Anaplastic Large-Cell Lymphoma (ALCL), ALK-positive (ALK+ ALCL)
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
Primary Cutaneous Anaplastic Large-Cell Lymphoma (C-ALCL), ALK-negative
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
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.
FIGURE 75-3. Cutaneous anaplastic large-cell lymphoma. A and B (low and intermediate magnification, 20× and 200×, respectively). There is a nodular infiltrate in the dermis, with focal epidermotropism of predominantly small lymphoid cells. C and D (low and intermediate magnification, 40× and 100×, respectively). Surface ulceration and associated spongosis is present. E and F (intermediate and high magnification, 200× and 400×, respectively). Spongosis is seen with small intraepidermal vesicle formation. The dermal infiltrate is composed of larger cells with vesicular nuclei and prominent nucleoli. Scattered mitotic figures are present. Admixed histiocytes and neutrophils are seen.
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 adults63,64
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
). 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
). 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.
FIGURE 75-4. Pediatric mycosis fungoides with hypopigmented areas and popular keratosis pilaris–like lesions in the thighs and posterior legs.
FIGURE 75-5. Pediatric mycosis fungoides—hypopigmented papules in the trunk.
FIGURE 75-6. Pediatric mycosis fungoides with keratotic papules, closer view.
FIGURE 75-7. Pediatric mycosis fungoides with keratotic papules on the dorsum of the toes.
FIGURE 75-8. Pediatric mycosis fungoides with alopecia.
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.
FIGURE 75-9. Pediatric hypopigmented mycosis fungoides. A and B (low magnification, 20× and 40×, respectively). There is a superficial dermal band-like infiltrate. C and D (intermediate magnification, 100× and 200×, respectively). The infiltrate is associated with extravasation of red blood cells. There is tagging of lymphoid cells at the dermal-epidermal junction. E and F (high magnification, 400× each). The infiltrate is composed of small-to-medium-sized lymphocytes, with hyperchromasia, and irregular nuclear borders. The epidermotropic cells do not reveal definitive intraepidermal collections of lymphocytes in the form of Pautrier microabscesses.
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
). 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.
FIGURE 75-10. Pediatric hypopigmented mycosis fungoides—immunohistochemistry. CD3 is positive in the majority of the dermal and epidermal lymphocytes. CD20 is predominantly negative. CD4 staining (low and medium magnifications) shows positive staining in many of the T cells and the dermal lymphocytes. However, the vast majority of the T cells in the epidermis are negative for CD4 and positive for CD8 (low and medium magnifications), which reveals extensive epidermotropism and tagging of cells along the dermal-epidermal junction.
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.
FIGURE 75-11. Clinical mimickers of mycosis fungoides. In pityriasis alba, hypopigmented patches in the trunk are present.
FIGURE 75-12. Clinical mimickers of mycosis fungoides. In idiopathic guttate hypomelanosis, there are small hypopigmented macules in the trunk.
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