Case 7 -

Primary Cutaneous Anaplastic Large Cell Lymphoma (ALCL) Marsha C. Kinney and Steven H. Swerdlow

Clinical History 90 year old male with pink, waxy nodular lesion, right shoulder Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma (ALCL) Case 7 - Figure 1 - Primary cutaneous anaplastic large cell lymphoma, skin biopsy. Tumor cells diffusely efface the dermis with sparing of the epidermis. Case 7 - Figure 2 - Primary cutaneous anaplastic large cell lymphoma, skin biopsy. The tumor cells are large, pleomorphic and have a high mitotic rate. Case 7 - Figure 3 - Primary cutaneous anaplastic large cell lymphoma, skin biopsy, paraffin immunoperoxidase, antibody Ber-h-12. The tumor cells have strong CD30 expression in a membrane and Golgi pattern. Case 7 - Figure 4 - Primary cutaneous anaplastic large cell lymphoma, skin biopsy, paraffin immunoperoxidase, antibody ALK1. The tumor cells are ALK1 negative (left panel) with a positive control (right panel). Immunophenotype: CD3-/+, CD4+, CD43+, CD45RO-/+, CD30+, CD15 (focal, cytoplasmic +), TIA-1-/+, EMA-, ALK-1-, CD56- Primary cutaneous ALCL is an indolent CD30+ lymphoma usually treated with local therapy. It must be distinguished from systemic ALCL as this is an aggressive disease which requires multiagent systemic chemotherapy and from lymphomatoid papulosis (LyP) which spontaneously regresses. Discussion of Case 7: Role of the ALK gene in defining ALCL Clinical and pathologic features of primary cutaneous ALCL Distinguishing primary cutaneous ALCL from systemic ALCL Relationship of primary cutaneous ALCL to LyP Other lymphomas and reactive processes in the differential diagnosis Anaplastic Large Cell Lymphoma: [97] Defined in 1985 as pleomorphic large cell lymphoma with strong, distinct membrane and Golgi associated CD30 expression in virtually every cell Prominent involvement of nodal sinuses Associated with a characteristic t(2;5)(p23;q35) Previously diagnosed as carcinoma, melanoma, malignant histiocytosis The heterogeneity in ALCL and the nonspecificity of CD30 expression led to controversy as to whether ALCL was a specific entity: Heterogeneity in ALCL: [98] Bimodal age distribution: young and old patients Varied clinical presentations:   systemic (nodal and extranodal)   primary cutaneous   HIV-related   secondary to mycosis fungoides, Hodgkin lymphoma, LyP Histologic spectrum: pleomorphic, monomorphic [99], small cell variant (SCV) [100], lymphohistiocytic [101], and Hodgkin-related [102, 103] types T, null and B-cell types with variable expression of EMA, CD15, cytotoxic granule proteins CD30 staining is non-specific and can be sensitive to fixation: CD30 expression is seen in:   Anaplastic large cell lymphoma   Classical Hodgkin lymphoma [105]   Other T and NK cell lymphomas and a subset of large B cell lymphomas [97, 105] (see Table 4)   Embryonal carcinoma [106]   Rarely in other tumors: pancreatic carcinoma [107], melanoma [108] and mesothelioma [109] (diffuse cytoplasmic rather than membrane or Golgi), granulocytic sarcoma [110]   Lymphomatoid papulosis   Large activated lymphocytes at the edges of follicles and interfollicular areas of reactive nodes; [97] strongly expressed in infectious mononucleosis [111] Immunoreactivity for CD30 is diminished after prolonged fixation In 1994, the t(2;5) was cloned by Morris et al. [112]and a new gene ALK, (anaplastic lymphoma kinase) that is important in the pathogenesis of some ALCL, was cloned. Subsequently antibodies to ALK protein were produced making it possible to evaluate large numbers of ALCL cases of many types for ALK expression. [113, 114, 115] Anaplastic lymphoma kinase (ALK): [112] Located on chromosome 2p23 Not normally expressed in lymphoid tissue Dysregulated by translocations including t(2;5)[NPM/ALK] in 80% and other variant translocations in 20%: inv(2) [ATIC/ALK]; t(2;17) [CLTC/ALK]; t(2;2) [RanBP2/ALK], t(2;3)[TFG/ALK], t(1;2) [TPM3/ALK]; t(2;19) [TPM4/ALK] [116, 117, 118] Detected immunohistochemically by antibodies ALK1, ALKc, p80 [114, 115, 119, 120]   nuclear and cytoplasmic staining usually seen   nuclear staining is due to the nuclear localization domain of NPM   cytoplasmic staining alone may indicate a variant translocation   ALK staining is generally present in all tumor cells but may be stronger near the edges of the tissue Anaplastic lymphoma kinase (ALK) gene dysregulation is used to define ALCL. ALK+ cases have the following characteristics: [98, 119, 120, 121] Present in 30%-60% of cases overall (range 13%-92%); higher incidence in pediatric series Morphologic spectrum that includes ALCL (pleomorphic and monomorphic)«small cell and lymphohistiocytic variants* T- or null-cell phenotype Frequent expression of EMA, cytolytic proteins Young patients with systemic disease Good prognosis * Approximately 80% of monomorphic, 75%-100% of small cell, and 30% of pleomorphic histologies are ALK+ ALK- CD30+ lymphomas are heterogeneous and include: Primary cutaneous ALCL* Hodgkin-related ALCL Secondary ALCL arising in patients with LyP, HD, MF Large B-cell lymphoma with anaplastic or non-anaplastic morphology◊ Large cell lymphoma in HIV+ patients * a small number (<5%) of cases reported as t(2;5)+, usually with sensitive nested PCR techniques [122] ◊ rare cases are positive; these likely represent a secondary translocation in lymphomagenesis rather than primary pathogenetic event Note: (2;5) translocations have been detected using very sensitive techniques in the blood of normal individuals similar to the t(9;22) and t(14;18) [123] Definition of primary cutaneous ALCL: ∆ [124] Skin involvement without evidence of systemic disease* No previous history of LyP, mycosis fungoides or Hodgkin lymphoma** ∆ The European Organization for Research and Treatment of Cancer (EORTC) uses the term CD-30 positive cutaneous large T-cell lymphoma (CTCL) as some have non-anaplastic morphology (immunoblastic or large cell pleomorphic); also, for purpose of their study, there was no evidence of extracutaneous disease for 6 months after diagnosis * Cases with regional (draining) node involvement are problematic; it is uncertain if they have a different prognosis or if they should be included as primary. [124] ** Some studies indicate that ALCL developing in LyP has a good prognosis Clinical features of primary cutaneous ALCL: [125, 126, 127, 128, 129, 130, 131] Older age, median 40-67 yrs but wide range 2-95 yrs; most over 50 yrs Male>female Nodule (>2 cm)>tumor (>2 cm rapidly growing)>papule (< 1 cm) or plaque (3-5 cm) Solitary>multiple; regional>generalized Larger lesions often ulcerated Extremities>head and neck>trunk>genitalia Spontaneous regression (partial or complete) in up to 23%-44% [122, 126] Indolent course [122, 125, 126, 131, 132]   Five year survival (90% -100%) as compared to ~65%-85% nodal (systemic)   Relapse common, 36%- 44% [123, 126] Approximately 25% develop nodal involvement [127]   median of 24 months (range 2-117 mos) after initial diagnosis   approximately 50% of these die   aggressive disease appears associated with early spread to nodes Treatment varies with extent of disease:   excision, with or without radiation in localized lesions is usual   generalized cutaneous disease appears to be more aggressive and at greater risk to develop extracutaneous disease; methotrexate may be used with muticentric disease [133] Note: Patients with systemic ALCL and secondary skin lesions require aggressive multiagent chemotherapy Note: Primary cutaneous ALCL is rare in children and has a high relapse rate despite systemic chemotherapy; however there is no systemic spread and the course is still favorable. Optimal therapy is not known. [130] Histologic features of primary cutaneous ALCL: [126, 127, 129] Dense and diffuse dermal infiltrate often extending into subcutaneous tissue Epidermal ulceration in 30%-50%; no significant epidermotropism Pseudoepitheliomatous epidermal hyperplasia may mimic carcinoma [134] Tumor cells are present in sheets or large clusters Most cases are anaplastic with large cells having folded or indented nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm 10-20% have more folded nuclei with denser chromatin Vascular invasion or perivascular cuffing, but not destruction, by tumor cells often present [129, 135, 136] Variable numbers of multinucleated, Reed-Sternberg-like giant cells Neutrophils and/or eosinophils may be prominent [124, 137, 137a] Large numbers of eosinophils may be predictive of subsequent lymph node involvement [126] Note: Cases previously diagnosed as regressing atypical histiocytosis are now thought to represent ALCL [126, 138, 139, 140] Immunophenotype of primary cutaneous ALCL: Strong CD30 expression in virtually all (>75%) tumor cells CD4+>>CD8+; variable loss of pan T-cell antigens CD2, CD3, CD5 EMA+ in <32% of cases; CD15+ in <10%† [122, 127] CD56+ reported in 12%-75% of cases [141, 142, 143] Roughly 75% express at least one cytotoxic protein [144] ALK protein expression is uncommon in primary cutaneous ALCL [116, 145] ; ALK positivity suggests systemic disease [146] EBV- in >90% [147, 148, 149] Clusterin (ApoJ)+/- (~40%-60% are +)* [150a, 150b] † Cytoplasmic (not membrane) CD15 expression has been reported in up to 40% of cases * Clusterin's function is not well defined but may be involved in cell to cell interaction and it may be proapoptotic Pathogenesis of primary cutaneous ALCL: As primary cutaneous ALCL is ALK negative, the pathogenesis is different from the usual systemic ALCL. HOX homeobox gene HOXC5 is preferentially expressed in primary cutaneous ALCL and MALT lymphoma. HOX genes are important in regulating trafficking as their target is genes encoding adhesion molecules. [151] Two molecules have been identified as important in predicting whether cutaneous lesions may or may not regress. BCL-2 expression correlates with non-regression [152]; CD30L (ligand) correlates with regression. [153] Recent molecular studies using comparative genomic hybridization and microarray based CGH have identified chromosome gains of 1/1p, 5,6,7,8/8p, and 19. Genomic imbalances included oncogene copy gains of FGFR1 (8p11), N-RAS (1p13.2), N-MYC (2p24.1), PAF1 (3p25), CTSB (8p22), FES (15q26.1) and CBFA2 (21q22.3). Real time PCR confirmed amplifications of CTSB, RAF1, REL, JUNB (19p13.2), REL (2p13p12), N-MYC, and YES1 (18p11.3). [153a] Diagnosing primary cutaneous ALCL: There are two common difficulties facing the pathologist in making a diagnosis of ALCL in the skin: Determining if the disease is primary and limited to the skin Distinguishing ALCL from lymphomatoid papulosis Importance of distinguishing primary versus secondary ALCL: Primary cutaneous ALCL has an excellent prognosis (90%-100% 5 year survival), whereas the prognosis of systemic ALCL with associated skin involvement is less favorable [126, 128] (see Table 9) Table 9. Five Year Cumulative Survival in Various Cutaneous Forms of ALCL Clinical type of ALCL 5 year cumulative survival (%) Primary cutaneous 90%-100% Skin involvement in systemic disease 29%-44% Simultaneous presentation of skin and extracutaneous lesions 15% Cutaneous ALCL following LyP/MF/Hodgkin lymphoma 65%-85% References [126, 128] Note: Most series report overall 5 year survival for ALCL (includes adults and children, all clinical types) as 65%-85% or better in ALK+ tumors in children and young adults. Distinguishing primary cutaneous ALCL from systemic disease: Careful staging is imperative; unfortunately there are no definitive tests Close followup is indicated as 25% develop nodal involvement [126] ALK expression correlates with systemic disease [146] Monomorphic histology is more often seen in systemic disease Clusterin positivity was initially reported as being exclusively expressed in systemic ALCL; Wellman et al., 2000 [150]showed 100% of systemic ALCL and no primary cutaneous ALCL were positive, however a small number of cases were tested; clusterin is rarely expressed in other lymphoma types such as T-cell rich B cell lymphoma and diffuse large B-cell lymphoma. Recent reports with larger number of cases have shown clusterin is present in approximately 40-60% of cases of primary cutaneous ALCL. [150a, 150b] Expression of CD44v6 (the variant isoform of cell surface adhesion molecule CD44) correlates with systemic ALCL but is not specific (90% of systemic ALCL vs. 50% of primary cutaneous ALCL) [150c] Rashes are rare in ALCL overall and are more often seen in reactive CD30+ infiltrates (see below), but if present in lymphoma suggests systemic disease Note EMA expression is not useful in distinguishing primary cutaneous disease versus systemic ALCL as it has been reported in 54% of simultaneous cutaneous and systemic and 100% of secondary skin involvement and up to one third of primary cutaneous ALCL [122] Note: Remember primary cutaneous ALCL is uncommon in children; must do careful staging and follow-up Differential Diagnosis of Primary Cutaneous ALCL: ALCL versus Lymphomatoid Papulosis (LyP) Overlapping clinical and pathologic features indicate LyP and some cutaneous ALCL represent a continuous spectrum [154, 155] Clinical and pathologic features of LyP: Multiple papular lesions, usually <1 cm Extremities and trunk>>face, genitalia Lesions usually ulcerate and heal with a scar in 4-6 wks Large atypical cells mixed with small lymphocytes, acute inflammatory cells Three histologic types [156]   Type A   wedge shaped infiltrate, perivascular   scattered CD30+ large atypical cells   dense background of inflammatory cells, neutrophils, and/or eosinophils may be particularly prominent   Type B (less common)   band-like dermal distribution   lymphocytes with convoluted "cerebriform" nuclei   some epidermotropism may be present   large CD30+ cells are rare or absent   distinguished from mycosis fungoides on clinical grounds (LyP remits spontaneously and does not have extensive patches and plaques)   Type C (diffuse large cell type)   indistinguishable from ALCL except invasion of the subcutis is minimal or absent   history of regression is the most important distinguishing feature   may have extracutaneous spread, so true "borderline" lesion EMA present in up to 31% of LyP [122] CD15+ in up to 33% in frozen tissue [157] There is no significant difference in expression of cell surface adhesion molecules CD44 and CD44v6 in primary cutaneous ALCL (100% and 50%, respectively) and LyP (100% and 44%, respectively) [157a]. Table 10. Clinical Features Useful in Distinguishing ALCL and LyP Clinical Features LyP ALCL Type of lesion Papules, nodules Nodules, tumors, rarely rash Number Multiple Single or grouped Size Usually < 1 cm* > 2 cm* Sites Extremities, trunk Extremities, head and neck Regression Yes, usually with scar ~25% of cases * > than 3 cm more predictive of lymphoma; borderline lesions are usually intermediate in size, 1-2 cm. Table 11. Pathologic Features Useful in Distinguishing ALCL and LyP Histology/Immunophenotype LyP ALCL Pattern of infiltration Wedge-shaped perivascular/periadnexal More diffuse Subcutaneous involvement Absent (or minimal) Present Mixed inflammatory cells Many Few to many CD30+Cells Scattered single or small clusters Large groups or sheets EMA Present in 10% to 30% of cases Present in 10% to 30% of cases ALK Usually negative Usually negative EMA = epithelial membrane antigen Primary cutaneous ALCL vs transformed mycosis fungoides (MF): Transformation of mycosis fungoides to large cell lymphoma: [158, 159, 160] Occurs in ~20-25% of cases of MF at a median of 12 months (range 0-128 months) Large cells form microscopic nodules or represent >25% of total cells CD30+ in 25%-50% of cases Aggressive disease   Median survival 29-37 months from diagnosis compared to 163 months for MF without transformation   Median survival after transformation 12-19 months Features useful in distinguishing transformed mycosis fungoides (MF) and primary cutaneous ALCL: Antecedent or coexistent patch or plaque stage lesions Small residual cerebriform lymphocytes usually present Primary cutaneous ALCL vs primary cutaneous Hodgkin lymphoma Hodgkin lymphoma (0.5%-3.4%) may secondarily involve the skin as secondary retrograde lymphatic spread from involved lymph nodes or infiltration of soft tissue in advanced (terminal) disease; primary cutaneous Hodgkin lymphoma is very rare. Primary cutaneous Hodgkin lymphoma: [161, 162, 163] Very rare Clinical course is variable; usually indolent; can develop nodal involvement 2 mos-46 years; rare cases with aggressive course Extremities >>trunk Tumor cells are scattered, not sheet-like Diagnostic, multinucleate RS cells present CD45-, CD30+, CD15+, EBV+/- Table 12. Pathologic Features Useful in the Differential Diagnosis of CD30+ Cutaneous Lymphomas/LyP Type of lesion No of tumor cells RS cells CD15 CD30 EMA CD45 EBV T cell antigens Other ALCL Many +/- -/+ + -/+ +/- -/+ +   LyP Few Rare +/- + -/+ + -/+ + Multiple papules with regression Transformed Mycosis Fungoides Many Rare -/+ +/- NT + NT + Admixed cerebriform lymphocytes; patches and plaques Hodgkin lymphoma Few + + + - - +/- - Very rare + = >50% of cases; +/- = 25-49%; -/+ = 5-24%; - < 5% Beware: CD30 expression has been reported in granulocytic sarcoma, which can occur in the skin [110] Primary cutaneous ALCL vs Cutaneous Nasal Type NK/T-Cell Lymphoma (see case 8): ALCL may show vascular invasion (angiocentricity) but lacks angiodestruction Zonal necrosis is rare or absent EBV expression is uncommon in ALCL The immunophenotype is not definitive; CD56 is present in some cases of ALCL and CD30 expression is seen in ~20% of nasal type NK/T-cell lymphoma Note: ALCL often involves the subcutaneous tissue, but the sheetlike growth of large tumor cells and strong CD30 expression distinguishes it from subcutaneous panniculitis-like T-cell lymphoma. Reactive cutaneous T-cell infiltrates often have CD30+ large cells and may mimic ALCL in the following circumstances: After multiagent chemotherapy for large cell lymphoma or leukemia [164] Following marrow ablative therapy and growth factor administration at the time of lymphocyte recovery (eruption of lymphocyte recovery) [165] Hypersensitivity reaction to carbamazepine [166] Herpesvirus infection [167] Note: These reactions generally have the gross appearance of a rash and CD30+ cells are often scattered rather than sheet-like; however, some may have a perivascular distribution with clustering of CD30+ cells [165] References 97. Stein H, Mason DY, Gerdes J, O'Connor N, Wainscoat J, Pallesen G, Gatter K, Falini B, Delsol G, Lemke H, Schwarting R, Lennert K: The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. 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