Edited excerpt from the discussion:

DR LEONARD: We have a patient who has skin-only involvement with follicular lymphoma. In general, I think skin involvement of lymphoma is among the more difficult pathologic diagnoses to make. This is one scenario in which eliciting an opinion from an experienced hematopathologist or dermatopathologist is important. Pathologists often have different opinions in this situation. The type of lymphoma isn’t always clear because lymphoid proliferations can arise in the skin for many reasons.

That being said, an interesting issue is MALT lymphoma (MALToma) of the skin, which is one of the more common B-cell subtypes. Some association has been made between MALToma of the skin and infectious agents; therefore, it’s something I always consider. Although this patient has a follicular lymphoma, not a MALToma, I wonder whether we should chase after that a little bit.

With those kinds of sidebars, I think a patient with a follicular lymphoma of the skin who has no disease elsewhere is likely to do well in the long term. Often these patients will have disease that, for whatever reasons, recurs only in the skin. These are four-millimeter lesions, so I would be inclined to do relatively little — topical steroid treatment, local radiation or no therapy.

Whether or not you chase after the skin lesions is a clinical judgment based on the scenario. I’m not sure systemic therapy, whether it is rituximab or chemotherapy, is going to change the big picture for this patient. I don’t know that we have any randomized trials showing that systemic therapy makes a difference. My inclination would be to do less, rather than more.

DR LOVE: From a psychosocial perspective, do you think the patient and his wife would have been able to accept watchful waiting?

DR GULATI: No. That was the major issue. Watchful waiting was offered to them, but they are clearly the nervous type. They chose rituximab, which we gave weekly for four weeks followed by monthly for four months, for a total of five months.

DR LOVE: What happened to the lesions?

DR GULATI: The lesions disappeared by the second treatment. The patient was doing fine, but he was obviously worried. Every time he came in, we would discuss the issue. An episode occurred during which the patient said he felt like fainting. He was rushed to the emergency room where he had a full coronary workup, but everything was normal.

I called him before this conference and he said he has a few new skin lesions near the initial site. The patient was anxious; he did not want these lesions on his skin. If a remission occurred, it lasted only about nine or 10 months. This is a Bcl-2-positive lymphoma, so I don’t think that it is follicular or lymphoid hyperplasia. He’s going to come in and have a biopsy, and the question will arise: What will be the next treatment?

DR C FARBER: I would be inclined to utilize electron beam radiation therapy with a wide field and an adequate margin in this patient. That would probably prevent at least a local recurrence. The lesions may keep recurring just outside the field, in which case it’s almost like spot welding. Electron beam therapy offers a low morbidity and it should be effective.

DR LOVE: What about electron beam therapy in this situation, Dr Leonard?

DR LEONARD: I think it’s certainly reasonable if the lesions are in the same area. It is probably not going to change his long-term outcome. You’re not going to prevent recurrence elsewhere by removing these lesions. It’s a matter of just chasing after them. It may reach a point at which you question whether it is worth the effort. If you treat him and then a month later a lesion pops up somewhere else, you start to wonder if it may be easier for him to receive a couple “squirts” of rituximab and go into remission, rather than undergo re-treatment.

Again, that’s a clinical judgment. I’d be inclined to do less, rather than more. If you’re forced to treat him, I think it’s a matter of the time and effort involved in chasing after this, which is really psychological palliation more than anything.

DR RADER: At some of the breast cancer meetings, we discuss immunohistochemistry for ER and how unreliable it is.

In patients with lymphoma, I’ve seen multiple different opinions on whether cells have been transformed — whether they’re large or small cells — or whether the flow cytometry agrees with the histological picture. Do you believe that, routinely, most lymphomas should have a second pathology opinion. When the second opinions are widely divergent, what type of evidence do you evaluate next?

Second opinions are often 180 degrees different. These opinions influence therapy — like CHOP versus watchful waiting — so should second opinions be routine?

DR SMITH: I see a lot of patients who were referred to me for a second opinion, and when I discuss the case with the referring doctor, it’s clear that I’m going to not change the oncologist’s opinion. However, whether it’s low grade or aggressive lymphoma, the key to a second opinion is a review of the pathology.

Approximately a third of the time we will have a change regarding pathology. Often the change is minor; however, sometimes it is major, making it low grade versus aggressive — particularly when the lymphoma is in extranodal sites, such as the stomach or skin. Second opinions are critical, but then what do you do? Is it best two out of three?

In community practices, I find that the slides are usually analyzed locally, and the flow goes to someone at an outside lab who knows nothing about the patient or the physician. At our place, after I’ve seen the patient, I sit down with my hematopathologist, who also does the flow. We discuss the issues, and come up with something. It’s not so much that the stain or the flow is wrong, but that you have to put the whole picture together before it can make sense. That’s one of the concerns, particularly if you’re in a small hospital.

DR LEONARD: I agree; it is easy to ascertain a pathologic second opinion — it’s simply a matter of sending the slides; the patient doesn’t have to go. Generally, pathologists will discuss it with you over the phone, even if you’re at another institution. It’s not a big deal to do, and the pathology is key. I believe a pathologic second opinion is more important than another lymphoma subspecialist’s opinion. We re-evaluate a situation based on our pathologist giving us information that the primary oncologist didn’t have; therefore, I encourage patients to ascertain a pathologic second opinion. It is a relatively easy thing to do, and it gives the patients some reassurance.

I think all patients diagnosed with mantle cell lymphoma should also have a second pathology opinion. That’s a hard diagnosis to make and the implications, as far as the prognosis, are enormous. Additionally, if the disease is acting like one type of lymphoma, but the pathologist is telling you it’s another type of lymphoma, maybe that’s a red flag that you ought to have it evaluated by someone else.

Finally, gray areas exist when you see follicular and diffuse lymphomas, and you are trying to decide if transformation has occurred and whether you need to use an anthracycline — this is an area in which I would encourage a second opinion from the pathological standpoint.

DR BHARDWAJ: Some changes have occurred in terms of how the insurance companies are reimbursing for second opinions. At some institutions, the Pathology Department is now billing the hospital Pathology Department, and not the patient. That puts a crimp in terms of where the patients’ slides are being sent.

DR LEONARD: Second-opinion slides are the best spent $300 or $500 that a patient will invest. Even if you have to tell the patient, “Insurance isn’t going to cover it,” this has such important implications, at least in lymphoma, that if the patient can do it, even if they have to pay out of pocket, I encourage it.

DR SMITH: A more difficult situation is when patients have large cell lymphoma isolated to the skin, because it looks ugly but often behaves indolently. Can you give rituximab as a single agent or local radiation to a patient who, histologically, has large cell lymphoma? According to the literature, large cell lymphoma in the skin tends to behave more indolently. That is a second opinion that we see often, and my reply is, “Maybe you need to be aggressive with this tumor.”

DR LOVE: Any hints in terms of pathophysiology of cutaneous lymphoma in terms of why it has this natural history?

DR SMITH: As John mentioned, the MALTomas of the skin might be infection-driven. We don’t know much about the lymphocytes that are normally in the skin, why they home there and how they behave day to day. There is probably something there that we should be learning about, but we don’t know that much about it.

DR LOVE: Dr Gulati, how are you going to treat this patient?

DR GULATI: My previous experience with electron beam, especially for large cell lymphoma, has not been good. This is the first time I’ve seen a follicular Bcl-2- positive, so I’m open-minded. Rituximab worked; therefore, I am tempted to give more rituximab although the remission didn’t last more than seven months. The story is incomplete. I think the workup will be important. If he has positive lymph nodes, then he’s going to receive chemotherapy.

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