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Hematopathology WHO T cell Neoplasms > Anaplastic Large Cell Lymphoma (ALK+ and ALK -) & Breast Implant Associated > Flashcards

Anaplastic Large Cell Lymphoma (ALK+ and ALK -) & Breast Implant Associated Flashcards

1
Q

What is the definition of Anaplastic Large Cell lymphoma

ALK+ (ALCL) ?

A
  • T cell lymphoma
  • ALK gene translocation and protein expression of ALK
  • CD30 positive
  • Tumor cells
    • large, pleomorphic
    • abundant cytoplasm
    • some horseshoe shaped
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2
Q

What neoplasms must ALK+ ALCL be differentiated from ?

A
  • ALK - ALCL
  • Primary cutaneous ALCL
  • T and B cell lymphomas with anaplstic features
  • CD30 positive lymphomas
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3
Q

What is the epidemiology of ALK + ALCL ?

A
  • 3% of adult NHLs
  • 10-20% of pediatric NHLs
  • the disease is most frequent in the first 30 years of life
  • male predominance
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4
Q

What is the localization of ALK+ ALCL ?

A
  • frequently involves both lymph nodes and extranodal sites
  • extranodal sites:
    • skin, bone, soft tissue, lung and liver
      • bone marrow involvement ranges from 10-30%
      • because it can be subtle use of IHC can help demonstrate tumor cells
    • note: involvement of the gut and CNS is very rare
  • mediastinal disease is less frequent than CHL
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5
Q

How can the small cell variant of ALCL ALK+ present ?

A
  • may have a leukemic presentation in the peripheral blood
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6
Q

What type of ALCL has been reported

in the skin ?

A
  • a few cases of indolent ALK+ ALCL restricted to the skin have been reported
  • IMP
    • must differentiate this from secondary involvement by systemic ALK+ ALCL
    • this is an aggressive disease
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7
Q

What are the clinical features of ALk+

ALCL ?

A
  • most patients present with advanced stage III-IV disease with peripheral lymphadenopathy, extranodal infiltrates and bone marrow involvement
  • most have B symptoms (>75%)
    • especially high fever
  • rare cases of skin and satellite lymph node involvement of ALK+ ALCL following insect bites have been reported
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8
Q

What is the morphology seen in ALK+ ALCL ?

A
  • broad morphological spectrum
  • variable proportion of cells with eccentric, horse-shoe shaped or kidney shaped nuclei
    • often have an eosinophilic region near the nucleus
    • called Hallmark cells
    • usually large, but can be smaller
    • Doughnut cell
      • appear to have a nuclear inclusion but not real
      • invagination of the abundant cytoplasm
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9
Q

There are many morphologic patterns of ALCL,

what are the features of the common pattern ?

A
  • represents 60% of cases
  • tumor cells with:
    • abundant cytoplasm: clear, basophilic, or eosinophilic
    • multiple nuclei can resemble RS cells
    • chromatin: finely clumped or dispersed
    • multiple small, basophilic nucleoli
    • larger cells will have more prominent nucleoli (eosinophilic, inclusion like)
  • Characteristic:
    • partial lymph node effacement
    • tumor cells growing within the sinuses
    • mimic a metastatic tumor
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10
Q

What are the microscopic findings of the lymphohistiocytic

pattern of ALK+ ALCL ?

A
  • tumor cells are admixed with numerous reactive histiocytes
    • can demonstrate erythrophagocytosis
    • mask the tumor cells
  • tumor cells
    • generally smaller than common pattern
    • often cluster around blood vessels
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11
Q

What are morphologic features of the small-cell pattern

of ALK+ ALCL ?

A
  • seen in 5-10% of cases
  • small to intermediate sized tumor cells
  • some cases have moderate clear cytoplasm and central nucleus
    • Fried egg cells
  • signet ring like cells have been documented
  • hallmark cells are always present
    • often concentrated around blood vessels

IMP: this morphological variant is often misdiagnosed as PTCL, NOS

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12
Q

What is the morphology of the tumor cells in peripheral blood

of the small cell variant of ALK+ ALCL ?

A
  • small atypical cells
  • folded nuclei
    • can look like flower cells
  • rare large cells with blue, vacuolated cytoplasm
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13
Q

What is the Hodgkin-like pattern of ALK+ ALCL ?

A
  • mimics the architecture of nodular sclerosing CHL
  • only 3% of all cases
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14
Q

What are the morphologic findings of the composite pattern ?

A
  • seen in 15% of cases
  • different morpholgies involving a single lymph node or extranodal site

IMP: relapses can have different morphology as compared to the original

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15
Q

What is the morphology of the hypocellular variant ?

A
  • myxoid or edematous background
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16
Q

Other morphologic findings of ALK+ ALCL ?

A
  • there is a spindle cell variant that can mimic sarcomas
  • sometimes malignant cells are so few in an otherwise reactive lymph node that they become hard to find/diagnose
  • capsular fibrosis and fibrosis associated with tumor nodules
    • can be so prominent it mimics metastatic malignancy
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17
Q

What is the immunophenotype of ALK+ ALCL ?

A
  • CD30
    • positive on the cell membrane and in the Golgi region
    • strongest stain in the large cells, small cells can be weakly positive to negative
    • in small cell and lymphohistiocytic variants:
      • large cells around blood vessels highlighted by CD30
  • ALK +
    • only rare, normal cells in brain can be ALK+, otherwise no other counterpart
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18
Q

What is the pattern of ALK staining for

cases with the t(2;5) between NPM1-ALK ?

A
  • cytoplasmic and nuclear
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19
Q

What is the pattern of ALK staining in the small cell variant ?

A
  • staining is restricted to the nucleus
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20
Q

What is the pattern of staining of ALK in cases with variant translocations?

(not NPM1)

A
  • ALK staining will be cytoplasmic rather than membranous (rare cases with membranous)
  • NPM1
    • in the translocated cases abnormally localizes to the cytoplasm
    • in non-translocated cases it is found in the normal location (nucleus)
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21
Q

What are other immunohistochemical markers seen in

ALK+ ALCL ?

A
  • EMA+
  • Variable expression of T cell markers
    • Null-phenotype is negative for all but still T cell at the genetic level
  • CD3
    • negative in 75% of cases
  • CD2, CD4, and CD5
    • more useful
    • positive in 70% of cases
  • cytotoxic markers usually positive
    • TIA-1, Granzyme B, Perforin
  • CD8
    • usually negative, but rare cases of positivity
  • CD43
    • positive in 2/3s of cases, but is not lineage specific
  • CD45 and CD45Ro
    • variable positive
  • CD25
    • strongly positive
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22
Q

What is the expression profile of ALK+ ALCL with

CD68 ?

A
  • tumor cells will be negative for CD68 that has the PGM1 monoclonal antibody
  • KP1 monoclonal antibody
    • shows granular positivity
    • as do other less specific clones
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23
Q

What other key markers are negative in ALCL ?

A
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24
Q

What is the differential diagnosis of

ALK+ ALCL ?

A
  • ALK+ DLBCL
    • also can grow in a sinusoidal pattern
    • express EMA
    • negative for CD30
    • ALK is cytoplasmic
  • ALK+ systemic histiocytosis
    • occurs in early infancy
    • proliferation of large histiocytes that look different from ALCL
    • CD30 negative and positive for CD68
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25
Q

What are some non-hematopoietic tumors that are

positive for CD30 ?

A
  • rhabdomyosarcoma
  • inflammatory myofibroblastic tumor
  • neural tumors
26
Q

What is the normal counterpart of ALK+ ALCL ?

A
  • activated, mature cytotoxic T cell
27
Q

What is the genetic profile of ALK+ ALCL ?

(antigen receptor genes)

A
  • 90% of ALCLs show clonal rearrangement of the TR genes
    • irrespective of whether they show T cell antigens
28
Q

What is the most common translocation identified in ALK+

ALCL ?

A
  • t(2;5)(p23.2;23.1)
  • ALK gene on chromosome 2
  • NMP1 gene on chromosome 5

IMP: FISH using an ALK break-apart probe is not necessary if ALK staining is positive

IMP: RT-PCR is usually reserved for detection of MRD in blood and bone marrow. The different ALK translocations lead to the different subcellular distribution of protein expression.

p.417 table- please review all for boards

29
Q

What are the roles of the ALK and NPM1 genes ?

A

ALK

  • encodes a tyrosine kinase receptor (belongs to insulin receptor superfamily)
  • normally is silent in lymphoid cells

NPM1

  • house keeping gene encoding a nucleolar protein
  • when fused with ALK it is fused to the intracytoplasmic portion
30
Q

What other genetic changes can be seen in ALK+ ALCL ?

A
  • often carry secondary chromosomal abnormalities
  • Losses
    • 4, 11q, and 13q
  • Gains
    • 7, 17p, and 17q

Note: ALK+ and ALK- cases have different secondary genetic alterations

31
Q

What are the prognostic and predictive factors

of ALK+ ALCL ?

A
  • no difference in prognosis has been found between the NPM1 mutated tumors vs. the variants
  • MYC rearrangement
    • concurrent
    • can be associated with a more aggressive clinical course
  • Small cell and lymphohistiocytic
    • worse prognosis compared to others, due to disseminated disease at diagnosis
32
Q

What is the long-term survivl rate of ALK+ ALCL ?

A
  • approaches 80%
  • better overall as compared to ALK(-) ALCL
    • likely due to the fact that it occurs in younger patients as compared to ALK-
33
Q

When is testing for MRD especially important ?

A
  • it is frequently used in pediatric patients (peripheral blood and bone marrow)
  • positive MRD during treatment identifies patients at risk of early relapse
    • this is likely linked to poor immune control of the disease
    • reflected by anti-ALK antibody titers
      • inversely correlated to prognosis
34
Q

What are the treatment options for ALK+ ALCL ?

A
  • relapses usually remain sensitive to treatment
  • in refractory cases bone marrow transplantation may also be effective
  • other new treatments
    • anti-ALK small-molecule inhibitors
      • ALK is essential for the proliferation and survival of ALK+ ALCL
    • anti-CD30
      • antibody-drug conjugates
35
Q

What is the definition of ALK - ALCL ?

A
  • CD30+ T cell neoplasm that is morphologically indistinguishable from ALK+ but it just lacks ALK expression
  • IMP
    • must differentiate this entity from primary cutaneous ALK- ALCL
    • also from other CD30+ entities
36
Q

What are some key differences between

ALK- and ALK+ ALCL clinically ?

A
  • older median age
  • poorer prognosis
  • Note:
    • the distinction between PTCL, NOS and ALK- ALCL is not always straightforward
37
Q

What is the epidemiology of ALK- ALCL ?

A
  • peak incidence is 40-65 (older patients)
  • modest male preponderance
38
Q

What is the localization of ALK- ALCL ?

A
  • both lymph nodes and extranodal tissues are involved
    • although extranodal disease is less common than seen with ALK+ ALCL
  • Important Considerations
    • GI tract: must be differentiated from CD30+ enteropathy associated and other T cell lymphomas
    • Skin: must be differentiated from lymph node involvement by a primary cutaneous ALCL
39
Q

What are the clinical findings of

ALK- ALCL ?

A
  • most patients present with advanced stage disease (III-IV)
  • peripheral and/or abdominal lymphadenopathy
40
Q

What are the architectural/microscopic

findings of ALK- ALCL ?

A
  • growth pattern is similar to common pattern ALK+ ALCL
  • no variant morphologies are identified in ALK-
  • nodal and extranodal architecture is usually effaced
    • growth of solid sheets of neoplastic cells
    • if not effaced the cells grow in the sinuses or among the T cells
    • they typically grow in a cohesive pattern, mimicking carcinoma
      • IF this is not present, there should be consideration of a PTCL, NOS
41
Q

Can T cell lymphomas morphologically

resemble CHL ?

A
  • yes they can resemble it
  • but if it is a T cell neoplasm with this morphology, it is better to classify it as a PTCL, NOS.
  • also, cases with CHL morphology can represent nodal involvement by lymphomatoid papulosis from the skin
42
Q

What are the cytological features of

ALK- ALCL ?

A
  • similar cytological features to ALK+ ALCL
  • importantly, the small tumor cells of the above entity should NOT be numerous in ALK- ALCL
  • typically see sheets of pleomorphic, sometimes multinucleated cells
    • hallmark cells are usually present
    • the cells are usually larger and more pleomorphic as compared to ALK+ ALCL
    • cells have a high N:C ratio
43
Q

What cytologically should raise the

suspicion of a PTCL, NOS rather than a

ALK- ALCL ?

A
  • in PTCL, NOS (unlike ALK- ALCL)
    • abnormal small to intermediate sized cells are admixed with morphologically homogeneous neoplastic cells
    • the sheet like or sinus pattern of ALCL is absent
44
Q

Which specific ALK- ALCL

shows different morphology ?

A
  • ALK- ALCL with DUSP22-IRF4 rearrangement
    • lacks the large pleomorphic cells
    • has more doughnut cells with central nuclear pseudoinclusions
45
Q

What is the immunophenotype of ALK-

ALCL ?

A
  • strongly positive for CD30 on the membrane and in the golgi
    • but diffuse cytoplasmic positivity is also common
    • staining should be strong and equal intensity in all the cells
      • this is important from differentiating other PTCL’s from ALK- ALCL
  • loss of T cell markers (similar to ALK+)
    • CD2 and CD3 positive > CD5
    • CD43 almost always
    • CD4+ usually, CD8+ is very rare
    • usually positive for cytotoxic markers
  • EMA is positive in 43%
46
Q

What is a pitfall IHC finding in both

ALK+/- ALCL ?

A
  • rare cases of ALCL can be positive for Pax-5
  • but expression of CD15 should raise the consideration of CHL
    • BUT some PTCL, NOS cases express CD15 AND CD30 strongly
    • these cases have a poor prognosis
47
Q

What is the expression of EBV

in ALK- ALCL ?

A
  • EBV is negative

Note: Clusterin

  • marker commonly expressed in both ALK- and ALK+ ALCL
    • rarely positive in PTCL, NOS
    • should be negative in CHL
48
Q

What is the main, difficult diagnostic differential

of ALK- ALCL ?

A
  • PTCL, NOS
  • some disagreement even with experts
  • conservative approach is best
    • if it looks and stains essentially like an ALK+ ALCL then go ahead and call ALK- ALCL
    • otherwise better to call it PTCL, NOS
  • primary cutaneous ALCL
    • also must be differentiated since both are negative for ALK
    • this has a better prognosis as compared to ALK- ALCL
49
Q

What is the normal counterpart

to the ALK- ALCL?

A
  • activated mature cytotoxic T cell
50
Q

In ALK- ALCL, what are the TR genes ?

A
  • most cases show clonal gene rearrangement of the TR genes
    • even if they do not express T cell antigens
51
Q

What genetic findings can be seen

in ALK- ALCL ?

A
  • recurrent activating mutations of JAK1 and or STAT3 have been shown frequently
  • translocations involving tyrosine kinase genes other than ALK also lead to STAT3 activation
    • this particularly explains why there are some similarities between ALK+ and ALK- ALCL
    • ALK fusions often lead to constitutive STAT3 activation
52
Q

What molecular alteration can be seen in

30% of cases ?

A
  • DUSP22 rearrangements
  • usually with IRF4 locus 6p25.3
  • Note:
    • rearrangements of TP63 occur in about 8% of cases and encode p63 fusion proteins
53
Q

What are the prognosis and predictive factors

of ALK- ALCL ?

A
  • generally poor prognosis
  • may be due to older patient age, high IPI score and genetic heterogeneity of the disease
  • still does slightly better than PTCL, NOS
  • IMP
    • ALCL with DUSP22 rearrangement has a 5 year survival similar to ALK+ ALCL
  • IMP
    • cases with TP63 rearrangements do even worse than regular ALK- ALCL
54
Q

What is the definition of breast-implant associated

ALCL ?

A
  • provisional entity
  • T cell lymphoma
  • morphologically and immunohistochemically similar to ALK negative ALCL
  • arises primarily associated with breast implants
55
Q

What is the epidemiology of implant associated

ALCL ?

A
  • very rare
  • usually rough implants cause this due to chronic inflammation
56
Q

What is the localization of these

tumors?

A
  • tumor cells can be localized to the seroma cavity or can be localized to the capsular fibrous tissue
  • sometimes form a mass
  • locoregional lymph nodes can be involved
57
Q

What are the key clinical features

of implant associated ALCL ?

A
  • mean patient age is 50
  • most patients have stage I disease
    • usually there is a peri-implant effusion
    • less frequently there is a mass
    • few cases have positive lymph nodes
    • rare cases have disseminated disease
  • mean interval from implant to development of disease
    • 10.9 years
58
Q

What are the microscopic findings

of implant associated ALCL ?

A
  • at capsulectomy the tumor cells line the capsule
    • may show varying degrees of capsule infiltration
    • if they extend beyond the capsule they typically form a mass
  • tumor cells
    • usually large and pleomorphic
    • hallmark cells can be seen
59
Q

What is the immunophenotype

of implant assocaited ALCL ?

A
  • phenotype is similar to ALK- ALCL
  • strong uniform CD30
  • negative for ALK
  • incomplete expression of pan T cell antigens
60
Q

What is the genetic profile of

implant associated ALCL ?

A
  • TR genes are clonally rearranged in most cases
  • Recurrent activating mutations
    • JAK1 and STAT3
61
Q

What are the prognostic and predictive factors ?

A
  • most patients have excellent outcomes after excision alone
  • overall survival is 12 years
  • Most important prognostic factor
    • presence of a solid mass of tumor cells
      • may indicate need for systemic therapy
    • if cells restricted to seroma cavity
      • addition of systemic chemotherapy does not seem to affect the outcome greatly

Hematopathology WHO T cell Neoplasms (14 decks)

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