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Case 254 - Discussion

Uploaded: 2011-12-24, Updated: 2011-12-24


Cytokeratin AE1/3




















This case shows focal sinusoid pattern with syncytial infiltration of large tumor cells, which resembles metastatic carcinoma.


Anaplastic Large Cell Lymphoma (ALCL)

The Key Features

  • "Horseshoe, donut or hallmark cells";

  • Systemic cases: ALK+ , younger age, better prognosis; ALK-, older, poorer prognosis;

  • Primary cutaneous cases, ALK-, good prognosis;

  • Most cases, CD30+, CD45+, CD3-, CD15-, CD4+, TIA1+, granzyme B+, perforin+, EMA+ ;

  • t(2:5)(p23;35), NPM-ALK fusion >> t(1;2)(q25; p23), TPM3-ALK fusion; t(2;3)(p23;q35), TFG-ALK fusion.

  • 3% of adult NHL and 10-30% of children lymphomas;
  • Systemic ALK+ ALCL most frequent <30 YO with good prognosis;
  • Systemic ALK- ALCL most frequent in elder patients with poor prognosis;
  • Primary cutaneous ALCL most frequent in elder patients, ALK-, good prognosis;
  • Highly pleomorphic, eccentric, horse-shoe or kidney-shaped nuclei with an eosinophilic region near the nucleus (hallmark cells);
  • Cytoplasm: abundant, clear, basophilic or eosinophilic;
  • Chromatin: finely clumped or dispersed with multiple small/prominent basophilic nucleoli.
  By location
Type Morphology ALK Age Clinical Features Outcome

Systemic ALCL

  ALK-pos (60%) All variants Present <30 yo stage III/IV Good
  ALK-Neg (40%) Mostly common type and giant cell type Absent old patients stage III/IV Poor

Primary Cutaneous ALCL

Common type to lymphomatoid populosis Absent old patients No systemic symptoms Good
  By Histology
Histologic subtypes CD30 Immunophenotype EMA+ ALK+ (%)
Common (classic) type Positive Most T/null Majority 60-90
Small cell Positive (mainly large cells) T Most 100
Lymphohistiocytic Positive T Most 80-100
Hodgkin-like Positive Null (rarely T) Minority ~ 15
Giant cell-rich Positive Most T/null Minority 30-40
Rare subforms        
       Sarcomatoid Positive NDA NDA NDA
       Neutrophil rich
       Eosinophil rich
       Signet ring
  • Common type (70%). Sheets of large, pleomorphic tumourcells with an abundant cytoplasm that appears grey-blue in  HE stain,  In imprint preparations, the cytoplasm frequently show numerous vacuoles. The tumour cell nucleus is frequently horse-shoe or kidney-shaped, and usually contains multiple small basophilic nucleoli. The nuclear lobes tend to surround the Golgi area, which is particularly prominent and appears as a clear, or more eosinophilic zone, in tissue sections . Cells with these cytological features are called as `hallmark cells'. Multinucleated cells with Reed Sternberg-like appearance may also occur. The cells usually contain multiple small basophilic nucleoli. Prominent inclusion-like nucleoli are relatively uncommon, aiding in the differential diagnosis with HD
  • Lymphohistocytic type (10%): Closely related to the small cell variant and often contains small neoplastic cells admixed with large `hallmark' tumour cells (frequently rosetting around vessels) and a large number of pale reactive histiocytes. Plasma cells can also be numerous. The histiocytes may be so abundant as to mask the tumour cell population.CD30 and ALK clarify the diagnosis because the histiocytes are reactive and are CD68-positive, lack CD30 and ALK.
  • Small cell type (5-10%): characterized by a mixture of large, medium-sized and small pleomorphic tumour cells. The large anaplastic cells, a minority of the tumour cell population, usually cluster around small vessels, a pattern that is highlighted by immunostaining for CD30 and ALK. Small and medium-sized cells are the dominant population and show a clear cytoplasm and an irregular nucleus. Because the small cells can be negative or weakly positive for CD30, this tumour cell population is better recognized with anti-ALK antibodies. The small cell variant can transform into the ALCL common type and vice versa, and is frequently associated with the t(2;5). Commonly misdiagnosed as pleomorphic T-cell lymphoma.
  • Giant cell rich type: many of the tumour cells contain more than one nucleus.
  • Sarcomatoid type: consists of large, bizarre, often spindle-shaped tumour cells that mimic a soft tissue sarcoma, particularly malignant fibrous histiocytoma. Immunohistochemistry can easily make a diagnosis since ALCL cells are positive for ALK and CD30.
  • Neutrophil-rich type: may mimic an acute inflammation.
  • Signet-ring type: may be confused with a metastatic carcinoma. Under these circumstances, cytokeratins should always be included in the panel of reagents because the epithelial membrane associated antigen (EMA) is frequently expressed in ALCL, and CD30 can be expressed in some carcinomas.
  • Hodgkin'-like' ALCL: Shows a capsular thickening and a vaguely nodular fibrosis that is associated with a significant number of tumour cells resembling classic Hodgkin and Reed-Sternberg cells. They should be diagnosed as ALCL only if malignant cells express the ALK protein.
  • Hodgkin lymphoma: B-cell origin.
  • The existence of a B-cell form of ALCL has been the subject of controversy, and it may be one morphological extreme of diffuse
    large B-cell lymphoma spectrum.
  • Comparison of primary cutaneous ALCL with lymphomatoid papulosis
    Features Cutaneous ALCL Lymphomatoid papulosis
    Gross morphology Nodules Papules
    Histology Clusters/sheets of CD30+ blasts, Hodgkin-like cellular background Few CD30+ blasts, variable number of cerebriform T cells, many inflammatory cells
    Distribution Localized Regional or generalized
    Extracutaneous spread Occasional Very rare
    Self-healing Variable Always
  • Use of Immunophenotypic Studies in the Differential Diagnosis of ALCL
      ALK CD30 EMA CD15 CD3 BSAP LCA TIA1 Clusterin
    ALCL + + + ± + + +
    PC-ALCL + ± + ±
    HD + + +
    PTCL ± + + ±






    ALCL, anaplastic large cell lymphoma; LCA, leukocyte common antigen (CD45); TIA-1, T-cell intracellular antigen; Hodgkin’s, Hodgkin’s lymphoma; PC-ALCL, primary cutaneous ALCL; PTCL, peripheral T-cell lymphoma, unspecified; DLBCL, diffuse large B-cell lymphoma.

  • CD30. The hallmark of ALCL is expression of the CD3O(Ki-1) molecule. CD30 is a 120 kDa transmembrane cytokine receptor of the Tumour Necrosis Factor (TNF) receptor family. In the large anaplastic tumour cells, positivity for CD30 is characteristically confined to the cell membrane and the Golgi region. In the small cell variant, only the large anaplastic cells (usually distributed around
    vessels) express CD30, whereas the small tumour cells are usually weakly positive or negative for CD30.
  • ALK+(60-85%), EMA+, CD4+, TIA1+, granzyme B+, perforin+, CD45+;
  • Clusterin is aberrantly expressed in systemic but not primary cutaneous ALCL.
  • Primary cutaneous ALCL consistently shows a T phenotype but differs from the systemic form because it is always ALK-negative and usually does not express EMA and cytotoxic molecules.
  • CD5-, CD7-, CD3-(75%), CD8-, EBV-
  • Clonal TCR rearrangement;
  • t(2:5)(p23;35), 70-80%, NPM-ALK fusion, fusion protein located in cytoplasm, nucleus or nucleolus;
  • t(1;2)(q25; p23), 10-20%, TPM3-ALK fusion, fusion protein located in cytoplasm;
  • t(2;3)(p23;q35), 2-5%, TFG-ALK fusion, fusion protein located in cytoplasm.
  • 5-year survival of systemic ALCL, ALK+ 80%, ALK- 40%.
  • WHO Pathology & Genetics. Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon 2001
  • British Journal of Haematology 114: 741-760
  • Blood, Vol. 96, Issue 12, 3681-3695, December 1, 2000
  • American Journal of Hematology 67:172–178 (2001)
  • Am J Clin Pathol. 2007 May;127(5):707-22.
  • Oncologist. 2006 Jul-Aug;11(7):831-40.
  • Leuk Lymphoma. 2004 Oct;45(10):2001-6
  • Am J Clin Pathol 2007;128:314-322