Idiopathic Follicular Mucinosis or Mycosis Fungoides? Classification and Diagnostic Challenges

When follicular mucinosis (FM) is defined as an epithelial reaction pattern characterized by intrafollicular and perifollicular mucin accumulation, it cannot be considered a distinct disease entity, as this pattern is ubiquitously present in various inflammatory and neoplastic skin conditions.^1,2 The distinction between idiopathic FM and lymphoma-associated follicular mucinosis (LAFM) was made several years ago by authors who evaluated the differences in the clinical presentation of these entities, including patient age at onset, number of lesions, pattern of distribution, and most importantly clinical progression.¹ In this article, we discuss the importance of close clinical follow-up in patients with FM or patch-stage mycosis fungoides (MF) in whom histopathologic evaluation is ambiguous or nondiagnostic. We also highlight the value of ancillary testing, including T-cell receptor gene rearrangement, flow cytometry, and immunohistochemistry, as a component in the diagnostic process rather than the sole diagnostic moiety. A review of the pertinent literature also is performed.

History of FM and MF
Pinkus³ first described an entity he termed alopecia mucinosa in 1957. Pinkus noted 3 distinct patterns: an idiopathic form of alopecia mucinosa, lymphoblastoma with associated FM, and alopecia mucinosa that later transformed into lymphoblastoma.⁴ In 1983, however, Pinkus⁴ described uncertainty if alopecia mucinosa represented the first stage of MF or if patients with alopecia mucinosa were simply at an increased risk for developing lymphoma. He believed there were too many cases of lymphoma following a diagnosis of alopecia mucinosa for the relation to be coincidental, yet he noted that many of the cases resolved either spontaneously or following treatment with x-rays or topical steroids. He concluded his report with a sentiment that is echoed in many current studies regarding this entity: “Many questions surrounding this entity are as unanswerable today as they were 25 years ago.”⁴

Jablonska et al⁵ were the first to coin the term mucinosis follicularis, now known as FM, to replace alopecia mucinosa because they felt the description was more accurate, as lesions also arise on non–hair-bearing skin. Although there is general agreement that there is a form of MF that has associated FM, this is where the agreement ends with regard to the diagnosis of MF versus FM. Böer et al⁶ discussed the historic evolution of these terms, mostly to highlight the origins of the confusion. The investigators proposed that FM should only be used as a descriptive term and that all cases of alopecia mucinosa represent MF. They also concluded that many benign dermatoses associated with a risk for evolution to MF (eg, small and large plaque psoriasis [LPP]) should simply be diagnosed as MF.⁶ Subsequently, the proposal that idiopathic FM and LAFM are not 2 distinct entities but rather a clinicopathologic continuum and that idiopathic FM is simply a variant of MF along this spectrum has gained some approval.^6,7 However, this belief is not shared among all authorities in the field, and attempts to define diagnostic criteria that distinguish between a benign clinical course and a course that is more progressive and fatal continue. Currently, it is agreed upon that when distinguishing between these 2 clinical courses, primary (idiopathic) follicular mucinosis refers to a benign course with no overt sign of malignancy, and lymphoma-associated follicular mucinosis refers to a diagnostic malignant condition. Lymphoma-associated follicular mucinosis refers to FM associated with cutaneous T-cell lymphoma, the most common form of which is FM. Many authors^8-15 have sought ancillary methodologies in addition to clinical parameters to assist in the evaluation between both disease courses. Methodologies have included assessment of T-cell receptor gene rearrangements, flow cytometry, and immunohistochemical staining, mostly as an effort to establish monoclonality as a defining characteristic of LAFM; however, monoclonality in cutaneous T-cell infiltrates should be interpreted with caution and should not be considered as a confirmation of malignancy due to recent findings of monoclonality in benign inflammatory dermatoses such as lichen planus. The Table outlines several of the most common benign inflammatory dermatoses that demonstrate monoclonality, but this list should not be considered exhaustive, as there are many others in which monoclonality is sometimes seen.^8-15 The lack of definitive criteria to distinguish between the 2 groups has led to confusion and consternation regarding the diagnosis of idiopathic FM versus LAFM and has led many in the field to consider the 2 conditions to be one and the same.

Diagnosis of FM and MF: Clinicopathologic Features
The World Health Organization (WHO) defined MF as an epidermotropic primary cutaneous T-cell lymphoma (CTCL) characterized by infiltrates of small- to medium-sized T lymphocytes with cerebriform nuclei. Further, the WHO stated that the term mycosis fungoides should be exclusively reserved for classical cases typified by the evolution of cutaneous patches, plaques, and tumors, or for variants that show a similar clinical course.¹⁶ Mycosis fungoides is divided into 3 stages—patch, plaque, and tumor—which are solely clinical descriptors.¹⁷ The WHO also described a clinical staging system with pathologic emphasis placed only on lymph node involvement and identification of Sézary cells.¹⁶ It lists folliculotropic MF as a variant, with only some cases presenting with mucinous degeneration of hair follicles. A lack of consensus among pathologists regarding criteria for diagnosis in patch-stage MF remains, but diagnosis of plaque-stage disease is not regularly debated due to its more reliably present, well-developed histologic features (eg, haloed lymphocytes, epidermotropism of lymphocytes, lymphocytes with convoluted nuceli, Pautrier microabscesses).¹⁸ Although there have been specific histologic findings reported to be associated with patch-stage MF, they have only been present in a few cases and are therefore of limited usefulness in practice.^1,19 The categorization of patients with subtle histologic features common to both MF and inflammatory conditions such as parapsoriasis en plaques (the term plaque in this case is a misnomer because the word plaque means patch in French) continues to be elusive. A lack of agreement regarding LPP persists in the current literature in the same manner as FM. Some researchers have contended for many years that LPP is a type of MF, while others remain unconvinced, mainly due to the lack of evidence that lumping a benign condition (LPP) with an increased risk for malignant transformation and a known malignancy (MF) together is of any benefit to the patient. Assessment of clinicopathologic correlation, immunohistochemistry, clonality, and T-cell gene rearrangement have failed to positively identify patients who are at risk for disease progression, whether the diagnosis is called LPP or early patch-stage MF.²⁰