Large CD30-positive cells in benign, atypical lymphoid infiltrates of the skin

Authors


Lorenzo Cerroni, MD, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria
Tel.: +43 316 385 2423
Fax: +43 316 385 2466
e-mail: lorenzo.cerroni@meduni-graz.at

Abstract

Background:  Cutaneous infectious and inflammatory diseases may contain a significant number of CD30-positive cells, thus mimicking lymphomatoid papulosis (LyP) or anaplastic large cell lymphoma.

Methods:  We reviewed our cases of non-neoplastic skin conditions with large, CD30-positive cells and searched the literature for similar cases.

Results:  A total of 28 cases were included in the study: Milker’s nodule (n = 8), Herpes simplex virus infection (n = 7), lymphomatoid drug reaction (n = 3), molluscum contagiosum (n = 3), nodular scabies (n = 2), leishmaniasis (n = 1), syphilis (n = 1), pernio (n = 1), ruptured infundibular cyst (n = 1) and pseudolymphoma in a scar (n = 1). CD30-positive cells were often arranged in clusters and revealed both Golgi and membrane positivity, similar to what was observed in LyP and CD30+ anaplastic large T-cell lymphoma.

Conclusions:  Analysis of our data and of those published in the literature shows that viruses and drugs are the most common cause for occurrence of large CD30-positive cells in cutaneous pseudolymphomatous infiltrates. Arrangement of these large, CD30-positive cells in small clusters is not unique to cutaneous CD30-positive lymphomas, and in many cases a precise diagnosis can be made only upon accurate clinicopathological correlation or using ancillary methods such as polymerase chain reaction analysis for viral DNA.

Expression of the CD30 antigen is the hallmark of a group of primary cutaneous T-cell lymphomas including the spectrum ranging from lymphomatoid papulosis (LyP) to primary cutaneous anaplastic large T-cell lymphoma (cALCL).1,2 CD30-positivity on neoplastic cells of cutaneous malignant lymphomas, however, is not a feature exclusive to LyP and cALCL, as it can be observed in cases of Hodgkin’s lymphoma involving secondarily the skin3 as well as in several T-cell4,5 and B-cell lymphomas,6–8 natural-killer cell lymphomas9,10 or even in granulocytic sarcoma.11 Furthermore, in the past years, CD30-positive cells have been detected in several reactive lymphocytic infiltrates of the skin12–32 and oral mucosa.33

We reviewed our cases of non-neoplastic (inflammatory or infectious) skin conditions in which large CD30-positive cells were detected among the infiltrating lymphocytes, analyzing the pattern of cell positivity and discussing the significance of the finding of CD30-positive lymphocytes in cutaneous lymphoid infiltrates.

Material and methods

Files from the Research Unit of Dermatopathology, Department of Dermatology, Medical University of Graz, Austria and cases sent in consultation to one of us (L. C.) were searched for pseudolymphomas (reactive benign inflammatory or infectious conditions) showing presence of large CD30-positive cells within the infiltrate. Biopsy specimens obtained in Graz were fixed in 10% buffered formalin and subsequently embedded in paraffin. All histological sections were stained with hematoxylin-eosin for routine histopathologic evaluation. Immunohistochemical analysis for CD30 was performed on formalin-fixed, paraffin-embedded tissue sections according to a previously described three-step immunoperoxidase method.34 Microwave enhancement was used in all cases. Second and third antibodies were obtained from Dakopatts (Glostrup, Denmark).

Results

A total of 28 cases were included in the study (Table 1): Milker’s nodule: eight cases, all but one presenting with solitary lesions (F : M = 3 : 5; age range: 31–47, median 39) (Fig. 1); Herpes simplex virus (HSV) and varicella-zoster virus (VZV) infection: seven cases (F : M = 5 : 2; age range: 20–66, median 46) (Fig. 2); lymphomatoid drug reaction: three cases, two of which because of antiepileptic drugs (F : M = 1 : 1, age 67 and 73 years, respectively) and one to terbinafine (60-year-old woman); molluscum contagiosum: three cases (F : M = 2 : 1, age range 1–15 and median 12) (Fig. 3); nodular scabies: two cases (F : M = 1 : 1, age 55 and 85, respectively), and finally, one case each of leishmania infection (24-year-old female with a solitary lesion of ‘oriental sore’), syphilis (51-year old with an ulcera on the penis), pernio (17-year-old man), ruptured infundibular cyst (26-year-old man) and pseudolymphoma in a scar (79-year-old woman, after re-excision of basal cell carcinoma).

Table 1.  Reactive cutaneous infiltrates containing large CD30-positive lymphocytes included in our study
ConditionNumber of cases
Milker’s nodule8
Herpes simplex virus or Varicella-Zoster virus infection7
Lymphomatoid drug reaction3
Molluscum contagiosum3
Nodular scabies2
Cutaneous leishmaniasis (oriental sore)1
Syphilis (stage I)1
Pernio1
Re-excision scar of basal cell carcinoma1
Ruptured infundibular cyst1
Total28
Figure 1.

Milker’s nodule presenting clinically with multiple lesions simulating lymphomatoid papulosis.

Figure 2.

Herpes simplex virus infection showing large, atypical cells positive for CD30. A) Ulcerated lesion with heavy lymphoid infiltrates. B) Large numbers of atypical cells. C) Positivity for CD30.

Figure 3.

Molluscum contagiosum with heavy inflammatory infiltrates (A), atypical lymphocytes (B) and large numbers of CD30-positive cells (C).

In all cases, positivity for CD30 was not limited to solitary large, activated lymphocytes, but was observed also in cells forming clusters similar to those observed in primary cutaneous CD30+ lymphoproliferative disorders (LyP and cALCL) (Fig. 4). In addition, in all cases, besides membranous positivity, the large cells displayed also a perinuclear dot in the Golgi region, thus simulating the pattern observed in CD30+ malignant lymphomas (Fig. 5).

Figure 4.

CD30 staining of a case of Herpes simplex virus infection with architectural, cytomorphologic and immunophenotypic features simulating lymphomatoid papulosis (A); note CD30-positive cells arranged in clusters and as solitary units (B).

Figure 5.

CD30 staining pattern with both membranous and Golgi positivity in a case of inflammatory response to ruptured infundibular cyst.

Discussion

Positivity for CD30 in cutaneous lymphocytic infiltrates in the past was thought to be exclusive of particular lymphomas including mainly cALCL, LyP and large cell transformation of mycosis fungoides.35 In fact, it has been suggested that expression of CD30 antigen could help in differentiating between LyP and pseudolymphomatous arthropod bite reactions.36 Because of advances in immunohistochemical staining methods and in epitope retrieval, however, it became clear that CD30-positivity was present in several non-neoplastic skin conditions.37 In fact, in 1998, Dummer et al. showed that CD30-positive cells were present in six skin biopsies of atopic dermatitis on frozen sections, but only in one of them when tested on paraffin material, suggesting that the expression of CD30 antigen in this condition is weak and fixation sensitive.38 Interestingly, CD30-positive lymphocytes have been observed also in the peripheral blood of patients with atopic dermatitis.39

Several conditions may present with large CD30-positive lymphocytes within reactive inflammatory infiltrates, as shown by our series and by review of cases published in the literature (Table 2). It should be underlined that in our series the large, CD30-positive cells showed always both membranous and Golgi positivity, and that they were arranged not only scattered in the inflammatory infiltrate, but also in clusters, thus simulating the histopathologic picture of cutaneous CD30+ lymphoproliferative disorders, particularly LyP.

Table 2.  Published cases of reactive cutaneous infiltrates containing large, CD30-positive lymphocytes
ReferencesAgent/conditionNumber of casesGenderAge (years)Clinical setting
  1. F, female; M, male, na, not available; PLEVA, pityriasis lichenoides et varioliformis acuta; PL, pseudolymphoma; AML, acute myeloid leukemia; CCB, calcium channel blocker; ACE, angiotensin converting enzyme

Panhans et al.13PLEVA1M7Generalized eruption with erythematous scaly or crusty papules mainly on limbs
Horn et al.14Human recombinant cytokines3nanaEruption of lymphocyte recovery after marrow ablative chemotherapy and human recombinant cytokines administration
Yeo et al.15Carbamazepine1 (lymph node)M22Pyrexia, lymphadenopathy, generalized rash and hepatosplenomegaly after receiving carbamazepine for a bipolar affective disorder; CD30+ PL in lymph node; skin not biopsied
Nathan and Belsito16Carbamazepine1F44Fever, lymphadenopathy, pneumonitis, hepatitis and morbilliform eruption after treatment with carbamazepine for 1 month (patient known to be allergic to phenytoin)
Rose et al.17Parapoxvirus (Milker’s nodule)3M : F = 1 : 239, 46 and 72Multiple erythematous nodules and plaques on the dorsum of both hands over a period of 4 weeks in three members of the same family
Chai et al.18Epstein-Barr virus21 M and 1 F61 and 38Two individuals with immunosuppression-related Epstein-Barr virus+ lymphoproliferative disorders involving primary the skin. One was 2 years after kidney transplantation and the other was being treated with methotrexate for dermatomyositis. In both cases, the lesions completely disappeared and have not recurred
Guitart and Hurt19Molluscum contagiosum21 ‘infant’ and 1 F7 months and 8 yearsPleomorphic lymphocytic infiltrates composed of CD8 cytotoxic/suppressor T cells with high expression of CD30 in two pediatric cases associated with molluscum contagiosum
Saeed et al.20Cefuroxime1F84Erythematous blotchy erythema and purpuric rash over the lower limbs 3 days after being started on intravenous cefuroxime for acute diverticulitis
Su and Duncan21Skin ‘rash’ in a patient with acute myeloid leukemia1F55Infiltrated plaque with ecchymosis on abdomen 12 days after diagnosis of AML
Su and Duncan21Skin ‘rash’ in a patient with large B-cell lymphoma of the vertebra1F49Non-pruritic maculopapular rash on the chest and upper trunk 6 days after chemotherapy and irradiation that improved after discontinuing Zantac. 2 weeks later she developed a similar rash in the arms, chest and back that was biopsied
Hwong et al.22Tick bite1F6Red papule on the posterior neck at the site of a previous tick bite
Marucci et al.23Gemcitabine1M69Bilateral multiple erythematous lesions in the abdominal-inguinal area following treatment with gemcitabine for carcinoma of the lung, stage IIIB
Miracco et al.24Red Sea coral1F56Streaks of red papules on right knee after Red Sea coral injury that happened 1 month before
Cesinaro and Maiorana25Verruca vulgaris1F51Viral wart presenting with an inflammatory infiltrate with numerous CD30+ atypical lymphoid cells, comprising approximately 10% of the reactive cell population
Gallardo et al.26Scabies8M : F = 3 : 526–79 (median: 53, 5)CD30+ cells in 8/11 patients with nodular scabies
Kim et al.27Gold acupuncture1F35Multiple erythematous papules on abdomen 1 year after gold acupuncture for abdominal discomfort
Magro et al.28Lupron injection1M84Consistent number of CD30+ cells in five patients (of a total of 15) with inflammatory infiltrates elicited by drugs
Doxepin1F86
Atenolol1F87
Lipid-lowering agent, benzodiazepine, CCB and ACE inhibitor1F52
Chemotherapy1M43
Cepeda et al.29Insect bite (n = 4), spider bite (n = 2), abscess (n = 2), cellulitis (n = 1), chromomycosis (n = 1), Herpes simplex (n = 2), hidradenitis (n = 4), ruptured cyst (n = 1), rhinophyma (n = 1), granulation tissue (n = 1) and pressure ulcer (n = 1)20M : F = 12 : 814–81 (median: 46)CD30+ lymphoid infiltrates in different reactive skin conditions rich in neutrophils and eosinophils
Moreno-Ramirez et al.30Molluscum contagiosum1F72Nodule on the external canthus
Massi et al.31Lymph node tuberculosis1F65Diffuse lymphadenopathy, involving the cervical and left axillary lymph nodes, associated with night sweats, weight loss and weakness. A computed tomography scan also showed the presence of enlarged mediastinal lymph nodes, whereas chest radiographs failed to show lung infiltration. The left axillary lymph node was surgically excised and revealed features consistent with a diagnosis of lymph node tuberculosis. The patient had a papular eruption on the head and neck region as well
Herron et al.32PLEVA1F8Hemorrhagic-crusted papules and plaques covering over 90% of patient’s body
Segura et al.33Eosinophilic ulcer of the oral mucosa1F93Two episodes of self-healing ulcers on the upper lip and on the lingual mucosa, respectively
Dummer et al.38Acute atopic dermatitis6M : F = 2 : 424–37 (median: 28, 5)CD30+ cells found in the infiltrate of six patients with acute atopic dermatitis in frozen sections, but only in one of these cases in formalin-fixed specimens

Viral infections

In our study, cutaneous viral infections were the most common cause (n = 18) for an inflammatory infiltrate with large atypical CD30-positive lymphocytes. Eight patients had Milker’s nodule, confirming a previous report on CD30-positive cells in skin lesions from three members of the same family infected with Parapoxvirus.17 Seven of our patients had either HSV or VZV infection. Cepeda et al. reported on two patients with HSV infection and CD30-positive lymphocytes;29 one of whom was also infected by the human immunodeficiency virus (HIV). Molluscum contagiosum is another condition where CD30-positive lymphocytes may be present in the inflammatory infiltrate. We collected three cases from our files and found three more in the literature.19,30 In one of our cases, the molluscum bodies were not seen in the first histological section, characterized only by a dense inflammatory infiltrate with large, blastoid CD30-positive cells. Step sections revealed the viral inclusions, once again showing the potential pitfalls in the diagnosis of cutaneous CD30-positive lymphoid infiltrates. Epstein-Barr virus,18 HIV40 and human papilloma virus25 are other viruses capable of eliciting activation of lymphocytes and expression of CD30 by large cells. As a rule of thumb, a viral infection should always be suspected in lesions showing dense lymphoid infiltrates with CD30-positive large lymphocytes arranged as solitary units or in clusters. In such cases, diagnosis of LyP or cALCL should be made only upon compelling clinicopathologic evidence. Immunohistochemical and/or molecular analyses may help in confirming the presence of the virus within the infiltrate.

Other infectious causes

To the best of our knowledge, syphilis and leishmaniasis have not been previously known to induce an inflammatory infiltrate containing large atypical lymphocytes positive for CD30, as in two of our cases. The case of syphilis was sent in consultation to one of us (L. C.) with a suspect diagnosis of cALCL, confirming that such cases indeed represent a diagnostic dilemma in daily practice. Cepeda et al. found CD30-positive cells in cases of abscess, cellulitis, hidradenitis and chromomycosis.29 It seems clear that many infectious agents are able to induce the presence of ‘activated’ CD30-positive lymphocytes in skin lesions, a fact that should be always remembered when evaluating histopathologic specimens with large, CD30-positive T cells.

Arthropod assaults

Nodular scabies may present diagnostic difficulties because of the presence of dense lymphocytic infiltrates with atypical lymphocytes, as in two of our cases characterized by the presence of many CD30-positive cells. Gallardo et al. reported similar findings in 8 of 11 patients infected by scabies,26 and similar features may be observed also after tick, insect and spider bites.22,29 The differential diagnosis between arthropod assault in general and LyP is a well-known pitfall in dermatopathology, and in many cases, a correct diagnosis can be made only upon careful clinicopathologic correlation.

Drugs

Lymphomatoid drug reactions are characterized by dense cutaneous lymphocytic infiltrates, often with large atypical cells. Differentiation from mycosis fungoides may be very difficult. Drugs that have been associated with the presence of CD30-positive atypical lymphocytes are listed in Table 2 14–16,20,23,28. In three of these cases, the infiltrate arose in the context of an eruption of lymphocyte recovery in which histopathologic features were altered by systemic cytokine administration.14 In our series, three cases of pseudolymphomatous infiltrates with CD30-positive cells were because of ingestion of drugs, namely antiepileptic (two cases) and antifungal (one case). Interestingly, in one case reported by Yeo et al., CD30+ cells were found within a pseudolymphomatous lymph node, showing that the skin is not the only organ affected by CD30+ pseudolymphomas.15 It should be mentioned also that cases of drug-induced cutaneous lymphoma have been reported as well, including one case of CD30-positive lymphoma after intake of carbamazepine, underlying the need for careful evaluation of these patients.41

Other inflammatory conditions

One of our patients presented with typical clinicopathologic features of pernio, but revealed immunohistochemically several large, CD30-positive cells. Lesions were located on the right ear and slowly resolved without treatment. Large CD30-positive lymphocytes could be observed also in the context of a dense inflammatory infiltrate within a scar after re-excision of basal cell carcinoma, and within the inflammatory infiltrate of a ruptured infundibular cyst. These are examples of conditions in which CD30 expression has no special meaning for the diagnosis, similar to previous reports on CD30-positive lymphoid infiltrates in reactions to Red sea coral24, gold acupuncture27, rhinophyma and pressure ulcer.29 In some instances, the presence of pseudolymphomatous CD30+ infiltrates cannot be clearly related to a well-identifiable cause, such as in the case of papular eruption in a patient with nodal tuberculosis reported by Massi et al.,31 or in the cutaneous ‘rash’ in patients with acute myeloid leukemia and extracutaneous B-cell lymphoma described by Su and Duncan.21 However, the presence of large, blastoid CD30-positive cells with a staining pattern similar to that observed in malignant lymphoproliferative disorders may create diagnostic problems in all of these benign conditions, regardless of the etiology and pathogenesis of the CD30-positive infiltrates.

Finally, although in the literature there are reports of pityriasis lichenoides et varioliformis acuta with CD30-positive T-lymphocytes, it may be that at least some of these patients have indeed LyP.13,42 In fact, the two diseases have overlapping clinical, histopathologic and molecular features (a clonal T-cell re-arrangement can be detected in both), and the interpretation of CD30 immunohistochemical stain should be very cautious in that setting.

Conclusion

Large lymphocytes positive for CD30 can be observed in many unrelated cutaneous inflammatory and neoplastic disorders, including conditions not reported before such as leishmaniasis, syphilis, pernio and inflammatory infiltrate in scar. Viruses are the most common cause for presence of CD30-positive cells in cutaneous inflammatory infiltrates, and a viral infection should always be suspected when evaluating histopathologic specimens with large CD30-positive cells. In contrast to what had been suggested previously, arrangement of large, CD30-positive lymphocytes in clusters is not unique to LyP or cALCL, and in many cases, a precise diagnosis can be made only upon accurate clinicopathological correlation or using ancillary methods such as polymerase chain reaction analysis for viral DNA. As a general rule, diagnosis of cutaneous CD30-positive T-cell lymphomas (LyP and cALCL) should be made only upon compelling clinicopathologic evidence, and when a reactive condition has been ruled out. In this context, step sections should be performed in all such cases searching for specific diagnostic features (viral inclusions, etc.).

Acknowledgements

This work has been supported by a International Union against Cancer (UICC) International Cancer Technology Transfer Fellowship and with Federal funds from the National Cancer Institute, National Institutes of Health under contract NO2-CO-41101.

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