INTRODUCTION

Cutaneous pseudolymphoma is a reactive polyclonal T- or B-cell lymphoproliferative process. Under the name sarcomatosis cutis, Kaposi originally characterized the condition known as cutaneous pseudolymphoma. It simply suggests that lymphocytes build up in the skin in response to various stimuli, without mentioning any particular illness or cause [1]. Since then, various terminologies have been used to describe cutaneous pseudolymphoma, including lymphocytoma cutis, pseudolymphoma of Spiegler and Fendt, actinic reticuloid, and Jessner’s lymphocytic infiltration [2].

Although there are a number of recognized triggers for the condition, including tattoos, mild trauma, insect bites, HIV, Varicella zoster virus, and photosensitivity, to name a few, the majority of cutaneous pseudolymphoma cases are idiopathic [3]. Numerous methods for classifying cutaneous pseudolymphoma are described in the literature. Some of them include grouping based on the predominant cell type (T-cell or B-cell), the etiology, the histopathologic development pattern, or specific clinical characteristics [4]. Cutaneous pseudo lymphomas have variable and indistinctive clinical presentations, ranging from solitary or multiple erythematous papules, nodules, or plaques to generalized erythroderma [3]. Therefore, a skin biopsy is needed to clarify the diagnosis and to exclude cutaneous lymphoma, and that might necessitate additional procedures such as immunohistochemistry and clonality. However, even with the smartest interdisciplinary efforts, the reactive character of some of the cases of cutaneous pseudolymphoma only becomes apparent after careful clinical follow-up [5].

The following case series emphasizes the alarming rise in cases of pseudolymphoma in Iraq and the complex nature of the disease with the accompanying diagnostic challenges.

MATERIALS AND METHODS

The present work was a case series of a total of fourteen patients presented between the years of 2016 and 2024. The study was conducted at the Center of Dermatology and Venereology, Medical City, Baghdad-Iraq. All patients included were diagnosed with idiopathic pseudolymphoma based on full demographic and clinical evaluation, in addition to histopathological and immunohistochemical assessments. The patients had no history of medications, borrelial infection, trauma, tattoos, or insect bites. Patients with chronic actinic dermatitis were also excluded. A full skin examination was performed, including checking for lymphadenopathy. Routine hematological and biochemical investigations, chest X-ray, and abdominal ultrasonography were performed searching for evidence of internal tumor. Serological testing for hepatitis C virus, hepatitis B virus antigen (HbsAg), human immunodeficiency virus (HIV), and SLE were also performed.

RESULTS

A total number of fourteen patients with idiopathic pseudolymphoma were included in this work, nine females and five males, with their age ranging from 37 to 70 years, with a mean of 53.5 years. All patients were well appearing; however, most were concerned about having a malignant tumor. The clinical presentation ranged from erythematous nodules on the face (Figs. 1a – 1d) to erythematous papules and plaques on upper and lower extremities (Figs. 2a – 2d). The most common site involved was the face, especially the cheeks (10 patients). The nodular lesions were either single or multiple nodules or lumps, bright to dull red in color but shiny in most cases, and the size ranged from 1 cm to several centimeters. No regional lymphadenopathy was detected. The duration of the rash ranged from 0.5 to 2 years. The rash was asymptomatic apart from slight discomfort and cosmetic concerns. Investigations did not show an internal tumor. Blood investigations were within normal limits. Serology was also negative. A biopsy of the lesional skin taken from the nodules revealed nodular lymphocytic infiltrate with denser distribution in the upper dermis. Well-formed follicles with germinal centers that contained tingible body macrophages and a preserved mantle zone were noted in one patient with facial nodules (Fig. 3a). Grenz zone-sparing of the papillary dermis and increased dermal blood vessels were present as well as the preservation of the adnexal structures. Noteworthily, the preserved polarity of the germinal center with dark and light zones was observed in one patient (Figs. 3b and 3c).

	Figure 1: (a and b) Involvement of the cheek area with a solitary nodular lesion. (c and d) Multiple erythematous nodules and papules involving the face and causing disfiguring enlargement of the nose.
	Figure 2: (a-c) Multiple erythematous papules involving the upper and lower extremities. (d) Some of these papules forming a semiannular configuration.
	Figure 3: (a) Multiple erythematous nodules coalescing and occupying the preauricular and mandibular areas. (b) Microscopic view showing well-formed follicles with germinal centers (H&E; 40x). (c) Preserved mantle zone, preserved polarity of the germinal center, and the presence of tingible body macrophages (H&E; 100x).

On the other hand, biopsies from patients with papular lesions showed patchy lymphocytic infiltrate both in the superficial and deep dermis (Figs. 4a – 4c). The inflammatory cells were mostly of the T-cell type, admixed with few histiocytes and eosinophils. Epidermal changes were variable, with acanthosis in some cases and atrophy in others.

Figure 4: a) Patchy lymphocytic infiltrate both in the superficial and deep dermis (note the Grenz zone) (H&E; 40x). b) Higher power showing lymphocytic infiltrate admixed with few histiocytes and eosinophils (H&E; 100x). c) Superficial and deep perivascular lymphocytic infiltrate in another patient with papular lesions (H&E; 40x).

Immunohistochemical analysis, including markers for both T and B lymphocytes, revealed polyclonal infiltrate of both T cells and B cells and positive Bcl-2 (Fig. 5).

Figure 5: a) Lymphocytic infiltrate in the superficial and deep dermis (H&E; 40x). b) Positive immunohistochemistry stain with CD3 (40x). cd) Positive staining with CD20 and Bcl2 (40x).

DISCUSSION

Pseudo lymphoma cutis is a diverse set of benign reactive T-cell or B-cell lymphoproliferative processes of various sources that mimic cutaneous lymphomas, with the reactive inflammatory infiltrates occasionally simulating lymphoma [2]. Histopathological examination is necessary to diagnose cutaneous pseudolymphoma and to distinguish the former from lymphoma. Unfortunately, there is no single histological feature that would confirm the diagnosis of pseudolymphoma. Every histological character is merely more or less suggestive of the benign nature of a lymphoid aggregate. Cutaneous pseudolymphoma cannot even be confirmed by the combination of histological characteristics [6]. Immunohistochemistry is useful in immunophenotypical differentiation of lymphocytes by their surface markers, into T and B cells. Lymphocytes in cutaneous pseudolymphoma are more likely to be polyclonal, i.e., mixed B- and T-cell infiltrate. Furthermore, the progression to T-cell-lymphoma is suggested by the loss of typical T-cell-surface-markers such as CD2, CD3, and CD5. The diagnosis of pseudolymphoma may be confirmed by negative T-cell receptor rearrangement (monoclonality) [5].

One logical approach is to perform basic panels for B-cell and T-cell markers initially, with the conclusion of lymphoid hyperplasia and recommendation of clinical follow-up if the infiltrate is mixed, or if it predominates T-cells but with a normal CD4 to CD8 ratio. Deferring additional workup is suggested if there is a monoclonal infiltrate, an abnormal CD4 to CD8 ratio, recurrence or persistence of the lesions, or if there is a clinical concern for malignancy [7].

In the past several years, there has been an unprecedented rise in the number of cases with a clinical presentation suggestive of cutaneous pseudolymphoma. Some of these patients provided an inciting agent as a possible etiological factor; however, a majority of the cases were idiopathic. The reason behind this upsurge in cases is unknown, and Iraq has witnessed an unexplained escalation of a large number of other diseases and malignancies such as mycosis fungoides [8], Kaposi sarcoma [9], morphea, including en coup de sabre [10,11], lichen planus [12], and dermatofibrosarcoma protuberance [13].

Several theories and speculations have been proposed to explain this escalation. The land of Iraq has long been a battlefield for territorial ambitions. Since 1980, the soil was swept away by armored vehicles and tanks causing desertification and sandstorm formation. Prohibited weapons were used in warfare. Soon afterward, contamination spread uncontrollably in the air, water, and soil, eventually leading to genetic alterations and possible mutations that modified countless diseases [14].

This change in the behavior of skin disease as a result of a change in the environment was probably based on epigenetics similar to that observed in rheumatological disease. In addition, the excessive and perhaps unjustifiable intake of drugs nowadays, whether prescribed or over-the-counter, might have influenced the behavior of numerous skin diseases by affecting gene functions [15].

This theory might explain why some diseases have re-emerged to the surface following decades of hiding. Two important examples are chronic benign bullous disease of childhood as an autoimmune disease and lipoid proteinosis as a genetic disease [16].

Several reports exist concerning the effects of the COVID-19 pandemic and its vaccinations on disease behavior modification and the upsurge of cases, such as hyper-reactivity to cosmetic botulinum toxin [17]. Similarly, the increased incidence of telogen effluvium induced by COVID-19 virus probably due to cytokine storm during the infection may initiate damage to the hair matrix [18]. On the other hand, autoimmune diseases such as psoriasis, alopecia areata, pemphigus, vitiligo, and lupus erythematosus do not confer protection against COVID-19 infection but, on the contrary, increase the risk of contracting this infection [19].

CONCLUSION

Idiopathic pseudolymphoma cutis has been encountered more frequently in the past decade alongside other diseases and malignancies. Environmental factors modify the behavior of the disease. All fourteen reported cases had a reactive lymphomatous nature and ran a benign course. Follow-up is only needed to support the clinical diagnosis. Histopathological and immunohistochemical panels are required to support clinical diagnosis, although they could be inconclusive in many cases in differentiating between the benign or malignant course of lymphoma.

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