Dermatopathology

Persistent Reaction to an Insect Bite with Increased CD30-Positive Forms

Alexander Lazar


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Clinical History:
Female age 52 with a 1 cm pruritic papule on right breast present for at least 2 months. The raised surface was smooth and somewhat erythematous. The clinical assessment was an "infiltrative process." Further clinical investigation raised suspicion for an "insect bite" that the patient noted was pruritic and erythematous for some time and then did not resolve. The duration suggested the possibility of a more concerning process. At more than 15 months of follow-up, the lesion has not recurred and no additional lesions have been noted


Slide 1
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Figure 1
A nodular infiltrate is present in the dermis, 20x.
Figure 2
The infiltrate is composed of a mixture of lymphocytes and histiocytes surrounding small vessels, 200x.
Figure 3
Larger forms are admixed in the infiltrate, 400x.

Figure 4 - CD30
CD30-positive forms represent around 5 % of the infiltrate, 100x.
Figure 5 - CD30
The CD30-positive forms occur as single cells and small clusters, 400x.


Histologic Features:
The sections show a multinodular lymphocytic infiltrate occupying the superficial to mid-level reticular dermis. Larger forms were scattered throughout the infiltrate. Deeper levels used for immunohistochemical studies showed areas suggestive of germinal center formation with tingible body macrophages.

Ancillary Studies:
Immunohistochemical studies revealed that the infiltrate was composed primarily of CD20-positive B-cells (60-70 %) with CD3-positive T-cells comprising the balance of the infiltrate. The larger cells were strongly reactive for CD30, occurred singly and in small clusters, and comprised approximately 5 % of the infiltrate. The B-cell infiltrate show very rare plasma cells reactive to kappa or lambda light chains; no restriction was noted. The T-cells were primarily CD4-positive forms (80 %) with admixed CD8-positive cells. The T-cells appeared to mark with both bcl-2 and CD43 while the B-cells did not express either of these markers. Both bcl-6 and CD10 highlighted a few germinal centers in deeper sections. No clonal population of T- or B-cells was noted on molecular studies.

Differential Diagnosis:
On the basis of the histologic images presented, the differential diagnosis would include:
  • Lymphomatoid papulosis (LyP)

  • Benign cutaneous lymphoid hyperplasia

  • Primary cutaneous B-cell lymphoma

  • Primary cutaneous T-cell lymphoma

  • Persistent reaction to external antigen (insect bite, etc.)

Diagnosis:
Persistent Reaction to an Insect Bite with Increased CD30-Positive Forms.

Discussion:
This lesion was ultimately interpreted as a persistent reaction to an insect bite with increased CD30-positive forms. The presence of CD30-positive forms in a cutaneous lymphoid infiltrate is concerning for LyP and increased number of these cells further increases the suspicion for this disease. Clusters of CD30-positive forms are also suggestive of LyP. A discussion of the differential diagnosis listed above follows:

Lymphomatoid Papulosis (LyP):
The presence of a CD3-positive T-cell infiltrate composed primarily of CD4-positive forms with enlarged CD30-positive forms present in single cells and clusters is suggestive of LyP. Although classically described as having many CD30 positive cells, these cells can be less prominent in LyP. Therefore, the amount of CD30 positive cells seen in this case does not exclude the possibility of LyP. However, the additional information that the majority of the infiltrate is composed of CD20-positive B-cells argues against this diagnostic consideration as does the clinical history of a solitary lesion. Furthermore, the infiltrate lacks the characteristic wedge-shape pattern, which is often, but not always, encountered with LyP. Lastly, the degree of cellular pleomorphism in the infiltrate is not as striking as in most cases of LyP. Since this lesion is solitary, anaplastic large cell lymphoma could be considered, but again the degree of pleomorphism or atypia (hyperchromasia, etc.) is not impressive in this case.

Primary cutaneous B-cell Lymphoma:
The two primary cutaneous B-cell lymphomas to consider would be follicular center lymphoma or marginal zone B-cell lymphoma under the WHO-EORTC classification [1]. However, this case lacks the expanded germinal centers of follicular lymphoma and the expanded marginal zone with lymphoplasmacytic forms of marginal zone lymphoma.

Cutaneous T-cell Lymphoma:
The histologic and immunohistochemical features do not suggest any recognized form of T- cell lymphoma [1]. LyP and ALCL discussed above are the most relevant neoplastic T-cell processes to consider.

Benign Cutaneous Lymphoid Hyperplasia:
In many ways, this case could be considered as a type of benign cutaneous lymphoid hyperplasia. But since an inciting etiology (insect bite) is clinically indicated, this case was categorized as a persistent reaction to an insect bite with increased reactive CD30-positive forms.

The CD30 antigen and monoclonal antibody was initially described in 1982 in association with Reed-Sternberg cells in Hodgkin Disease [2]. CD30-reactivity defines the family of CD30-positive lymphoproliferative disorders including anaplastic large cell lymphoma (ALCL) and LyP [3, 4]. These two entities can certainly have overlapping histologic features and may even coexist, but they can usually be distinguished from each other by their clinical presentation [5]. A variety of other lymphomatous processes involving the skin can express CD30 including mycoses fungoides, most T-cell lymphomas and, at times, even B-cell lymphomas.

CD30-positivity can also be seen in activated, non-neoplastic lymphocytes (usually T-cells [6, 7]) and has been described in numerous non-neoplastic processes (inflammatory and infectious) including: drug reactions [8, 9], in the setting of systemic chemotherapy [10], atopic dermatitis [11], insect bites [12, 13] , hidradenitis suppurativa, ruptured cyst, rhinophyma, Sweet syndrome [14], bacterial infections (e.g., mycobacteria [15], necrotizing fasciitis), and a variety of viral infections (e.g., HSV, EBV, poxvirus [16], parapoxvirus [17], HIV, HTLV-I). Infiltrates that are rich in neutrophils and/or eosinophils have been suggested to be particularly prone to expression of CD30-positive forms [14]. Thus, it is important to remember that a variety of benign and malignant processes can be associated with CD30-positive forms. Careful correlation with the clinical setting can be extremely revealing.

Studies have shown that CD30 is helpful in the differential diagnosis of persistent insect bite reaction and LyP and this is true in most cases [18]. However, it is important to remember that some cases of insect bite (and other non-neoplastic infiltrates) can show reactive CD30-positive forms [19]. These are usually less in number than usually seen in LyP or ALCL and often tend to occur as single cells rather than clusters or sheets of cells, but this is not invariant as this present case demonstrates.

References:
  1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. May 15 2005;105(10):3768-3785.

  2. Schwab U, Stein H, Gerdes J, et al. Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin's disease and a subset of normal lymphoid cells. Nature. Sep 2 1982;299(5878):65-67.

  3. Kempf W. CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators. J Cutan Pathol. Feb 2006;33 Suppl 1:58-70.

  4. Kadin ME. Pathobiology of CD30+ cutaneous T-cell lymphomas. J Cutan Pathol. Feb 2006;33 Suppl 1:10-17.

  5. Droc C, Cualing HD, Kadin ME. Need for an improved molecular/genetic classification for CD30+ lymphomas involving the skin. Cancer Control. Apr 2007;14(2):124-132.

  6. de Bruin PC, Gruss HJ, van der Valk P, Willemze R, Meijer CJ. CD30 expression in normal and neoplastic lymphoid tissue: biological aspects and clinical implications. Leukemia. Oct 1995;9(10):1620-1627.

  7. Gruss HJ, Boiani N, Williams DE, Armitage RJ, Smith CA, Goodwin RG. Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines. Blood. Apr 15 1994;83(8):2045-2056.

  8. Saeed SA, Bazza M, Zaman M, Ryatt KS. Cefuroxime induced lymphomatoid hypersensitivity reaction. Postgrad Med J. Sep 2000;76(899):577-579.

  9. Nathan DL, Belsito DV. Carbamazepine-induced pseudolymphoma with CD-30 positive cells. J Am Acad Dermatol. May 1998;38(5 Pt 2):806-809.

  10. Su LD, Duncan LM. Lymphoma- and leukemia-associated cutaneous atypical CD30+ T-cell reactions. J Cutan Pathol. May 2000;27(5):249-254.

  11. Dummer W, Rose C, Brocker EB. Expression of CD30 on T helper cells in the inflammatory infiltrate of acute atopic dermatitis but not of allergic contact dermatitis. Arch Dermatol Res. Nov 1998;290(11):598-602.

  12. McCalmont TH, LeBoit PE. A lymphomatoid papule, but not lymphomatoid papulosis! Am J Dermatopathol. Apr 2000;22(2):188-190.

  13. Gallardo F, Barranco C, Toll A, Pujol RM. CD30 antigen expression in cutaneous inflammatory infiltrates of scabies: a dynamic immunophenotypic pattern that should be distinguished from lymphomatoid papulosis. J Cutan Pathol. Jul 2002;29(6):368-373.

  14. Cepeda LT, Pieretti M, Chapman SF, Horenstein MG. CD30-positive atypical lymphoid cells in common non-neoplastic cutaneous infiltrates rich in neutrophils and eosinophils. Am J Surg Pathol. Jul 2003;27(7):912-918.

  15. Munk ME, Kern P, Kaufmann SH. Human CD30+ cells are induced by Mycobacterium tuberculosis and present in tuberculosis lesions. Int Immunol. May 1997;9(5):713-720.

  16. Guitart J, Hurt MA. Pleomorphic T-cell infiltrate associated with molluscum contagiosum. Am J Dermatopathol. Apr 1999;21(2):178-180.

  17. Rose C, Starostik P, Brocker EB. Infection with parapoxvirus induces CD30-positive cutaneous infiltrates in humans. J Cutan Pathol. Nov 1999;26(10):520-522.

  18. Smoller BR, Longacre TA, Warnke RA. Ki-1 (CD30) expression in differentiation of lymphomatoid papulosis from arthropod bite reactions. Mod Pathol. Sep 1992;5(5):492-496.

  19. Diaz-Cascajo C. Strong immunoexpression of the monoclonal antibody CD-30 in lymphocytic infiltrates of the skin not by itself evidence for diagnosing malignant lymphoma. Am J Dermatopathol. Feb 2001;23(1):79-80.