Case 1 -
Primary Cutaneous Anaplastic Large Cell Lymphoma
Marsha C. Kinney
University of Texas
San Antonio, TX
Click on each slide thumbnail image for an enlarged view
This 57 year-old female presented in March 2004 with a
several week history of a
1.5 x 1.0 cm focally ulcerated, nodular lesion on the right elbow. There was no past history of
similar lesions or any other pertinent disease process. The clinical impression was a pyogenic
granuloma. A pathologic diagnosis was rendered, and the lesion was totally excised and treated with
local irradiation to the area. Within a few weeks, new lesions developed on the left elbow and the left
upper arm. The skin of the right elbow was free of disease.
The patient was referred to a university hospital in July of 2004 where she was noted to have a >
1 cm lesion on the left upper arm and several plaques with satellite nodules on the left elbow. The
largest lesion measured
2 x 1.3 cm and the satellite nodules measured from 0.6-1.0 x 0.5-0.7 cm. There was no lymphadenopathy
or hepatosplenomegaly. The skin lesions were totally excised. The specimen for review is from one of
the satellite lesions on the left elbow. CT scans were negative. Bone marrow examination was not
Case 1 - Figure 1 - Skin biopsy shows a dense lymphoid infiltrate extending from the superficial through the deep dermis to the subcutaneous tissue (H&E, original magnification X20).
Case 1 - Figure 2 - The epidermis has pseudoepitheliomatous hyperplasia (H&E, original magnification X40).
Case 1 - Figure 3 - The epidermis is focally ulcerated (H&E, original magnification X100).
Case 1 - Figure 4 - The lymphocytes are predominantly large. Small lymphocytes surround the tumor mass and focally infiltrate the epidermis (H&E, original magnification, X400).
Case 1 - Figure 5 - The large lymphocytes have dysplastic, large, folded, indented or U-shaped nuclei with dispersed chromatin, prominent nucleoli, and abundant eosinophilic cytoplasm. Small lymphocytes with somewhat irregular, hyperchromatic nuclei focally infiltrate the epidermis (H&E, original magnification X600).
Case 1 - Figure 6 - The tumor cells have a sheet-like growth pattern and numerous mitotic figures are present (H&E, original magnification X600).
Case 1 - Figure 7 - The large dysplastic lymphocytes and the small lymphocytes are CD3+ T-cells (Clone PSI, Novocastra, paraffin immunoperoxidase, original magnification X60).
Case 1 - Figure 8 - The large dysplastic lymphocytes are CD4+ T-cells (Clone 1F6, Novocastra, paraffin immunoperoxidase, original magnification X600).
Case 1 - Figure 9 - Scattered small lymphocytes are CD8+, and the large dysplastic lymphocytes are CD8 negative. Most of the small lymphocytes at the edges of the tumor mass and infiltrating the epidermis (as shown in Figure 4) are CD8+, reactive lymphocytes (not illustrated in this image) (Clone C8/144B, Dako Cytomation, paraffin immunoperoxidase, original magnification X600).
Case 1 - Figure 10 - The lymphocytes are strongly CD30+ in a sheet-like distribution. (Clone BerH2, Neomarker, paraffin immunoperoxidase, original magnification X100).
Case 1 - Figure 11 - Virtually all of the large lymphocytes are strongly CD30+ with a membrane and Golgi pattern of staining (Clone BerH2, Neomarker, paraffin immunoperoxidase, original magnification X600).
Case 1 - Figure 12 - The epidermis strongly expresses epithelial membrane antigen (EMA) and the large lymphocytes are EMA- (Clone E29, Dako Cytomation, paraffin immunoperoxidase, original magnification X600).
Case 1 - Figure 13 - Some of the large lymphocytes and scattered small lymphocytes have cytoplasmic expression of the cytolytic granule protein TIA-1. (Clone 2G9, Immunotech, paraffin immunoperoxidase, original magnification X600).
Case 1 - Figure 14 - The large lymphocytes lack expression of anaplastic lymphoma kinase (ALK) protein. (Clone ALK01, Ventana, paraffin immunoperoxidase, original magnification X600).
A large tumor mass extends from the papillary dermis into the
subcutaneous tissue. The neoplastic cells are pleomorphic, cohesive appearing, large lymphocytes with
abundant pale to eosinophilic cytoplasm. The nuclei are large with dispersed chromatin and one or more
prominent nucleoli. The nuclei vary from round to oval and many are folded, indented and have an
"embryoid" appearance. There is a high mitotic rate. Admixed small lymphocytes are present,
particularly at the edges of the infiltrate. The epidermis overlying the tumor mass is ulcerated and
shows pseudoepitheliomatous hyperplasia. There is focal epidermotropism by small lymphocytes.
Paraffin immunoperoxidase studies reveal the
tumor cells are CD3+, CD4+ T-cells with strong expression of CD30 in a membrane and Golgi pattern. The
tumor cells lack EMA, ALK-1, and BCL-2; TIA-1 expression is focally present in rare large cells and some
small lymphocytes. The small lymphocytes surrounding the tumor and infiltrating the epidermis are
Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma (ALCL)
The patient declined CHOP chemotherapy. One month later there was no evidence of
disease, however, by the end of September of 2004 the patient had developed a small lesion on the buttock
but declined biopsy at that time. In November of 2004, the buttock lesion had grown to a 3 X 1.5 cm
erythematous raised lesion, compatible with recurrent disease.
Primary cutaneous ALCL is an indolent CD30+ lymphoma usually treated with local therapy.
It must be distinguished from systemic ALCL, an aggressive disease that requires multiagent,
systemic chemotherapy and from lymphomatoid papulosis (LyP) which spontaneously regresses.
Topics for Discussion:
| Clinical and pathologic features of primary cutaneous ALCL|
| Treatment 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|
Definition of primary cutaneous ALCL: 
| Skin involvement without evidence of systemic disease for 6 months after diagnosis†|
| No antecedent history of LyP, mycosis fungoides or Hodgkin lymphoma|
†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 cutaneous ALCL.
 One recent study has shown only a slightly decreased overall 5 year survival
for primary cutaneous ALCL versus ALCL with regional node involvement (83% vs. 76%, respectively);
however, it should be noted that 82% of the patients in this study received multiagent chemotherapy.
Clinical features of primary cutaneous ALCL:
| Older age, median 40-67 yrs (range 2-95 yrs; most over 50 yrs)|
| Male to female ratio of 2-3:1|
| 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|
| Rarely described in the post transplant setting
Note: Localized disease refers to a few clustered lesions restricted to one
anatomic area, and generally not exceeding
15 x 15 cm. Multifocal disease has skin involvement of two or more anatomic sites. 
Histologic features of primary cutaneous ALCL:
| Dense and diffuse dermal infiltrate often extending into subcutaneous tissue|
| Epidermal ulceration in 30%-50%; no significant epidermotropism|
| Pseudoepitheliomatous epidermal hyperplasia may mimic carcinoma |
| 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% -25% have non-anaplastic morphology (pleomorphic folded nuclei with denser chromatin or an immunoblastic appearance)|
| Vascular invasion or perivascular cuffing, but not destruction, by tumor cells often present
| Variable numbers of multinucleated, Reed-Sternberg-like giant cells|
| Neutrophils and/or eosinophils may be prominent
| Reactive lymphocytes are often present at the periphery of the lesion|
| Large numbers of eosinophils may be predictive of subsequent lymph node disease |
Note: Regressing atypical histiocytosis is now considered as ALCL
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%
| CD56+ in 12% - 75%; does not appear associated with a worse prognosis
| Roughly 75% express at least one cytotoxic protein (TIA-1, granzyme B, perforin) |
| ALK protein expression is uncommon, but is seen in rare cases of primary cutaneous ALCL
. In most cases ALK positivity suggests systemic disease |
| EBV- in > 90%
| Clusterin + (41% - 100%)
† Cytoplasmic (not membrane) CD15 expression has been reported in up to 40% of
Note: Two molecules have been identified as important in predicting whether
cutaneous lesions may or may not regress. BCL-2 expression correlates with non-regression 
CD30L (ligand) correlates with regression. 
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. 
Amplification of JUNB has been reported in 70% of primary cutaneous
ALCL and JUNB protein expression has been detected in 100% in the small number of cases tested.
Diagnosing Primary Cutaneous ALCL
Two common difficulties face pathologists in making a diagnosis of primary cutaneous ALCL:
- Determining if the disease is indeed 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 (83% - 100% overall 5 year survival; disease related
survival is > 90%), whereas the prognosis of systemic ALCL with associated skin involvement is less
(see Table 1)
Table 1. Five-Year Cumulative Survival in Various Cutaneous Forms of ALCL
|Clinical type of ALCL ||5-year cumulative survival (%)|
|Primary cutaneous ||83% - 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%*|
* ALCL developing in LyP appears to have a good prognosis 
Note: Most series report overall 5-year survival for ALCL (includes adults
and children, all clinical types) as 65% - 85%.
Distinguishing primary cutaneous ALCL from systemic disease
| Careful staging is imperative; there are no foolproof markers to distinguish|
| Close follow-up is indicated as 10% - 25% develop extracutaneous disease
| ALK expression correlates with systemic disease (but is rarely seen in primary cutaneous ALCL)
| Monomorphic histology is more often seen in systemic disease|
| Clusterin was initially reported as being exclusively expressed in systemic ALCL; Wellman et al., 2000  reported 100% of systemic ALCL and no primary cutaneous ALCL were positive, however a small number of cases were tested. Recent larger studies have shown clusterin expression in approximately 41% - 100% of cases of primary cutaneous ALCL.
| Rashes are rare in ALCL overall and are more often seen in reactive CD30+ infiltrates (see below); but, if present in lymphoma suggest 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 ALCL,
100% of secondary skin involvement, and up to one third of primary cutaneous ALCL 
Note: Remember primary cutaneous ALCL is uncommon in children; careful
staging and follow-up to rule out systemic disease is important.
Disease course, prognosis, and treatment:
|Spontaneous regression (partial or complete) in up to 23% - 44%
| ||Overall 5 year survival (83% - 100%) with a disease related survival > 90% versus ~ 65% - 85% in nodal (systemic) ALCL
| ||Cutaneous relapse common (32% - 44%)
, particularly with multifocal disease |
|Overall, 10% - 25% (17% - > 40% in patients with multifocal disease) develop nodal (or other extracutaneous) disease
| ||Median of 24 months (range 2-117 mos.) after initial diagnosis|
| ||Aggressive disease appears associated with early spread to nodes other than regional nodes; approximately 50% with disseminated disease die|
|Treatment varies with extent of disease:|
| ||excision, with or without radiation in localized lesions is usual|
| ||imiquimod (Aldara) an immune reponse modifier may be helpful |
| ||generalized cutaneous disease appears to be more aggressive and at greater risk to develop extracutaneous disease; methotrexate, systemic retinoids w/ or w/o interferon alpha; monoclonal anti-CD30 therapy may be used with muticentric disease; combination chemotherapy and transplant have not been shown to prevent relapse
Remember: Patients with systemic ALCL and secondary skin lesions require
aggressive multi-agent 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. 
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
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 weeks|
|Large atypical cells mixed with small lymphocytes, acute inflammatory cells|
|Three histologic types
| ||Type A|
| ||• Wedge shaped infiltrate, perivascular|
| ||• Scattered CD30+ large atypical cells|
| ||• Dense background of inflammatory cells, neutrophils, and/oreosinophils 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 parameters; (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 |
|CD15+ in up to 33% in frozen tissue |
Clinical (Table 2) and pathologic (Table 3) features are used to distinguish ALCL and LyP:
Table 2. 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 ||colspan=2 25% of cases|
* > 3 cm more predictive of lymphoma; borderline lesions are usually intermediate in size, 1-2 cm.
Table 3. 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 versus Transformed Mycosis Fungoides (MF):
Transformation of mycosis fungoides to large cell lymphoma:
| 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|
| Epidermotropism may be absent|
| 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
| Antecedent or coexistent patch or plaque stage lesions|
| Small residual cerebriform lymphocytes usually present|
Remember: Do immunohistochemistry for CD4 and CD8; Small, reactive CD8+
lymphocytes with irregular nuclei may surround and infiltrate primary cutaneous ALCL.
Primary Cutaneous ALCL versus 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:
| 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 4. Pathologic Features Useful in the Differential Diagnosis of CD30+ Cutaneous
| 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% of cases
-/+ = 5% - 24% of cases
- = < 5% of cases
Beware: CD30 expression has been reported in granulocytic sarcoma, which can
occur in the skin  ; CD30 can beweakly expressed in malignant melanoma.  CD30 expression in
these other tumors is usually weak and more diffuse.
Primary Cutaneous ALCL versus Cutaneous Nasal Type NK/T Cell Lymphoma
| 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
Primary Cutaneous ALCL versus Reactive Infiltrates:
Reactive cutaneous T-cell infiltrates often have CD30+ large cells and may mimic ALCL
or LyP in the following circumstances:
| After multiagent chemotherapy for large cell lymphoma or leukemia |
| Following marrow ablative therapy and growth factor administration at the time of lymphocyte recovery (eruption of lymphocyte recovery) |
| Hypersensitivity reaction to carbamazepine |
| Herpesvirus infection |
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 
Note: Scattered CD30+ large lymphocytes can be seen
in reactive cutaneous infiltrates that contain a prominent neutrophilic or eosinophilic component
including insect and spider bites, hidradenitis suppurativa, Sweet syndrome. 
- A diagnosis of primary cutaneous ALCL can only be made after careful staging and lack of systemic disease for 6 months. Regional node involvement is controversial and currently most cases are treated with systemic chemotherapy.
- ALK expression is rarely present in primary cutaneous ALCL and usually indicates systemic disease.
- Borderline lesions between ALCL and LyP should be diagnosed as LyP type C if there is lack of involvement of the subcutaneous tissue and a clinical history of regression.
- If CD4+ cerebriform small lymphocytes are present, or if there is an antecedent history of patch or plaque lesions, transformation of mycosis fungoides to "secondary" ALCL should be considered.
- The treatment of primary cutaneous ALCL is conservative and usually local (complete excision with or without local irradiation); systemic treatment may be indicated in multicentric disease.
- CD30+ large cells may be present in reactive conditions; the CD30+ cells are usually scattered and do not form large clusters.
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