Acute lymphoblastic leukemia (ALL) is the most common form of leukemias in children, accounting for nearly 80% of them.¹ The peak is between the ages of 2 and 5 years of life. Although the etiology of the disease is still poorly understood, certain genetic disorders are associated with a higher incidence of the disease, such as trisomy 21 and ataxia-telangiectasia. Some cases arise in association with MLL (mixed leukemia lymphoma) gene rearrangements, and might be secondary to chemotherapy. As opposed to T-ALL, B-ALL typically has a predominant leukemic form.

It has been described that approximately 20% to 30% of patients can develop cutaneous involvement² by the disease. Clinically, the lesions present as erythematous or violaceous nodules, tumors, or plaques. Sometimes, multiple papules can be seen. The distribution of lesions is typically around the head and neck, upper back, chest, and abdomen. In a series of six cases,² most cases presented between the ages of 5 and 15 years and all occurred in girls. Occasional cases of aleukemic forms have been reported.^3,4,5,6 A single case with a congenital presentation has also been described in association with an MLL rearrangement.⁷

Histologically, B-ALL presents as a diffuse dermal infiltrate with extension into the subcutaneous tissue^{2,4,5,6,7,8,9,10} (Fig. 75-1). A grenz zone was present in all cases with sparing of the epidermis. Occasionally, surface ulceration can be seen. Cytologically, the infiltrates consist of small lymphoblasts with scant cytoplasm, irregular nuclei, and inconspicuous nucleoli. Linear arrangements of lymphoblasts forming “Indian files” can be seen. Infiltration of the skin adnexa is frequently seen, as well as peripheral nerves and adjacent muscle. Mitotic activity is typically brisk. Earlier in the course of the lesions, a more perivascular distribution of the immature cells is seen.

The immunophenotype of the immature blasts include expression of CD19, PAX5, CD79a, and CD43. TdT and CD34 markers of immature blasts are often expressed in the malignant cells, and CD99 can be seen in more than 50% of cases. CD99 expression should not lead to a diagnosis of a small blue round cell sarcoma, such as Ewing sarcoma (ES). Expression of CD45 is dim or negative, and most cases are negative for CD20. CD10 is present in most, but not all cases. Cases of B-ALL with MLL rearrangement are typically CD15⁺ and CD10⁻. Cases of B-ALL with the t(12;21) translocation (Philadelphia chromosome) have a worse prognosis and are associated with CD10 coexpression.

The differential diagnosis could be challenging in the primary lymphomatous lesions, or aleukemic forms. In fact, a case originally diagnosed as ES, represented an example of B-ALL with CD99 coexpression. However, ES does not show expression of B-cell antigens. Indeed, CD99, CD34, and TdT in B-ALL could be useful to distinguish them from mature B-cell lymphomas on the skin, which, overall, are extraordinarily uncommon. In the differential, Merkel cell carcinoma can rarely present in children,^11,12 and similarly to B-ALL, can show the distinction. Cutaneous involvement by neuroblastoma is also rare and might be a pitfall as CD99 is also expressed.^13,14 Other small round cell sarcomas can be distinguished with the presence of specific markers (e.g., myogenin and desmin).

Extranodal marginal zone lymphoma (MZL) is a low-grade B-cell lymphoma composed of small B cells, monocytoid cells, lymphoplasmacytoid cells, and mature plasma cells.^15,16 Many cases are associated with infectious etiologies, such as Helicobacter pylori (in gastric mucosa-associated lymphoid tissue [MALT]), Borrelia burgdorferi (in cutaneous cases only in Europe), and Chlamydia (ocular MALT). There appears to be some site specificity of the infectious agents. More recently, IgG4 expression has been shown in cutaneous cases with prominent plasmacytic differentiation.¹⁷ Primary cutaneous MZL (PCMZL) is extraordinarily rare in children. A series from Kempf et al.¹⁸ evokes a total of three cases, mostly in teenagers. In a study of cutaneous lymphomas in individuals younger than 20 years of age, Fink-Puches et al.¹⁹ showed a total of seven cases of MZL. There is a slight predominance in girls, compared with boys.^{8,20,21,22,23} The first case of the disease reported in the states was found in association with chronic antihistaminic use.²² Rare cases in association with medications for attentional deficit disorders (ADDs) have been seen.¹⁸ Cases in relationship to medications use usually resolve upon cessation of the medication.

Clinically, most cases present with multiple lesions on the arms, upper trunk, and face. Lesions are typically papules, plaques, and/or nodules. Most recently, a 15-year-old boy with multiple lesions representing PCMZL and juxta-articular fibrotic nodules showing on histology nodular sclerosis with peripheral plasma cell–rich infiltrates, or features reminiscent of quiescent lesions of chronic localized fibrosing leukocytoclastic vasculitis has been reported.²⁴ Histologically, early lesions have a perivascular and periadnexal infiltrate, although more advanced ones may have a nodular and/or diffuse cellular infiltrate extending into the subcutaneous fat. There are small lymphocytes, lymphoplasmacytoid, and plasma cells that demonstrate monotypic cytoplasmic Ig on paraffin stains. Reactive T cells may be present and can represent a significant proportion of the infiltrate. It is not uncommon to see varying amounts of plasma cells, eosinophils, and histiocytes. In MZL, reactive lymphoid follicles are often seen^20,25 (Fig. 75-2).

The immunophenotype of MZL is not specific; the marginal zone cells show expression of CD20, CD79a, BCL-2, and are usually negative for CD10, CD5, and BCL-6. Coexpression of CD43 is usually rare in the cutaneous sites. Tumors with prominent plasma cell differentiation show expression of CD138. IgG4, though found common in adults, has not been seen in the pediatric group.¹⁸ Clusters of plasmacytoid dendritic cells using a CD123 immunostain can be seen. Only one of the pediatric cases has been found in association with B. burgdorferi. Clonality studies for IGH gene rearrangements are useful to prove a clonal population of B cells. Similarly to adults, trisomy 3 can be seen using fluorescent in situ hybridization (FISH). Trisomy 3 is the most frequent chromosomal aberration seen in this type of lymphoma in adult patients, with ∼20% of studied cases displaying this anomaly, either singly or in combination with t(14;18)(q32;q21) or t(3;14)(p14.1;q32).^26,27,28 The t(11;18) translocation linked to gastric and lung MALTs has not been seen in cutaneous sites. Guitart and Gerami²⁹ have proposed the term “atypical marginal zone hyperplasia” to describe a subset of cases in young individuals with λ-restriction and lack of BCL-2 expression. This term has been previously used by Attygalle et al.³⁰ on subsets of pediatric cases presenting in the tonsils, and are polyclonal by gene rearrangement studies and with CD43 coexpression by IHC.

The differential diagnosis of PCMZL in children includes Borrelia-associated lymphocytoma cutis, which mostly affects the ear lobes, nipples, and scrotum in children and presents with a solitary lesion in most patients; which contrasts to the multifocal lesions in the majority of PCMZL.³¹ The so-called tibial lymphoplasmacytic plaque occurs in the tibial location.³² Some people regard this lesion within the spectrum of linear acral pseudolymphomatous angiokeratoma of children (APACHE). Cutaneous plasmacytosis and cutaneous plasmacytoma are now recognized as MZL. Among other B-cell lymphomas, primary cutaneous follicle center lymphoma (PCFCL) has a germinal center phenotype (BCL-6 and ±CD10). Prominent plasmacytic infiltrates can be seen in Melkerson–Rosenthal syndrome, usually in association with granulomas with an intralymphatic distribution.

This tumor is exceptionally rare in children and is described elsewhere in this book.^19,33 The single case of this entity was reported by Condarco et al.³⁴ in an 8-year-old boy with a scalp lesion. The tumor was positive for CD10 and BCL-6, but negative for BCL-2, with features typical of PCFCL.

This lymphoma accounts for 10% to 30% of childhood lymphomas and is more frequent in the first three decades of life. There is a slight male predominance. The majority of patients (70%) present with stage III or IV disease and B symptoms. The skin is the most frequent extranodal site of involvement, with an overall frequency of involvement of 26%. Other extranodal sites include bone, soft tissues, lung, and liver.^35,36,37,38

ALK+ ALCL has a variety of morphologic presentations. However, in all cases, there is a malignant population of large cells with eccentric horseshoe or kidney-shaped nuclei with an eosinophilic region near the nucleus. These cells are the so-called “hallmark” cells. In some variants, the hallmark cells can be small. Occasionally, the hallmark cells can mimic Reed–Stenberg cells or variants. There are five distinctive variants of ALK+ ALCL: common, small-cell variant, Hodgkin-like pattern, lymphohistiocytic pattern, and combined forms.^{39,40,41,42,43} Any of these patterns can be seen on the skin. The immunophenotype of ALK+ ALCL includes, by definition, CD30 and ALK reactivity. The pattern of CD30 expression is both Golgi and cytoplasmic. The majority of cases are positive for EMA, TIA-1, granzyme B, and perforin. Most cases show loss of T-cell antigens such as CD3, CD5, and CD7. Some cases can be null for all T-cell markers. CD43, CD2, and CD4 are more frequently positive. Certain patterns of ALK expression correlate with specific rearrangements of the ALK gene. However, the most common cytogenetic rearrangement represents the t(2;5) translocation, creating a fusion transcript involving the ALK and NPM genes (nucleophosmin).

Lamant et al.⁴⁴ suggested a possible relationship between insect bites and development of ALK+ ALCL. They described a series of five patients who had insect bites who developed nodal disease in close proximity to the skin lesions. Two of the skin biopsies revealed the presence of ALK+ cells. Of the five cases, three had complete remission after chemotherapy, one developed progression, and one died. More recently, Oschlies et al.⁴² described a series of 6 children within the context of 487 patients enrolled in the Anaplastic Large-Cell Lymphoma-99 trial with disease limited to the skin. These patients had complete remission on follow-up, and most of them were treated with surgical excision only. Only one of the patients was also treated with chemotherapy. In all cases but one, the pattern of ALK staining was nuclear and cytoplasmic, and FISH was positive for the ALK-NPM translocation. Clinically, five of six cases had lesions that were solitary (maculopapules or nodules) and one patient had multiple lesions. Previous isolated case reports of cutaneous presentations of ALK+ ALCL have been described.^45,46,47

C-ALCL is a primary cutaneous lymphoid neoplasm composed of large and pleomorphic cells (indistinguishable from ALK+ ALCL) with diffuse expression of CD30 in the majority of the tumor cells (>75%).^48,49 The diagnosis is limited to cases without history of lymphomatoid papulosis (LyP) or mycosis fungoides (MF).^50,51 C-ALCL is very rare in children compared to adults.^{52,53,54,55,56} In some cases of C-ALCL in childhood, an association with HIV infection was established.⁵²

Clinically, these patients have a rapidly growing, asymptomatic, solitary or multiple skin nodules/tumors with a tendency to ulcerate.⁵⁵ A neutrophilic variant (aka: pyogenic) of C-ALCL contains a neutrophilic-rich inflammatory background. Although the conventional variant does not have a predilection for immunocompromised individuals, the pyogenic variant has been described in association with HIV,⁵⁷ transplant recipients,⁵⁸ and patients with hematologic malignancies.^53,59 It has also been described in young individuals.⁵³ The pyogenic variant might have a higher mortality than the conventional variant of C-ALCL, with an overall mortality of ∼18% (mean survival of 10 months of age).

Morphologically, the tumor consists of diffuse, cohesive sheets of large pleomorphic cells, strongly CD30⁺, morphologically indistinguishable from ALK+ ALCL (Fig. 75-3). Even among the conventional variants, a rich inflammatory infiltrate is present, which can lead to a misdiagnosis of an inflammatory process in the skin.⁶⁰ The tumors are frequently CD4⁺, and also show expression of cytotoxic markers (TIA-1, perforin, granzyme B). There is variable loss of T-cell antigens and, as opposed to systemic ALCL, C-ALCL is usually negative for EMA.⁶¹ CD99 can also be positive.⁵² The pyogenic variant might have a higher rate of CD8 and EMA (57%) expression than the conventional form.^53,62 Clonality is proven in the vast majority of cases by conventional T-cell receptor (TCR) studies.

The clinical differential for the pyogenic variant of C-ALCL includes pyoderma gangrenosum, pyoderma faciale (rosacea fulminans), Sweet syndrome, leishmaniasis, deep fungal infection, or pyogenic granuloma. Bacterial cellulitis has been described as a differential diagnostic consideration. Among the neoplastic conditions, the main differential diagnoses include LyP (see discussion below) and tumor stage MF. ALK− staining is useful to rule out the possibility of cutaneous involvement by ALK+ ALCL, which is overall more frequent than C-ALCL.⁵³

MF represents the most common form of cutaneous T-cell lymphoma in both adults^63,64 and kids.^{9,65,66,67,68} Pediatric MF usually has a hypopigmented clinical appearance and can present in adolescents and children. It has been reported to occur in children as young as 3 years of age.^{19,66,69,70,71,72} The male-to-female ratio is nearly equal in the pediatric setting.^66,69,72,73 The study from Fink-Puches et al.¹⁹ showed that MF represented 34.8% of all skin lymphomas in individuals younger than 20 years of age.

Clinically, pediatric and adult MF is a protean disease that can potentially mimic numerous benign inflammatory dermatoses. In fact, a delay on the diagnosis can take several years and numerous biopsies are often required to be certain. Werner et al.⁷⁴ raised significant concerns on the diagnosis of this disease in the pediatric setting: in their review of 106 cases, they claim that only 23 cases have information “sufficient” for a diagnosis of hypopigmented MF. Indeed, in 83 of those cases, there was no significant clinicopathologic correlation to accurately establish the diagnosis. From a pediatric standpoint, MF can enter in the differential diagnosis of psoriasis, tinea corporis, pityriasis lichenoides (PL), lichen aureus, atopic dermatitis, and hypopigmented dermatoses, including vitiligo⁷⁵ and pityriasis alba; the latter two are the most frequent misdiagnoses in children.⁷⁶ A recent case series from Castano et al.⁶⁵ illustrates that all cases (100%, n = 69) present at a patch stage. In this series, nearly all cases show hypopigmented lesions and most of them occur in African American children. The more frequent lesions in adults of sharply demarcated patches with atrophy, and a “cigarette paper” appearance are less common in kids. The earlier study from Crowley et al.⁶⁶ of 58 patients with MF (<35 years of age) showed that 17% of cases presented with tumor stage and ∼4% with generalized erythroderma. In the series of 46 cases from Heng et al.,⁷⁷ 92% were also hypopigmented. The most common locations of presentation included the buttocks, trunk, and extremities (sun-protected areas) (Figs. 75-4, 75-5 and 75-6). About 6% of patients have solitary lesions. Rare cases of MF can present following organ transplantation.⁷⁸ Folliculotropic MF (FMF) is follicular papules, sometimes with an erythematous base and sometimes plugging and/or alopecia (Figs. 75-7 and 75-8). This is the second most common clinical variant.^{79,80,81,82,83} It appears that FMF occurs more frequently in individuals less than 40 years of age (8% of all variants). In FMF, the lesions are usually located in the head and neck region, with the presentation of plaques and/or tumors. Most of these patients have intense pruritus.

Less common clinical variants in the pediatric population include granulomatous slack skin, or granulomatous MF (GMF),^84,85,86,87 characterized by development of areas of pedunculus lax skin in the major skin folds, especially axillae and groins.⁸⁸

Localized pagetoid reticulosis (aka: Woringer–Kolopp disease) presents as a solitary, slowly growing, erythematous, and verrucous plaque on the extremities. Rare case reports in children have been described.^89,90,91

Sézary syndrome (SS) is a distinctive erythrodermic cutaneous T-cell lymphoma, characterized by pruritic erythroderma, generalized lymphadenopathy, and circulating malignant cells with cerebriform nuclei. It is a disease of adults, with rare case reports in the pediatric population.^92,93,94

Morphologically, MF in children is histologically and immunophenotypically indistinguishable from that seen in adults (Fig. 75-9). According to the series from Castano et al.,⁶⁵ the most frequent histologic findings include lymphocytes in clusters, patchy lichenoid infiltrate, perivascular/periadnexal infiltrate, psoriasiform hyperplasia, papillary dermal fibroplasia, dermal melanophages, and lymphoid collections of cells (27.3%). The infiltrate shows epidermotropism with tagging of cells along the dermal–epidermal junction.⁹⁵ The atypical lymphocytes show nuclear hyperchromasia and irregular, and sometimes cerebriform, nuclei. Distinctive perinuclear halos are seen surrounding the intraepidermal cells. Admixed histiocytes, plasma cells, and eosinophils can be present. Although epidermal atrophy is frequently seen, particularly in poikilodermatous forms of adults, it is extraordinarily rare in children. As the lesions progress clinically, so does the extent of the infiltrate. Large-cell transformation is defined as the presence of large cells (at least four times the size of a small lymphocyte) comprising more than 25% of the infiltrate or in nodular aggregates. In FMF, there is infiltration of the hair follicle epithelium with or without epidermotropism; epidermotropism is more frequently seen. The infiltrate involves the infundibulum of the hair follicle and sometimes deeper portions of the hair. Very frequently, cases are accompanied by follicular mucinosis; a feature that can be better demonstrated using a colloidal iron or Alcian blue stains. Additionally, FMF is often accompanied by a syringotropic infiltrate.⁷⁹ However, a Dutch study revealed that interfollicular epidermotropism is actually rare.⁸³ FMF does not show Pautrier microabscesses. Dermal eosinophilia can be prominent, particularly during the progression of the disease, and might be a manifestation of an autoimmune response to the keratin of the hair shafts in the dermis (author’s personal experience). In GMF, dense nodular and diffuse granulomas are present in the dermis, with or without epidermotropism, and with destruction of elastic fibers and elastophagocytosis.

The immunophenotype of pediatric MF is distinctive from the adult forms: hypopigmented MF is a CD8⁺ cytotoxic lymphoma, whereas most cases in adults are CD4^{+ 19, 65,66,67,68,69,70,74,75,77,79,96,97,98,99,100,101,102,103} (Fig. 75-10). Also, CD30 expression is usually negative, or stains few scattered positive cells (80% of cases are negative). Decreased expression of both CD4 and CD8 can also be seen in some cases of hypopigmented MF.^104,105 Similarly to adult patients, there is usually preserved expression of CD2 and CD5 with loss of CD7. A single rare case with coexpression of CD56 has been reported with an associated indolent clinical course.¹⁰⁶ In FMF, the infiltrate usually shows a predominance of CD4⁺ cells, similar to what is seen in adults.⁷⁹ GMF is also a disease of CD4⁺ T cells. Similarly, the diagnosis of SS is based on CD4 coexpression and decrease of CD7 and CD26. The genetics of MF and SS is less well understood in the pediatric population compared to adults. Among the population of children where T-cell gene rearrangement studies were done (TCR), clonality was proven in ∼64% of cases, and a polyclonal result was seen in 16% of cases. These numbers appear to be lower when compared to adults (80% clonal results), and this might reflect a relatively lower number of neoplastic cells in the skin. However, sensitivity for TCR is lower in early lesions of MF (up to 60%).¹⁰⁷ The study from Hodak et al.⁷⁹ revealed monoclonality in only 43% of cases.

In the differential diagnosis of MF, only few conditions will be considered here, with emphasis and focus on the pediatric population. Among the inflammatory conditions, pityriasis alba usually presents with hypopigmented macules and patches, situated in the face, but also on the trunk and arms (Fig. 75-11). Histologically, there is a very sparse lymphoid infiltrate, with very slight spongiosis, and without the dermal fibrosis seen in MF. Vitiligo consists of depigmented macules and patches in localized, segmental, or widespread distribution. The lesions are usually on the face and distal extremities. Histologically, the findings are minimal and, if present, there is a subtle perivascular infiltrate of lymphocytes, with few of them in the epidermis. As lesions evolve, a decrease in the number of melanocytes at the dermal–epidermal junction is seen. APACHE can also mimic pityriasis alba. APACHE is composed of a dense infiltrate beneath the epidermis, and thick wall vessels are seen.¹⁰⁸ In idiopathic guttate hypomelanosis, there are hypopigmented macules in the legs, which often spread to the trunk, but characteristically spare the face (Fig. 75-12). Typical histologic findings are epidermal atrophy of the actinic type, a patchy decrease or absence of melanocytes and melanin, flat rete ridges, and basket weave hyperkeratosis.

Treatment modalities for pediatric MF include topical steroids (20%) alone or in combination with narrow-band ultraviolet B radiation (54.3%) and, much less frequently, psoralen and ultraviolet light A (PUVA, 2%). Topical nitrogen mustard has also been used with success. Surgical excision can be used in solitary lesions. Cases of FMF usually require more aggressive treatment, where most patients receive PUVA or a combination with nitrogen mustard.^65,79 Oral minocycline and retinoids (bexarotene) was used in the series from the Mayo Clinic.⁸⁰ Cases of pagetoid reticulosis can be treated with surgical excision and/or localized photodynamic therapy on the field.⁹⁰ The majority of patients improve with phototherapy by at least 50%, but the areas of hypopigmentation do not usually completely re-pigment. Approximately 20% of patients have recurrences after therapy discontinuation. Although some original studies suggested that pediatric MF has a more aggressive clinical course,⁷⁰ most of the current data indicated that the natural history of the disease is stage-dependent and similar to that in adults.^{66,69,71,72,96,101}

A series of 10 cases of small-to-medium–sized CD4⁺ pleomorphic T-cell lymphoma show the occurrence of 4 cases in children.¹⁰⁹ It still remains a provisional category in the World Health Organization (WHO) classification.¹⁰⁹ All cases described in children present as a solitary lesion; usually a papule, nodule, or plaque in the head and neck region. In these lesions, the infiltrate consists of a nodular, diffuse, and interstitial infiltrate with sparing of the epidermis. Immunohistochemistry shows invariable expression of CD4 with a rich background of B cells; CD30 is usually negative. The prominent feature associated with this entity is the presence of a rich background of B cells. The T cells show a T-helper phenotype with expression of germinal center markers (BCL-6, CD10, PD-1).^40,110,111