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ASCO recommendations for pathologic diagnosis of breast implant-associated anaplastic large-cell lymphoma

Jun 11, 2020

Following the review on the Lymphoma Hub about breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) pathogenesis, incidence, clinical presentation, and treatment recommendations, this article will be focused on diagnosis according to the guideline recently published in the Journal of Clinical Oncology. 1

  The objective of the guideline published by Elaine S. Jaffe and colleagues is to guide the recognition and diagnosis of BIA-ALCL, establishing a standardized pathologic protocol for the evaluation of the periprosthetic fluid when present, and of the capsulectomy specimens.

  Clinical evaluation and sample collection

  The most common clinical presentation is the onset of periprosthetic fluid surrounding the breast implant, frequently referred to as effusion or seroma that could be accompanied by pain. These symptoms can appear from 4 months to 10 years after initial implantation. The initial evaluation of a patient with suspected BIA-ALCL should include the following:

  1. Confirm by ultrasound that effusion is not due to implant rupture or capsular contracture (scar tissue around the implant). Most patients with BIA-ALCL have an effusion confined by a fibrous capsule around the implant
  2. If a mass is detected, assess and document by imaging and perform a biopsy
  3. Conduct an ultrasound-guided aspiration of a minimum of 10–50 ml of fluid
  4. Prepare cytopathology smears, cell block with immunohistochemistry (IHC) for CD30 and other lineage-associated markers (see Table 1), and, if possible, flow cytometry and molecular genetic studies
  5. If BIA-ALCL in the effusion fluid is confirmed, remove the implant, and perform a complete capsulectomy; specimens should be collected to assess both the distribution of residual disease and presence of invasion

Effusion fluid evaluation

The aspirated effusion fluid is typically the first sample obtained from all patients with suspected BIA-ALCL, and in most cases, it is more informative on a diagnostic level than specimens obtained later from surgery.

The sample preparation will follow standard procedures. Recommended staining is

  • Giemsa, Wright-Giemsa, or another Romanowsky-type stain within 48 hours
  • Papanicolaou, hematoxylin and eosin (H&E), or both

  If possible, reserve additional air-dried cytocentrifuged slides for IHC, although it is better to prepare a cell block, and, if available, leftover fluid might be used for testing by flow cytometry or molecular genetic analysis.

  1. Morphologic evaluation

In benign seroma aspirate, there is a predominance of histiocytes (macrophages), and small lymphocytes. Some histiocytes might be confused with ALCL cells, but their size is less than half of the aberrant cells, and they also present smaller nucleoli.

The key findings in an effusion sample to confirm BIA-ALCL diagnosis are

  • pleomorphic cells several times larger than a normal lymphocyte
  • irregular nuclei with dispersed or vesicular chromatin
  • large prominent nucleoli
  • moderately abundant basophilic cytoplasm sometimes with small vacuoles
  • “Hallmark” cells, a subpopulation of cells with horseshoe- or kidney-shaped nuclei
  1. IHC studies

  The panel of IHC stains to confirm the diagnosis of BIA-ALCL and exclude other entities in the differential diagnosis can be found in Table 1. The authors point out some considerations, as follows:

  • A pan-keratin stain is appropriate to exclude poorly differentiated carcinoma, particularly in patients with a prior history of breast cancer
  • If cytomorphology is not well preserved, IHC for CD68 or CD163 might be helpful to distinguish reactive histiocytes from lymphoma cells
  • Flow cytometry analysis is recommended as a second line: Many stains, essential to exclude other entities in the differential diagnosis of BIA-ALCL, are not routinely available by flow cytometry

 

Table 1 . IHC staining panel for differential diagnosis of BIA-ALCL using the effusion sample and the capsulectomy specimen 1

ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase; BIA-ALCL, breast implant-associated ALCL; CHL, classic Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; EBER, Epstein-Barr virus-encoded RNA; EBV, Epstein-Barr virus; EMA, epithelial membrane antigen; ERG, avian v-ets erythroblastosis virus E26 oncogene homolog; HHV-8, human herpesvirus-8; IHC, immunohistochemistry; ISH, in situ hybridization; LANA, latency-associated nuclear antigen; LBCL, large B-cell lymphoma; PBL, plasmablastic lymphoma; PEL, primary effusion lymphoma

Stain(s)

Justification

CD30

Strongly and uniformly positive

ALK1

If negative, excludes systemic ALK-positive ALCL

EMA

Variably positive

CD4, CD43

More commonly preserved among pan-T-cell antigens

CD2, CD3, CD5, CD7

More commonly diminished or lost among pan-T-cell antigens

TIA-1, granzyme B, Perforin

Cytotoxic granule proteins frequently positive in BIA-ALCL

CD68 or CD163

Positive in histiocytes

Pan-keratin

Excludes carcinoma, particularly in patients with EMA-positive disease or previous breast cancer

CD20

Excludes DLBCL

PAX5

Excludes DLBCL and CHL

CD138

Excludes PBL and PEL

HHV-8 LANA

Excludes PEL

EBER ISH

Excludes neoplasms with EBV coinfection, including EBV-positive DLBCL, fibrin-associated LBCL, CHL, and PBL

S-100 or Melan-A

Excludes metastatic melanoma

CD31, CD34 or ERG

Excludes angiosarcoma, particularly in patients with prior radiation therapy for breast cancer

 

  1. Molecular genetic testing  

Clonal T-cell receptor ( TCR ) gene rearrangements have been identified by polymerase chain reaction (PCR), and next-generation sequencing in nearly all patients with BIA-ALCL. Therefore, if there is enough cellular material from the collected sample, PCR can be helpful for diagnosis. For a correct interpretation of the results, one should remember that TCR mutations are also found in other entities, and even in a non-neoplastic condition when the overall number of T cells is low.  

  • Activating mutations of STAT3 were described in 64% of patients with BIA-ALCL
  • Other detected genes mutated include JAK1 , JAK3 , DNMT3A , and TP53
  • Fluorescence in situ hybridization testing might be helpful if the primary site of the tumor is in question, but it is not required in the routine evaluation of patients with localized disease

  Capsulectomy specimen evaluation

  The examination of capsulectomy specimens will help in confirming BIA-ALCL diagnosis and staging the disease. In some cases, it could be challenging to identify a gross lesion in the collected tissue, or even the lymphoma cells might only be detected in the effusion fluid in a minority of patients.

  1. Preparation and sectioning

After the intact resection of the capsule containing the implant, surrounding effusion, and any masses associated, is performed, the next steps must be followed:

  1. Ensure that the surgeon marks the original orientation of the specimen
  2. Aspirate any remaining effusion fluid
  3. Open the specimen transversely on the posterior aspect of the capsule
  4. Open longitudinally through the superior and inferior aspects of the capsule
  5. Pin the capsule open and flat on a paraffin board and leave overnight submerged in formalin
  6. Ink the external surface of the capsule using six different colors to represent all sides of a “cube”
  7. Submit two sections of each of the six sides
  8. Perform routine H&E-stained sections and recommended IHC ( Table 1) to detect microscopic evidence of involvement by BIA-ALCL
  1. Histology and staging

Pathologic evaluation of the specimens from patients with BIA-ALCL at different degrees led to the development of a staging system, to reflect tumor progression from the luminal surface to the outer boundaries of the capsule ( Table 2).

Table 2 . Pathologic staging of BIA-ALCL 1

Stage

Characteristic

T0

Presence of tumor cells in the effusion but not detected in the capsule

T1

Lymphoma cells lie on the luminal side of the capsule, and CD30 highlights both viable and necrotic tumor cells. Tumor cells are insulated from the rest of the capsule by a dense acellular collagenous layer

T2

Early capsular invasion: few inflammatory cells admixed with deeper lymphoma cells

T3

Tumor cell aggregates or sheets within the capsule. Numerous inflammatory cells surround lymphoma cells

T4

Tumor cells are beyond the boundaries of the fibrous capsule, invading the breast or surrounding soft tissue, with or without lymph node involvement

  CONCLUSIONS

  The vast majority of patients with BIA-ALCL presented a relatively indolent clinical course. However, deaths have been reported due to the progression of the disease. Therefore, it is of the utmost importance to continue developing recommendations consensus to guide an early and accurate diagnosis.

  Future perspectives for BIA-ALCL include a better understanding and definition of the early stages and the advanced stages of the disease, when lymphoma extends to regional lymph nodes and surrounding tissue, to develop an appropriate treatment strategy.

  1. Jaffe ES, Ashar BS, Clemens MW, et al. Best practices guideline for the pathologic diagnosis of breast implant-associated anaplastic large-cell lymphoma. J Clin Oncol. 2020;38(10):1102‐1111. DOI: 1200/JCO.19.02778