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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

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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
What are some non-hematopoietic tumors that are positive for CD30 ?
* rhabdomyosarcoma * inflammatory myofibroblastic tumor * neural tumors
26
What is the normal counterpart of ALK+ ALCL ?
* activated, mature cytotoxic T cell
27
What is the genetic profile of ALK+ ALCL ? (antigen receptor genes)
* 90% of ALCLs show clonal rearrangement of the TR genes * irrespective of whether they show T cell antigens
28
What is the most common translocation identified in ALK+ ALCL ?
* 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
What are the roles of the ALK and NPM1 genes ?
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
What other genetic changes can be seen in ALK+ ALCL ?
* 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
What are the prognostic and predictive factors of ALK+ ALCL ?
* 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
What is the long-term survivl rate of ALK+ ALCL ?
* 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
When is testing for MRD especially important ?
* 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
What are the treatment options for ALK+ ALCL ?
* 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
What is the definition of ALK - ALCL ?
* 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
What are some key differences between ALK- and ALK+ ALCL clinically ?
* older median age * poorer prognosis * Note: * the distinction between PTCL, NOS and ALK- ALCL is not always straightforward
37
What is the epidemiology of ALK- ALCL ?
* peak incidence is 40-65 (older patients) * modest male preponderance
38
What is the localization of ALK- ALCL ?
* 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
What are the clinical findings of ALK- ALCL ?
* most patients present with advanced stage disease (III-IV) * peripheral and/or abdominal lymphadenopathy
40
What are the architectural/microscopic findings of ALK- ALCL ?
* 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
Can T cell lymphomas morphologically resemble CHL ?
* 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
What are the cytological features of ALK- ALCL ?
* 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
What cytologically should raise the suspicion of a PTCL, NOS rather than a ALK- ALCL ?
* 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
Which specific ALK- ALCL shows different morphology ?
* ALK- ALCL with DUSP22-IRF4 rearrangement * lacks the large pleomorphic cells * has more doughnut cells with central nuclear pseudoinclusions
45
What is the immunophenotype of ALK- ALCL ?
* 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
What is a pitfall IHC finding in both ALK+/- ALCL ?
* 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
What is the expression of EBV in ALK- ALCL ?
* 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
What is the main, difficult diagnostic differential of ALK- ALCL ?
* 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
What is the normal counterpart to the ALK- ALCL?
* activated mature cytotoxic T cell
50
In ALK- ALCL, what are the TR genes ?
* most cases show clonal gene rearrangement of the TR genes * even if they do not express T cell antigens
51
What genetic findings can be seen in ALK- ALCL ?
* 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
What molecular alteration can be seen in 30% of cases ?
* DUSP22 rearrangements * usually with IRF4 locus 6p25.3 * Note: * rearrangements of TP63 occur in about 8% of cases and encode p63 fusion proteins
53
What are the prognosis and predictive factors of ALK- ALCL ?
* 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
What is the definition of breast-implant associated ALCL ?
* provisional entity * T cell lymphoma * morphologically and immunohistochemically similar to ALK negative ALCL * arises primarily associated with breast implants
55
What is the epidemiology of implant associated ALCL ?
* very rare * usually rough implants cause this due to chronic inflammation
56
What is the localization of these tumors?
* 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
What are the key clinical features of implant associated ALCL ?
* 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
What are the microscopic findings of implant associated ALCL ?
* 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
What is the immunophenotype of implant assocaited ALCL ?
* phenotype is similar to ALK- ALCL * strong uniform CD30 * negative for ALK * incomplete expression of pan T cell antigens
60
What is the genetic profile of implant associated ALCL ?
* TR genes are clonally rearranged in most cases * Recurrent activating mutations * JAK1 and STAT3
61
What are the prognostic and predictive factors ?
* 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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