perinuclear positivity for CD68 in the Golgi zone of neoplastic cells (Figure 2, C and D). None of the other [CD8.sup.+] cutaneous lymphomas expressed CD68, leading the authors to conclude that CD68 with a dotlike pattern may be helpful in identifying primary cutaneous acral [CD8.sup.+] T-cell lymphoma. (3) Although the preliminary data are promising, testing with more cases is warranted to substantiate the sensitivity of this marker. (11,14)
Knowledge of the clinical course and distribution of lesions in primary cutaneous acral [CD8.sup.+] T-cell lymphoma is instrumental in making the correct diagnosis. The indolent clinical course helps exclude rapidly progressing lymphomas, such as primary cutaneous aggressive epidermotropic [CD8.sup.+] cytotoxic T-cell lymphoma, peripheral cutaneous Tcell lymphoma, not otherwise specified, and primary cutaneous [gamma][delta] T-cell lymphoma. (2-5,7-10) The absence of preexisting patches and plaques helps to distinguish primary cutaneous acral [CD8.sup.+] T-cell lymphoma from [CD8.sup.+] mycosis fungoides. (4) There is no predilection for the subcutaneous tissue, as observed in subcutaneous panniculitis-like T-cell lymphoma. (15) The frequent acral localization and solitary nature of these lesions make lymphomatoid papulosis less likely. (2-5,7-9)
Although some authors describe the infiltrates of primary cutaneous acral [CD8.sup.+] T-cell lymphoma as more monomorphic than those of primary cutaneous small/medium-sized pleomorphic cutaneous T-cell lymphoma, the 2 entities may be morphologically indistinguishable. (10) Furthermore, there is striking overlap in clinical features, such as an adult patient population, a predilection for the face and neck, solitary tumors lacking ulceration, and indolent clinical behavior. (8,16) Although it may be reasonable to regard primary cutaneous acral [CD8.sup.+] T-cell lymphoma as a [CD8.sup.+] analogue to [CD4.sup.+] primary cutaneous small/medium-sized pleomorphic cutaneous T-cell lymphoma, studies have shown that the neoplastic [CD4.sup.+] T cells in the latter coexpress programmed death receptor-1 (PD-1), B-cell lymphoma 6 (BCL6), chemokine ligand 13 (CXCL13), and inducible T-cell costimulator (CD278), indicating a follicular helper T-cell phenotype. (5,7,12,17) These markers have been negative in primary cutaneous acral [C8.sup.+] T-cell lymphoma. (2,9) Fortunately, primary cutaneous small/medium-sized pleomorphic cutaneous T-cell lymphoma and primary cutaneous acral [CD8.sup.+] T-cell lymphoma are defined by, and are readily distinguished by, expression of CD4 or CD8, respectively.
The main morphologic clue in distinguishing primary cutaneous acral [CD8.sup.+] T-cell lymphoma from [CD8.sup.+] variants of mycosis fungoides, [CD8.sup.+] aggressive T-cell lymphoma, and type D lymphomatoid papulosis, is epidermotropism. (8-10) Although rare cases of primary cutaneous acral [CD8.sup.+] T-cell lymphoma have exhibited epidermotropism and single intraepidermal Pautrier collections, most cases demonstrate epidermal sparing with a discrete grenz zone. (2)
Immunoperoxidase studies are effective in distinguishing primary cutaneous acral [CD8.sup.+] T-cell lymphoma from morphologic mimickers. Primary cutaneous [gamma][delta] lymphoma is excluded by the presence of T-cell receptor-[beta]F1 expression and the lack of association with Epstein-Barr virus excludes cutaneous extranodal natural killer/T-cell lymphoma. (5) The absence of CD30 excludes primary cutaneous [CD30.sup.+] lymphoproliferative disorders, such as cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis. (4,10)
The morphologic and immunophenotypic overlap between primary cutaneous acral [CD8.sup.+] T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma present a formidable diagnostic challenge. Classic features of subcutaneous panniculitis-like T-cell lymphoma, such as lobular infiltration with septal sparing (Figure 3, A) and adipocyte rimming (Figure 3, B), may not be evident in a limited biopsy specimen. (7,8,10,15) Although CD68 is expressed in the neoplastic cells of primary cutaneous acral [CD8.sup.+] T-cell lymphoma in an unusual, dotlike perinuclear pattern localized to the Golgi zone, (3) subcutaneous panniculitis-like T-cell lymphoma may have abundant histiocytes, (7,8,10,15) making assessment of the neoplastic cells challenging. Although both entities are known to have a cytotoxic immunophenotype (Figure 3, C) and often show aberrant loss of T-cell markers (Figure 4, A), granzyme B is typically negative in primary cutaneous acral [CD8.sup.+] T-cell lymphoma and positive in most subcutaneous panniculitis-like T-cell lymphomas (Figure 4, B). (4,18) Fat necrosis is frequently a prominent feature in subcutaneous panniculitis-like T-cell lymphoma (Figure 4, C), whereas it is absent in primary cutaneous acral [CD8.sup.+] Tcell lymphoma. (2,7,9,10,12) Possibly, the most helpful distinguishing finding is Ki-67. The proliferation index in subcutaneous panniculitis-like T-cell lymphoma is high (Figure 4, D), whereas primary cutaneous acral [CD8.sup.+] T-cell lymphoma typically exhibits a proliferation rate of less than 20%. (4) A clinical history of autoimmune disease, (7,10) lupus erythematosus panniculitis, (7,10) and the presence of indurated violaceous plaques (7) or subcutaneous nodules (8,15) is associated with the diagnosis of subcutaneous panniculitis-like T-cell lymphoma. A summary of clinical, morphologic, and immunophenotypic findings for [CD8.sup.+] cutaneous T-cell lymphomas is provided in the Table. (19-31)
PROGNOSIS AND TREATMENT
Despite the high-grade morphologic features and cytotoxic immunophenotype, the clinical course for primary cutaneous acral [CD8.sup.+] T-cell lymphoma is invariably indolent. Although there have been cases of cutaneous relapse, there are no reports of extracutaneous disease at diagnosis, and no staging investigations have shown progression to systemic disease during follow-up periods of 3 to 168 months, regardless of treatment modality (topical steroids, radiotherapy, surgical excision, or simple observation). (4) Interferon, psoralen-ultraviolet A phototherapy, and methotrexate have been used in patients with multifocal cutaneous disease to minimize the occurrence of relapse with varying degrees of success. (4,32)
Correct diagnosis of primary cutaneous acral [CD8.sup.+] T-cell lymphoma is essential because the prognostic and therapeutic implications are distinct among other [CD8.sup.+] cytotoxic lymphoid proliferations. Aggressive epidermotropic cutaneous [CD8.sup.+] lymphoma and primary cutaneous peripheral Tcell lymphoma, not otherwise specified (NOS) warrant staging investigations and aggressive therapy. (3) In contrast, primary cutaneous acral [CD8.sup.+] T-cell lymphoma can be managed conservatively and tends to follow an indolent clinical course regardless of treatment modality. (4) Knowledge of the clinical setting and morphologic and immunophenotypic features can aid in correct diagnosis.
(1.) Petrella T, Maubec E, Cornillet-Lefebvre P, et al. Indolent CD8-positive lymphoid proliferation of the ear--a distinct primary cutaneous T-cell lymphoma? Am J Sur Pathol. 2007;31(12):1887-1892.
(2.) Greenblatt D, Ally M, Child F, et al. Indolent [CD8.sup.+] lymphoid proliferation of acral sites: a clinicopathologic study of six patients with some atypical features. J Cutan Pathol. 2012;40(2):248-258.
(3.) Wobser M, Roth S, Reinartz T, Rosenwald A, Goebeler M, Geissinger E. CD68 expression is a discriminative feature of indolent cutaneous CD8-positive lymphoid proliferation and distinguishes this lymphoma subtype from other CD8-positive cutaneous lymphomas. Br J Dermatol. 2015;172(6):1573-1580.
(4.) Kluk J, Kai A, Koch D, et al. Indolent CD8-positive lymphoid proliferation of acral sites: three further cases of a rare entity and an update on a unique patient. J Cutan Pathol. 2015;43(2):125-136.
(5.) Kempf W, Kazakov DV, Cozzio A, et al. Primary cutaneous [CD8.sup.+] small- to medium-sized lymphoproliferative disorder in extrafacial sites. Am J Dermatopathol. 2013;35(2):159-166.
(6.) Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20): 2375-2390.
(7.) Magro CM, Crowson AN, Mihm MC. The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin. Hoboken, NJ: John Wiley & Sons Inc.;2016.
(8.) Cerroni L. Skin Lymphoma: The Illustrated Guide. Chichester, England: Wiley Blackwell;2014.
(9.) Wobser M, Petrella T, Kneitz H, et al. Extrafacial indolent CD8-positive cutaneous lymphoid proliferation with unusual symmetrical presentation involving both feet. J Cutan Pathol. 2013;40(11):955-961.
(10.) Jaffe ES, Arber DA, Campo E, Harris NL, Quintanilla-Martinez L. Hematopathology. Philadelphia, PA: Elsevier; 2017.
(11.) Goodlad J. Indolent CD8-positive lymphoid proliferation of acral sites: identifying the sheep in wolf's clothing [comment]. Br J Dermatol. 2015;172(6): 1480-1481.
(12.) Swick BL, Baum CL, Venkat AP, Liu V. Indolent CD8+ lymphoid proliferation of the ear: report of two cases and review of the literature. J Cutan Pathol. 2010;38(2):209-215.
(13.) Beltraminelli H, Mullegger R, Cerroni L. Indolent CD8+ lymphoid proliferation of the ear: a phenotypic variant of the small-medium pleomorphic cutaneous T-cell lymphoma? J Cutan Pathol. 2010;37(1):81-84.
(14.) Lecamwasam K, Mathew B, Gilson D, Burton C, Laws P. Correspondence article regarding CD68 as a marker of CD8+ lymphoid proliferation suggested by Wobser, et al. Br J Dermatol. 2016;174(5):1158-1159.
(15.) Tomasini D, Berti E. Subcutaneous panniculitis-like T-cell lymphoma. G Ital Dermatol Venereol. 2013;148:395-411.
(16.) Beltraminelli H, Leinweber B, Kerl H, et al. Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance?: a study of 136 cases. Am J Dermatopathol. 2009;31(4):317-322.
(17.) Lan TTH, Brown NA, Hristov AC. Controversies and considerations in the diagnosis of primary cutaneous CD4 small/medium T-cell lymphoma. Arch Pathol Lab Med. 2014;138(10):1307-1318.
(18.) Takeshita M, Okamura S, Oshiro Y, et al. Clinicopathologic differences between 22 cases of CD56-negative and CD56-positive subcutaneous panniculitis-like lymphoma in Japan [published correction appears in Hum Pathol. 2004;35(3):388].Hum Pathol. 2004;35(2):231-239.
(19.) Bekkenk MW. Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood. 2003;102(6): 2213-2219.
(20.) Dewar R, Andea AA, Guitart J, Arber DA, Weiss LM. Best practices in diagnostic immunohistochemistry: workup of cutaneous lymphoid lesions in the diagnosis of primary cutaneous lymphoma. Arch Pathol Lab Med. 2015;139(3): 338-350.
(21.) Diamantidis MD, Myrou AD. Perils and pitfalls regarding differential diagnosis and treatment of primary cutaneous anaplastic large-cell lymphoma. Scientific World Journal. 2011;11:1048-1055.
(22.) Dummer R, MichieSA, Kell D, et al. Expression of bcl-2 protein and Ki-67 nuclear proliferation antigen in benign and malignant cutaneous T-cell infiltrates. J Cutan Pathol. 1995;22(1):11-17.
(23.) Hsu Y-J, Su L-H, Hsu Y-L, Tsai T-H, Hsiao C-H. Localized lymphomatoid papulosis. J Am Acad Dermatol. 2010;62(2):353-356.
(24.) James E, Sokhn JG, Gibson JF, et al. CD4 primary cutaneous small/ medium-sized pleomorphic T-cell lymphoma: a retrospective case series and review of literature. Leuk Lymphoma. 2014;56(4):951-957.
(25.) Merrill ED, Agbay R, Miranda RN, et al. Primary cutaneous T-Cell lymphomas showing gamma-delta ([gamma][delta]) phenotype and predominantly epidermotropic pattern are clinicopathologically distinct from classic primary cutaneous [gamma][delta] T-Cell lymphomas. Am J Sur Pathol. 2017;41(2):204-215.
(26.) Quintanilla-Martinez L, Jansen PM, Kinney MC, Swerdlow SH, Willemze R. Non-mycosis fungoides cutaneous T-cell lymphomas: report of the 2011 Society for Hematopathology/European Association for Haematopathology Workshop. Am J Clin Pathol. 2013;139(4):491-514.
(27.) Robson A, Assaf C, Bagot M, et al. Aggressive epidermotropic cutaneous CD8 lymphoma: a cutaneous lymphoma with distinct clinical and pathological features: report of an EORTC Cutaneous Lymphoma Task Force Workshop. Histopathology. 2015;67(4):425-441.
(28.) Sen F, Rassidakis GZ, Jones D, Medeiros LJ. Apoptosis and proliferation in subcutaneous panniculitis-like T-cell lymphoma. Mod Pathol. 2002;15(6):625-631.
(29.) Willemze R. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105(10):3768-3785.
(30.) Willemze R, Meijer CJLM. Classification of cutaneous T-cell lymphoma: from Alibert to WHO-EORTC. J Cutan Pathol. 2006;33(S1):18-26.
(31.) Wood GS, Strickler JG, Deneau DG, Egbert B, Warnke RA. Lymphomatoid papulosis expresses immunophenotypes associated with T cell lymphoma but not inflammation. J Am Acad Dermatol. 1986;15(3):444-458.
(32.) Friedmann D. Primary cutaneous pleomorphic small T-cell lymphoma. Arch Derm. 1995;131(9):1009.
Vivian M. Hathuc, DO; Alexandra C. Hristov, MD; Lauren B. Smith, MD
Accepted for publication May 25, 2017.
From the Sections of Hematopathology (Drs Hathuc and Smith) and Dermatopathology (Dr Hristov) in the Department of Pathology, University of Michigan Medical Center, Ann Arbor.
The authors have no relevant financial interest in the products or companies described in this article.
Presented in part at the New Frontiers in Pathology meeting; October 13-15, 2016;Ann Arbor, Michigan.
Reprints: Lauren B. Smith, MD, Section of Hematopathology, Department of Pathology, University of Michigan Medical Center, 5242 Medical Science 1, 1301 Catherine St, Ann Arbor, MI 48109 (email: email@example.com).
Please Note: Illustration(s) are not available due to copyright restrictions
Caption: Figure 1. Primary cutaneous acral [CD8.sup.+] T-cell lymphoma. A, Hematoxylin-eosin-stained section showing a dense, monomorphic infiltrate within the subcutaneous tissue composed of intermediate-sized cells. B, CD8 showing diffuse positivity. C, Hematoxylin-eosin-stained section showing grooved/folded nuclei, delicate chromatin, abundant cytoplasm, and small nucleoli. D, T-cell receptor pF1 showing diffuse coexpression with the [CD8.sup.+] population (original magnifications X100 [A] and X500 [C]; original magnification X100 [B and D]).
Caption: Figure 2. Primary cutaneous acral [CD8.sup.+] T-cell lymphoma. A, T-cell intracytoplasmic antigen-1 (TIA-1) expression in the neoplastic cells. B, Ki-67 showing a low proliferation index. C and D, CD68 highlighting the neoplastic cells with dotlike perinuclear positivity localized to the Golgi zone (original magnification X500 [A]; original magnification X100 [B]; original magnifications X100 [C] and X500 [D]).
Caption: Figure 3. Subcutaneous panniculitis-like T-cell lymphoma. A, Hematoxylin-eosin-stained section showing an atypical lymphoid infiltrate confined to the subcutaneous tissue. Lobular involvement with septal sparing is characteristic. B, Hematoxylin-eosin-stained section showing atypical lymphocytes rimming individual adipocytes. C, CD8 highlighting the neoplastic cells (original magnifications X20 [A] and X400 [B]; original magnification X200 [C]).
Caption: Figure 4. Subcutaneous panniculitis-like T-cell lymphoma. A, CD5 showing diminished expression within the neoplastic cells. B, Granzyme highlighting a subset of the neoplastic cells. C, Lysozyme highlighting abundant histiocytes within areas of fat necrosis. D, Ki-67 showing a high proliferation index (original magnification X200 [A]; original magnification X200 [B]; original magnification X200 [C]; original magnification X100 [D]).
Differential Diagnosis of [CD8.sup.+] Cutaneous T-Cell Lymphomas Loss of Cell Epidermo- T-Cell Skin Lesions Size tropism Markers [CD8.sup.+] cutaneous lymphomas Primary Solitary, slow- Small- -- + cutaneous acral growing medium [CD8.sup.+] T- erythematous cell lymphoma nodule; head and neck (especially ear), hands, feet Primary Rapidly Medium + + cutaneous growing, aggressive generalized, epidermotropic and ulcerated [CD8.sup.+] papules, cytotoxic T- plaques, cell lymphoma nodules; trunk, extremities, face; rapidly disseminated lesions to visceral sites Subcutaneous Solitary or Small- -- +/- panniculitis- multiple, medium, like T-cell deeply seated rarely lymphoma plaques or large subcutaneous nodules; often extremities CD8 variants of CD4 or null cutaneous lymphomas Mycosis Generalized, Variable + + fungoides, scaly patches cytotoxic and plaques, ulcerated nodules; predilection for buttocks and sun- protected areas Cutaneous Solitary or Large -/+ + anaplastic grouped large cell ulcerating lymphoma nodules that can regress but often recur; head, extremities Peripheral Scattered or Medium- -- + cutaneous T- diffuse, large cell lymphoma, ulcerating not otherwise nodules with specified rapid dissemination and systemic involvement; no specific site Primary Usually Small- -- +/- cutaneous solitary, medium small-medium- erythematous sized nodules on pleomorphic face, neck, or cutaneous T- upper trunk cell lymphoma [PD-1. Potentially Cytotoxic sup.+] Distinguishing TCR0F1 Markers Cells Features [CD8.sup.+] cutaneous lymphomas Primary + + -- Monotonous cutaneous acral infiltration of [CD8.sup.+] T- the dermis with cell lymphoma a grenz zone below the unaffected epidermis; CD68 localized to Golgi zone Primary + + N/A Prominent cutaneous epidermotropism, aggressive folliculotropism epidermotropic common [CD8.sup.+] cytotoxic T- cell lymphoma Subcutaneous + + N/A Only subcutis panniculitis- involved; like T-cell associated with lymphoma autoimmune disorders (nearly 20%); lobular infiltration with septal sparing, adipocyte rimming; necrosis and granulomas common CD8 variants of CD4 or null cutaneous lymphomas Mycosis + -/+ -/+ Pautrier fungoides, microabscesses, cytotoxic intraepidermal vesiculation, cerebriform nuclei, haloed lymphocytes Cutaneous + + N/A Markedly anaplastic atypical large cell [CD30.sup.+] lymphoma cells Peripheral + + -/+ Advanced cutaneous T- clinical stage cell lymphoma, at presentation; not otherwise significant specified immuno- phenotypic aberrations Primary + -- + [CD4.sup.+], cutaneous follicular small-medium- helper T-cell sized phenotype pleomorphic cutaneous T- cell lymphoma Ki-67 [CD8.sup.+] cutaneous lymphomas Primary Frequently cutaneous acral low [CD8.sup.+] T- (<10); cell lymphoma some low- moderate (<20) Primary High cutaneous aggressive epidermotropic [CD8.sup.+] cytotoxic T- cell lymphoma Subcutaneous Moderate- panniculitis- high like T-cell lymphoma CD8 variants of CD4 or null cutaneous lymphomas Mycosis Varies fungoides, with cytotoxic stage of disease Cutaneous High anaplastic large cell lymphoma Peripheral High cutaneous T- cell lymphoma, not otherwise specified Primary Low to cutaneous low- small-medium- moderate sized (5%- pleomorphic 20%) cutaneous T- cell lymphoma Abbreviations: + positive; - negative;+--, variable but more frequently positive; --+, variable but more frequently negative;N-A, not available; PD-1, programmed death-1;TCR, T-cell receptor.
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|Author:||Hathuc, Vivian M.; Hristov, Alexandra C.; Smith, Lauren B.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Nov 1, 2017|
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