A thyroid cancer with PTC and MASC components

Colombians Paula Rodrıguez-Urrego MD and Snjezana Dogan MD collaborated with Oscar Lin, MD of the  Memorial Sloan Kettering Cancer Center Department of Pathology. They presented a  report of a 47 year old man who presented for what appeared to papillary thyroid carcinoma and was treated accordingly. In this post secretory carcinoma of the thyroid will be referred to as “MASC” simply to stay consistent with with the publication.

Why testing even old tumor blocks matters

Over a decade later, a tumor “came back” a second time. Closer examination of the old FFPE preserved tumor revealed a growth that had both PTC and MASC components. The recurrence resembled MASC. Cytological and histological differentiation of  MASC from other thyroid neoplasms is necessary to lead the oncologist to the optimal treatment. Thyroid MASCs are unlikely to respond to radioactive iodine and may not be associated with serum thyroglobulin levels. Patients diagnosed with MASC may be eligible for targeted treatment with Trk inhibitors in an open clinical trial.

The first go around

A 47 year old man with no history of radiation exposure underwent a thyroidectomy and limited removal of left neck lymph nodes.  His cancer was  cytologically diagnosed papillary thyroid carcinoma. This 7 cm tumor was reported as

  • well differentiated
  • tall cell features
  • extra thyroid extension to lymph nodes and beyond
  • margins of resection were reported as negative

The patient was disease free for 4 years after receiving  200 mCi of ablative radioactive iodine. Contrast this to precision medicine.

Four years later, the second go around

The patient presented with local recurrence of the papillary carcinoma despite having undetectable serum hyroglobulin levels. Low thyrogobulin levels would be expected as a result of the thyoidectomy.

The patient was treated with a completion of the left neck dissection followed by  external beam radiation (6300cGy) and thyroid hormone replacement therapy.

13 years later, the third go around

Thirteen years after the initial presentation, the patient presented with a subcutaneous neck nodule. Starting with a fine needle biopsy, the investigators sought an in depth explanation of the disease process. The authors did not mention therapies they gave this patient so many years later. They were to learn that there was a second type of tumor lurking with what originally diagnosed as PTC.

Starting with cytology,  a closer look at what is going on

Pathologists like to start with  less invasive fine needle biopsies (Fig 1 A-B). This particular biopsy was stained with Diff Quick. Some of the features noted in the third tumor:

  • hypercellular
  • atypical epithelial cells arranged as single cells and clusters with “microfollicular” architecture
  • The single cells demonstrated abundant vacuolated cytoplasm, eccentric nuclei, and smooth nuclear contours.
  • The small vacuoles appear to cover the nuclei focally (Fig. 1A).
Biopsy samples stained with Diff Quick stain showing neoplastic sell sheets (A), microfollicle like tridimensional structure with pink/magenta extracellular secretions. Background shows several neoplastic cells with vacuolated cytoplasm.

Figure 1A-B Rodrıguez-Urrego 2017

A second set of attributes were noted in the PAP stained cells shown in figure 1C

  • sheets of cells with dense cytoplasm

  • distinct cytoplasmic membranes leading to “window-like” spaces between the cells

  • distinct cell borders with polygonal shape

  • small vacuoles arranged at the periphery of the cytoplasm in some cells

  • smooth nuclear contours, and prominent nucleoli

  • dense metachromatic magenta secretion

  • epithelial cells arranged in a 3D configuration in a concentric pattern with occasional acinar formation

  • prominent nucleoli or one or two distinct “chromocenters”

  • cytoplasm vacuolated with indistinct borders

  • a single psammoma body (Fig. 1D).

PAP stained cells shown in picture C. H&E stains of psammoma body in picture D.

Figure 1C-D

Overall, the third tumor showed unusual morphology suggestive of MASC, which was not in the literature at the time of the original diagnosis.

The first tumor, a retrospective examination

A retrospective 40x image of the first tumor (Fig. 2A) shows features of

  • PTC, upper portion of Panel 2A

Figure 2A Rodrıguez-Urrego 2017

  • MASC or adenocarcinoma, lower portion of Panel 2B

Figure 2B-C Rodrıguez-Urrego 2017

    • The classical PTC component showed scattered psammoma bodies and a background of chronic lymphocytic thyroiditis (Panel 2B)

  • A papillary architecture and dense eosinophilic secretions were seen in the adenocarcinoma/MASC component (Panel 2C).

  • The immunohistochemistry signal for the thyroid transcription factor Pax8 was strong and diffuse in the PTC component (Panel 2D)

Figure 2D-E Rodrıguez-Urrego 2017

  • The MASC component showed a weak and focal PAX8 labeling (Panel 2E).

  • The salivary and mammary gland secretory carcinoma marker mammaglobin was positive only in rare scattered PTC cells (Panel 2F)

Figure 2F-G Rodrıguez-Urrego 2017

  • The majority of MASC cells were mammaglobin positive (Panel 2G).

The third tumor

  • Only the adenocarcinoma/MASC component was noted in the third tumor (Panel 3A) isolated as a subcutaneous nodule over a decade after the primary tumor was removed.

Figure 2A Rodrıguez-Urrego 2017

  • No psammona bodies were noted in this tumor.

  • The prominent nucleoli associated with secretory carcinomas were observed (Panel 3B)

Figure3B-C Rodrıguez-Urrego 2017

  • The cyoplasmas was bubbly and vacuolated (Panel 3C)

  • The thyroid transcription factor Pax8 was also observed in this tumor (Panel 3D)

Figure 3D-E Rodrıguez-Urrego 2017

  • The secretory carcinoma marker mammaglobin was also observed (Panel 3E).

When PTC could be thyroid secretory carcinoma, formerly known as MASC

Distinguishing salivary secretory carcinoma from acinic cell carcinoma and related tumors has been a much discussed topic in peer reviewed literature since 2010. Distinguishing thyroid secretory carcinoma from PTC appears to be emerging as a similar challenge to the pathologist. Being able to do so helps the oncologist choose the best treatment option.

Cytology, where suspicion starts

Rodríguez-Urrego and coworkers focused much of their discussion on cytology of fine needle aspirates.

Table 1 Rodrıguez-Urrego 2017

Only a few indicators range from non existent in one and moderately strong in another.

Immunohistochemistry, another tool

The proteins S100 and DOG1 are positive indicators of salivary gland secretory carcinoma and acinic cell carcinoma, respectively.

Table 1 Rodrıguez-Urrego 2017

The secretory carcinoma  versus PTC markers are not as proven.

    • TTF1, transcription termination factor 1, was used as a marker for cells of follicular origin. This nucleolar protein plays a role in ribosomal DNA transcription. A follicle is a grouping of cells containing a cavity.
    • Thyroglobulin is a major thyroid bound protein that synthesizes thyroid hormone.
    • Pax8 is a transcription factor needed for the expression of thyroid specific genes.
    • Mammaglobin is a member of the secretoglobin family as well a marker for breast cancers and salivary gland secretory carcinoma.
    • S100B is a small calcium binding protein that is useful in distinguishing salivary gland secretory carcinoma from acinic cell carcinoma. The caveat is the many isoforms of the S100 protein. The Dako S100 is perhaps the most popular.  This one is said to have selectivity for the S100B isoform.
  • GCDFP-15 is another name for prolactin inducible protein. PIP is a regulator of water transport in glands. PIP is discussed further on the cutaneous secretory carcinoma page on this site.

The clinical picture

Table 1 Rodrıguez-Urrego 2017

Age, unlike other secretory carcinoma, there does not seem to be predisposition for younger individuals

Gender, like salivary gland MASC/secretory carcinoma, there is a male predisposition.

Extra thyroidal/soft tissue extension  lymph node involvement were not discussed extensively by the authors.

Serum thyroglobulin is not detected in individuals with healthy thyroids. Like liver enzymes, its presence in the serum component of whole blood is a sign of organ disease. While serum Tg might signal the return of PTC, thyroid secrectory carcinoma can fly completely under this particular radar.

Size does not appear to be a significant means of differentiating one tumor type from another.

Iodine refractory status in thyroid secretory carcinoma is consistent with lack of thyroglobulin leaking into the serum. Radioactive iodine is a convenient way of targeting radiation to the thyroid tumor and normal tissue. When  a thyroid tumor does not take up iodine, the oncologist must look for  another actionable target.

Molecular detection and definition of Thyroid secretory carcinoma

If cytology, immunohistochemistry, and clinical features are sometimes ambiguous, molecular diagnosis is unambiguous and paves the way to an actionable target.

The Rodríguez-Urrego report

Rodríguez-Urrego and coworkers used ETV6 break apart FISH to detect rearrangement in the ETV6 gene on chromosome 12 in the primary tumor and two metastases. All three cases were confirmed with next generation sequencing. The authors referenced literature reporting the ETV6-NTRK3 rearrangement in radiation induced thyroid cancer. We have covered radiation induced ETV6-NTRK3 on another site.

A simple way to detect thyroid secretory carincomas

Many reports in the literature describe efforts to diagnose salivary gland secretory carcinoma with IHC markers.  The rationale is that not all clinical laboratories have fluorescence microscopes needed for FISH or funds for next generation sequencing. A simple two step process can screen a tumor for specific RTK for which there is a small molecule inhibitor.

    1. over expression for any receptor tyrosine kinase recognized by a pan-RTK antibody.  A positive reaction is followed by a panel of antibodies.  In this particular example, a second panel would reveal over expression of Trk C.
  1. Immunohistochemical results are confirmed with targeted next generation sequencing.

More information on submitting a sample for Trk testing is available online.

TrkC, the target of the Trk Treatment

A more in depth discussion of Trk family and what a kinase is is discussed elsewhere.  While the ETV6-NTRK gene product, TEL-TrkC is pathognomic of thyroid secretory carcinoma, formerly MASC, the other two family members, TrkA and TrkB may drive other thyroid cancers. Patients with thyroid tumors driven by any Trk fusion kinase are eligible  for a clinical trial testing a Trk treatment.

Reference

Rodríguez-Urrego PA, Dogan S, Lin O (2017) Cytologic findings of mammary analogue secretory carcinoma arising in the thyroid.Diagn Cytopathol. 45(6)552-556  PubMed