Do we need a new name for early mycosis fungoides to reduce fear and improve patient care?

Prognosis in early MF

Early MF, i.e., stages I-IIA, is characterised by patches and plaques without progression to erythroderma or the presence of tumour nodules and is indolent in the vast majority of patients. Disease-specific survival is good, and progression to more advanced stages is uncommon.

In a prospective single-center study on 1263 patients with MF/Sezary syndrome, early MF was observed in 71.5% of patients. Progression to a higher stage occurred in less than 12% of patients, while mortality was seen in less than 10% of patients over the 27 years of data collection.¹ In another study, only 8.04% of 82 patients progressed from an initial stage (IA–IIA) to more advanced stages (> IIB) over a 10-year follow-up period. This disease progression is generally limited to the skin, with progression to extracutaneous disease noted in <1% over 15 years.²

The 5-year disease-specific survival rate for early MF ranges from 89% to 98% (compared to 18-56% in stage IIB to IVB).³ Using the Cutaneous Lymphoma International Prognostic Index (CLIPi), which stratifies early-stage MF into low, intermediate, and high-risk groups based on various prognostic factors (male, age >60, plaques, folliculotropic disease, and stage N1/Nx), the 5-year survival rates were 98.4%, 88.2%, and 60.8% for the respective groups.⁴

Diagnostic uncertainty in early MF

The varied clinical and histopathological presentations of early MF overlap with benign dermatoses, and this often leads to delayed or missed diagnosis.⁵ In our experience, overdiagnosis is also common for the same reasons. Fortunately, the consequences of a missed/delayed diagnosis are minor. On the other hand, an incorrect diagnosis of MF may cause considerable distress and disruption.

An international registry of MF found diagnostic delays/misdiagnosis in 86% of 430 patients, with a median of 3 years (range: 1–7.5 years).⁶ Diagnosis is challenging due to varied clinical presentations ranging from erythematous to hypo- or hyperpigmented patches and plaques, sometimes with skin atrophy. The disease also resembles pityriasis alba, atopic dermatitis, psoriasis, follicular-based rashes, and chronic pigmented purpuric dermatosis, among several other conditions. Frequently, different types of lesions may be seen in the same patient; it is helpful to take multiple biopsies in such cases. Patients should thereafter be monitored clinically with a repeat biopsy in case of a lesional change or progression.

However, histopathology may be of limited value in these patients. The European Organisation for Research and Treatment of Cancer (EORTC) diagnostic algorithm emphasises two histological markers: epidermotropism and lymphoid atypia. A 5-year study of 66 skin biopsies from 58 patients with clinically suspicious early patch-stage MF found the sensitivity of these markers to be low: 28.9% and 52.6%, respectively.⁷ Epidermotropism, while characteristic of MF, is not exclusive to it and can also appear in conditions like pityriasis lichenoides, pityriasis rosea, lichenoid dermatoses, drug eruptions, lichen sclerosus, inflammatory vitiligo, actinic reticuloid, and reactive erythroderma.⁸ Additionally, Pautrier’s microabscesses, though considered pathognomonic, are reported in fewer than 40% of MF cases.⁹

Immunophenotyping and T-cell receptor rearrangement (clonality) studies are best regarded as ancillary tests. A study validating the EORTC diagnostic criteria in early MF found that the immunophenotypic aberration of CD7 was not statistically significantly different in MF cases (45.8%, 11/24) compared with controls (30%, 3/10). Diminished expression of CD2, CD3, and/or CD5 and epidermal/dermal discordance regarding CD2, CD3, CD5, or CD7 expression had low sensitivity, each observed in only two cases (8.3%). Similarly, clonal rearrangement of the T-cell receptor γ gene was found in 10 of 24 MF cases (42%) and in three of 10 controls (30%), which did not reach statistical significance.¹⁰

Expanded T-cell clones have been reported in various benign dermatoses, including pityriasis lichenoides, parapsoriasis, pigmented purpuric dermatoses, idiopathic follicular mucinosis, and even in the peripheral blood of the healthy elderly population.^11,12 Therefore, the presence of an immunophenotyping abnormality or T-cell clonality is only one component of a possible diagnosis.

Ferrara et al.¹³ evaluated the diagnostic utility of an algorithm for the diagnosis of early MF proposed by the International Society for Cutaneous Lymphomas that includes clinical, histopathological, immunophenotypic, and molecular criteria. They found that clinical and pathological features were sufficient to make the diagnosis of early MF in 45 (62.5%) of 72 patients with erythematous and scaly dermatoses. Only a single additional patient was identified using immunophenotyping and T-cell clonality studies, negating their contribution to diagnosis.¹³

There is little published work on the overdiagnosis of early MF. LeBoit indicated that a histopathological diagnosis consistent with patch stage MF may be returned if the requisition form carries that clinical diagnosis.¹⁴ Accordingly, dermatologists need to be careful when they use the label of early MF, e.g., in children with hypopigmented patches or adults with chronic/recurrent patches of dermatitis [Figure 1]. We have seen this elicit a histopathological diagnosis of MF with needless, unpleasant consequences for the patient.

Close

Figure 1:

Multiple small, barely elevated dermatitic plaques, some with an ill-defined border on the trunk that was labelled mycosis fungoides.

Export to PPT

Treatment of early MF

The first-line treatment for early-stage MF primarily involves observation and skin-directed therapy (SDT) such as topical corticosteroids and phototherapy, treatments that would be used even in the absence of a diagnosis of MF.¹⁵

The PROCLIPI study analysed 395 patients with early-stage MF recruited from 41 centres across 17 countries. Most patients (81.6%, 322 cases) received skin-directed therapy as first-line treatment, while a smaller subset (11.1%, 44 cases) underwent systemic therapy, while the rest received no treatment. Only 22 (5.6%) of patients showed disease progression. The study concluded that early systemic therapy does not yield better outcomes than skin-directed therapy with systemic therapy showing a lower response rate (73% vs. 57%).¹⁶ Thus, by avoiding or postponing the diagnosis of MF, the physician is not delaying the initiation of effective treatment.

Psychosocial implications of a diagnosis of early MF

Graier et al. examined quality of life (QoL), anxiety, and depression in 24 patients with early-stage MF and found that 7% experienced severe impairment (DLQI > 10) and 29% experienced moderate impairment (DLQI 6–10) in QoL.¹⁷ Additionally, 33% of patients reported anxiety (as indicated by HADS scores), and 21% reported depression. A survey by the National Cutaneous Lymphoma Foundation revealed that over 93% of surveyed MF patients expressed concerns about the severity of their disease, with more than 80% fearing mortality.¹⁸

Aside from research studies, we often encounter patients who endure unnecessary emotional and financial strain. These include paying for immunohistochemical and molecular tests, extensive radiological investigations, local and whole skin radiation therapy, and multi-agent chemotherapy. Additionally, they and their family are greatly troubled by the belief that they have a disease that can kill, if it is not eradicated.

A call for new terminology

To summarise, early MF is an indolent disease with good outcomes in most patients. Skin-directed therapy or observation is appropriate for this condition. Starting aggressive, lymphoma-directed therapy early does not provide any benefits and may be associated with harm. Diagnosis is difficult, and some patients with other diseases may be labelled early MF because of clinical and histopathological overlap. The diagnosis of MF imposes a greater burden than the disease ever will, in many patients. Is there a way to avoid the negative consequences of a diagnosis of early MF? We suggest that the condition be called by another name.

Revision of nomenclature to reduce the stigma of a ‘cancer’ diagnosis is not unprecedented.¹⁹ Robin Marks advocated eloquently against the classification of solar keratosis as squamous cell carcinoma. He emphasised the significant clinical, social, and psychological implications associated with labelling a condition as ‘carcinoma.’²⁰ Another example is the reclassification of the thyroid tumour known as encapsulated follicular variant of papillary carcinoma (eFVPC) to noninvasive follicular thyroid neoplasm with papillary nuclear features (NIFTP). This change was made because the tumour did not exhibit malignant behaviour, and a simple partial thyroid resection was often curative, unlike the typical cases of papillary carcinoma.²¹ Plasma cell dyscrasia is designated monoclonal gammopathy of undetermined significance (MGUS) till other evidence of multiple myeloma is available.²² The introduction of the term “papillary urothelial neoplasm of low malignant potential” (PUNLMP) in younger patients serves a similar purpose. It allows for the diagnosis of a bladder urothelial neoplasm with a favourable prognosis without the burden of a “bladder cancer” label, especially in very young patients.²³

Clearly, a change in nomenclature requires discussion and consensus among all stakeholders. It is also likely that problems of overdiagnosis and overtreatment persist after changing the name. However, we believe it is important to recognise these problems and to find a solution that may also include other additional measures.

A suggested approach

What should a dermatologist who suspects early MF do? He/she should label the patient “parapsoriasis” or one of several other terms that may be used [Table 1]. As pointed out by de Castro et al., parapsoriasis lacks the psychological and clinical burden of a lymphoma diagnosis.²⁴ Other terms in the Table may have the same advantage. Radiological imaging is unnecessary at this stage of the disease. Wait-and-watch or skin-directed therapy with topical corticosteroids/other agents is appropriate.¹⁵

Table 1: Alternative nomenclature for early MF (Mycosis fungoides)

1.	Pre-mycotic eruption
2.	Parapsoriasis
3.	Chronic superficial scaly dermatitis
4.	Digitate dermatosis
5.	Poikiloderma vasculare atrophicans
6.	Cutaneous T-cell dyscrasia

The pathologist who sees findings suggestive of early MF on a skin biopsy [Figure 2] should be guided by the clinical picture. If MF was not suspected clinically, particular care must be exercised. We recommend a descriptive report with a statement like “please evaluate the patient for the extent of skin involvement and the presence of nodular lesions.” It is unwise to label it as MF in this setting.

Close

Figure 2:

Lymphocytic exocytosis, single lymphocyte tagging along the basal layer and papillary dermal fibrosis (Haematoxylin and eosin, 400x).

Export to PPT

If the clinical diagnosis was MF, we suggest a descriptive report with a statement like “these findings may be seen in early MF, lymphomatoid drug eruptions, pigmented purpuric dermatosis, among other conditions.” This provides some space for maneuver in case the diagnosis is reconsidered by the referring dermatologist or those consulted subsequently. Immunohistochemistry and clonality studies are not required or reliable in these cases and do not help to increase diagnostic certainty.¹¹

A small number of patients with early MF will progress to more advanced stages of the disease. Progression is easily recognised by an increase in the extent of skin involvement [Figure 3] and by the development of tumour nodules. Surveillance can be carried out effectively during routine clinical follow up similar to that for any chronic skin condition. Biopsy in this stage of disease usually shows unequivocal features of a cutaneous T-cell lymphoma [Figure 4]. If the disease has progressed, patients should be staged and managed appropriately. At this point, patients should be informed that they have a cutaneous lymphoma. We believe it is not necessary to use that label earlier.

Close

Figure 3:

Poikilodermatous plaques with linear erosions on the upper trunk.

Export to PPT

Close

Figure 4:

Marked epidermotropism with Pautrier’s microabscesses; lymphocytes also obscure the dermo-epidermal junction (Haematoxylin and eosin, 400x).

Export to PPT