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Sonography and decision-making in the management of canine cutaneous mast cell neoplasia

It’s a frequent request: to scan and stage dogs which have received a diagnosis of high grade cutaneous mast cell tumour (MCT) on histopathology.  Or sometimes the request comes after cytological diagnosis and before surgery.

The main issues arising here for sonographers are:

• What’s the sensitivity of sonography in picking up mast cell infiltrates in lymph nodes and viscera (liver and spleen primarily)? Should we needle biopsy liver and spleen as a routine or only when they look abnormal?
• Should we needle biopsy local nodes as a routine or only when they are enlarged? And if they are enlarged would it be better to just surgically remove them in toto for histopathology.
• How much difference does full staging make to decision-making and outcomes?  Is it worth it?

This blog post is an attempt to answer those questions.

What’s the sensitivity of sonography in picking up mast cell infiltrates in lymph nodes and viscera (liver and spleen primarily)? Should we needle biopsy liver and spleen as a routine or only when they look abnormal?

Well, this has been a matter of some debate in the published literature.  Different investigators have come to varying conclusions.  However, I think overall, we have to conclude that even with modern ultrasound machines there are a significant number of dogs in which mast cell infiltrates in liver and spleen are not accompanied by gross sonographic changes.

The case for this rests on several good studies:

Vet Radiol Ultrasound . Sep-Oct 2011;52(5):548-54. Correlation of ultrasound findings, liver and spleen cytology, and prognosis in the clinical staging of high metastatic risk canine mast cell tumors
Alison P Book 1, Janean Fidel, Tamara Wills, Jeffrey Bryan, Rance Sellon, John Mattoon

https://pubmed.ncbi.nlm.nih.gov/21689203/

‘The sensitivity of ultrasound for detecting mast cell infiltration was 43% for the spleen and 0% for the liver. …… Routine splenic aspiration should be performed regardless of ultrasonographic appearance in dogs with a clinically aggressive mast cell tumor.’

In that particular study, a positive cytological diagnosis of mast cell infiltration was specified as ‘large numbers and clusters of well-differentiated mast cells or mast cells with atypical morphology’.  There is support for the hypothesis that this distinction is clinically-relevant in that median survival for dogs diagnosed with splenic infiltrates was 100 days vs 291 days in those without.  For dogs with liver samples judged positive median survival was 100 days vs 276 without.

In the bigger picture, there was no significant survival difference between dogs with and without abnormal sonographic findings.  Again, this broadly supports the contention that we’re not getting optimal discrimination with sonography alone.

And:

Vet Comp Oncol. 2020 Sep;18(3):389-401. 
Ultrasound is a poor predictor of early or overt liver or spleen metastasis in dogs with high-risk mast cell tumours
Evi Pecceu 1, Juan Carlos Serra Varela 1, Ian Handel 1, Chiara Piccinelli 1, Elspeth Milne 1, Jessica Lawrence 1

https://pubmed.ncbi.nlm.nih.gov/31863546/

‘US was a poor predictor of metastasis with sensitivity, specificity, positive predictive value and negative predictive value for the spleen of 67%, 68%, 21% and 94%, respectively and for the liver of 29%, 93%, 56% and 82%, respectively‘

Again, we have pretty good evidence that cytological findings were meaningful.  ‘Median time to progression (TTP) for dogs with no metastasis, early metastasis and overt metastasis was not reached, 305 and 69 days, respectively (P < .001). Median survival time (MST) for the 3 groups were not reached, 322 and 81 days, respectively (P < .001)‘

A conclusion supported by:

J Vet Intern Med Sep-Oct 2009;23(5):1051-7. 
Ultrasound-guided cytology of spleen and liver: a prognostic tool in canine cutaneous mast cell tumor
D Stefanello 1, P Valenti, S Faverzani, V Bronzo, V Fiorbianco, N Pinto da Cunha, S Romussi, M Cantatore, M Caniatti

https://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2009.0354.x

‘Dogs with evidence of mast cell infiltration at distant sites have a shorter survival times than dogs without evidence of infiltration at distant sites. This study suggests that cytology of spleen and liver is indicated either for ultrasonographically normal or for ultrasonographically abnormal spleen and liver in dogs with cMCT‘

It’s worth noting that CT isn’t really any better:

Vet Radiol Ultrasound 2019 May;60(3):306-315. 
Abdominal CT evaluation of the liver and spleen for staging mast cell tumors in dogs yields nonspecific results
Jonathan R Hughes 1, Balazs Szladovits 2, Randi Drees 1

https://pubmed.ncbi.nlm.nih.gov/30786323/

It seems to me that the only thing we can say to owners is that, for full and accurate staging, routine ultrasound-guided aspiration of liver and spleen regardless of sonographic appearance, is recommended.

The case against?

I think everyone agrees that normal, healthy dogs have mast cells in viscera. And, as we’ve seen above, there’s a consensus that pathologists have a grasp of what constitutes ‘abnormal’.

The joker in the pack here is:

Vet Comp Oncol . 2006 Sep;4(3):178-83. 
Cytological comparison of fine-needle aspirates of liver and spleen of normal dogs and of dogs with cutaneous mast cell tumours and an ultrasonographically normal appearing liver and spleen
K Finora 1, N F Leibman, M J Fettman, B E Powers, T A Hackett, S J Withrow

https://pubmed.ncbi.nlm.nih.gov/19754814/

This study compared cytological findings from normal dogs vs those from dogs with grade II and III MCTs.

‘There were no statistically significant differences in each of the parameters evaluated for the liver aspirates. For splenic aspirates, affected dogs showed significantly more mast cells per cluster (P = 0.04) and more isolated mast cells per slide (P = 0.03) compared with unaffected dogs. However, no clinically important difference existed between the unaffected and affected dogs; thus, routine aspiration of an ultrasonographically-normal appearing liver and spleen of dogs with cutaneous MCT does not appear to be a clinically useful staging tool.’

It seems to me that simply comparing the average number of mast cells in aspirates from normal dogs vs those from high risk MCTs may conceal the fact that a minority of those MCT dogs do have clinically-significant mast cell infiltrates. In fact, I think all studies agree that the majority of dogs with high risk MCTs don’t have visceral involvement.

Should we needle biopsy local nodes as a routine or only when they are enlarged? And if they are enlarged would it be better to just surgically remove them in toto for histopathology.

OK, here we have it all on a plate:

BMC Vet Res . 2021 Oct 15;17(1):331.
A retrospective study on prophylactic regional lymphadenectomy versus nodal observation only in the management of dogs with stage I, completely resected, low-grade cutaneous mast cell tumors
Silvia Sabattini, Matti Kiupel, Riccardo Finotello, Damiano Stefanello, Eugenio Faroni, Walter Bertazzolo, Ugo Bonfanti, Antonella Rigillo, Sara Del Magno, Armando Foglia, Luca Aresu, Matteo Gambini , Mario Caniatti, Laura Marconato 

https://bmcvetres.biomedcentral.com/articles/10.1186/s12917-021-03043-0

….always good when blog-writing to find a bang-up-to-date review 😉

This study looked at 64 dogs with the lowest grade of cutaneous MCT.  And even for the lowest risk tumours, there was significant benefit in terms of number of dogs suffering disease progression when sentinel nodes were removed immediately as a prophylactic measure regardless of whether they were judged enlarged or not. No complications of prophylactic regional lymphadenectomy were reported.

The details

‘In the group without lymphadenectomy….. 6 dogs (17.1%) experienced cMCT progression after a median of 822 days (range, 560–1380): 4 (11.4%) experienced local relapse, 2 (5.7%) experienced nodal metastases in the LNs that had been previously aspirated, and 1 (2.9%) developed visceral metastasis. Twelve (34.3%) dogs developed new cMCTs after a median of 734 days (range, 197–1409)‘

‘In the prophylactic regional lymphadenectomy group……..The median follow-up time was 763 days (range, 181–2039). None experienced cMCT progression. Three dogs (10.3%) developed de novo cMCTs at the trunk after 321, 417 and 1092 days.’

In their literature review, the authors found that..

‘..based on the current literature, the proportion of cytologically negative, histologically positive cases ranges from 10 to 50%‘

Thus, there is a good case that sentinel nodes should be removed for therapeutic reasons.  Cytology is not only relatively insensitive it’s also an irrelevance if local nodes are to be removed anyway. It’s important to say that the authors themselves describe their study outcome as ‘a preliminary judgment’ to be verified by future work.  Some nodes are more technically difficult to remove than others (axillary nodes for example): this may be a consideration.

How much difference to outcomes does it actually make if we fully stage dogs to identify liver and splenic spread? 

This is the kind of question that owners ask in the real world.  If visceral metastasis is rare and treatment is associated with significant morbidity then they may decide that sampling is not justified even if it is theoretically the optimal protocol.

According to Pecceu et al., dogs with metastasis to the spleen or liver have median survival times between one and 3.5 months. However, with surgery and subsequent chemotherapy this rises to 10.5 months. One in five dogs with early evidence of metastasis to the spleen or liver lived for more than 500 days.

We can only put these statistics to owners of affected dogs and let them decide.