Similar to MF, SS is a disease of older adults with average age of onset of 50 to 60 years.² Recent studies examining the US Surveillance Epidemiology and End Results 17 dataset report the incidence of SS to be 0.01/100,000 person-years from 2005 to 2008 (MF incidence was 0.55/100,000 person-years) with a male:female incidence ratio of 1.57 and Black:Caucasian incidence ratio of 1.55 in the United States.⁶ Interestingly, African American patients with MF or SS were diagnosed at a younger age and presented with a higher stage than the Caucasian patient cohort. Incidence of CTCL had increased since 1970^7,8 as have all lymphomas in general.

MF and SS are sporadic non-Hodgkin lymphomas (NHLs) derived from mature skin-derived T cells (SALT—skin-associated lymphoid tissue) that currently have neither a confirmed driver genetic defect nor a familial pattern of inheritance (though familial MF has been rarely reported in certain populations).⁹ Environmental exposures (chemical, viral) have also not been definitively shown to be oncogenic triggers of MF/SS despite extensive epidemiologic and molecular studies.^{10,11,12,13,14}

The majority of SS cases have a shorter duration of onset prior to formal diagnosis than MF typically does. However, there are cases of SS that arise in patients with long-standing MF that progresses slowly over many years (erythrodermic MF) demonstrating the overlapping features of MF and SS as related entities.

Erythroderma is currently defined by the ISCL/EORTC 2007 MF/SS classification system as generalized confluent erythema >80% body surface area (BSA)⁴ (Fig. 13-1) and is often accompanied by other clinical features in SS including exfoliation/scaling of skin (Fig. 13-2), alopecia (scalp and/or other body areas), ectropion (eversion of eyelids and exposure of conjunctiva), palmoplantar scaling/keratoderma (Fig. 13-3), and onychodystrophy. Erythrodermic SS patients may demonstrate sparing of the skin folds on the trunk. Secondary skin changes are common due to the intense pruritus and barrier dysfunction that is observed in majority of patients including excoriations, skin fissuring, bacterial impetiginization, and skin lichenification. Less commonly, patients can present with a generalized morbilliform eruption mimicking an allergic drug reaction or viral exanthem; these patients are often minimally scaly (Fig. 13-4). Similar to MF, SS can be the “great imitator” and at times can have clinical features identical to psoriasis or atopic dermatitis. Given this, we advise that patients with refractory “eczema” or “psoriasis” who are not improving with standard therapies should have skin biopsies (and appropriate blood studies if erythrodermic), to rule out MF/SS (especially prior to using immunosuppressive systemic agents such as TNF-α inhibitors, cyclosporine, or mycophenolate mofetil, where such treatment can potentially cause acceleration/progression of unrecognized MF/SS/CTCL).^15,16

Erythroderma can wax and wane in severity during the day and can be exacerbated by heat, exercise, stress, or other factors that trigger vasodilation. Lower extremity edema is a commonly observed finding in older erythrodermic patients with underlying venous stasis (Fig. 13-1B) and or patients with significantly enlarged groin lymph nodes. With severe erythroderma, patients can rarely develop signs of high cardiac output such as pericardial or pleural effusions due to the large amount of blood flow diverted to the erythrodermic skin. Some cases of SS develop concomitant follicular papules/plaques, follicular mucinosis, or classic plaques and tumors in addition to underlying erythroderma (Fig. 13-5) and generally portend a more aggressive course.

Palpable peripheral lymphadenopathy is often noted in cervical, axillary, inguinal areas, and if >1.5 cm in diameter clinically or on imaging, generally warrant excisional lymph node biopsy to distinguish between reactive dermatopathic lymphadenopathy (N1 nodal classification) versus involvement by CTCL (N2, N3) for staging purposes.⁴ Bulky lymphadenopathy (defined here as >3 cm in long axis) is unusual and should raise the possibilities of large-cell transformed disease or a second separate lymphoma (i.e., Hodgkin lymphoma, systemic anaplastic large cell lymphoma [sALCL], other NHL)¹⁷; lymph node biopsy is necessary to confirm diagnosis (excisional or core biopsy greatly preferred over fine needle aspirate to assess architecture).⁴ Some patients will have thickening of the skin of the forehead, eyebrows, cheeks, and/or chin because of infiltration by malignant T cells resulting in the so-called “leonine facies” described in the past. Some SS patients can also develop follicular papules/plaques, or overlying plaques/tumors, indicating a more aggressive course. Eruptive seborrheic keratoses (sign of Leser–Trelat) on the upper back/trunk/scalp (Fig. 13-6) are reported by some patients as a paraneoplastic phenomenon accompanying their SS. SS patients with darker skin types may have less prominent erythema than patients with fair skin and can present with generalized dyspigmentation (typically generalized hyperpigmentation but may be admixed with hypopigmented and depigmented areas) that masks the diffuse erythema though in body folds may see alternating bands of normal and involved skin (Fig. 13-7).¹⁸

Symptoms reported by SS patients often include intense pruritus, burning sensation of the skin, severe exfoliation, chills due to temperature dysregulation, impairment of sweating, fatigue, lower extremity edema (especially in older individuals with underlying venous stasis), and rarely low-grade fevers. Higher fevers (i.e., “tumor fever”) or drenching night sweats are uncommon in typical SS in the absence of infection or transformed disease and should prompt an infectious workup (most likely source is bacteremia from skin colonization or superinfection from skin flora bacteria such as Staphylococcus aureus). Infection is the leading cause of mortality in MF/SS patients.¹⁹ SS patients can also develop herpes family viral reactivations (herpes simplex virus [HSV], varicella-zoster virus [VZV]) that can disseminate because of their barrier dysfunction and their endogenous immunosuppression. The clinical differential diagnosis of SS erythroderma is extremely broad (see Differential Diagnosis section later) and accurate clinicopathologic diagnosis is essential. Not infrequently, the workup of the erythrodermic patient can be nondiagnostic and have to be repeated over time. In addition, interestingly, degree of erythema or exfoliation or pruritus in SS patients does not necessarily correlate with degree of peripheral blood burden by tumor cells.

SS historically has had an overall poor prognosis with infection as the leading cause of mortality. Median survival of SS patients as strictly defined (T4B2) has ranged from 2.5 to 4.6 years (26% 5-year survival, risk of disease progression in SS cohort 70% at 5 years) in several large single academic center retrospective studies with a trend toward improved survival with more recent studies, likely due to better control of infections and avoidance of indwelling central lines which are susceptible to line infection in such a population.^21,22,23,24 It is difficult to ascertain if the modest trend toward improved survival is related to newer therapies as randomized controlled data are lacking to confirm effects of current therapies on overall survival (Cochrane review). In a recent study by Agar and colleagues,²⁴ a multivariate analysis of their large MF/SS revealed that decreased overall survival and increased risk of disease progression were associated with advanced skin (T) stage, increased LDH, B0b status, and folliculotropic MF. Approximately 30% of SS skin biopsies harbor Epstein–Barr virus (EBV)-DNA, which is thought to be related to immunosuppression. EBV infection had been linked to worse clinical outcome.¹⁴

MF/SS patients are at higher risk for secondary malignancies due to skin-directed therapies such as phototherapy, and the use of alkylating agents. Therapy-related malignancies include nonmelanoma skin cancers, melanoma, and other lymphoproliferative disorders such as Hodgkin lymphoma and non-Hodgkin B-cell lymphomas comprising CLL.^17,25 In addition, 5% of MF/SS patients will develop a concomitant primary cutaneous CD30⁺ lymphoproliferative disorder such as lymphomatoid papulosis (LyP) or primary cutaneous anaplastic large-cell lymphoma (pcALCL) independent of their MF/SS disease activity.²⁶ Concomitant LyP appears to be a positive prognostic factor in MF/SS patients.^21,24

Similar to MF, SS can be a challenge to diagnose promptly owing to a broad clinical differential diagnosis (see Differential Diagnosis section later), but also because skin biopsies may be nonspecific/nondiagnostic in up to one-third of SS cases.³⁴ Because of this phenomenon, we recommend that peripheral blood studies be performed in erythrodermic patients if SS is clinically suspected.¹⁶

Definitive skin biopsies will demonstrate the hallmark features as described in MF: atypical small- to medium-sized hyperchromatic lymphocytes with cerebriform, hyperconvoluted nuclei demonstrating epidermotropism in a variety of patterns (“lining up”) along the dermal–epidermal junction, single-cell epidermotropism without spongiosis, and discrete collections in the epidermis around Langerhans cells (“Pautrier microabscesses”) (Fig. 13.8). Skin biopsies of the plaques/tumors often demonstrate large-cell morphology (Fig. 13.9). Skin “large-cell transformation” is defined as >25% of the atypical infiltrate demonstrating enlarged nuclei more than four times the size of normal lymphocytes.^35,36,37