Other Lymphoproliferative and Myeloproliferative Diseases

History

Lymphocytic infiltrate of Jessner (LIJ) was initially described in 1953 by Jessner and Kanof as circinate papules on the face, surrounding a central area of clearing.

Epidemiology

This entity occurs primarily in middle-aged adults. There is no gender predilection.

Pathogenesis

Benign lymphocytic infiltrate of the skin remains a controversial entity. Some authors believe it is a variant of either lupus erythematosus (primarily LE tumidus) or polymorphic light eruption versus a form of cutaneous lymphoid hyperplasia (pseudolymphoma). There are cases of co-occurrence with LE and with polymorphic light eruption, while in Europe, it has been associated with Borrelia burgdorferi infection . Lastly, rare cases of drug-induced disease (e.g. angiotensin-converting enzyme [ACE] inhibitors, glatiramer acetate) have been described as have familial cases .

Clinical features

Cutaneous lesions appear primarily on the head, neck and upper back as one or several asymptomatic, erythematous papules, plaques, and less commonly nodules, with an absence of secondary epidermal changes such as scale ( Fig. 121.1 ). Annular plaques with central clearing are commonly observed and individual lesions last several weeks to months. There are no associated systemic manifestations. Although spontaneous resolution occurs, recurrences are common.

Pathology

The epidermis is unremarkable, with little evidence of interface dermatitis. There is a superficial and deep, primarily perivascular, lymphocytic infiltrate that may surround hair follicles ( Fig. 121.2 ). A mild increase in dermal mucin may be seen. By immunohistochemistry, a mixed T-cell infiltrate with a predominance of CD8 ⁺ lymphocytes is observed , admixed with CD123 ⁺ plasmacytoid dendritic cells. The distribution of plasmacytoid dendritic cells is identical to that seen in LE tumidus, further supporting a close relationship .

Differential diagnosis

The differential diagnosis includes the plaque form of polymorphic light eruption, LE tumidus, cutaneous lymphoid hyperplasia (pseudolymphoma), reticular erythematous mucinosis, and cutaneous lymphoma ( Fig. 121.3 ). Subacute and chronic cutaneous LE are distinguished by the presence of secondary changes, including scale, follicular plugging and central hypopigmentation, along with interface changes histologically. Because interface changes are sparse, if present at all, in LE tumidus, distinction from LIJ may prove impossible. Reticular erythematous mucinosis, which is considered by some as synonymous with LE tumidus, has abundant dermal mucin.

Polymorphic light eruption is associated with sun exposure and usually has a self-limited clinical course. Histologically, papillary dermal edema is often seen and usually there are no clusters of CD123 ⁺ plasmacytoid dendritic cells. For some patients, phototesting may provide additional helpful information (see Fig. 121.3 ).

Cutaneous lymphomas can have significant clinical and histopathologic overlap with LIJ. If the dermal lymphocytic infiltrate is extensive, immunophenotypic analyses may help to distinguish between the two entities (see Chs 119 & 120 ). Although individual lesions of borderline lepromatous leprosy may resemble LIJ, these patients have a greater number of widespread lesions.

Treatment

The cutaneous manifestations of LIJ may resolve spontaneously within months to years, without scarring. Oral antibiotics and topical or intralesional corticosteroids have been used with limited success. Up to 50% of patients may improve with hydroxychloroquine. In general, the disorder is resistant to radiation therapy. A crossover study of oral thalidomide (100 mg/day) versus placebo in 25 patients resulted in a clinical response of 76% for thalidomide and 16% for placebo. In isolated case reports, improvement following pulsed dye (595 nm) laser treatment or chemotherapy (for an unrelated malignancy) has been described .

History

Cutaneous lymphoid hyperplasia (pseudolymphoma) was first reported by Spiegler in 1894. He described patients who presented with clinical features of a malignant neoplasm but experienced a benign clinical course. Although a characteristic feature is the resemblance to cutaneous lymphoma, there is a spectrum of clinical and histologic findings, reflecting its heterogeneous nature .

Epidemiology

Precise data regarding incidence, prevalence, and geographic distribution are lacking. Both children and adults can be affected.

Pathogenesis

Cutaneous lymphoid hyperplasia (CLH) does not represent a single disease, but rather reflects an exaggerated local immunologic reaction to a stimulus, often unrecognized. The possibility of a hapten-driven immunologic response to cells damaged by a direct toxic effect of stimuli has been suggested . Inciting agents include arthropod bites (including ticks and mites), tattoos, metal implants, contact allergens, vaccinations, and medications ( Table 121.1 ) . In addition, several infections such as herpes zoster and Lyme borreliosis have been associated with CLH .

Clinical features

CLH usually presents as a single, 1–3 cm, firm, erythematous to violaceous plaque or nodule located on the head, neck or upper extremities ( Fig. 121.4A,B ). That said, presentations can vary from multiple clustered papules to larger panniculitis-like nodules . The vast majority of lesions lack surface changes such as scale.

Pathology

The histopathological features are variable and the pattern may resemble either a low-grade B-cell lymphoma (follicle center lymphoma, marginal zone lymphoma) or a T-cell lymphoma, in particular mycosis fungoides, lymphomatoid papulosis (LyP), cutaneous anaplastic large cell lymphoma (cALCL), or subcutaneous T-cell lymphoma .

In CLH with B-cell predominance , there is typically a superficial and deep nodular or diffuse infiltrate of lymphocytes, admixed with histiocytes and occasional plasma cells and eosinophils. In florid cases, germinal centers with prominent tingible-body macrophages may be observed ( Fig. 121.5 ). Distinction from follicle center lymphoma can be made on routine histologic sections or with the addition of immunohistochemical stains ( Table 121.2 ). Clonality, based upon IgH gene rearrangements or restricted κ or λ expression, is usually not seen in pseudolymphomas (see Fig. 119.10 ) . PCR analysis for Borrelia burgdorferi DNA is positive in Borrelia -associated lymphocytoma cutis and pseudolymphomatous acrodermatitis chronica atrophicans .

In T-cell-predominant infiltrates, CD4 ⁺ T helper lymphocytes are commonly observed within the dermis, admixed with a minority of CD8 ⁺ cytotoxic/suppressor T cells. A mycosis fungoides-like pattern is most often encountered in drug-induced pseudolymphomas (see Table 121.1 ). Histologically, epidermotropism, spongiosis, vacuolar degeneration of the basal layer, papillary dermal edema, and red cell extravasation may be seen. Prominent papillary dermal fibrosis, which can be seen in mycosis fungoides, is absent, but T-cell clonality may be present.

CD30 ⁺ pseudolymphomas include persistent arthropod bite reactions, drug reactions, and the atypical lymphoid infiltrates associated with cutaneous poxvirus infections (e.g. molluscum contagiosum, orf). Additional findings related to the underlying disorder can aid in diagnosis, and there is polyclonal rearrangement of the TCR .

Differential diagnosis

Pseudolymphomas may be difficult to differentiate from cutaneous lymphomas (see Pathology section). Although the presence of clonality may aid in distinguishing reactive from neoplastic processes, it should not be used to establish malignancy. In addition to clinicopathologic correlation, longitudinal evaluation plays a key role in making this distinction.

Acral pseudolymphomatous angiokeratoma of children (APACHE), originally thought to represent a vascular nevus, is now categorized as a pseudolymphoma. In contrast to other pseudolymphomas, it favors the extremities of children between the ages of 2 and 16 years, usually presenting as a unilateral grouping of small, red to violet, “angiomatous” papules. Histologically, there is a dermal infiltrate of lymphocytes, histiocytes and plasma cells accompanied by prominently thickened capillaries .

Kikuchi–Fujimoto disease , also known as histiocytic necrotizing lymphadenitis, is an idiopathic systemic inflammatory disease most commonly seen in young adult women. It is associated with a variety of viral and bacterial infections (e.g. Epstein–Barr virus, cytomegalovirus) as well as autoimmune diseases (e.g. systemic LE). In addition to fevers, malaise, weight loss and gastrointestinal symptoms, patients develop cervical lymphadenopathy. Histologically, there is necrosis and histiocytic infiltration of the paracortical areas of involved lymph nodes, without an identifiable pathogen. Cutaneous findings, present in 40% of patients, include acneiform eruptions, urticaria, ulcers and indurated erythematous plaques. Histologically, dense superficial and deep perivascular lymphohistiocytic infiltrates with nuclear debris (in the absence of neutrophils) are seen; interface changes are commonly present .

In “pseudolymphomatous folliculitis” , there is typically a solitary facial nodule that is due to a predominantly perifollicular and periadnexal dermal infiltrate. The latter is typically mixed, with a predominance of T or B cells that may have cellular atypia; granulomas are variably present . There is irregular hyperplasia and distortion of the follicular epithelium, with blurring of the dermal–epidermal junction, and infiltrates of CD1a ⁺ /S100 ⁺ mononuclear cells surround and infiltrate these distorted follicles. This entity should be distinguished from primary cutaneous CD4 ⁺ small/medium-sized pleomorphic T-cell lymphoproliferative disorder, which is characterized by more pronounced pleomorphism and often has phenotypic aberrations such as PD1 expression .

Cutaneous and systemic plasmacytosis is a benign condition of unknown etiology observed primarily in Asians, especially those of Japanese ancestry. It is characterized by multiple, reddish-brown, infiltrated maculopapules and plaques, most often on the trunk. Histopathologically, variably dense superficial and deep perivascular infiltrates composed predominantly of mature polyclonal plasma cells are seen . The plasmacytosis may be accompanied by anemia, B symptoms and hypergammaglobulinemia, as well as lymphadenopathy, hepatosplenomegaly, interstitial pneumonia, and mesangial proliferative glomerulonephritis. A reactive dysfunction of plasma cells triggered by various stimuli has been postulated . As in Castleman disease, there is an elevation in circulating/tissue IL-6, but in the absence of HHV-8 infection .

Additional examples of pseudolymphoma are outlined in Table 121.3 .

Treatment

CLH is a benign, reactive condition and it should be treated conservatively. Spontaneous resolution may occur without scarring. For persistent lesions, topical and/or intralesional corticosteroids may lead to improvement. Simple excision, cryosurgery, laser ablation, and radiation therapy are other options. Thalidomide has been utilized with success in recalcitrant cases . Performance of a biopsy, even if partial, can be followed by spontaneous regression. For Borrelia -associated pseudolymphoma, appropriate antibiotics are administered (see Ch. 19 ).