Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
Dr. Michi Shinohara
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.