Bonus images for this chapter can be found online at http://www.expertconsult.

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Cutaneous Lymphoid Hyperplasia, Cutaneous T-cell Lymphoma, Other Malignant Lymphomas, and Allied Diseases
symptoms are absent and, except for rare cases with regional lymphadenopathy, there are no other physical or laboratory abnormalities. It is usually idiopathic, but can be caused by tattoos, Borrelia infections, herpes zoster scars, antigen injec tions, acupuncture, and, in rare cases, drug reactions, tumor necrosis factor (TNF)- inhibitors, and persistent insect bite reactions. Lesions that result from a known stimulus tend to be localized to the site of the original processtattoo, injection, or insect bite. Borrelia-induced cutaneous lymphoid hyperplasia is an uncommon manifestation of this infection, occurring in 0.61.3% of cases reported from Europe. The lack of borrelial pseudolymphoma in the US compared with Europe may relate to the fact that there are different borrelial species in Europe, specifically Borrelia afzelii, that cause borreliosis. Lesions occur at the site of the tick bite or close to the edge of a lesion of erythema migrans. They may appear up to 10 months after infection. Lesions may be multiple and favor the earlobes, nipple and areola, nose, and scrotal area, and vary from 1 to 5cm in diameter. Usually, there are no symptoms, but associ ated regional lymphadenopathy may be present. Late mani festations of Borrelia infection are uncommon. The diagnosis is suspected from a history of a tick bite or erythema migrans, the location (earlobe or nipple), and the histologic picture. The diagnosis is confirmed by an elevated anti-Borrelia antibody (present in 50% of cases) and the finding of borrelial DNA in the affected tissue. The treatment is penicillin. Some cases progress to true lymphoma. Histologic examination of nodular cutaneous lymphoid hyperplasia reveals a dense, nodular infiltrate that occupies primarily the dermis and lessens in the deeper dermis and subcutaneous fat, i.e. it is top-heavy. The process is usually separated from the epidermis by a clear Grenz zone. The infiltrate is composed chiefly of mature small and large lymphocytes, histiocytes, plasma cells, dendritic cells, and eosinophils. In the deeper portions, well-defined germinal centers are usually seen, with central large lymphoid cells with abundant cytoplasm and tingible body macrophages, and a peripheral cuff of small lymphocytes. A plasma cellpredominant variant has been described. Reactive hyperplasia of adnexal epithelium is common and characteristic, but may also occasionally be seen in true lymphomas. Germinal centers are symmetrical and surrounded by a mix of B and T cells. BCL-6 and CD10 expression is limited to the germinal centers, which also have an intact CD21+ network of dendritic cells. Typically, more than 90% of the cells in the germinal center express the proliferative marker Ki-67 (MIB-1). There is no evidence of light chain restriction by in situ hybridization. CD30+ cells may occasionally be prominent, raising concern about the development of a CD30+ lymphoproliferative disorder. As most lesions are asymptomatic, treatment is often not required. If the process has been induced by a medication, use of the medication should be discontinued. Infection should be

Cutaneous lymphoid hyperplasia (lymphocytoma cutis, lymphadenosis benigna cutis, pseudolymphoma)

The term cutaneous lymphoid hyperplasia refers to a group of benign disorders characterized by collections of lymphocytes, macrophages, and dendritic cells in the skin. These processes can be caused by known stimuli (such as medications, injected foreign substances, infections, or the bites of arthropods) or they may be idiopathic. They may have a purely benign his tologic appearance or resemble cutaneous lymphoma. If there is a histologic resemblance to lymphoma, the term pseudo lymphoma is sometimes used. Most cases contain a mixed population of T and B cells, but they may contain mostly T cells. By standard techniques, most cases of cutaneous lym phoid hyperplasia will be found to lack clonality. Cases of monoclonal B- and T-cell cutaneous lymphoid hyperplasia do occur. Thus, a finding of monoclonality does not equate to the diagnosis of malignancy or lymphoma, nor does it predict biologic behavior. A subset of polyclonal or monoclonal (T- or B-cell) cutaneous lymphoid hyperplasias does progress to cutaneous B-cell and, less commonly, T-cell lymphoma. Even when the initial evaluation detects a T-cell rich infiltrate (>90%), which may be monoclonal, the lymphoma that eventu ates from this form of cutaneous lymphoid hyperplasia may be B-cell. Thus, as in many cancer syndromes, cutaneous lym phoid hyperplasia represents the benign end of a spectrum of cutaneous lymphoid proliferation, with cutaneous lymphoma at the other end, and cases falling everywhere along that spec trum of progression. Unfortunately, current techniques cannot always predict which cases will progress. Two clinical patterns of cutaneous lymphoid hyperplasia exist. The nodular form consists of nodular and diffuse dermal aggregates of lymphocytes, macrophages, and dendritic cells. The clinical and histologic differential diagnosis is cutaneous B-cell lymphoma. The diffuse type is usually associated with drug exposure or photosensitivity (actinic reticuloid). Histologically, it is to be distinguished from cutaneous T-cell lymphoma.

Cutaneous lymphoid hyperplasiasnodular B-cell pattern

The nodular pattern of cutaneous lymphoid hyperplasia is the most common pattern. It usually presents in adults and is 23 times more common in women. It favors the face (cheek, nose, or earlobe), and the majority of cases present as a solitary or localized cluster of asymptomatic, erythematous to violaceous papules or nodules (Fig. 32-1). Less commonly, lesions may affect the trunk (36%) or extremities (25%). At times, the lesions may coalesce into a plaque or be widespread in one region, in which case they present as miliary papules. Systemic

other forms of cutaneous lupus erythematosus include the absence of an interface dermatitis, lack of mucin, and negative direct immunofluorescence. Tumid lupus erythematosus also lacks interface dermatitis but has ample mucin. Polymorphous light eruption (PMLE) is distinguished from Jessner infiltrate by having edematous papules and plaques that are more tran sient, and by the presence of dermal edema. In PMLE the infiltrating cells are CD8+. There may still exist true cases of lymphocytic infiltration of the skin. To distinguish them clearly from lupus erythematosus and PMLE, the lesions must contain predominantly CD8+ suppressor T cells, lack dermal mucin and dermal edema, and be fixed (not transient like PMLE); patients must have negative direct immunofluores cence and serologic testing for lupus erythematosus. Both Jessner and chronic cutaneous lupus erythematosus can respond to antimalarials.
Fig. 32-1 Reactive lymphoid hyperplasia.
Belousova IE, et al: Atypical histopathological features in cutaneous lymphoid hyperplasia of the scrotum. Am J Dermatopathol 2008 Aug; 30(4):407408. Ber A, et al: Pseudoclonality in cutaneous pseudolymphomas: a pitfall in interpretation of rearrangement studies. Br J Dermatol 2008 Aug; 159(2):394402. Cerroni L, et al: Cutaneous B-cell pseudolymphoma at the site of vaccination. Am J Dermatopathol 2007 Dec; 29(6):538542. Guis S, et al: Cutaneous pseudolymphoma associated with a TNF-alpha inhibitor treatment: etanercept. Eur J Dermatol 2008 JulAug; 18(4):474476. Kazakov DV, et al: Hyperplasia of hair follicles and other adnexal structures in cutaneous lymphoproliferative disorders: a study of 53 cases, including so-called pseudolymphomatous folliculitis and overt lymphomas. Am J Surg Pathol 2008 Oct; 32(10):14681478. Nervi SJ, et al: Plasma cell predominant B cell pseudolymphoma. Dermatol Online J 2008 Oct 15; 14(10):12. Shin JB, et al: Cutaneous T cell pseudolymphoma at the site of a semipermanent lip-liner tattoo. Dermatology 2009; 218(1):7578. Tomar S, et al: Treatment of cutaneous pseudolymphoma with interferon alfa-2b. J Am Acad Dermatol 2009 Jan; 60(1):172174.

treated and localized foci of infection removed. Intralesional steroidal agents are sometimes beneficial, but lesions may recur in a few months. Potent topical steroids may also be tried for superficial lesions. Intralesional corticosteroids, cryosur gery, thalidomide, 100mg/day for a few months, interferon (IFN)-, IFN- 2b, laser ablation, and surgical excision can all produce good results. Low-dose radiation therapy is usually very effective and may be used on refractory facial lesions that cannot be satisfactorily removed surgically. If monoclonality is detected in a localized lesion, complete removal and local radiation have been recommended, but there is no evidence that this improves outcome, and lesions that are not initially monoclonal may also progress to lymphoma.

Cutaneous lymphoid hyperplasiasbandlike T-cell pattern

Cutaneous lymphoid hyperplasias may histologically show a bandlike and perivascular dermal infiltrate, at times with epidermotropism. They may be idiopathic, or caused by photosensitivity (formerly called actinic reticuloid; now called chronic actinic dermatitis), medications (usually anticonvul sants, but also many others), or contact dermatitis (so-called lymphomatoid contact dermatitis). Clinically, these patients have lesions that clinically resem ble mycosis fungoides: widespread erythema with scaling. Thicker plaques may occur as well and these cases are fre quently caused by medications. The treatment is to stop any implicated medication. If stopping the medication is ineffec tive, topical and intralesional steroids, PUVA, and, for persist ent localized lesions, radiotherapy may be considered. Histologically, a T cell-rich band of lymphocytes is present. Epidermotropism, atypia, and even clonality may suggest mycosis fungoides, but the lesions resolve when the drug or other inciting agent is withdrawn.

Cutaneous lymphomas
Because cutaneous Hodgkin disease is very rare, the term nonHodgkin lymphoma has little meaning when speaking of a lymphoma in the skin, because virtually all cutaneous lym phomas are non-Hodgkin lymphomas. Cutaneous lym phoma can be considered to be either primary or secondary. Primary cutaneous lymphomas are those that occur in the skin and where no evidence of extracutaneous involvement is found for some period after the appearance of the cutaneous disease. Secondary cutaneous lymphoma includes cases that have simultaneous or preceding evidence of extracutaneous involvement. These cases are best classified and managed as lymph node-based lymphomas with skin involvement. This conceptual separation is not ideal, but it has been important in developing classification schemes and determining progno sis in cutaneous lymphomas. For many years classification of lymphomas has been based on their histologic appearance, and lesions from all organ systems were classified histomorphologically in an identical manner to lymphomas arising in lymph nodes. It had been recognized that these classification schemes have major short comings when applied to extranodal lymphomas. Specifically, they did not uniformly predict clinical behavior. The new World Health Organization (WHO) classification scheme rec ognizes distinct forms of primary cutaneous lymphoma. Cutaneous lymphomas are classified based on their cell type. There are B-cell lymphomas and T-cell lymphomas, but B-cell lymphomas can be T cell-rich. In such cases, atypia is restricted to the B-cell population and immunoglobulin gene rearrangements are detected. Histologic features used in the
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Jessner lymphocytic inltrate of the skin

The existence of this entity has recently been challenged. Even the coauthors of the original paper feel their cases would now best be classified as a variant of lupus erythematosus. Clinically, Jessner infiltrate is a persistent papular and plaquelike eruption that is photosensitive and occurs primarily on the face. Histologically, there is a superficial and deep perivas cular and periadnexal lymphocytic infiltrate. Interface derma titis is absent. The infiltrating lymphocytes are suppressor T cells (CD8+). Features that suggest this may be distinct from

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classification system include cell size (large versus small), nuclear morphology (cleaved or non-cleaved), and immuno phenotype. Because appropriate classification may be prognostically important, experienced dermatopathology con sultation should be sought in cases of cutaneous lymphoma.

Primary cutaneous T-cell lymphomas

A major insight into cutaneous lymphoma was the finding that the majority of lymphomas in the skin were of T-cell origin. This is logical, since T cells normally traffic through the skin and are important in skin-associated lymphoid tissue. Unfortunately, dermatologists frequently use the term cutane ous T-cell lymphoma synonymously with mycosis fungoides. Although mycosis fungoides represents the large majority of primary cutaneous T-cell lymphomas, up to 30% of primary cutaneous T-cell lymphomas are not mycosis fungoides. The following discussion is divided into mycosis fungoides and related conditions, Szary syndrome, lymphomatoid papulo sis, and non-mycosis fungoides primary cutaneous T-cell lymphomas.

in evolution. Skin involvement is divided into less than 10% (T1), more than 10% (T2), tumors (T3), and erythroderma (T4). Node involvement is normal clinically and pathologically (N0), palpable but pathologically not mycosis fungoides (N1), not palpable but pathologically mycosis fungoides (N2), or clinically and pathologically involved (N3). Viscera and blood are either not involved (M0 and B0) or involved (M1 and B1). Stage IA is T1,N0,M0. Stage IB is T2,N0,M0. Stage IIA is T12,N1,M0. Stage IIB is T3,N01,M0. Stage IIIA is T4,N0,M0. Stage IIIB is T4,N1,M0. Stage IVA is T14, N23,M0. Stage IVB is T14,N03,M1. The B or blood status does not alter staging of the disease. A staging work-up would include a complete history and physical examination, with careful palpation of lymph nodes and mapping of skin lesions; a complete blood cell count with assays for circulating atypical cells (Szary cells); serum chem istries, including renal and liver function tests with lactic dehydrogenase; a chest radiograph evaluation; and a skin biopsy. If lymph nodes are palpable, they should be examined histologically. Fine-needle aspiration is not an ideal mode of evaluation, since early lymph node involvement may be local ized to certain areas of the affected nodes, and architectural evaluation is often required to detect early lymph node involvement. If any abnormalities are detected through the above evaluations, they should be pursued. Computed tom ography (CT) can be performed to assess chest, abdominal, and pelvic lymph nodes, and visceral organs. These are useful in patients with stage IIIV disease, but are not indicated in patients with stage IA disease. Whether patients with stage IB disease should undergo these tests is unknown. The value of this staging system is confirmed in large series. Stage IA patients have a life expectancy identical to that of a control population; only 89% progress to have more advanced disease; and only 2% die of their disease. By contrast, patients with T2 disease have a shorter survival time than control subjects (median survival of 11.715.6 years). Twenty-four percent of T2 patients progress to more advanced disease. T3 patients have a median survival of 3.28.4 years, and T4 patients 1.83.7 years. Palpable adenopathy is associated with a median survival of only 7.7 years, whereas patients without adenopathy have a survival of 21.8 years. Lymphadenopathy, tumors, and cutaneous ulceration are cardinal prognostic factors; no patient dies without having developed one of them and patients with all three (in any order) survive a median of 1 year.

Mycosis fungoides
Mycosis fungoides is a malignant neoplasm of T-lymphocyte origin, almost always a memory T-helper cell. The incidence has been cited as 1 in 300 000 per year, but has been increasing. Mycosis fungoides affects all races. In the US black persons are relatively more commonly affected than white persons. The condition is twice as common in males as in females.

Natural history
In most cases, mycosis fungoides is a chronic, slowly progres sive disorder. It usually begins as flat patches (patch stage), which may or may not be histologically diagnostic of mycosis fungoides. This inability to diagnose early cases has more to do with the limits of diagnostic capabilities, rather than a transformation from some non-neoplastic (premycotic) condi tion to mycosis fungoides, and these cases are best considered mycosis fungoides from the onset. Pruritus, sometimes severe, is usually present at this stage. Over time, sometimes years, the lesions become more infiltrated, and the diagnosis is usually confirmed with repeated histologic evaluation. Infiltrated plaques occur eventually (plaque stage). In some cases, tumors may eventually appear (tumor stage). Some patients may present with or progress to erythroderma. Most rarely, patients may present with tumors de novo, the so-called demble form. With immunophenotyping, many of these cases are now recognized as non-mycosis fungoides T-cell lymphomas. Eventually, in some patients, noncutaneous involvement is detected. This is most commonly first identi fied in lymph nodes. Peripheral blood involvement and vis ceral organ involvement may also occur. In general, mycosis fungoides affects elderly patients and has a long evolution. However, once tumors develop or lymph node involvement occurs, the prognosis is guarded and mycosis fungoides can be fatal. In most fatal cases the patient dies of septicemia. Early, aggressive chemotherapy in an attempt to cure mycosis fungoides is associated with exces sive morbidity and mortality, and is not indicated.

Clinical features
In the early patch/plaque stage, the lesions are macular or slightly infiltrated patches or plaques varying in size from 1 to 5cm or more. Folliculotropic disease can resemble lichen nitidus. Except for the folliculotropic variant, lesions >5cm in size are virtually always present in true cases of mycosis fun goides. In contrast, most histologic simulators present with smaller skin lesions. The eruption may be generalized or begin localized to one area and then spread. The lower abdomen, buttocks, upper thighs, and breasts of women are preferen tially affected. The lesions may have an atrophic surface, or present as true poikiloderma with atrophy, mottled dyspig mentation, and telangiectasia. Poikiloderma vasculare atroph icans most commonly represents a clinical form of patch-stage mycosis fungoides. Likewise, large-plaque parapsoriasis and cases of small-plaque parapsoriasis with poikilodermatous change are early patch-stage lesions of mycosis fungoides. In

Evaluation and staging

The North American Mycosis Fungoides Cooperative Group has developed a staging system. Because mycosis fungoides is a systemic disease from the onset (as lymphocytes naturally traffic throughout the body), concepts used for solid tumors, such as tumor burden and metastasis, cannot be readily applied. The TNMB system scores involvement in the skin (T), lymph node (N), viscera (M), and peripheral blood (B), and is

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contrast, typical digitate dermatosis probably never evolves into mycosis fungoides. Invisible mycosis fungoides is gen eralized skin involvement that is not visible to the naked eye but can be documented histologically. With current diagnostic methods, this can usually be confirmed. In general, the patchstage lesions resemble an eczema, being round or ovoid, but annular, polycyclic, or arciform configurations can occur. Less common forms are the verrucous or hyperkeratotic form, the hypopigmented form (Fig. 32-2), lesions resembling a pig mented purpura, and the vesicular, bullous, or pustular form. The hypopigmented form seems to be more common in persons of color and is a common presentation for adolescents and children with mycosis fungoides. Subtle lesions of mycosis fungoides may manifest clinically during anti-TNF therapy. In the plaque stage, lesions are more infiltrated and may resemble psoriasis (Fig. 32-3), a subacute dermatitis, or a gran ulomatous dermal process such as granuloma annulare. The palms and soles may be involved, with hyperkeratotic, pso riasiform, and fissuring plaques. The infiltration of the plaques, at first recognized by light palpation, may be present in only a few of the lesions. It is a manifestation of diagnostic impor tance. Different degrees of infiltration may exist even in the same patch and sometimes it is more pronounced peripher ally, the central part of the plaque being depressed to the level of the surrounding skin. The infiltration becomes more marked

and leads to discoid patches or extensive plaques, which may be as wide as 30cm. Eventually, through coalescence of the various plaques, the involvement becomes widespread, but there are usually patches of apparently normal skin interspersed. When the involvement is advanced, painful superficial ulcerations may occur. During this phase, enlarged lymph nodes usually develop. They are nontender, firm, and freely movable. The tumor stage is characterized by large, various-sized and shaped nodules on infiltrated plaques and on apparently normal skin. These nodules have a tendency to break down early and to form deep oval ulcers, whose bases are covered with a necrotic grayish substance and which have rolled edges (Fig. 32-4). The lesions generally have a predilection for the trunk, although they may be seen anywhere on the skin or may involve the mouth and upper respiratory tract. Uncommonly, tumors may be the first sign of mycosis fungoides. The erythrodermic variety of mycosis fungoides is a general ized exfoliative process, with universal redness. The hair is scanty, nails are dystrophic, palms and soles are hyperkera totic, and at times there may be generalized hyperpigmenta tion (Fig. 32-5). Erythroderma may be the presenting feature. Alopecia mucinosa The infiltrating cells of mycosis fun goides can demonstrate a predilection for involving the hair follicle (Fig. 32-6). This may be observed simply by

Fig. 32-2 Mycosis fungoides, hypopigmented patches.

Fig. 32-4 Tumor-stage mycosis fungoides. (Courtesy of Ellen Korn, MD)

Fig. 32-3 Plaque stage mycosis fungoides. (Courtesy of Ellen Korn, MD)

Fig. 32-5 Erythrodermic mycosis fungoides.

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Fig. 32-6 Follicular mycosis fungoides.

Fig. 32-8 Syringotropic mycosis fungoides.

about 7 years. Any other evidence of visceral involvement is a grave prognostic sign. An abnormal result on liverspleen scan, chest radiograph or CT evaluation, abdominal or pelvic CT scans, or bone marrow biopsy is associated with a survival of about 1 year. The prognosis is worse in non-Caucasian patients with early-onset mycosis fungoides, especially African American women.

Pathogenesis
Mycosis fungoides is a neoplasm of memory helper T cells in most cases. Rare cases of suppressor cell (CD8+) mycosis fun goides have been reported. These CD8+ cases may behave indolently, like mycosis fungoides, or aggressively. The latter aggressive subset tends to present with plaques rather than patches. The events leading to the development of the malig nant T cells are unknown. It has been speculated that it is caused by chronic exposure to an antigen, but this has yet to be confirmed. Patients with atopic dermatitis appear to be at increased risk for the development of mycosis fungoides, sug gesting that persistent stimulation of T cells may lead to devel opment of a malignant clone. The inflammatory nature of the skin lesions has led to investigation of the interactions of the malignant T cells and both keratinocytes and antigen-presenting cells (including Langerhans cells) in mycosis fungoides. Mycosis fungoides skin lesions have many features of skin that is immunologi cally activated. Mycosis fungoides cells express cutaneous lymphocyte antigen (CLA), the ligand for E selectin, which is expressed on the endothelial cells of inflamed skin. This allows the malignant cells to traffic into the skin from the peripheral blood. CCR4, another homing molecule, is expressed on mycosis fungoides cells, and the ligand for this receptor is on basal keratinocytes. Antigen-presenting cells are increased in mycosis fungoides lesions and have increased functional capacity to activate T cells. There is increased expression of major histocompatibility complex (MHC) class II antigens on the surface of the antigen-presenting cells. Through cytokines, infiltration of neoplastic and reactive T cells is increased. The pattern in early mycosis fungoides is more T-helper 1 (Th1)like and the non-neoplastic infiltrating cells (tumor infiltrating lymphocytes [TILs]) may play a role in downregulating and controlling the neoplastic cells. There are more CD8+ cells in these early lesions and these TILs may control the malignant clone. In fact, mycosis fungoides patients with more than 20% CD8+ cells in their skin survive longer than those with less than 15%. In summary, early mycosis fungoides is a condition in which host immunity is intact and the host immune system effectively limits proliferation of the malignant T-cell clone. In more advanced mycosis fungoides and in Szary syndrome,

Fig. 32-7 Alopecia mucinosa.

folliculotropism of the cells (pilotropic or follicular mycosis fungoides) or by the appearance of follicular mucinosis (Fig. 32-7). In all cases of follicular mucinosis, the histologic speci men should be carefully examined and the diagnosis of mycosis fungoides considered. Among patients older than 40 years of age who have follicular mucinosis, a large percent age will have mycosis fungoides or go on to develop it. However, the finding of a T-cell clone in lesions of follicular mucinosis without mycosis fungoides is not predictive of the development of cutaneous T-cell lymphoma. Selective tropism of the cutaneous T-cell lymphoma cells to the sweat glands and ducts is termed syringotropic cutaneous T-cell lymphoma (Fig. 32-8). This is often seen in conjunction with follicular involvement. Syringolymphoid hyperplasia may be seen in these cases histologically and may mimic eccrine carcinoma. Cases previously termed syringolym phoid hyperplasia with alopecia are now considered to be cutaneous T-cell lymphoma. Clinically, the lesions present as discrete follicular and nonfollicular erythema, along with alo pecia, milia, and follicular cysts. The initial clinical diagnosis in such cases is often discoid lupus erythematosus. The prog nosis in mycosis fungoides with adnexal involvement is as predicted by the staging system for other forms of mycosis fungoides.

Systemic manifestations
Mycosis fungoides as a form of malignant lymphoma may progress to include visceral involvement. Lymph node involve ment is most common; it predicts progression of the disease in at least one-quarter of patients and reduces survival to
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perhaps through interleukin (IL)-4 and 10, a Th2 environment exists. This downregulates suppressor cell function and allows the malignant clone to proliferate. In addition, the Th2dominant environment reduces effective helper T-cell func tion, explaining the increased risk of infection and secondary cancer in patients with advanced cutaneous T-cell lymphoma. Correcting the aberrant immune response in advanced cutane ous T-cell lymphoma is the basis of some treatment approaches. Common chromosomal alterations in mycosis fungoides include gain of 7q36 and 7q217q22, and loss of 5q13 and 9p21. This characteristic pattern differs from that seen in Szary syndrome, suggesting that the two disorders are distinct. Low levels of human herpesvirus (HHV) 8 have been detected in large-plaque parapsoriasis as well as mycosis fungoides, but an etiologic link has not been established. As mycosis fungoides advances, the number of circulating malignant T cells increases. Standard cytologic evaluation (the Szary preparation) is expensive and not very accurate, even when enhanced by specific labeling techniques. Use of stand ard laboratory tests, such as the CD4/CD8 ratio test, which increases as mycosis fungoides progresses, and assessment of the number of CD4+,CD7 or CD4+,CD26 circulating cells, which relatively specifically identify mycosis fungoides cells, yield indicators of tumor burden with advanced disease but are of limited value in early disease.

epidermotropism of lymphocytes, with disproportionately scant spongiosis more lymphocytes within the epidermis than would normally be seen in an inflammatory dermatosis, with little accompanying acanthosis or spongiosis lymphocytes in the epidermis larger than those in the dermis papillary dermal fibrosis with bundles of collagen arranged haphazardly prominent folliculotropism or syringotropism of the lymphocytes, especially with intrafollicular mucin deposition (follicular mucinosis). Features that should suggest a diagnosis of inflammatory dermatosis over mycosis fungoides include the following: prominent upper dermal and papillary edema marked epidermal spongiosis accumulation of the intraepidermal inflammatory cells in flask-shaped collections, with the top open to the stratum corneum. Immunohistochemistry is of some value in assessing mycosis fungoides. Mycosis fungoides cells characteristically are CD4+, but lose the CD7 and CD26 antigens, i.e. they are CD4+,CD7,CD26. This phenotype is very unusual for nonmalignant T cells and thus is useful in evaluating biopsy specimens and peripheral blood lymphocytes. Loss of CD7 expression within the large dark lymphocytes in the epider mis, with normal expression in the benign recruited lym phocytes in the infiltrate below, suggests a diagnosis of mycosis fungoides. DNA hybridization or a Southern blot test is frequently performed in equivocal cases to detect clonal rearrangement of the T-cell receptor (TCR). However, these data must be interpreted with caution; clonality does not confirm a diagnosis of malignancy. Benign processes may contain clonal TCR rearrangements. In early lesions of mycosis fungoides, the number of infiltrating cells may be insufficient for a clone to be detected, so a negative test does not exclude the diagnosis of mycosis fungoides. Testing with fresh tissue is somewhat more sensitive than with fixed tissue using current methods. Similar techniques can be used to evaluate lymph nodes in mycosis fungoides patients. Lymph node involvement can be detected by these molecular methods, while the routine histologic evaluation yields normal results. Patients with more advanced disease are more likely to have clones in their lymph nodes, and the presence of clonality is predictive of shorter survival.

Histopathology
Perhaps more than in any other situation in dermatopathol ogy, the ability to diagnose mycosis fungoides histologically correlates closely with the skill, training, and experience of the reviewing pathologist. When the clinician is considering a diagnosis of mycosis fungoides, consultation with a skilled dermatopathologist should be strongly considered if original histologic reports are nonconfirmatory or nonspecific. In patch-stage lesions there is subtle epidermotropism of lymphocytes that resembles a vacuolar interface dermatitis with a lymphocyte in every vacuole. As lesions progress, there is a distinct bandlike distribution of lymphocytes with epider motropism. At this stage, there is a large dark lymphocyte in every vacuole. The lymphocytes within the epidermis may be numerous or few in number, but are typically larger, darker, and more angulated than those in the dermis. Papillary dermal fibrosis is typically present. The superficial perivascular lym phoid infiltrate that surrounds the postcapillary venule is typi cally more prominent above the vessel than below the vessel (bare under-belly sign). Plaques of mycosis fungoides show a more prominent superficial bandlike lymphoid infiltrate and a deeper perivas cular dermal component than patch-stage lesions. Papillary dermal fibrosis is more prominent and the subpapillary plexus is shifted downward. Epidermotropism is much more marked and is typically associated with very little spongiosis. This helps distinguish patch-stage mycosis fungoides from spongi otic dermatitis. Vesicular variants are an exception to this rule. In vesicular variants, spongiosis is prominent and results in intraepidermal and subcorneal vesiculation. Eosinophils are common in folliculotropic mycosis fungoides (with or without follicular mucinosis), but are uncommon in other forms of mycosis fungoides. In thick plaques and tumors, epidermotropism may be sub stantially diminished. The diagnosis is confirmed by the pres ence of dense sheets of infiltrating lymphocytes in the dermis and subcutaneous fat. These cells may have cerebriform nuclei. Cardinal features that should suggest a diagnosis of mycosis fungoides include the following: solitary or small groups of lymphocytes in the basal cell layer

Differential diagnosis
In the early patch stage, mycosis fungoides may be difficult to diagnose. The skin lesions usually resemble a nondescript form of eczema with some scale. Interestingly, despite the itching, scratch marks and lichenification are usually absent. Mycosis fungoides presenting as papuloerythroderma of Ofuji is an obvious exception. The multiple morphologies of mycosis fungoides make the differential diagnosis vast. Plaque-like lesions may resemble subacute dermatitis or psoriasis. Tumors must be differentiated from other forms of lymphoreticular malignancy and metastases.

Treatment
Effective therapy that reliably prolongs survival has not yet been documented. Many forms of therapy induce remissions of variable length. The choice between them depends on extent of disease, the patients overall health and physical status, the physicians experience and preference, and the availability of various options. Topical steroids, topical nitrogen mustard or 1,3-bis (2-chloroethyl)-l-nitrosourea (carmustine) (BCNU),
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bexarotene gel 1%, and PUVA (or narrow-band UVB) are gen erally good choices for stages IA, IB, and IIA disease. Patchstage mycosis fungoides has responded to alefacept. Total skin electron beam (TSEB) therapy can be used for refractory stage IIA and IIB cases. Single-agent chemotherapy or photophore sis can be employed as initial management for stage III patients. Low-dose methotrexate may control the skin lesions of mycosis fungoides, but has been associated with the development of a secondary aggressive lymphoma in a few patients. Pegylated liposomal doxorubicin and combinations of IFN-, retinoids (bexarotene or isotretinoin), photophoresis, IFN-, skindirected PUVA, sargramostim (granulocyte macrophage colony-stimulating factor), alemtuzumab, and perhaps IL-2, IL-12, and IFN- may be effective in stage IV disease, and for patients who have failed the above therapies for stages IIB and III mycosis fungoides. Multiagent systemic chemotherapy is used much less commonly with the advent of immunomodu latory treatments for mycosis fungoides. It should only be considered when all other treatment options have failed. Treatment of early-stage disease is in general restricted to skindirected treatments. More advanced disease is treated with different modalities at different institutions. Combinations of agents are often used, and those combinations and their order of use vary from one institution to the next. In general, thera pies that also enhance the patients immune system are favored in persons with more advanced disease. Complete remission has been noted following a severe reaction to combined therapy with bexarotene, vorinostat, and high-dose fenofi brate. The reaction included fever, extensive skin necrosis, and granuloma formation. Topical corticosteroids The availability of superpotent class I topical corticosteroids has led to a reassessment of their pos sible role in the management of early (patch-stage, T1 and T2) mycosis fungoides. Zackheim reported a 63% complete remis sion for patients with T1 disease and a total response rate of 94% in T1 patients. In T2 patients, complete responses were only 25% but total responses were 82%. The predominant side effect was a temporary and reversible suppression of the hypothalamicpituitary axis in about 13% of patients. The responses were short-lived if therapy was stopped, but given the limited toxicity, this is not necessary in many patients. The adjunctive value of topical corticosteroids in T1 mycosis fun goides requires reappraisal because the response rates are similar to other modalities used for early mycosis fungoides and the toxicity is very low. Topical nitrogen mustard The contents of a 10mg vial of mechlorethamine hydrochloride (Mustargen-MSD) are dis solved in 60mL of tap water and applied to the entire skin surface, except the face, axillae, and genitalia, with a 2 inch paint brush or gauze pad. The last milliliter may be diluted to half-strength or greater dilution for application to the face, axillae, and genitalia. Daily applications are made until com plete clearing occurs, which usually takes several months or longer, and may be continued indefinitely. Such treatment leads to complete responses in 80% of patients with stage IA disease, 68% in patients with stage IB, 61% in stage IIA, 49% in stage IIB, and 60% in stage III patients. About 10% of patients obtain a durable and long-lasting remission of over 8 years. The major side effects of topical nitrogen mustard (NH2) therapy are cutaneous intolerance, which occurs in almost 50% of patients, and allergic contact dermatitis, which occurs in 15%. Short (1h) contact does not reduce this rate of sensitiza tion. This can be reduced by the use of an ointment formula tion, but response rates have been reported to be inferior with the ointment form. At least half of patients will relapse when therapy is stopped, but frequently will respond again to NH2. The duration of maintenance therapy after achieving remission varies in different centers. Some treat for an additional 6 months and others taper treatment over a year

or more, or continue treatment indefinitely. In many centers, topical nitrogen mustard has been a proven mainstay of therapy for patch- or plaque-stage mycosis fungoides without lymphadenopathy. Topical BCNU (carmustine) BCNU, 2mg/mL in 150mL aliquots, dissolved in ethanol, is dispensed to the patient. From this stock solution the patient takes 5mL and adds it to 60mL of water at room temperature. This is applied once a day to the whole body, sparing the folds, genitals, hands, and feet (if they do not have lesions). If the extent of disease is limited, only the affected areas are treated. The average treat ment course is 812 weeks. If, after 36 months, the patients condition is not responding, the concentration may be doubled and the treatment repeated for 12 weeks. For small or persist ent lesions, the straight stock solution may be applied daily. Patients tolerate BCNU better than nitrogen mustard, contact sensitization is uncommon, and responses are more rapid. Complete blood counts should be monitored monthly during treatment, but marrow suppression occurs in less than 10% of patients treated with the low concentrations. Telangiectasia, which may be persistent and severe, can occur after prolonged BCNU therapy or following an adverse cutaneous reaction to the medication. Ultraviolet therapy Both UVB (narrow- or broad-band) and PUVA (systemic or bath) have been effective in the manage ment of mycosis fungoides. About 75% of patients with patchstage disease will have a complete clinical remission with UVB therapy. Home therapy is successful. PUVA has been used more extensively and, because of its deeper penetration, is perhaps better suited to the treatment of a disorder with a dermal component. Complete clearing is seen in 88% of patients with limited patch/plaque disease and in 52% of patients with extensive disease. Tumor-stage patients do not clear. Erythrodermic patients have poor tolerance for PUVA. Up to 50% of patients with a complete response to PUVA may have a remission of up to 10 years. Retinoids and IFN- may be added to PUVA. Retinoids may reduce the total number of PUVA treatments required. Low-dose IFN- plus PUVA may be used in patch-stage patients in whom topical therapy and PUVA alone are ineffective. The excimer laser may be used once or twice a week to deliver the phototherapy if the patient has a limited number of lesions. On average, 56 weeks of treatment are required, and remissions of up to 2 years or more can be achieved. Extracorporeal photochemotherapy (photophoresis, ECP) is a therapeutic modality in which the circulating cells are extracted and treated with UVA outside the body; the patient ingests psoralen before the treatment. Complete responses are seen in a small percentage of mycosis fungoides patients, about 20%, and a partial response occurs in a similar percent age of patients. In the original reports, the overall response rate for erythrodermic patients was 80%, but many of these patients failed to have at least the 50% clearing required to be considered a partial response. In one comparative trial, stand ard PUVA was significantly more effective than photophoresis alone, and photophoresis was judged ineffective in plaquestage (T2) mycosis fungoides. ECP is now used in combination with other agents, especially IFN-, and appears to have better efficacy. Insulin-dependent diabetics respond poorly. Radiation TSEB therapy in doses in excess of 3000Gy is very effective in the management of mycosis fungoides. Stage T1 patients have a 98% complete response; stage T2, 71%; stage T3, 36%; and stage T4, 64%. Long-term remissions occur in about 50% of T1 patients and 20% of T2 patients. Erythrodermic patients tolerate TSEB therapy poorly; other modalities should be attempted initially. Adjuvant therapy with a topical agent or PUVA can be considered if the patient relapses, which is a frequent occurrence. The most common side effects of TSEB therapy are erythema, edema, worsening of lesions, alopecia,

and nail loss. Persistent hyperpigmentation and chronically dry skin are also problems after TSEB therapy. Orthovoltage radiation may be used to control tumors or resistant thick plaques in patients whose conditions have been otherwise controlled with another modality. Biologic response modiers (multimodality immunomodulatory therapy) The appearance of circulating malignant T cells in mycosis fungoides may indicate failure of the host immune system to control the disease. Immunomodulatory agents are used in an attempt to enhance host immune function and gain control of the disease. It is often combined with treatments that increase malignant cell apoptosis, so that the tumor antigens released will be recognized and immunologically attacked by the host immune system. These immunomodulatory agents both activate antigen-presenting cells and enhance Th1 immune function directed against the malignant T-cell clone. IFN- and IFN- have been shown to have efficacy against mycosis fungoides. IFN- is associated with a positive response in about 60% of patients and a complete response in 19%. If it is used as a single agent, toxicity is high and includes fever, chills, myalgias, neutropenia, and depression. Low-dose IFN- and IFN- treatments and granulocyte macrophage colonystimulating factor are now used in an adjunctive fashion in combination with retinoid therapy, phototherapy, and other modalities. This is termed multimodality immunomodulatory therapy. IL-2 and 12 may be used in a similar fashion in the future. Retinoids Both isotretinoin and etretinate have efficacy in the treatment of mycosis fungoides. A clinical response is noted in about 44% of patients. Dosage of isotretinoin is about 1mg/kg/day to start, and may be increased up to 3mg/kg/ day as tolerated. Retinoids may be effective in stage IB (T2) and stage III patients, and as a palliative treatment in those with stage IVA disease. Bexarotene (Targretin), a synthetic retinoid that is bound preferentially by the retinoid X receptor (RXR), is felt to work by inducing apoptosis in the malignant T cells. It is available as a 1% topical gel and as an oral tablet. Topical therapy is used in patients with stage IAIIA cutane ous T-cell lymphoma. Patients improve about 50% with this treatment. Oral bexarotene at a dose of 300mg/m2 also has a response rate of about 50% in early-stage cutaneous T-cell lymphoma. This dose is complicated by hypercholesterolemia, marked hypertriglyceridemia (at times complicated by pan creatitis), central hypothyroidism, and leukopenia. It may be combined with PUVA and other forms of treatment at a lower dose. Systemic chemotherapy For most forms of cancer, combi nations of chemotherapeutic agents are given. In mycosis fun goides, however, multidrug chemotherapy often exacerbates the ongoing immune imbalance and may prevent the patients immune system from attacking the malignant T cells. For this reason, and due to the enhanced efficacy of combination immunomodulatory treatment regimens, systemic chemother apy is now very uncommonly used for mycosis fungoides. Methotrexate, in doses from 5 to 125mg/week, is effective for the management of T3 patients. In these patients, Zackheim et al demonstrated that 41% had a complete response, and an additional 17% a partial response, giving a total response of 58%. The median overall survival was 8.4 years and 69% of patients were alive at 5 years. For advanced mycosis fun goides, higher doses of methotrexate with citrovorum-factor rescue were successful in obtaining a response, which was then maintained with lower doses of methotrexate, not requir ing rescue. Similarly, pentostatin, etoposide, fludarabine, and 2-chlorodeoxyadenosine have been used. Systemic chemo therapy beyond methotrexate, especially multiagent chemo therapy, is best managed by an oncologist. Systemic chemotherapy is only indicated in stage III and IVA patients who have failed all the available immunoenhancing treatment

protocols noted above. A number of new agents are being evaluated for the treatment of mycosis fungoides. Histone deacetylase inhibitors including vorinostat demonstrate responses in a subgroup of patients. Forodesine is a novel inhibitor of purine nucleoside phosphorylase and pralatrexate is a novel targeted antifolate agent. Fusion toxin DAB389IL-2 is the fusion of a portion of the diphtheria toxin to recombinant IL-2. This selectively binds to cells expressing the IL-2 receptor and leads to their death. A series of mycosis fungoides cases that expressed the IL-2 receptor demonstrated a response rate of 37%, including a complete response in 14% of cases. These patients had failed conventional therapies. Patients in stages IIII achieved response, but no patient with stage IV disease did so. Fever, chills, hypotension, nausea, and vomiting were common and at high doses a vascular leak syndrome occurred. This agent is reserved for advanced-stage patients who have failed other modalities.
Arulogun SO, et al: Long-term outcomes of patients with advancedstage cutaneous T-cell lymphoma and large cell transformation. Blood 2008 Oct 15; 112(8):30823087. Carter J, et al: Phototherapy for cutaneous T-cell lymphoma: online survey and literature review. J Am Acad Dermatol 2009 Jan; 60(1):3950. Enke CA: New options in diagnosis and management of mycosis fungoides and Szary syndrome. Oncology (Williston Park) 2010 May; 24(6):507508. Galper SL, et al: Diagnosis and management of mycosis fungoides. Oncology (Williston Park) 2010 May; 24(6):491501. Gerami P, et al: Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma. Arch Dermatol 2008 Jun; 144(6):738746. Green WH, et al: Patch-stage mycosis fungoides in remission after therapy with alefacept. J Am Acad Dermatol 2008 May; 58(5 Suppl 1): S110S112. Kempf W, et al: Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization for Research and Treatment of Cancer (EORTC). Arch Dermatol 2008 Dec; 144(12):16091617. Lansigan F, et al: Current and emerging treatment strategies for cutaneous T-cell lymphoma. Drugs 2010 Feb 12; 70(3):273286. Lafaille P, et al: Exacerbation of undiagnosed mycosis fungoides during treatment with etanercept. Arch Dermatol 2009 Jan; 145(1):9495. McGirt LY, et al: Predictors of response to extracorporeal photopheresis in advanced mycosis fungoides and Szary syndrome. Photodermatol Photoimmunol Photomed 2010 Aug; 26(4):182191. Novelli M, et al: Flow cytometry immunophenotyping in mycosis fungoides. J Am Acad Dermatol 2008 Sep; 59(3):533534. Olsen E, et al: Revisions to the staging and classication of mycosis fungoides and Szary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization for Research and Treatment of Cancer (EORTC). Blood 2007 Sep 15; 110(6):17131722. Quereux G, et al: Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Szary syndrome. Arch Dermatol 2008 Jun; 144(6): 727733. Steinhoff M, et al: Complete clinical remission of tumor-stage mycosis fungoides after acute extensive skin necroses, granulomatous reaction, and fever under treatment with bexarotene, vorinostat, and high-dose fenobrate. J Am Acad Dermatol 2008 May; 58(5 Suppl 1):S8891. Sun G, et al: Poor prognosis in non-Caucasian patients with early-onset mycosis fungoides. J Am Acad Dermatol 2009 Feb; 60(2):231235.

Pagetoid reticulosis
Localized epidermotropic reticulosis, Pagetoid reticulosis, or WoringerKolopp disease is an uncommon lymphoprolifera tive disorder considered be a form of mycosis fungoides. Other terms suggested for these cases have been acral mycosis fungoides or mycosis fungoides palmaris et plantaris. In large mycosis fungoides clinics, such cases represent about 0.6% of all mycosis fungoides cases. Pagetoid reticulosis is divided

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into classic WoringerKolopp, which usually describes soli tary lesions, and cases with multiple lesions (KetronGoodman variant). The unique features of WoringerKolopp disease are clinical. The disease presents as a solitary lesion that is often located on an extremity and frequently has a keratotic rim. If there is more than a single lesion, there is often a propensity for lesions to involve both the palms and soles. Frequently, over months to years, the lesion gradually enlarges, reaching a size of over 10cm. In some cases, the lesions spontaneously come and go over many years. Twenty percent of cases occur in patients who are younger than 15 years of age. The long duration without progression has been a clinical hallmark of WoringerKolopp disease. Histologically, there is prominent epidermotropism of lymphocytes, with many lining up in the basal cell layer. This histologic pattern correlates with strong E7 and 47 integrin expression by the infiltrating cells. This integrin expression is also seen in the epidermotropic cells of classic mycosis fungoides and contact dermatitis. In mycosis fungoides, most cases are CD4+, but in the acral mycosis fungoides cases they may be CD4+, CD8+, or negative for both. TCR gene rearrangements can be detected in many cases of WoringerKolopp disease. Therapeutically, local exci sion and radiation therapy have been curative in many cases. Topical and systemic PUVA has also proved effective. Local recurrence is possible.

hypersensitivity, elevated IgE, and eosinophilia seen in these patients. Szary syndrome is difficult to treat. Low-dose methotrexate has a reasonable response rate of about 50% and an overall survival of 101 months, suggesting a survival benefit with its use. Photophoresis, used in combination with other agents, is effective in some patients, but the median survival time is only between 39 and 60 months (see above). TSEB radiation has produced some complete cutaneous responses, as well as improvement in the blood burden of malignant cells. Zanolimumab has also been used in this setting.
Arulogun S, et al: Extracorporeal photopheresis for the treatment of Szary syndrome using a novel treatment protocol. J Am Acad Dermatol 2008 Oct; 59(4):589595. Contassot E, et al: Resistance to FasL and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in Szary syndrome T-cells associated with impaired death receptor and FLICE-inhibitory protein expression. Blood 2008 May 1; 111(9):47804787. Dores GM, et al: Assessment of delayed reporting of mycosis fungoides and Szary syndrome in the United States. Arch Dermatol 2008 Mar; 144(3):413414. Introcaso CE, et al: Total skin electron beam therapy may be associated with improvement of peripheral blood disease in Szary syndrome. J Am Acad Dermatol 2008 Apr; 58(4):592595.

Granulomatous slack skin

Granulomatous slack skin is a rare variant lymphoma that typically presents in middle-aged adults and gradually progresses over years. It occurs more often in men. Lesions are erythematous, atrophic, bulky, infiltrated, pendulous, and redundant plaques in the axillae and groin (Fig. 32-9). Unusual presentations may resemble Hansens disease or acquired ichthyosis. Histologically, there is a lymphohistio cytic infiltrate extending through the dermis into the subcuta neous fat. Focal collections of huge, multinucleated cells with 2030 nuclei arranged in a wreath-like pattern are characteristic. Elastophagocytosis is prominent and elastic tissue is absent in areas of inflammation. Lymphocytes are also found within the multinucleate giant cells and are arranged around them. Epidermotropic lymphocytes are also seen. Immunohistologically, the cells are CD4+. T-cell gene re arrangements can be detected. In most patients, the condition evolves into mycosis fungoides, but about one-third of patients with granulomatous slack skin develop Hodgkin disease after years to decades.
Hsiao PF, et al: Granulomatous slack skin presenting as acquired ichthyosis and muscle masses. Am J Clin Dermatol 2009; 10(1):2932. Pratchyapruit W, et al: Granulomatous slack skin clinically and histologically masquerading as borderline leprosy in its early stages. Eur J Dermatol 2009 JanFeb; 19(1):8889.

Szary syndrome
Szary syndrome is the leukemic phase of mycosis fungoides. The characteristic features are generalized erythroderma, superficial lymphadenopathy, and atypical cells in the circu lating blood. Although patients with classic mycosis fungoides may progress to Szary syndrome, usually patients with Szary syndrome are erythrodermic from the onset. The skin shows a generalized or limited erythroderma of a typical fiery red color. Associated features can include leonine facies, eyelid edema, ectropion, diffuse alopecia, hyperkeratosis of the palms and soles, and dystrophic nails. Some patients develop lesions identical to vitiligo, especially on the lower legs. The symptoms are those of severe pruritus and burning, with epi sodes of chills. Prognosis is poor, with an average survival of about 5 years. Superficial lymphadenopathy is usually found in the cervi cal, axillary, and inguinal areas. Leukocytosis up to 30 000/ mm3 is usually present. In the peripheral blood, skin infiltrate, and lymph nodes, helper T cells with deeply convoluted nuclei are foundthe so-called Szary cells. Chromosomal aberra tions are common, but differ from the typical pattern seen in mycosis fungoides. Resistance to Fas-ligand and TNF-related apoptosis has been demonstrated. Histologically, and by immunohistochemistry, there are no reproducible differences between cases of mycosis fungoides and Szary syndrome. In a fair number of cases of the latter, the cutaneous histology may be nonspecific, showing a spon giotic dermatitis. Additional hematologic evaluation may be necessary to confirm the diagnosis in the erythrodermic patient. T-cell gene rearrangement studies are frequently used to confirm the diagnosis of Szary syndrome. In addition, an increased CD4/CD8 ratio in the blood, with an increase in the number of CD3+/CD4+/CD7/CD26 circulating cells, is suggestive of leukemic mycosis fungoides. The erythroderma of Szary syndrome must be distin guished from chronic lymphocytic leukemia (CLL), psoriasis, atopic dermatitis, photodermatitis, seborrheic dermatitis, contact dermatitis, drug reaction, and pityriasis rubra pilaris. This is done primarily by histopathologic and immunopatho logic examination. In Szary syndrome, the infiltrating T cells in the skin have a Th2 phenotype, and Th2 cytokines are pro duced by these cells. This explains the reduced delayed-type

Fig. 32-9 Granulomatous slack skin.

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Lymphomatoid papulosis
Lymphomatoid papulosis (LyP) is an uncommon, but not rare disorder. It occurs at any age, including childhood, but is most common in adults with a mean age of 44. In most typical cases, the lesions and course are very similar to that of Mucha Habermann disease (pityriasis lichenoides et varioliformis acuta), except that the lesions tend to be slightly larger and fewer in number, and have a greater propensity to necrosis. Symptoms are usually minimal. The primary lesion is a red papule up to about 1cm in diameter (Fig. 32-10). The lesions evolve to papulovesicular, papulopustular, or hemorrhagic, then necrotic papules over days to weeks. They typically heal spontaneously within 8 weeks, somewhat longer in larger lesions. Lesions are usually generalized, although cases limited to one anatomic region have been reported. There may be crops of lesions or a constant appearance of a few lesions. In most patients, however, the condition tends to be chronic, and lesions are present most of the time if no treat ment is given. The average number of lesions present at any one time is usually 1020, but cases with more than 100 lesions occur. Lesions heal with varioliform, hyperpigmented, or hypopigmented scars. Cases previously reported as solitary, large nodules of lymphomatoid papulosis would now be clas sified as CD30+ large-cell lymphomas or as overlaps between LyP and lymphoma, termed borderline cases. Localized agmi nated LyP may be seen in areas typical for mycosis fungoides. The diagnosis of LyP is confirmed histologically. There is a dermal infiltrate that is wedge-shaped, patchy, and perivascu lar. In larger lesions, the infiltrate may occupy the whole dermis. It may also be bandlike. The infiltrate may involve the epidermis, with epidermotropism of inflammatory cells. As lesions evolve, epidermal necrosis and ulceration may occur. The dermal vessels may demonstrate fibrin deposition and, more rarely, a lymphocytic vasculitis. The dermal infiltrate is composed of lymphoid cells, eosinophils, neutrophils, and larger mononuclear cells. Atypical large or small lymphoid cells are present and may represent up to 50% of the infiltrate. Histologically, lesions have been classified into type A, type B, and type C lesions. Type A lesions contain atypical large cells with abundant cytoplasm and prominent nuclei, with prominent eosinophilic nucleoli. If these cells contain two nuclei, they closely resemble ReedSternberg cells. In type B lesions, the atypical cells are smaller, with a smaller cerebriform, hyperchromatic nucleus. These resemble the atypical cells of mycosis fungoides. In both types of lesion, atypical mitotic figures may be observed.

Immunophenotypically, the large atypical cells mark as T cells, usually of the helper type. The atypical cells, especially those of the type A lesions, stain for the activation marker Ki-1 or CD30. Bcl-2 expression occurs in about 50% of cases. When clonal rearrangement studies are performed, clonal rearrange ments may be found in up to 40% of LyP lesions, but this finding is not predictive of the behavior of that lesion or the case in general. Type C lesions overlap with primary cutane ous large-cell lymphoma with no clear distinction between the two. CD8+ LyP is a rare variant in which the Tc2 subset of CD8+ T cells proliferates and attracts eosinophils. Lymphomatoid papulosis types A and B are associated with lymphoma. In the general literature this number is about 510%, but some reports have documented rates as high as 20%, and at the University of California at San Francisco (UCSF) up to 40% of cases of LyP have an associated lym phoma. The lymphoma may occur before, concurrently with, or after the appearance of the LyP. In most cases, the LyP precedes the development of lymphoma, sometimes by a long periodup to 20 years. The associated lymphoma is most commonly mycosis fungoides (40%), a CD30+ T-cell lym phoma (30%), or Hodgkin disease (25%). The lymphoma and LyP may behave quite independently. If the lymphoma is suc cessfully treated and cleared, the LyP typically continues. Despite this independent behavior, the lymphoma and the LyP may contain the same clonal TCR gene rearrangement. Patients with pure type B lesions are much less likely to develop lymphoma than patients with type A lesions. Lesions of LyP may occur on a background of mycosis fungoides and must be distinguished from CD30-positive large-cell transfor mation of mycosis fungoides. Papular lesions of LyP tend to occur in crops. Even though the LyP lesions may demonstrate the same clonal rearrangements as the mycosis fungoides, they often continue to appear in crops, even when the mycosis fungoides lesions respond to therapy. Therapy may not be necessary; there is no evidence that treatment of LyP prevents the development of secondary lym phoma. When any therapy is stopped, the LyP invariably returns. Therefore, patients only need to be treated if they are moderately symptomatic and the treatment has fewer poten tial complications than the benefits gained. Superpotent topical corticosteroids have been beneficial in some childhood cases. Topical bexarotene may abort early lesions, and oral bexaro tene may suppress lesion formation. PUVA systemically or topically may be effective, although maintenance treatment is usually required. Both narrow- and broad-band UVB may be successful. Of all the systemic agents, methotrexate gives the most dependable response, with up to 90% of LyP patients improving significantly. It is given in weekly doses similar to those used for rheumatoid arthritisusually 7.515mg/week. Higher doses may be required in some patients. Response is rapid. Some patients treated with methotrexate may have remissions of the LyP. In most, however, maintenance therapy is required.
Heald P, et al: Persistent agmination of lymphomatoid papulosis: an equivalent of limited plaque mycosis fungoides type of cutaneous T-cell lymphoma. J Am Acad Dermatol 2007 Dec; 57(6):10051011. Kamstrup MR, et al: Potential involvement of Notch1 signalling in the pathogenesis of primary cutaneous CD30-positive lymphoproliferative disorders. Br J Dermatol 2008 Apr; 158(4):747753. Slone SP, et al: IL-4 production by CD8+ lymphomatoid papulosis, type C, attracts background eosinophils. J Cutan Pathol 2008 Oct; 35(Suppl 1):3845.

Pityriasis lichenoides
Fig. 32-10 Lymphomatoid papulosis. (Courtesy of M. Rosenbach, MD)

Both the acute and chronic forms of pityriasis lichenoides are lymphocytic vasculitides. The lymphoid infiltrate may contain
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a clonal proliferation. However, progression to cutaneous lymphoma is rare.

Pityriasis lichenoides chronica

Pityriasis lichenoides chronica (PLC) is a chronic form of pit yriasis lichenoides, related to PLEVA by its common histol ogy. Lesions are erythematous, scaly macules and flat papules with very slow evolution. Lesions each last several months. The eventual resolution of lesions of PLC distinguishes it from guttate parapsoriasis, which it may resemble clinically. Lesions of small-plaque parapsoriasis do not spontaneously resolve. Lesions of PLC favor the lateral trunk and proximal extremi ties. Patients may have from 10 to hundreds of lesions, but usually fewer than 50. Resolution may leave persistent areas of hypopigmentation, which last for months to years. In many patients, the hypopigmented macules are the most prominent clinical finding. Unlike PLEVA, PLC tends to last for many years. Lesions may occur at any age. The condition commonly affects children, and onset at birth has been described. Histologically, the changes are similar to PLEVA but much more subtle. A mild interface or perivascular lymphocytic infiltrate with overlying parakeratosis may be present. T-cell gene rearrangement studies may demonstrate monoclonality; however, the meaning of this finding is unclear at this time. Treatment with phototherapy (natural sunlight, UVB, UVA1, or PUVA) is most effective. Topical steroids or tacrolimus may be tried. No treatment is required. PLC is generally a benign disease. There are rare patients who have progressed to develop cutaneous T-cell lymphoma. The authors recommend that patients with PLC be followed regularly and changes in lesion morphology, including indu ration, erosion, atrophy, persistent erythema, or poikiloderma, should trigger repeat pathologic evaluation.
Aydogan K, et al: Narrowband UVB (311nm, TL01) phototherapy for pityriasis lichenoides. Photodermatol Photoimmunol Photomed 2008 Jun; 24(3):128133. Ersoy-Evans S, et al: Narrowband ultraviolet-B phototherapy in pityriasis lichenoides chronica. J Dermatolog Treat 2008 Nov; 14:15. Fernandes NF, et al: Pityriasis lichenoides et varioliformis acuta: a disease spectrum. Int J Dermatol 2010 Mar; 49(3):257261. Fernndez-Guarino M, et al: Pityriasis lichenoides chronica: good response to photodynamic therapy. Br J Dermatol 2008 Jan; 158(1):198200. Lpez-Ferrer A, et al: Pityriasis lichenoides chronica induced by iniximab, with response to methotrexate. Eur J Dermatol 2010 JulAug; 20(4):511512. Nikkels AF, et al: Etanercept in therapy multiresistant overlapping pityriasis lichenoides. J Drugs Dermatol 2008 Oct; 7(10):990992. Skinner RB, et al: Rapid resolution of pityriasis lichenoides et varioliformis acuta with azithromycin. J Am Acad Dermatol 2008 Mar; 58(3):524525. Smith JJ, et al: Febrile ulceronecrotic MuchaHabermann disease associated with herpes simplex virus type 2. J Am Acad Dermatol 2009 Jan; 60(1):149152. Sotiriou E, et al: Febrile ulceronecrotic MuchaHabermann disease: a case report and review of the literature. Acta Derm Venereol 2008; 88(4):350355.

Pityriasis lichenoides et varioliformis acuta (MuchaHabermann disease)

Pityriasis lichenoides et varioliformis acuta (PLEVA) is a dis order that usually appears suddenly in children or young adults. Individual lesions are erythematous macules, papules, or papulovesicles. Lesions tend to be brownish-red and evolve through stages of crusting, necrosis, and varioliform scarring. Lesions tend to appear in crops, and may number from a few to more than 100 (Fig. 32-11). In general, PLEVA patients have more and smaller lesions than patients with LyP. The trunk is favored, but even the palms and soles may infrequently be involved. The patient feels otherwise well. The natural history is benign, with spontaneous involution occurring over 13 years. In children, diffuse cases resolved more quickly than cases that were purely central; cases with primarily peripheral lesions took almost twice as long to resolve. Histologically, PLEVA is characterized by epidermal necro sis, together with prominent hemorrhage and a dense perivas cular infiltrate in the upper and mid-dermis in a wedge-shaped pattern. Lymphocytic vasculitis may be seen. T-cell gene re arrangements may be detected, but the significance of that finding is unclear at this time. Treatment of PLEVA may include oral erythromycin or tetracyclines and phototherapy (broad- or narrow-band UVB, PUVA, or photodynamic therapy). Topical tacrolimus may be effective. Low-dose methotrexate, 5.015mg/week, may be required in severe cases. A rapid response to azithromycin has been reported. Etanercept has been reported as effective, but infliximab has been reported to cause pityriasis lichenoides. An unusually severe form of PLEVA (febrile ulceronecrotic MuchaHabermann disease) is characterized by the acute onset of diffuse, coalescent, large, ulceronecrotic skin lesions associated with high fever and constitutional symptoms. The condition may begin as typical PLEVA, but the ulceronecrotic lesions usually begin to appear within a few weeks. Skin necrosis may be extensive, especially in the intertriginous regions. Associated symptoms include gastrointestinal and central nervous system (CNS) symptoms, pneumonitis, myo carditis, and even death (in adult cases). The condition favors boys who are l8 years of age or younger. This severe form of PLEVA usually lasts several months with successive out breaks, then resolves or converts to more classic PLEVA. Reported triggers include viral infections and radiocontrast injection. Treatment is systemic steroids, and if response is limited, methotrexate. Dapsone may also be useful, for main tenance and as a steroid-sparing agent.

Primary cutaneous T-cell lymphomas other than mycosis fungoides

Once a cutaneous lymphoma has been identified as being of T-cell origin and the diagnosis of mycosis fungoides and its variants has been excluded, the most important evaluation is to determine the CD30-staining pattern. CD30 is a marker found on some activated, but not resting T and B cells. It also marks the ReedSternberg cells of Hodgkin disease. Monoclonal antibodies Ki-1 and Ber H2 are used to identify CD30 positiv ity. A cutaneous lymphoma is considered to be CD30+ if there are large clusters of CD30+ cells or more than 75% of the ana plastic T cells are CD30+. Systemic CD30+ lymphoma with cutaneous involvement has a poor prognosis. Those cases that

Fig. 32-11 MuchaHabermann disease.

730

express anaplastic lymphoma kinase (ALK-1) associated with a 2:5 translocation have a somewhat better prognosis. Primary cutaneous large T-cell lymphomas that are CD30+ are typically ALK-1-negative, have a very good prognosis, and tend to run a relapsing course similar to that of lymphomatoid papulosis. Individual lesions respond to irradiation and the relapsing course may remit with low-dose methotrexate. Large-cell lym phomas of the skin have similar histologic and clinical fea tures, so immunophenotyping is essential for prognosis. Clonal TCR gene rearrangements are present in large-cell T-cell lymphoma. The group of T-cell lymphomas that are not large-cell and CD30+ are classified in the WHO system as peripheral T-cell lymphomas. CD56 is rapidly becoming the second most important immunophenotypic marker for cutaneous lymphomas. Four important variants of CD56+ cutaneous lymphomas have been identified: a subset of subcutaneous panniculitis-like T-cell lymphoma; natural killer (NK)/T-cell lymphoma; blastic NK cell lymphoma; and CD8+ aggressive epidermotrophic cyto toxic T-cell lymphoma. Peripheral T-cell lymphoma is a heterogeneous grouping that includes primary cutaneous CD30+ nonanaplastic largecell lymphoma, primary cutaneous CD30 anaplastic and nonanaplastic large-cell lymphoma, and primary cutaneous CD30 pleomorphic small-/medium-cell lymphoma.

papulosis and CD30+ anaplastic T-cell lymphoma have been described, sometimes under the designation type C lympho matoid papulosis. Histologically, there is a dense dermal non epidermotropic infiltrate with atypical tumor cells whose large nuclei have one or several prominent nucleoli and abundant cytoplasm. The malignant cells can be further characterized as anaplastic, pleomorphic, and immunoblastic, but this distinc tion may be difficult and has yet to be determined to be of prognostic or therapeutic value. This form of primary cutane ous T-cell lymphoma has an excellent prognosis, with a 5-year survival of 90%. Lesions are highly responsive to radiother apy. Early individual lesions can even be surgically excised. Topical imiquimod has been therapeutically successful. Chemotherapy causes regression of lesions, but a rapid relapse usually occurs. Other than low-dose methotrexate, chemo therapy generally has little role in the treatment of this disease. Local hyperthermia has been used successfully, as has inhibi tion of the mammalian target of rapamycin.

Secondary cutaneous CD30+ large-cell lymphoma

CD30+ large-cell lymphomas may arise in cases of mycosis fungoides, in patients with lymphomatoid papulosis, and in patients who have documented extracutaneous disease (sec ondary cutaneous anaplastic large-cell lymphoma). Skin lesions of pyogenic lymphoma may be seen secondary to a pyogenic lymphoma of other organs. The prognosis is poor in patients who have extracutaneous disease preceding or near the time of cutaneous involvement. Among those with sys temic disease, the expression of Alk-1 associated with a t(2; 5) translocation is a favorable prognostic feature. Kempf et al reported that MUM1 expression is common in secondary ana plastic large-cell lymphoma and in LyP, but uncommon in primary cutaneous anaplastic large-cell lymphoma. Other authors have disputed that MUM1 is a useful marker. Patients with lymphomatoid papulosis, who develop cutaneous CD30+ lymphoma and who do not have systemic lymphoma or mycosis fungoides, typically have an excellent prognosis. The prognosis for patients with mycosis fungoides who develop CD30+ anaplastic large-cell lymphoma is poor.

CD30+ cutaneous T-cell lymphoma (primary cutaneous anaplastic large-cell lymphoma)

Clinically, these lymphomas present as solitary or localized skin lesions that have a tendency to ulcerate (50%), spontane ously regress (25%), and relapse. They are rare in children and occur with slightly greater frequency in males. Lesions are usually firm, red to violaceous tumors up to 10cm in diameter (Fig. 32-12). Tumors may grow in a matter of weeks. There is no favored anatomic site. Onset has been reported during glatiramer acetate treatment of multiple sclerosis. Relapses in the skin are common, but the development of extracutaneous, bone marrow, or lymph node involvement is uncommon. Clonal populations may occasionally be demon strated in peripheral blood, but differ from those in the skin. Lymph node involvement is associated with a poorer progno sis. The pyogenic lymphoma of the skin is a neutrophil-rich CD30+ lymphoma with skin lesions that clinically resemble Sweet syndrome, pyoderma gangrenosum, halogenoderma, leishmaniasis, or deep fungal infection. IL-8 overexpression by the anaplastic CD30+ cells causes the neutrophilic infiltration. The number of neutrophils present may make histologic inter pretation difficult. Cases with features of both lymphomatoid

Non-mycosis fungoides CD30 cutaneous large T-cell lymphoma

Non-mycosis fungoides CD30 cutaneous large T-cell lym phomas usually present as solitary or generalized plaques, nodules, or tumors of short duration. There is no preceding patch stage that distinguishes it from mycosis fungoides. The prognosis is poor, with a 5-year survival rate of 15%. The malignant cells are pleomorphic large or medium cell types or are immunoblastic. The cells may be cerebriform and epidermo tropism may be present. Some cases previously called demble mycosis fungoides are better classified in this group. Multiagent chemotherapy is recommended.

Pleomorphic T-cell lymphoma (non-mycosis fungoides CD30 pleomorphic small/medium-sized cutaneous T-cell lymphoma)
This group comprises about 3% of all primary cutaneous lym phomas. Pleomorphic small/medium-sized cutaneous T-cell lymphoma is distinguished from the large-cell type by having less than 30% large pleomorphic cells. It is distinguished from mycosis fungoides by clinical features (lack of patch or plaque lesions). These primary cutaneous lymphomas usually present with one or several redpurple papules, nodules, or tumors (5mm to 15cm in size). Immunophenotypically, they are usually of helper T-cell origin and clonal rearrangements of the TCR gene are usually present. A CD4 phenotype, as opposed to a CD8 phenotype, is associated with a more
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Fig. 32-12 Large-cell anaplastic lymphoma.

Cutaneous lymphomas

32
Cutaneous Lymphoid Hyperplasia, Cutaneous T-cell Lymphoma

favorable prognosis, but a CD4/CD56 phenotype has a poorer prognosis. The presence of a mixed population of suppressor cells, B cells, and histiocytes usually favors the diagnosis of reactive lymphoid hyperplasia. The overall prognosis is inter mediate, with a 5-year survival rate of 62%. The optimal therapy for this form of lymphoma has not been determined. Therapeutically, localized lesions have been treated with radi ation therapy or surgical excision. Chemotherapy, retinoids, interferons, and monoclonal antibodies have been used in widespread or progressive disease.

Lennert lymphoma (lymphoepithelioid lymphoma)

Lennert lymphoma is a rare CD4+ systemic T-cell lymphoma. Cutaneous lesions occur in less than 10% of cases and present as papules, plaques, or nodules. The skin lesions may not represent lymphoma cutis because palisaded granulomatous and nonspecific dermal infiltrates may occur. The clinical and histologic appearance may resemble granuloma annulare very closely. The course is low-grade until the lymphoma trans forms to a high-grade, large-cell lymphoma.

frequent. Benign histiocytes are present in large or small numbers and demonstrate erythrophagocytosis (bean-bag cells). Immunophenotypically, the neoplastic cells mark as T cells (CD2+, CD3+). Most cases are derived from / T cells and are CD56. They have a less aggressive course. A subset of subcutaneous T-cell lymphomas are derived from / T cells and are CD56+. These cases have been misdiagnosed as lupus profundus or alopecia areata; histologically prominent dermal and even epidermal (interface) involvement may be seen. They have a more aggressive course and are now classi fied separately. SPTCL may evolve from the benign variant of cytophagic histiocytic panniculitis, which may also have a hemophagocytic syndrome. Multiagent chemotherapy is rec ommended, at times with stem-cell support. Denileukin difti tox (Ontak) was reported to produce a favorable response.

Nasal/nasal-type NK/T-cell lymphoma (angiocentric lymphoma)

NK/T-cell lymphoma most frequently presents in extranodal tissue and is characterized by a high incidence of nasal involvement. It is more common in Asia, where it affects pri marily women with a mean age of 40. In Korea it is reported to be the most common form of cutaneous lymphoma after mycosis fungoides. It is uncommon in the US. It presents clini cally as dermal or subcutaneous papules or nodules that may ulcerate. Lesions are usually widespread and involve the lower extremities. A hydroa vacciniforme-type has been described in children in Mexico and in adults and children in Japan and Korea. Skin lesions are facial and extremity papulo vesicles ulcerate and heal with scarring. Skin lesions are exac erbated by sun exposure and are reproduced with UVA irradiation. Histologically, the dermis and subcutaneous fat are infil trated with intermediate-sized, atypical lymphocytes, within and around the walls of small and medium-sized vessels. Epidermotropism may be noted. The lymphoma cells express a spectrum of T- and NK-cell immunophenotypic markers, variably expressing CD2, CD3, CD4, CD8, and the NK-cell marker CD56. CD56 is not cell lineage-specific, and a subset of CD56 cutaneous lymphoma cases is classified under the SPTCL category. EpsteinBarr virus is present in the NK vari ants and variably present in the T-cell variants. T-cell clonality is detected if the T-cell immunophenotype is present. The prognosis is poor.

Subcutaneous (panniculitis-like) T-cell lymphoma

Clinically, patients are usually young adults who present with subcutaneous nodules (Fig. 32-13), usually on the lower extremities, and are frequently diagnosed as having erythema nodosum or some other form of panniculitis. Weight loss, fever, and fatigue are common and may herald the onset of a rapidly progressive hemophagocytic syndrome, which is often fatal. Extracutaneous involvement is rare, even in fatal cases. An indolent chronic course can also be seen, but even in these cases the prognosis is poor. This variant of lymphoma may also rarely be seen in childhood. Histologically, there is a lace-like infiltration of the lobules of adipocytes, mimicking panniculitis, especially lupus pro fundus. A characteristic feature is rimming of neoplastic cells around individual adipocytes. The infiltrate contains prima rily small cells with hyperchromatic, irregular nuclei and large anaplastic cells in varying proportions. The small cells are atypical, karyorrhexis is prominent, and mitotic figures are

Blastic plasmacytoid dendritic cell neoplasm (blastic NK-cell lymphoma, CD4, CD56+ hematodermic neoplasm)
The majority of patients are males, with a mean age of about 60 years. All patients present with multiple, rapidly expanding plaques and/or nodules on noncontiguous sites. Lesions are characteristically purple in color. The course is aggressive in most patients, with rapid cutaneous relapse after chemother apy with systemic involvement. Histologically, the cells infil trate the dermis or subcutaneous fat, with a tendency for the neoplastic cells to Indian file in dermal collagen. There is usually a Grenz zone below the epidermis. The lymphoma cells are small/medium to large blastic lymphocytes. Angiocentricity may be noted, but is not prominent. Immunophenotyping is usually CD4+,CD56+. MIB-1 shows a proliferation activity of over 50%. T-cell gene rearrangements are negative. A response to pralatrexate has been reported, but in general the results with radiation therapy and chemother apy have been poor. Bone marrow transplantation (BMT) may play an important role in therapy.
Fig. 32-13 Subcutaneous T-cell lymphoma.
Benner MF, et al: Bone marrow examination has limited value in the staging of patients with an anaplastic large cell lymphoma rst

732

presenting in the skin. Retrospective analysis of 107 patients. Br J Dermatol 2008 Nov; 159(5):11481151. Chumsri S, et al: Inhibition of the mammalian target of rapamycin (mTOR) in a case of refractory primary cutaneous anaplastic large cell lymphoma. Leuk Lymphoma 2008 Feb; 49(2):359361. Ehst BD, et al: Primary cutaneous CD30+ anaplastic large cell lymphoma responds to imiquimod cream. Eur J Dermatol 2008 JulAug; 18(4):467468. Fernndez-Torres R, et al: Extranodal NK/T-cell lymphoma, nasal type presenting as a pyogenic granuloma-like on a ngertip. Eur J Dermatol 2009 JanFeb; 19(1):7980. Fujita H, et al: Primary cutaneous anaplastic large cell lymphoma successfully treated with low-dose oral methotrexate. Eur J Dermatol 2008 MayJun; 18(3):360361. Herling M, et al: CD4+/CD56+ hematodermic tumor: the features of an evolving entity and its relationship to dendritic cells. Am J Clin Pathol 2007 May; 127(5):687700. Honma M, et al: Primary cutaneous anaplastic large cell lymphoma successfully treated with local thermotherapy using pocket hand warmers. J Dermatol 2008 Nov; 35(11):748750. Humme D, et al: Dominance of nonmalignant T-cell clones and distortion of the TCR repertoire in the peripheral blood of patients with cutaneous CD30+ lymphoproliferative disorders. J Invest Dermatol 2009 Jan; 129(1):8998. Kempf W, et al: MUM1 expression in cutaneous CD30+ lymphoproliferative disorders: a valuable tool for the distinction between lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Br J Dermatol 2008 Jun; 158(6):12801287. Leitenberger JJ, et al: CD4+ CD56+ hematodermic/plasmacytoid dendritic cell tumor with response to pralatrexate. J Am Acad Dermatol 2008 Mar; 58(3):480484. Madray MM, et al: Glatiramer acetate-associated, CD30+, primary, cutaneous, anaplastic large-cell lymphoma. Arch Neurol 2008 Oct; 65(10):13781379. Massone C, et al: The morphologic spectrum of primary cutaneous anaplastic large T-cell lymphoma: a histopathologic study on 66 biopsy specimens from 47 patients with report of rare variants. J Cutan Pathol 2008 Jan; 35(1):4653. Parveen Z, et al: Subcutaneous panniculitis-like T-cell lymphoma: redenition of diagnostic criteria in the recent World Health Organization-European Organization for Research and Treatment of Cancer classication for cutaneous lymphomas. Arch Pathol Lab Med 2009 Feb; 133(2):303308. Querfeld C, Khan I, Mahon B, Nelson BP , Rosen ST, Evens AM: Primary cutaneous and systemic anaplastic large cell lymphoma: clinicopathologic aspects and therapeutic options. Oncology (Williston Park) 2010 Jun; 24(7):574587. Savage KJ: Prognosis and primary therapy in peripheral T-cell lymphomas. Hematology Am Soc Hematol Educ Program 2008; 2008:280288. Savage KJ, et al: ALK anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specied: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008 Jun 15; 111(12):54965504.

Cutaneous B-cell lymphoma

Primary cutaneous B-cell lymphomas (Fig. 32-14) occur less commonly than cutaneous T-cell lymphomas (25% of cases of primary cutaneous non-Hodgkin lymphomas are B-cell in origin). Although the morphologic appearance of the malig nant lymphocytes composing these primary cutaneous lym phomas is identical to lymphomas based in lymph nodes, they have a distinctly different clinical behavior and immuno phenotypic profiles. This renders the classification systems based on lymph node histology of limited benefit in the diag nosis of primary cutaneous B-cell lymphomas. More simpli fied schemes have thus been proposed that apply to primary cutaneous lymphomas only. While most entities classified by the European Organization for Research and Treatment of Cancer (EORTC) have now been accepted in the WHO classification, some remain provisional entities. The great majority of primary cutaneous B-cell lymphomas are composed of cells with the morphologic characteristics of the B cells normally found in the marginal zone or germinal centers of lymph nodes. Classification schemes used primarily for lymph node-based lymphomas divide these lymphomas into multiple types based on histomorphology. Secondary cutaneous involvement can occur with all forms of B-cell lym phoma based primarily in lymph node or other sites. The clinical features are similar to those of primary cutaneous lymphoma, with violaceous papules or nodules (Fig. 32-15). Typically, the histologic structure of secondary lesions in the skin is similar to that of the lymphoma at the site of origin, usually the lymph nodes. The pattern in the skin may not, however, be sufficient to classify the lymphoma, making lymph node biopsy necessary in most cases. In secondary cutaneous B-cell lymphomas the prognosis is generally poor. It is therefore critical to evaluate any patient suspected of having primary cutaneous B-cell lymphoma to exclude involvement at another site. Radiation is most commonly used for indolent forms of cutaneous B-cell lymphoma, but excision, rituximab, intralesional corticosteroids, and systemic chemo therapy have also been used in selected cases. Higher-grade lymphomas, including leg-type lymphoma, primary cutane ous follicle center lymphoma occurring on the leg, and precur sor B-cell lymphoblastic lymphoma, are typically treated with systemic chemotherapy regimens including combinations of anthracycline-containing chemotherapies and rituximab.

Adult T-cell leukemia/lymphoma

Infection with human lymphotropic virus type 1 (HTLV-1) may lead to acute T-cell leukemia/lymphoma (ATL) in 0.01 0.02% of infected persons. This virus is endemic in Japan, Southeast Asia, the Caribbean, Latin America, and equatorial Africa. ATL usually has an acute onset, with leukocytosis, lymphadenopathy, and HOTS (hypercalcemia, osteolytic bone lesions, T-cell leukemia, and skin lesions). Lesions resemble mycosis fungoides, except that patches are uncommon and plaques and nodules predominate. Histologically, the skin lesions contain lichenoid infiltrates of medium-sized lym phocytes with convoluted nuclei. Epidermotropism and involvement around and within adnexa occur. Granuloma formation may occur in the dermis. ATL cells are usually CD4+/CD7 and show T-cell gene rearrangements.

Fig. 32-14 Lymphoma, B-cell.

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Cutaneous B-cell lymphoma

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Cutaneous Lymphoid Hyperplasia, Cutaneous T-cell Lymphoma

Fig. 32-15 Secondary cutaneous B-cell lymphoma.

Primary cutaneous marginal zone lymphoma (PCMZL, MALT-type lymphoma, including primary cutaneous immunocytoma)
These lymphomas present as solitary or multiple dermal or subcutaneous nodules or tumors primarily on the upper part of the body, trunk, or extremities. Widespread lesions suggest secondary skin involvement by systemic lymphoma. Women are affected more than men. Immunocytomas are associated with European Borrelia and occur as tense, shiny, pink to red nodules on the legs of older patients. Histologically, the infiltrate may be nodular or diffuse. The neoplastic cells are medium-sized gray cells with predomi nantly cleaved nuclei that proliferate within the space sur rounding and between benign germinal centers. Plasma cells are typically present and may be numerous. Light chain restriction is easiest to identify in the plasma cell population by means of in situ hybridization. The lymphoma cells may contain Dutcher bodies, intranuclear collections of immuno globulin. Initially, the malignant cells may represent a very small proportion of the infiltrate and an incorrect diagnosis of pseudolymphoma may be made. Over time, the marginal zone cells predominate and the germinal centers are dimin ished. Immunophenotypically, the cells are CD20+, CD79+, and BCL-2+. Clonal immunoglobulin gene rearrangements can usually be demonstrated. The prognosis is excellent, with 5-year survival close to 100%. Local radiation therapy, or exci sion if lesions are few, is recommended. In some Borreliaendemic areas in Europe, immunocytomas are common. They present with sheets of plasmacytoid B cells with Dutcher bodies. Treatment is similar to other forms of PCMZL.

phomas are more common in men than women. Males outnumber females 4:1 in trunk lesions, whereas women disproportionately have head and leg lesions. Untreated, the lesions gradually increase in size and number, but extracuta neous involvement is uncommon. The prognosis is excellent, 5-year survival with treatment approaching 100%. Secondary cutaneous involvement of systemic follicular lymphoma has a poor prognosis. Histologically, the neoplasm is composed of centroblasts (uncleaved nuclei with a peripheral nucleolus) and centrocytes (cleaved nuclei with a peripheral nucleolus). The diffuse form is more common than the follicular form. In the diffuse form, the neoplastic cells retain the normal BCL-6+ phenotype of a follicle center cell, but typically lose expression of CD10. The follicular growth pattern is composed of irregularly shaped asymmetrical follicles that crowd together like pieces of a jigsaw puzzle. The cells typically stain for both BCL-6 and CD10, and these stains demonstrate neoplastic cells that have wandered beyond the confines of the follicle center. Elongated carrot-shaped nuclei are often present within the follicular centers, and CD21 staining shows defects in the net of dendritic cells in the follicle center. In early lesions, the neoplastic cells are of smaller size and there is a substantial portion of normal T cells surrounding and mixed with the neoplastic B cells. Over time, the neoplas tic B cells become a more predominant portion of the infiltrate, the neoplastic cells are larger in size, and tumor-infiltrating T cells diminish. Immunophenotypically, the neoplastic cells stain with B-cell markers (CD20) and may be monotypic for immunoglobulin production, i.e. they stain for either or light chains, but not both. Immunoglobulin staining is com monly negative in tumorous lesions, but clonal rearrangement of the immunoglobulin gene can be demonstrated by polymer ase chain reaction (PCR). The absence of expression of BCL-2, lack of adenopathy, and lack of involvement of the bone marrow help to exclude nodal follicular center lymphoma. Nodal follicular lymphoma usually expresses BCL-2 and there is a t(14:18) translocation in more than 80% of cases. BCL-2 expression is usually lacking in primary cutaneous follicular lymphoma. Radiation therapy totaling 3040Gy and including all ery thematous skin and a 2cm margin of normal skin is very effective for lesions of the head and trunk. A combination of intralesional IFN-, 5MU every 4 weeks, and topical bexaro tene gel, 1% twice, has also been used. Anthracycline-based chemotherapy or rituximab may be used for relapses, as well as for more aggressive lesions of the leg. In Europe, a few cases of PCFCL are associated with Borrelia infection and may arise in lesions of acrodermatitis chronica atrophicans.

Diffuse large B-cell lymphoma (primary cutaneous large B-cell lymphoma)

Clinically, lesions present as solitary or localized red or purple papules, nodules, or plaques. In general, solitary or localized lesions are typical of primary disease, and widespread lesions suggest secondary cutaneous involvement of primary nodal lymphoma. Lesions on the head and neck have an excellent prognosis. Lesions on the leg have a poorer prognosis, with a 5-year survival of about 50%, and are considered in some clas sifications as a separate entity (Fig. 32-16). This group of lymphomas is composed of large lymphocytes. Tumors made up of sheets of centroblasts and immunoblasts (non-cleaved nuclei with peripheral or central nucleoli, respec tively) should be stained for MUM1, a marker for leg-type lymphoma. If the tumor cells express MUM1, the prognosis is worse. Immunophenotypically, cells usually express CD20 and

Primary cutaneous follicle center cell lymphoma (PCFCCL, diffuse and follicular types)
Clinically, most patients present with single or multiple papules, plaques, or nodules, with surrounding erythema, in one anatomic region. About two-thirds of cases present on the trunk, about one-fifth on the head and neck (the vast majority of these on the scalp), and about 15% on the leg. These lym
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Fig. 32-16 B-cell lymphoma of the leg.

Fig. 32-17 Plasmacytoma extending from the sternum.

Hallermann C, et al: New prognostic relevant factors in primary cutaneous diffuse large B-cell lymphomas. J Am Acad Dermatol 2007 Apr; 56(4):588597. Morales AV, et al: Indolent primary cutaneous B-cell lymphoma: experience using systemic rituximab. J Am Acad Dermatol 2008 Dec; 59(6):953957. Senff NJ, et al: Results of radiotherapy in 153 primary cutaneous B-cell lymphomas classied according to the WHO-EORTC classication. Arch Dermatol 2007 Dec; 143(12):15201526. Senff NJ, et al: European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 2008 Sep 1; 112(5):16001609. Shafer D, et al: Cutaneous precursor B-cell lymphoblastic lymphoma in 2 adult patients: clinicopathologic and molecular cytogenetic studies with a review of the literature. Arch Dermatol 2008 Sep; 144(9):11551162. van Tuyll van Serooskerken AM, et al: Coincidence of cutaneous follicle center lymphoma and diffuse large B-cell lymphoma. Int J Dermatol 2008 Nov; 47(Suppl 1):2124. Yamazaki ML, et al: Primary cutaneous Richter syndrome: prognostic implications and review of the literature. J Am Acad Dermatol 2009 Jan; 60(1):157161.

monotypic immunoglobulin, and leg-type lymphoma expresses BCL-2. Secondary cutaneous involvement with nodal large B-cell lymphoma is also associated with a poor prognosis. Richter transformation of chronic lymphocytic leukemia into a high-grade lymphoma occurs in 310% of patients with chronic lymphocytic leukemia. Its onset is often heralded by fever, night sweats, and weight loss. The lymphoma com monly arises in the lymph nodes or bone marrow, but can also present in the skin or internal organs.

Intravascular large B-cell lymphoma (malignant angioendotheliomatosis, angiotropic large-cell lymphoma)

Clinically, these patients present with variable cutaneous morphologies, often very subtle and nonspecific. Some cases resemble classic lymphoma with violaceous papules or nodules. Others more closely resemble intravascular throm botic disorders, with livedo reticularis-like lesions or telangiec tatic patches. Sclerotic plaques may also occur. Even normal skin can show the characteristic changes on biopsy. Patients often present with fever of unknown origin. CNS symptoms are prominent, with progressive dementia or multiple cere brovascular ischemic events that may precede skin findings by many months. Histologically, the features are characteristic and diagnostic. Dermal and subcutaneous vessels are dilated and filled with large neoplastic cells. Focal extravascular accumulations may be seen. The neoplastic cells are CD20+ and CD79a+, and monotypic for immunoglobulin. Clonal immunoglobulin gene rearrangements may be detected. Despite the large number of intravascular cells in the skin and other affected organs, the peripheral blood smears and bone marrow may be normal histologically. The prognosis is very poor. Multiagent chemo therapy is recommended. Rare cases of intravascular lym phoma may be of T-cell origin.
Adam DN, et al: Review of intravascular lymphoma with a report of treatment with allogenic peripheral blood stem cell transplant. Cutis 2008 Oct; 82(4):267272. Gerami P, et al: Applying the new TNM classication system for primary cutaneous lymphomas other than mycosis fungoides and Szary syndrome in primary cutaneous marginal zone lymphoma. J Am Acad Dermatol 2008 Aug; 59(2):245254. Grange F, et al: Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases. Arch Dermatol 2007 Sep; 143(9):11441150.

Plasmacytoma (multiple myeloma)

True cutaneous plasmacytomas are seen most commonly in the setting of myeloma. They are, however, rare, occurring in only 2% of myeloma cases. These cases are called secondary cutaneous plasmacytoma. They may also occur by direct extension from an underlying bone lesion (Fig. 32-17). They may appear at sites of trauma, such as biopsies or intra venous catheters (inflammatory oncotaxis). Most commonly, secondary cutaneous plasmacytomas occur in the setting of advanced myeloma and the prognosis is poor. Less commonly, the skin lesions may be the initial clinical finding, leading to the diagnosis of myeloma. Many cutaneous lesions formerly classified as primary cutaneous plasmacytomas are now clas sified as plasma cell-rich primary cutaneous marginal zone lymphoma. Anetoderma may show plasmacytoma on biopsy. A rare manifestation of a solitary plasmacytoma of bone is an overly ing erythematous skin patch that may be 10cm or more in diameter. The chest is the most common location. Lymphadenopathy is present and some of the patients have or develop POEMS syndrome (polyneuropathy, organomeg aly, endocrinopathy, monoclonal protein, and skin changes). This syndrome has been called adenopathy and extensive skin patch overlying a plasmacytoma, or AESOP.
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Cutaneous B-cell lymphoma

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Cutaneous Lymphoid Hyperplasia, Cutaneous T-cell Lymphoma

Histologically, there are nodular and diffuse collections of plasma cells with varying degrees of pleomorphism and atypia. The degree of atypia may predict prognosis. The cells are monotypic for immunoglobulin production and produce the same light chain as the myeloma. The immunoglobulin produced is most commonly IgG or IgA, and rarely IgD or IgE. CD79 is positive, but CD19 and CD20 are negative. In addition to plasmacytomas, patients with myeloma may develop a vast array of cutaneous complications. These include normolipemic plane xanthomas, amyloidosis, vasculitis, and calcinosis cutis. An unusual but characteristic skin finding in myeloma is multiple follicular spicules of the nose, forehead, cheeks, and chin. They are yellowish and firm to palpation, and can be removed without bleeding. Numerous small ulcer ations may occur on the trunk. Both the spicules and ulcers contain an eosinophilic material composed of the abnormal monoclonal protein produced by the malignant cells. The spi cules are not made of keratin. Clinically similar cutaneous spicules composed of keratin can be seen in vitamin A defi ciency, chronic renal failure, acquired immunodeficiency syndrome (AIDS), Crohns disease, and other malignant diseases. The appropriate treatment of plasmacytomas is determined by the presence or absence of associated systemic disease. Solitary or paucilesional primary cutaneous plasmacytomas have been treated successfully with local surgery and radia tion therapy. Systemic chemotherapy may be required if these modalities fail. The treatment for secondary plasmacytomas and for patients with numerous primary cutaneous plasma cytomas is chemotherapy.

involvement is thus difficult to prove and is very, very rare, if it exists. Most cases of Hodgkin disease of the skin usually originate in the lymph nodes, from which extension to the skin is either retrograde through the lymphatics or direct. Lesions present as papules or nodules, with or without ulceration. Lesions resembling scrofuloderma may occur. Miliary dissemination to the skin can occur in advanced disease. Nonspecific cutaneous findings are common in patients with Hodgkin disease. Generalized, severe pruritus may precede other findings of Hodgkin disease by many months or may occur in patients with a known diagnosis. Secondary prurigo nodules and pigmentation may occur as a result of scratching. An evaluation for underlying lymphoma should be consid ered in any patient with severe itching, no primary skin lesions, and no other cause identified for the pruritus. Acquired ichthyosis, exfoliative dermatitis, and generalized and severe herpes zoster are other cutaneous findings in patients with Hodgkin disease.

Malignant histiocytosis (histiocytic medullary reticulosis)

Most cases considered to be malignant histiocytosis in the past are now considered to be other forms of lymphoma or lym phomas with large components of reactive histiocytes. Very rare cases of true malignancies of histiocytes may still occur and can have cutaneous lesions, most characteristically ery thematous nodules. Often, the bone marrow examination in these patients is initially normal, but cases are rapidly progres sive and fatal, and the bone marrow becomes involved.
Introcaso CE, et al: Cutaneous Hodgkin disease. J Am Acad Dermatol 2008 Feb; 58(2):295298.

Cutaneous and systemic plasmacytosis

Cutaneous plasmacytosis and systemic plasmacytosis occur largely in Asians, slightly favoring males. They typically occur between the ages of 20 and 55. These conditions are character ized by polyclonal proliferations of plasma cells and hyper globulinemia, and were originally considered variants of Castlemans disease. Cutaneous plasmacytosis affects only the skin but patients may have lymphadenopathy and systemic symptoms of fever and malaise. Systemic plasmacytosis has involvement in two or more organ systems, usually, in addi tion to skin, the lung, bone marrow, and liver. Dyspnea may occur due to interstitial pneumonia. Uncommonly, cases of systemic plasmacytosis may progress to lymphoma. The course is chronic and benign, and response to various cyto static and immunosuppressive treatments has been poor. PUVA and topical tacrolimus have been reported to be effec tive for skin lesions. The skin lesions in cutaneous and sys temic plasmacytosis are identical. They consist of multiple brownred plaques, mostly of the central upper trunk, but also of the face. Lesions range from 1 to 3cm in diameter. They are often considered simply postinflammatory hyperpigmenta tion until they are palpated. Histologically, they show a dense perivascular infiltrate of mature plasma cells, which stain for both and light chains (polyclonality). Elevated IL-6 has been reported in some patients.

Leukemia cutis Clinical features

Cutaneous eruptions seen in patients with leukemia may be divided into specific (leukemia cutis) and nonspecific lesions (reactive and infectious processes). Overall, about 30% of biop sies from patients with leukemia will show leukemia cutis. All forms of leukemia can be associated with cutaneous findings, but skin disease is more common in certain forms of leukemia. Myeloid leukemia with monocytic differentiation involves the skin more commonly than other types of myeloid leukemia. CD68 and lysozyme immunostains can be helpful in distin guishing this form of leukemia. Dermatologic manifestations are commonly seen in patients with acute myelogenous leuke mia (AML) and myelodysplastic syndrome (MDS). AML includes types M1M5. In AML and MDS patients, only about 25% of skin biopsies will show leukemia cutis, the remainder showing complications of the leukemia. These include infec tions, graft versus host disease, drug reactions, or the reactive conditions associated with leukemia that are sometimes referred to as leukemids. By contrast, in patients with acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL), about 50% of biopsies will show leukemia cutis. Lesion presentation may be subtle, and may include macular erythema, hyperpigmen tation, or morbilliform rash.

Hodgkin disease
The vast majority of reports of cutaneous Hodgkin disease actually represent type A lymphomatoid papulosis (LyP). These two diseases have a considerable number of overlap ping features. The type A cells of LyP have similar morphol ogy and share immunophenotypic markers with ReedSternberg cells. LyP can be seen in patients with Hodgkin disease. Primary cutaneous Hodgkin disease without nodal
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Specic eruptions
The most common morphology of leukemic infiltrations of the skin in all forms of leukemia is multiple papules or nodules

Fig. 32-20 Gingival involvement in leukemia. Fig. 32-18 Leukemia cutis.

Fig. 32-19 Leukemia cutis.

(60% of cases) or infiltrated plaques (26%). These lesions are usually flesh-colored, erythematous, or violaceous (plumcolored) (Figs 32-18 and 32-19). They are rubbery on palpation and ulceration is uncommon. Extensive involvement of the face may lead to a leonine facies. Less common manifestations of leukemia cutis are subcuta neous nodules resembling erythema nodosum or panniculitis, arciform lesions (in juvenile CML), ecchymoses, palpable purpura, erythroderma, ulcerations (which may resemble pyoderma gangrenosum or venous stasis ulceration), and urticaria-like, urticaria pigmentosa-like (in ALL), and guttate psoriasis-like lesions. Rare manifestations are a lesion resem bling Sister Mary Joseph nodule and cutaneous sarcoidal lesions. Myelogenous leukemia may be complicated by lesions resembling stasis dermatitis or chilblains. Gingival infiltration causing hypertrophy is common in and relatively unique to patients with acute myelomonocytic leukemia (Fig. 32-20). Leukemia cutis most commonly occurs concomitant with or following the diagnosis of leukemia. The skin may also be a site of relapse of leukemia after chemotherapy, especially in patients who present with leukemia cutis. Uncommonly, leukemia cutis may be identified while the bone marrow and peripheral blood are normal. These patients are classified as aleukemic leukemia cutis, as they have normal bone marrow evaluations and no circulating blasts. These cases are often misdiagnosed as cutaneous lymphomas and undertreated. They eventually relapse, with full-blown leukemia. The key to the diagnosis is a Leder stain, which will identify the atypical cells as myeloid. Systemic involvement occurs within 3 weeks

to 20 months (average 6 months). Leukemia cutis is a poor prognostic finding in patients with leukemia, with 90% of such patients having extramedullary involvement and 40% having meningeal infiltration. The term congenital leukemia applies to cases appearing within the first 46 weeks of life. Leukemia cutis occurs in 2530% of such cases, the vast majority being congenital mye logenous leukemia. The typical morphology is multiple, red or plum-colored nodules. In about 10% of cases of congenital leukemia cutis (or 3% of all cases of congenital leukemia), the skin involvement occurs while the bone marrow and periph eral blood are normal. Systemic involvement is virtually always identified in 516 weeks. Unlike in other forms of leukemia, in congenital leukemia, cutaneous infiltration does not worsen prognosis. Congenital leukaemia cutis has been complicated by disseminated linear calcinosis cutis. Earlyonset aleukemic leukemia cutis can occasionally undergo spontaneous regression. One report involved a child with mastocytosis, who also developed a leukemia clone with a t(5; 17)(q35; q12), nucleophosmin (NPM)-retinoic acid receptor- (RARA) fusion gene.

Granulocytic sarcoma (chloroma)

Granulocytic sarcomas are rare tumors of immature granulo cytes. They occur in about 3% of patients with myelogenous leukemia. Granulocytic sarcoma is seen in four settings: in patients with known AML; in patients with CML or MDS as a sign of an impending blast crisis; in undiagnosed patients as the first sign of AML; or after BMT as the initial sign of relapse. Most lesions occur in the soft tissues, periosteum, or bone. Skin lesions represent 2050% of reported cases. They may be solitary or multiple. They appear as red, mahogany, or violaceous firm nodules with a predilection for the face, scalp, or trunk. The name chloroma comes from the green color of fresh lesions, which can be enhanced by rubbing with alcohol; this is caused by the presence of myeloperoxidase. This appear ance is variable, so the preferred term is now granulocytic sarcoma. The diagnosis is not difficult if the diagnosis of leukemia has been established. Such patients are treated with appropriate chemotherapy. However, if the skin lesion is the initial mani festation of leukemia, and the blood and bone marrow are normal, the lesion may be misdiagnosed as a large-cell lym phoma. The treatment of such patients is controversial, but most go on to develop AML within months, so chemotherapy is often given.
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Leukemia cutis

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Cutaneous Lymphoid Hyperplasia, Cutaneous T-cell Lymphoma

Hairy cell leukemia

Skin involvement is rare in hairy cell leukemia, and violaceous papules and nodules, which are the characteristic morphology of other forms of leukemia cutis, are extremely rare in hairy cell leukemia. Rather, a diffuse erythematous, nonpruritic eruption occurs, often in the setting of a systemic mycobacte rial infection or a drug reaction. This may progress to erythroderma or a severe blistering eruption. Stopping the offending medication usually leads to resolution of the eruption. This is especially common in patients treated with 2-chlorodeoxyadenosine and allopurinol. The former treat ment alone does not lead to these severe skin reactions, sug gesting that the allopurinol is the cause. Patients with hairy cell leukemia also develop lesions of pustular vasculitis of the dorsal hands, a neutrophilic dermatitis closely related to bullous Sweet syndrome. This is sometimes termed a vasculitis in the oncology literature.

Nonspecic conditions associated with leukemia (leukemids)

Leukemia and its treatment are associated with a series of conditions that may also be seen in patients without leukemia, but which are seen frequently enough in leukemic patients to be recognized as a complication of that condition or its treatment. When a dermatologist or dermatopathologist is consulted to evaluate a patient with leukemia and skin lesions, the differ ential diagnosis usually includes four groups of conditions: drug reactions, leukemia cutis, an infectious complication, and a reactive condition. Drug reactions include all forms of reac tions, but are most commonly erythema multiforme, morbil liform reactions, or acral erythema. Infections may present in many ways but are usually purpuric papules, pustules, or plaques, if they are caused by bacteria or fungi. Ulceration is typical. Herpes simplex and herpes zoster should be consid ered in all erosive, ulcerative, or vesicular lesions. The reactive conditions include a group of neutrophilic dermatoses with considerable clinical overlap. These include Sweet syndrome, pyoderma gangrenosum, neutrophilic hidradenitis, and leuko cytoclastic vasculitis. Transient acantholytic dermatosis and eosinophilic reactions resembling insect bites may occur, most commonly in patients with CLL. In CLL a pruritic and unre mitting exfoliative erythroderma is a unique feature. A granu lomatous rosacea-like leukemid and cutaneous reactive angiomatosis have also been described in patients with leukemia. Evaluation of these patients must be complete, and exten sive diagnostic tests and empiric treatment are often pursued until the diagnosis is established. In the acute setting, a clinical diagnosis is made based on morphology. Possible infectious complications are covered by appropriate antibiotics, espe cially if the patient is febrile or the diagnosis of a herpesvirus infection is made. A skin biopsy is often diagnostic. For herpes infections, a direct fluorescent antibody test should be done, as the results are virus-specific and rapid, so appropriate treat ment can be given quickly. Once the diagnostic tests return, the therapy is tailored to the appropriate condition. Except for herpes infections, a skin biopsy is often required. If infection is considered, a portion of the biopsy should be sent for culture.
Angulo J, et al: Leukemia cutis presenting as localized cutaneous hyperpigmentation. J Cutan Pathol 2008 Jul; 35(7):662665. Cho-Vega JH, et al: Leukemia cutis. Am J Clin Pathol 2008 Jan; 129(1):130142. Cibull TL, et al: Myeloid leukemia cutis: a histologic and immunohistochemical review. J Cutan Pathol 2008 Feb; 35(2):180185.

DOrazio JA, et al: Spontaneous resolution of a single lesion of myeloid leukemia cutis in an infant: case report and discussion. Pediatr Hematol Oncol 2008 Jun; 25(5):457468. Hattori T, et al: Leukemia cutis in a patient with acute monocytic leukemia presenting as unique facial erythema. J Dermatol 2008 Oct; 35(10):671674. Hejmadi RK, et al: Cutaneous presentation of aleukemic monoblastic leukemia cutisa case report and review of literature with focus on immunohistochemistry. J Cutan Pathol 2008 Oct; 35(Suppl 1):4649. Kanegane H, et al: Spontaneous regression of aleukemic leukemia cutis harboring a NPM/RARA fusion gene in an infant with cutaneous mastocytosis. Int J Hematol 2009 Jan; 89(1):8690. Marias EA, et al: Cutaneous reactive angiomatosis associated with chronic lymphoid leukemia. Am J Dermatopathol 2008 Dec; 30(6):604607. Remkov A, et al: Acute vasculitis as a rst manifestation of hairy cell leukemia. Eur J Intern Med 2007 May; 18(3):238240. Skiljevic D, et al: Granulomatous rosacea-like leukemid in a patient with acute myeloid leukemia. Vojnosanit Pregl 2008 Jul; 65(7):565568. Stern M, et al: Leukemia cutis preceding systemic relapse of acute myeloid leukemia. Int J Hematol 2008 Mar; 87(2):108109. Weinel S, et al: Therapy-related leukaemia cutis: a review. Australas J Dermatol 2008 Nov; 49(4):187190.

Cutaneous myelobrosis
Myelofibrosis is a chronic myeloproliferative disorder charac terized by a clonal proliferation of defective multipotential stem cells in the bone marrow. Overproduction and premature death of atypical megakaryocytes in the bone marrow produce excess amounts of platelet-derived growth factor, a potent stimulus for fibroblast proliferation and collagen production. Extramedullary hematopoiesis (EMH) is a hallmark of myelo fibrosis. Myelofibrosis may coexist with signs of mastocytosis. Blast cells and committed stem cells escape the marrow in large numbers, enter the circulation, and form tumors of the same atypical clone in other organs, especially the spleen, liver, and lymph node. EMH in the skin of neonates is usually caused by intrauterine viral infections. In adults, cutaneous EMH has rarely been reported, characteristically associated with myelofibrosis. Skin lesions are dermal and subcutaneous nodules. Histologically, the cutaneous lesions are composed of dermal and subcutaneous infiltrates of mature and imma ture myeloid cells, erythroid precursors (in only half of cases), and megakaryocytic cells (which may predominate). There is marked production of collagen fibers in the cutaneous lesions by the mechanism described above. Myelofibrosis must be distinguished from CML, since both have elevated white blood cell counts with immature myeloid forms, defective platelet production, and marrow fibrosis. Both may terminate in blast crisis, and myelofibrosis may rarely convert to CML. CML is associated with the Philadelphia chromosome, whereas chromosomal abnormalities occur in 40% of myelofibrosis cases on various chromosomes.
Haniffa MA, et al: Cutaneous extramedullary hemopoiesis in chronic myeloproliferative and myelodysplastic disorders. J Am Acad Dermatol 2006 Aug; 55(2 Suppl):S2831. Miyata T, et al: Cutaneous extramedullary hematopoiesis in a patient with idiopathic myelobrosis. J Dermatol 2008 Jul; 35(7):456461. Turchin I, et al: Unusual cutaneous ndings of urticaria pigmentosa and telangiectasia macularis eruptiva perstans associated with marked myelobrosis. Int J Dermatol 2006 Oct; 45(10):12151217.

Hypereosinophilic syndrome
Idiopathic hypereosinophilic syndrome (HES) is defined as eosinophilia with more than 1500 eosinophils/mm3 for more than 6 months, with some evidence of parenchymal organ involvement; there must also be no apparent underlying disease to explain the hypereosinophilia and usually no

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evidence of vasculitis. Ninety percent of patients reported have been men, mostly between the ages of 20 and 50. Childhood cases are rare. Presenting symptoms include fever (12%), cough (24%), fatigue, malaise, muscle pains, and skin eruptions. Two pathogenic variants of HES have been defined: m-HES (myeloproliferative HES) and l-HES (lymphocytic HES). M-HES patients are overwhelmingly males, and anemia, thrombocytopenia, elevated serum B12 levels, mucosal ulcera tions, splenomegaly, and endomyocardial fibrosis are the clini cal features. Isolated Loefflers endocarditis has been reported as a presenting sign. Eosinophil clonality and interstitial dele tion on 4q12 result in fusions of FIP1qL1 and PDGFRa genes, forming an F/P fusion protein displaying constitutive activity, are pathogenically related to m-HES cases. Increased mast cells and elevated tryptase levels with myeloid precursors in peripheral blood and myelofibrosis may be found, suggesting that mast cells may be pathogenically related to this form of HES. Leukemia may develop in patients with m-HES. L-HES has been associated with circulating T-cell clones of CD4+ phenotype, which secrete Th2 cytokines, especially IL-5. Females and males are equally affected by l-HES and cutane ous manifestations are observed in virtually all patients. Skin manifestations include urticaria, angioedema, pruritus, eczema, and erythroderma. Splinter hemorrhages and necrotic skin lesions are seen in some HES patients as well. Endomyocardial fibrosis is uncommon, but pulmonary and digestive symptoms are common. Some cases of l-HES are clinically identical to Gleich syndrome or episodic angioedema and hypereosinophilia. Over time some patients with l-HES will develop lymphoma. Treatment is determined by classifying cases appropriately as m-HES or l-HES. M-HES patients may be treated with cor ticosteroids, hydroxyurea, IFN-, and chemotherapeutic agents. Imatinib mesylate (Gleevac, 100mg/day or less) can be highly effective for m-HES patients with the F/P mutation, as imatinib inhibits the phosphorylation of the F/P protein and leads to apoptosis of cells producing this protein. This has rapidly become first-choice treatment for this subset of patients. Response may be dramatic, with eosinophil levels improving, and skin and gastrointestinal manifestations clearing in days. For l-HES patients, systemic glucocorticoids, and perhaps IFN- with glucocorticoids, can be used and are usually effec tive. Monoclonal anti-IL-5 antibody, cyclosporine A, anti-IL2R-, infliximab, and CTLA-4-Ig may be treatment options. If lymphoma supervenes, intense chemotherapy and allogenic stem cell transplantation can be considered.
Dahabreh IJ, et al: Management of hypereosinophilic syndrome: a prospective study in the era of molecular genetics. Medicine (Baltimore) 2007 Nov; 86(6):344354. Hayashi M, et al: Case of hypereosinophilic syndrome with cutaneous necrotizing vasculitis. J Dermatol 2008 Apr; 35(4):229233. Leiferman KM, et al: Dermatologic manifestations of the hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007 Aug; 27(3):415441. Sen T, et al: Hypereosinophilic syndrome with isolated Loefers endocarditis: complete resolution with corticosteroids. J Postgrad Med 2008 AprJun; 54(2):135137. Taverna JA, et al: Iniximab as a therapy for idiopathic hypereosinophilic syndrome. Arch Dermatol 2007 Sep; 143(9):11101112.

ulinemia (65%), and generalized adenopathy (87%). Pruritus occurs in 44% and a rash in 46%. The skin eruption is usually morbilliform in character, resembling an exanthem or a drug reaction. Petechial, purpuric, nodular, ulcerative, and erythro dermic eruptions have also been reported, and may mimic infection. In about 30% of cases the eruption is associated with the ingestion of a medication. The eruptions usually resolve with oral steroids, misleading the clinician into believing that the eruption was benign. Reversible myelofibrosis has been described. Recent evidence suggests that the neoplastic cells are derived from germinal center T-helper cells, as they express genes unique to this population, including programmed death-1 (PD-1) and CXCL13. Histopathologically, there is a patchy and perivascular dermal infiltrate of various types of lymphoid cells, plasma cells, histiocytes (enough to rarely give a granulomatous appearance), and eosinophils. The lymphoid cells are usually helper T cells (CD4+). Some portion of the lymphoid cells is atypical in most cases, suggesting the diagnosis. Blood vessels are increased and the endothelial cells are prominent, often cuboidal. Unfortunately, these changes may not be adequate to confirm the diagnosis. However, clonal T-cell gene re arrangement is found in three-quarters of these skin lesions and is the same as the clone in the lymph node. Immuno phenotyping of the skin lesions does not give a consistent pattern. At times, the skin lesions will show leukocytoclastic vasculitis on biopsy. Lymph node biopsy is usually required to confirm the diagnosis and exclude progression to lymphoma. AILD appears to develop in a stepwise fashion. Initially, there is an immune response to an unknown antigen. This immune reaction persists, leading to oligoclonal T-cell prolif eration. Monoclonal evolution may occur, eventuating in lym phoma (angioimmunoblastic lymphoma [AILD-L]). These are usually T-cell lymphomas, but B-cell lymphomas can also occur. In the case of AILD-L, skin lesions may contain the neoplastic cells (secondary lymphoma cutis). In up to 50% of cases, multiple unrelated neoplastic cell clones have been iden tified. Clones identified in the skin may be different from clones found in lymph node. Trisomy 3 or 5, or an extra X chromosome may be found. AILD is an aggressive disease, with mortality ranging from 48% to 72% in various series (average survival time is 1160 months). The cause of death is usually infection. EpsteinBarr virus and HHV 6 and 8 have been implicated in AILD. Treatment of AILD has included systemic steroids, metho trexate plus prednisone, combination chemotherapy, fludara bine, 2-chlorodeoxyadenosine, IFN-, and cyclosporine. Early treatment with systemic steroids during an oligoclonal or pre lymphomatous stage may induce a long-lasting remission. Asymptomatic patients may not be treated initially but must be watched very closely. More aggressive chemotherapy achieves better remission. None the less, recurrence rates are high, and average survival is between 1 and 3 years.
Matsui K, et al: Angioimmunoblastic T cell lymphoma associated with reversible myelobrosis. Intern Med 2008; 47(21):19211924. Shah ZH, et al: Monoclonality and oligoclonality of T cell receptor beta gene in angioimmunoblastic T cell lymphoma. J Clin Pathol 2009 Feb; 62(2):177181. Yu H, et al: Germinal-center T-helper-cell markers PD-1 and CXCL13 are both expressed by neoplastic cells in angioimmunoblastic T-cell lymphoma. Am J Clin Pathol 2009 Jan; 131(1):3341.

Angioimmunoblastic lymphadenopathy with dysproteinemia (angioimmunoblastic T-cell lymphoma)

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is an uncommon lymphoproliferative disorder. Patients are middle-aged or elderly and present with fever (72%), weight loss (58%), hepatomegaly (60%), polyclonal hyperglob

Sinus histiocytosis with massive lymphadenopathy (RosaiDorfman disease)

Sinus histiocytosis with massive lymphadenopathy (SHML), or RosaiDorfman disease, usually appears in patients in the first or second decade of life as a febrile illness accompanied
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Sinus histiocytosis with massive lymphadenopathy

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Cutaneous Lymphoid Hyperplasia, Cutaneous T-cell Lymphoma

Ohnishi A, et al: Cutaneous RosaiDorfman disease. J Dermatol 2008 Sep; 35(9):604605.

Polycythemia vera (erythremia)

Polycythemia vera (PCV) is characterized by an absolute increase of circulating red blood cells, with a hematocrit level of 5580%. Leukocyte and platelet counts are also increased. The skin changes are characteristic. There is a tendency for the skin to be red, especially on the face, neck, and acral areas. The mucous membranes are engorged and bluish. The phrase red as a rose in summer and indigo blue in winter has been ascribed to Osler in describing PCV. Telangiectases, bleeding gums, and epistaxis are frequently encountered. Cyanosis, purpura, petechiae, hemosiderosis, rosacea, and koilonychia may also be present. In 50% of patients with PCV, aquagenic pruritus occurs. In about two-thirds of patients, this is of limited severity and does not require treatment. The pruritus is typically triggered after a bath or shower, and the feeling induced may be itching, burning, or stinging. It usually lasts 3060min and is inde pendent of the water temperature. Pruritus unassociated with water exposure may also occur. There is a concurrent elevation of blood and skin histamine. Pruritus is present in about 20% of patients at presentation and develops in the remaining 30% over the course of their disease. Patients with pruritus have lower mean corpuscular volumes and higher leukocyte counts. Some have suggested that iron deficiency plays a role in PCVassociated pruritus, so a ferritin level and a trial of iron therapy may be indicated. Platelet counts are no different between PCV patients who itch and those who do not. The treatment of PCV-associated pruritus may be difficult. Initial therapy would include first- or second-generation H1 antihistamines. Hydroxyzine was reported as the most effec tive antihistamine by a group of PCV patients. H2 blockers can be added. Narrow-band UVB has been reported to be effective in 80% of patients. Topical therapy is of limited benefit, but paroxetine (Paxil), 2060mg/day, may be dramatically effec tive. Phlebotomy may be useful in patients with elevated hematocrits, and imatinib mesylate appears effective in many patients.
Abdel-Naser MB, et al: Cutaneous mononuclear cells and eosinophils are signicantly increased after warm water challenge in pruritic areas of polycythemia vera. J Cutan Pathol 2007 Dec; 34(12):924929. Jones CM, et al: Phase II open label trial of imatinib in polycythemia rubra vera. Int J Hematol 2008 Dec; 88(5):489494.

Fig. 32-21 RosaiDorfman disease. (Courtesy of Ellen Korn, MD)

by massive cervical (and commonly other) lymphadenopathy, polyclonal hyperglobulinemia, leukocytosis, anemia, and an elevated sedimentation rate. Males and black persons are espe cially susceptible. Extranodal involvement occurs in 40% of cases, with skin being the most common site. Ten percent of patients with SHML have skin lesions and 3% of patients have disease detectable only in the skin. The terms cutaneous sinus histiocytosis or cutaneous RosaiDorfman disease have been applied to these cases. Skin lesions consist of isolated or dis seminated yellowbrown papules, pustules, or nodules (Fig. 32-21), or macular erythema. Large annular lesions, resem bling granuloma annulare, may occur. Most patients with cutaneous RosaiDorfman are older (4060 years). Histologically, there is a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. Nodular and diffuse infiltration of the dermis by large, foamy histiocytes is present. A very important diagnostic feature is the finding of intact lymphocytes (and less commonly, plasma cells) in the cyto plasm of the histiocytic cells. This is called emperipolesis. Foamy histiocytes may be seen in dermal lymphatics. The cutaneous histology in some cases may be very nonspecific (except for the finding of emperipolesis), and only on evalua tion of lymph node or other organ involvement does the diag nosis become clear. Immunohistochemistry and electron microscopy may be very useful, as the infiltrating cells are positive for CD4, factor XIIIa, and S-100, but do not contain Birbeck granules. The cause of this condition is unknown, but numerous reports have identified HHV 6 in involved lymph nodes. The condition usually clears spontaneously, so no treatment is required. Numerous agents have been used therapeutically with variable success, but are only indicated if the condition puts the patient at risk for death or a significant complication (usually by compressing a vital organ). Treatments have included radiation, systemic corticosteroids, and thalidomide. Single and multiagent chemotherapy is met with mixed to poor response. To treat skin lesions, cryotherapy, topical ster oids, acitretin, and intralesional steroids may be tried.
Kong YY, et al: Cutaneous RosaiDorfman disease: a clinical and histopathologic study of 25 cases in China. Am J Surg Pathol 2007 Mar; 31(3):341350. Mebazaa A, et al: Extensive purely cutaneous RosaiDorfman disease responsive to acitretin. Int J Dermatol 2007 Nov; 46(11):12081210. Merola JF, et al: Cutaneous RosaiDorfman disease. Dermatol Online J 2008 May 15; 14(5):8.

Bonus images for this chapter can be found online at http://www.expertconsult.com

Fig. 32-1 Jessners lymphocytic inltrate. Fig. 32-2 Mycosis fungoides, patch stage, with small and large patches. Fig. 32-3 Tumor-stage mycosis fungoides. Fig. 32-4 Pagetoid reticulosis. Fig. 32-5 Szary syndrome. Fig. 32-6 MuchaHabermann disease. Fig. 32-7 Lymphoma, B-cell. Fig. 32-8 Intravascular lymphoma. Fig. 32-9 Plasmacytoma in myeloma. Fig. 32-10 Malignant histiocytosis. Fig. 32-11 RosaiDorfman disease. (Courtesy of Ellen Korn, MD) Fig. 32-12 Mycosis fungoides, patch/plaque stage. Fig. 32-13 Mycosis fungoides, plaque stage. Fig. 32-14 Lymphomatoid papulosis.

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