Tumors showing TRK (tropomyosin receptor kinase) gene fusion

Recent molecular studies have revealed that,  several tumors harbor TRK fusion. However fusion frequencies vary. 

Several NTRK1/2/3 (neurotrophic tyrosine receptor kinase) fusions have been reported. It is important to identify them since they serve as potential targets for therapy

The NTRK1, 2, and 3 genes encode a family of tyrosine kinase receptors with an active role
in neural development.

They are encoded by three different NTRK genes:

1. NTRK1 located on chromosome 1q21-q22 – corresponding receptor TrkA binds to NGF (nerve growth factor)

2. NTRK2 on chromosome 9q22.1- corresponding receptor TrkB binds to BDNF (brain derived natriuretic factor)

3. NTRK3 on chromosome 15q25- corresponding receptor TrkC.

NTRK oncogenic fusions can be encountered in two main different scenarios:

  1. Consists of rare tumors in which NTRK fusions are found at very high frequencies, as dominant oncogenes.
  2. Comprises common tumors in which NTRK fusions are identified at low frequencies, including both solid and hematological malignancies.

Here are a few tumors with high frequency TRK gene fusion – [ETV6-NTRK3 fusion]  – t(12;15)

1.Mammary analogue secretory carcinoma (MASC)- >75%-  Some MASC harbour ETV6- RET fusion -t(10;12)- They have poor outcome since they are non-responsive to TRK fusion therapy.

2.Secretory carcinoma of breast- >75%

3. Cellular and mixed mesoblastic nephroma (>75%)

4. Infantile fibrosarcoma. >75%

5. Ossifying renal tumor of infancy

DIAGNOSIS :  As yet, there are no FDA-approved NTRK gene fusion tests.

IHC : Pan-Trk IHC has the power to become an incredibly rapid and efficient screening tool for NTRK rearrangements.

NGS : Molecular methods like NGS and reverse transcription polymerase chain reaction (RT-PCR) provide a more comprehensive look at the NTRK genes, these tests are expensive and slow, potentially delaying treatment.

TREATMENT: Entrectinib and Larotrectinib are TRK inhibitors

Other tumors with NTRK fusion  partners is shown below.

NTRK gene fusions in cancers.  Partners of NTRK1, NTRK2, and NTRK3 are stratified according to the cancer
type where they are most frequent. Reference: doi:10.3390/ijms21100000

Reference: Federica Zito Marino et.al. NTRK Fusions, from the Diagnostic Algorithm to Innovative Treatment in the Era of Precision Medicine. Int. J. Mol. Sci. 2020, 21, 0.

Click below for summary and a mnemonic.

6 KEY POINTS FOR BOARDS – MICROPAPILLARY BREAST CARCINOMA

Micropapillary breast carcinoma is a rare variant.

Micropapillary carcinoma of breast has a few unique clinical, microscopic and immunological features which aid in their differentiation from other subtypes of breast carcinoma.

Let’s look at them!!

1. Tufts of cells arranged in pseudopapillae ( lack fibrovascular cores). These pseudopapillae are surrounded by empty clear spaces formed by fibrocollagenous stroma.

Micropapillary breast carcinoma- microscopy

2. Aggressive tumor usually present with angiolymphatic invasion. They present with nodal invasion at the time of presentation.


3. Molecular and cytogenetics: BC-1514 (C21orf118) is commonly upregulated in the micropapillary area.

4. ER positive in 90% and PR positive in 50%

5. Micropapillary breast carcinomas show

‘INSIDE OUT’ staining pattern with EMA and CD15s.

INSIDE OUT staining pattern refers to – staining localized to the apical surface of tumor cells abutting the stroma but absent staining in the basolateral region.

Staining pattern of EMA ( Epithelial membrane antigen) and CD 15s in micropapillary breast carcinoma.

6. Another characteristic of micropapillary breast carcinoma is Incomplete basolateral or CUP SHAPED staining with apical sparing seen with E- cadherin,  Her-2-neu and p-120.

‘Cup shaped’ staining with EMA – stained basolateral surface and apical sparing.

Below is a picture which will help you remember all characteristics of micropapillary breast carcinoma.