Peripheral T-cell and NK-cell Lymphomas
Dr. Elaine S. Jaffe
Dr. Philippe Gaulard
Case 5 -
Anaplastic Large Cell Lymphoma: After Twenty Years the Controversy Continues
Marsha C. Kinney, M.D.
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17 year-old white male with one-month history of adenopathy, fever (103.5 °F), pharyngitis, hepatosplenomegaly, and weight loss of 25 pounds over three months. On admission to a local hospital, the patient was found to have a white blood count of 45,000 uL with 58% lymphocytes, some atypical. Liver function tests were mildly elevated. The patient developed a maculopapular, generalized rash. CT examination revealed bilateral pleural effusions and a possible abscess around the gallbladder. The patient was taken to laparotomy, which showed no abscess. A liver biopsy revealed a polymorphic, periportal, lymphocytic infiltrate. Clinical diagnosis was hepatitis. Monospot was negative. A screen for hepatitis A, B, and C was negative. CMV serum titer was positive at 1:160 for IgM. The patient developed progressive respiratory distress, a worsening rash, and ascites.
The patient was transferred to a tertiary care hospital. On physical examination, his temperature was 105.8 °F. White blood count was 48,300 uL with 47% lymphocytes and 14% monocytes. SGOT was 251 IU/L and LDH of 799 IU/L and alkaline phosphatase of 206 IU/L and total billirubin of 5.8 mg/dl.
An axillary lymph node biopsy was performed and is available for review.
Case 5 - Figure 1
Introduction and Historical Perspective:
While evaluating a new antibody Ki-1 directed against an epitope on Reed-Sternberg cells, Harald
Stein, Karl Lennert and others in Kiel, West Germany recognized a unique lymphoma composed of pleomorphic
large cells with strong expression of the antigen detected by the Ki-1 antibody (now designated as
CD30).  This "Ki-1 lymphoma" had a prominent sinus growth pattern and was previously
misdiagnosed as metastatic carcinoma, melanoma, malignant histiocytosis, or lymphocyte depleted Hodgkin
lymphoma (HL). Important events in the definition of anaplastic large cell lymphoma (ALCL) in late
1980's and early 1990s included inclusion in the updated Kiel  and REAL 
classifications, the discovery by Delsol et al. that ALCL frequently expressed epithelial membrane
antigen (EMA)  and recognition by several groups of its association with a unique chromosomal
Despite these advances, considerable debate continued concerning whether ALCL was an entity or a
heterogeneous group of diseases based on variability in morphology (large cell with monomorphic and
pleomorphic histology, small cell predominant, lymphohistiocytic, and cases that resembled HL, so called
Hodgkin-related), immunophenotype (T-cell, null, and B-cell types) and clinical presentation (systemic
with nodal and/or extranodal sites of disease, primary cutaneous, ALCL arising in association with other
lymphoproliferative processes such as lymphomatoid papulosis, mycosis fungoides or HL), or in
The ALK (Anaplastic Lymphoma Kinase) Gene and its Role in Classification of ALCL:
In 1994, Morris et al. cloned the t(2;5)(p23;q35) and identified a unique fusion gene formed from the
N-terminal portion of the constitutively expressed nucleophosmin ( NPM )
gene involved in ribosomal shuttling between the nucleolus and the cytoplasm and the intracellular
portion of a new receptor tyrosine kinase gene they called anaplastic lymphoma kinase (ALK). 
ALK is expressed in portions of the nervous system but is not normally present in lymphoid tissue. The
fusion gene encodes a protein with a dimerization domain (contributed by NPM) that activates signaling
through the ALK receptor tyrosine kinase. Other fusion proteins have been identified that create a
similar dimerization domain but have only cytoplasmic ALK expression and lack the nuclear pattern seen
with staining NPM-ALK as it dimerizes with normal NPM and is transported into the nucleus. 
ALK signaling leads to activation of multiple pathways, leading to enhanced proliferation, and inhibition
of apoptosis. 
Antibodies created against the ALK protein
lead to wide scale testing of ALCL cases
and further definition of the spectrum of diseases included in ALCL.
The ALK + subset of
ALCL represents approximately 60% - 80% of ALCL overall and defines a distinct lymphoma predominantly
occurring as a systemic disease in children (>90% ALK+) and young adults with a morphologic spectrum
from a small cell predominant variant to typical large cell histology, and a T-cell or null cell
phenotype with frequent expression of EMA and cytotoxic granule protein TIA-1. The ALK- group is
heterogeneous and includes systemic ALCL usually in older adults, primary cutaneous ALCL (PC-ALCL), and
ALCL arising in other lymphoproliferative disorders or in immunocompromised patients.
Pitfalls in the Diagnosis of ALK+ ALCL (Case presentation of the small cell
The diagnosis of ALK+ ALCL has become relatively straightforward. The case submitted for the
conference workshop is the index case of the small cell variant (SCV) of ALCL  and is
presented to illustrate potential pitfalls that remain even for ALK+ lymphoma.
The clinical history is that of a 17 year-old male with a several weeks of fever, weight loss,
generalized adenopathy, and hepatosplenomegaly with elevated liver function tests. The clinical
impression was viral hepatitis. The WBC was 45,000/mm3 with 58% lymphocytes. The initial
specimens obtained for diagnosis were small biopsies from a skin rash and the liver. A limited work up
showed a cutaneous perivascular and hepatic periportal T-cell infiltrate composed of small lymphocytes.
A minor population of large CD30+ lymphocytes was present. A diagnosis of abnormal T-cell infiltrate
compatible with viral infection was made. The illness progressed and a lymph node biopsy was obtained
and showed a paracortical and sinus infiltrate with a predominance of small lymphocytes with irregular
nuclei and pale to clear cytoplasm and evidence of hemophagocytosis in the sinuses. Immunostaining for
CD30 revealed a minor population of predominantly large CD30+ lymphocytes with a prominent distribution
around blood vessels. Immunophenotyping studies revealed an abnormal T-cell population with expression
of CD2, CD7, CD8, CD25, CD30, HLA-DR, and EMA and loss of CD3 and CD5. Cytogenetic studies demonstrated
a t(2;5)(p23;q35) in the tumor cells and a subset had a +X.
This case illustrates the features that make the diagnosis of the SCV difficult: young patient age
(reported in some infants less than 6 months), clinical features suggesting a viral illness (fever, rash,
hemophagocytic syndrome), partial effacement of lymph node architecture, predominance or small
lymphocytes, and initial biopsies from extranodal sites. As CD30 is an activation antigen and can be
expressed in numerous reactive conditions, other lymphoid proliferations due to viral infection, drug
reactions, and lymphocyte recovery after stem cell transplant have to be excluded. CD30 is also
expressed in tumor cells (usually a minor population) in other T-cell and even B-cell lymphomas, germ
cell tumors, and other solid tumors. A particularly important feature in the diagnosis of the SCV is the
predilection for the large, CD30+ cells to be distributed around blood vessels rather than randomly as
would be seen in reactive processes or other lymphomas with CD30+ cells. The SCV is often a disseminated
disease with involvement of lymph nodes and extranodal sites including the skin, liver, pleural fluid,
bone marrow, peripheral blood.
Bone marrow examination for staging of ALCL should always
include immunostaining for CD30 and ALK, if the tumor is ALK+. Overall, bone marrow involvement is
present in at least 50% of cases of the SCV and much less common in other histologic types of ALCL
(approximately 20% - 25%). When considering the SCV, peripheral blood films should be examined for the
presence of large lymphocytes with finely vacuolated basophilic cytoplasm that, despite an elevated white
blood count, may represent less than 1% of the white blood cells. In the case presented, rare large
tumor cells and more numerous small lymphocytes with irregular nuclei were present in the peripheral
blood and bone marrow. A large clonally rearranged band (representing at least 50% of the cells present)
on a T-cell receptor beta chain rearrangement performed by Southern blotting on DNA isolated from the
peripheral blood and the finding of a t(2;5) in 23/25 cells in the bone marrow (where large tumor cells
were rare) provided indirect evidence that the small cells were part of the neoplastic
clone.  Later studies confirmed the presence of the t(2;5) in the small lymphocytes by
his case also illustrates that although most cases of ALCL
(including the SCV) arise from CD4+ T-cells, a small subset CD8+. The SCV can transform to typical ALCL
morphology (more often monomorphic) and both histologies may be seen in a single lymph node. 
While ALK expression has been reported to be favorable, the SCV is aggressive.
Recent evidence suggests decreased SHP1 phosphatase activation may be related to the aggressive nature of
Expression of myeloid antigens (CD13, and rarely CD117) and keratin (particularly KL1) 
can be seen in ALK + ALCL and cause difficulty in the diagnosis, particularly if the tumor is of null
immunophenotype. It should be also be pointed out that ALK expression alone is not diagnostic of ALCL.
Other ALK+ tumors include inflammatory myofibroblastic tumor and other soft tissue tumors,
tumors of neural origin (neuroblastoma, glioblastoma)
and a very rare ALK+
B-cell tumor (that lacks CD30 but expresses EMA and some CD4 and CD57). 
Primary Cutaneous ALCL, the Most Well-defined Entity of the ALK- ALCL Group:
The CD30+ clonal lymphoproliferative disorders lymphomatoid papulosis (LyP) and primary cutaneous
ALCL (PC-ALCL) represent approximately 30% of primary cutaneous lymphoid neoplasms
form a histologic and biologic spectrum. PC ALCL arises in older patients (median 40 - 67 years) but can
rarely occur in children.
Lesions are typically solitary, or less frequently multiple,
nodules or tumors (1 - 2 cm or greater) that are often ulcerated and occur on the extremities>head and
neck>trunk. Tumor cells are present in large clusters and sheets with the exception of those
neutrophil-rich or pyogenic variants.
Pseudoepitheliomatous hyperplasia can lead to
confusion with squamous cell carcinoma.  Greater than 90% PC ALCL are CD4+ T-cell
proliferations with variable loss of pan-T-cell antigens. Approximately 75% express one cytotoxic
granule protein (TIA-1 or granzyme B) and approximately 20% - 30% express EMA. CD56 expression has been
reported in 12% - 75% and does not appear associated with a worse prognosis.
expressed in the majority of cases. 
Skin involvement is present in approximately 15% - 25% of systemic ALCL.
importance of distinguishing PC ALCL from secondary skin involvement in systemic disease is illustrated
by the excellent prognosis of PC ALCL with a disease related 5-year survival of > 90% as compared to
the latter with a 5 year cumulative survival of 24% - 44%.
nfortunately there are no
markers that reliably distinguish primary cutaneous and systemic ALCL with secondary skin lesions, and
careful staging and follow-up are indicated as 10% 20% of patients may develop systemic disease
(particularly those with multifocal lesions).
he differential diagnosis of PC ALCL
includes transformed mycosis fungoides (MF) and is principally distinguished by the presence of small
cerebriform lymphocytes and a previous history of patches and plaques in MF. Acute myeloid leukemia can
rarely express CD30 and is distinguished by the presence of myeloid antigens (CD13, CD15, CD33, CD68, and
myeloperoxidase), CD34, and the weaker more diffuse cytoplasmic expression of CD30.
LyP typically occurs in adults with a median age of 45 years
and can rarely be
present in children.
Multiple papular, papulonecrotic, or nodular lesions (usually <
1 cm) that ulcerate and heal with a scar in 3 – 12 weeks are present. LyP may be chronic and recur for
months or years. Other lymphomas (ALCL, MF, or HL) can develop concurrently, before, or after LyP in 5%
- 20% of patients. ALCL and MF arising in a patient with LyP do not appear to have a more aggressive
LyP is classified as Type A when scattered single or small clusters of
dysplastic (often Reed-Sternberg-like) CD30+ large cells are present in a wedge-shaped perivascular
infiltrate often admixed with acute inflammatory cells. LyP type B is the least common (<10%) variant
and is band-like with epidermotropism and more cerebriform nuclei; CD30+ large cells are absent or
sparse. LyP type C shows overlap with ALCL, but typically has little involvement of the subcutis; a
history or regression is the most important distinguishing feature. The immunophenotype of LyP is
similar to PC ALCL with a CD4+ (rarely CD8+) phenotype with EMA present in 31%.  TIA-1 and/or
granzyme B is expressed in 74% 100%.
CD56 has been reported in 0% - 50%.
LyP must be distinguished from other reactive conditions with CD30+ large cells such as drug
reactions (anti-convulsants, histamine receptor antagonists, anti-depressants, phenothiazines, calcium
channel blockers, angiotensin converting enzyme inhibitors, and antibiotics) arthropod assault, viral
infection (herpes virus and parapoxvirus), insect and spider bites, and lymphocyte recovery after marrow
Diagnosis and Classification of ALK- ALCL:
Approximately 20% - 60% of ALCL are ALK- with more cases seen in older adults. Due to lack of a
well-defined pathogenetic mechanism or specific clinico-pathologic features (other than PCALCL),
hematopathologists have debated whether ALK- ALCL is a specific entity or a heterogeneous condition that
should be included in peripheral T-cell lymphoma, unspecified (PTCL-U). Recent studies have shown common
features shared by ALK+ and ALK- ALCL that are not typically present in PTCL-U. Defects in T-cell
receptor signaling have been noted and include the lack of expression of the T-cell receptor alpha-beta
protein (seen in > 90% of ALK+ and ALK- ALCL) as compared to approximately 10% of PTCL-U. 
Ninety-six percent of ALK+ and 40% of ALK- ALCL also lack expression of CD3 as compared to 29% of PTCL-U.
ZAP-70, a tyrosine kinase that integrates cognate and co-stimulatory signals for downstream TCR
signaling, is expressed in only 25% - 30% of ALCL (8% - 25% of ALK+ and 20% - 41% of ALK-) versus 59% -
74% of PTCL-U and 29% - 57% of PC ALCL.
In addition, clusterin, a ubiquitous
glycoprotein, is expressed in 82% - 100% of systemic ALK+ and ALK- ALCL and 41% - 100% of PC ALCL while
only 3.5% of PTCL-U express clusterin.
Although ALK+ and ALK- ALCL show differential
gene expression on microarray analysis, both groups highly express kinase genes
LCK , protein kinase C, vav2 and NKIAMR E and anti-apoptotic
molecules. Comparative genomic hybridization studies have also shown significant losses of
5q21 and 9p21-pter in PTCL-U that were not detected in ALK-ALCL. 
To make a diagnosis of ALK- ALCL there must be strict adherence to the characteristic cytology (large
cell predominant population with abundant cytoplasm and pleomorphic, embryoid or hallmark or wreath-like
nuclei) and strong expression of membrane and Golgi (dot-like cytoplasmic) CD30 expression in virtually
every cell. In lymph nodes, some involvement of nodal sinuses should be seen. In ALK- ALCL with a null
phenotype and genotype, care must be taken to exclude other tumors that may express CD30 (HL, carcinoma,
and acute leukemia).
Since the original description of ALCL in 1985, there have been many difficulties and much
controversy in its diagnosis and classification. Frequent involvement of extranodal sites, lack of
specificity of CD30, expression of EMA and frequent lack of CD45RB (leukocyte common antigen), and rare
expression of myeloid antigens or keratin have contributed to the potential for misdiagnosis.
Recognition of the (2;5)(p23;q35) translocation and abnormal expression of ALK in lymphoid tissue, as
detected by commercially available antibodies, has led to clarification in the classification and
diagnosis of ALCL and recognition of an ALK+ ALCL that occurs predominantly as systemic disease in
children and younger adults, has a morphologic spectrum from large to small cell predominant, T or null
cell phenotype, and frequent expression of EMA. ALK expression is usually associated with systemic
disease and a better prognosis, but there are rare cases of ALK+ systemic ALCL and most cases of the SCV
(which is typically ALK+) that have an aggressive course. Presently, the classification of ALK- ALCL
(other than PC ALCL) remains controversial. Recent genetic and biologic discoveries suggest that ALK-
ALCL is more closely related to ALK+ ALCL than PTCL-U.
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