Carcinoma of Unknown Primary

[RadOnc007]

I have a 32 y/o female with a large 4 cm fungating mass from the left groin. The mass was biopsied and shown to be poorly differentiated SCC. She was evaluated by GYN/ONC and GI and they did not identify a primary. PET/CT showed an FDG avid left groin mass and a smaller left external iliac LN. MRI also was not helpful in identifying a primary cancer and showed the same left groin and external iliac LN. The Heme/Onc gave her carbo/taxol and the mass shrank but then rapidly grew back. Would you treat this as a primary vagina/vulva SCC or an anal SCC? I was planning to treat pelvic and inguinal LN to 50.4 Gy and boost the FDG avid LN to 60-66 Gy. Thanks for your thoughts.

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[RadOncDoc21]

Why no lymph node dissection? I would likely treat as a vulva especially since that’s the chemo med onc chose to use.

 

[Neuronix]

p16 or HPV testing?

 

[medgator]

Why no lymph node dissection? I would likely treat as a vulva especially since that’s the chemo med onc chose to use.

Vulva and anus have the same chemo I thought... 5fu /mmc

 

[RadOnc007]

I referred the patient to Gyn/Onc and she did not recommend an inguinal dissection. The heme/onc suspects that the primary is vulva but my exam and the imaging showed no disease there. A PRO article ( Carcinoma of unknown primary in the inguinal lymph node region of squamous cell origin: A case series. - PubMed - NCBI ) treated the disease as a GI primary. It was p16 positive.

After posting on SDN, I found a similar post on the TheMedNet and Dr. Chris Crane recommended treating it as an anal cancer. If it was a vulva cancer, he said it would be easier to identify and treated surgically. He did not recommend specifically targeting the vagina, but that it would be in the volume if I am treating the mesorectal and internal illiac nodes.

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[Neuronix]

p16 positive and that age make anus most likely. I'd treat it like an anal cancer, though could consider treating the bulky disease to 59.4 Gy instead of 54 Gy. If it was p16 negative then I'd recommend treating like vulvar since the predicted response to chemoRT would be weaker and surgery would help with control.

The other question is then do you treat all the standard anal cancer fields including the anus? If so, what dose do you take the anus to?

No right answer, but I would say yes and treat anus to microscopic dose (45 Gy).

Not sure why they treated this with chemo alone up front. Carbo/taxol is not standard anal cancer therapy and neoadjuvant chemotherapy has no role in any of the possible cancers here. You should be giving the usual mmc/5-fu concurrently in my opinion.

 

[RadOncDoc21]

Yes, I agree HPV status would help to identify the primary. I figured this case was presented and the consensus was that it was likely a vulva primary since she received carbo/taxol vs. 5-FU/MMC.

I know usually with our surgeons, they would do a dissection if that was only area of disease. I’m not sure why the med onc chose to do upfront chemo in this situation.

 

[nkmiami]

medonc has kind of messed this up with induction chemo. Anecdotally, I had similar case, where submucosal anal primary was found on ano/colonoscopy and ultrasound- I thought I deserved an award for sending to gi to find it, but sadly went unrecognized. Taxane based chemo while treating the anus would be rough. Given her age, more likely to be anal or even cervical if hpv pos. Vulvar hpv + about 50%. Check an HIV as well.

My bias is that if this HPV neg- you should consider a dissection at some point.

 

[Radiator20]

Similar to others, I'm surprised that:
1) med onc started w/chemo, and w/ carbo/tax in particular - I don't see how either was appropriate given the ddx here;
2) gyn onc wasn't enthusiastic about a groin dissection... I thought they were hardwired to believe in those for vulvar. Perhaps unresectable, or perhaps gyn onc also thinks it's anal?

Part of what makes this situation so tricky is that vulvar vs anal paradigms point so strongly in opposite direction w/ regard to dissection. I'm not sure p16+ really makes it more likely that this is anal (though I do think p16- would make more likely vulvar).

In any case, if she's not getting a dissection, then personally I'd imagine RT with either 5FU/MMC or 5FU/cis, taking gross disease to whatever you feel you can accomplish safely (at least 54 Gy, would prefer more). What to do with elective volumes seems like a tricky question and personally I'm really not sure of the right answer. If one were going to do standard anal volumes like Neuronix mentions, then given the uncertainty about primary, would anyone consider also covering the vulva electively, say to 45 Gy?

Unfortunately, I fear her prognosis is not great given CUP, locally advanced (N2 anal vs FIGO III vulvar), aggressive (fungating), and initial mismanagement with inappropriate induction chemo.

 

[Palex80]

I think that this a grey area. There is very little evidence telling you treat the suspected/presumed primary site, even if vulva/vagina/anus seem probable sites of origin. I've never actually seen a vaginal cancer (although I've only seen a few) that spread to the groins without spreading to the pelvis first/too. An isolated inguinal node coming from an undetectable vaginal cancer seems unlikely in my opinion.

There's a lot of controversy on target volumes for CUP of the neck, where we have a lot more evidence (even a few trials): i've seen people target only the affected neck side, others doing bilateral neck irradiation and some opting to treat the pharynx entirely or just presumed sites of origin. There's no clear data which approach is better and there's considerable bias when people point out at data showing that comprehensive irradiation leads to better overall survival (the fitter patients are obviously also the ones that get more radiation too).

Therefore I think I wouldn't treat any suspected site in this case.
Even if you were to do it, you would have to decide on the dose. If it's vulvar cancer, you'd probably need something like 20% more dose than you would need in anal cancer to kill it? So what would you give? 50 Gy (anal cancer, microscopic disease seems reasonable) or 60Gy (vulvar cancer).

 

[evilbooyaa]

Agree with most. No role for induction chemotherapy in this scenario (never mind likely inappropriate chemo). Treat non-metastatic disease definitively.

If it's p16+ I'd plan to treat with RT, no surgery especially if surgeons aren't enthusiastic. It's either anal or vulvar. About 50% of vulvar are HPV+ but those also do better (The Prognostic Significance of p16 Status in Patients With Vulvar Cancer Treated With Vulvectomy and Adjuvant Radiation. - PubMed - NCBI and Does HPV status influence survival after vulvar cancer? - PubMed - NCBI)

However, doing inguinal LND and adjuvant RT wouldn't be unreasonable with the unknown primary. Likely felt to be fixed and unresectable lymph nodes per gyn-onc.

If P16- then it's vulvar until proven otherwise (multiple blind bunch biopsies of vulva to rule out submucosal disease???).

I think 45Gy to whichever primary you think it is (or both if unclear) is fine. I'd probably go with concurrent Cis/5-FU for the chemo to cover both the anal and vulvar bases.

 

[Radiator20]

The last two comments illustrate why I feel very uncertain about elective volumes. Treat both anus and vulva? Neither? I think either of those options seems reasonable but worry there is too much uncertainty about primary site to pick just one site or the other.

 

[RadOnc007]

Thanks everyone for your input. It's been very helpful to hear your thoughts.

Maybe in the community practice, the GynOncs are not as aggressive to perform a lymph node dissection to remove gross disease as those where I trained. I didn't know the patient received induction chemo since she was in the process of preserving her eggs. If I knew, carbo/taxol wouldn't have been my choice for an anal or vulva primary.

Ultimately, my treatment volumes included anus, inguinal, external, and internal iliac LN to 50.4 Gy, and I'm going to escalate dose of the gross disease >66 Gy. I choose not to electively treat the vulva since its rare for this age group to develop vulva cancer. I will just examine the vulva closely to make sure the primary doesn't appear there and if it does then she can go for resection. Since I'm treating her like an anal cancer, the vagina will get close to 50 Gy. I'll talk to the med onc again to switch her chemo regiment to either cis/5-FU or MMC/5-FU.

 

[Radiator20]

I think p16 status would be a significant help here.

The answer may have gotten lost above:

It was p16 positive.

I agree a p16(-) vulvar cancer in a 32yo would be particularly unusual (wouldn't have had time for the chronic inflammation from lichen sclerosus, etc to play out into differentiated VIN and finally invasive cancer). But given p16+, and the the incidence and age distributions below, it seems to me that vulvar is at least as likely as anal... probably more so.

Vulvar: 1.7% of cases in 20-34 yo * 6190 US cases in 2018 = 105 cases
Anal: 1.2% of cases in 20-34 yo * 8580 US cases in 2018 = 102 cases (and ~40% of those are male... so really, ~60 cases in women)

Folks who think this is more likely anal - am I missing something?

Since I'm treating her like an anal cancer, the vagina will get close to 50 Gy.

I don't see how dose to the vagina is relevant here from a disease control perspective - this is even less likely to be a primary vaginal cancer than anal or vulvar.

 

[evilbooyaa]

Whoops, missed that Radiator. Thanks.

Agree with your analysis overall, despite it flying in the face of our oft-loved 'dogma'.

 

[thecarbonionangle]

Would treat vulva as well. Just as likely if not more likely. you have a chance to get it all with some toxicity, of course. Surgery for a vulvar primary (in a young pt) is morbid and they may not even operate depending on your gyn oncs if it comes back, putting you in a tougher retreat situation. Tough case. Good luck!