Chapter 46 Leukemic and lymphomatous infiltrates of the skin
1. Define lymphoma.
A lymphoma is a malignancy of the immune system that is characterized by an abnormal proliferation of lymphocytes and related cell types. Most lymphomas begin in lymph nodes and are divided into Hodgkin’s and non–Hodgkin’s lymphomas. The non–Hodgkin’s lymphomas are further subdivided into T-cell and B-cell subtypes.
3. What type of lymphoma is mycosis fungoides?
Mycosis fungoides is a low-grade T-cell lymphoma. Histologically, it has a polymorphous cellular infiltrate with polymorphonuclear leukocytes, eosinophils, lymphocytes, and atypical mononuclear cells. The atypical mononuclear cells are moderately large and have a folded (cerebriform) nucleus. These cells are typically seen within the epidermis either singly or in small clusters (Pautrier’s microabscesses). The mycosis cells are primarily CD4-positive helper T cells.
4. How common is mycosis fungoides?
The incidence of cutaneous T-cell lymphoma (CTCL) in the United States is approximately 1,500 new cases per year. The prevalence of CTCL in the United States ranges from 16,000 to 20,000 cases.
Cutaneous Lymphoma Foundation. CTCL-MF fast facts. Available at: http://www.clfoundation.org/publications/publications.htm. Accessed December 6, 2006.
5. How does mycosis fungoides begin?
Typically, mycosis fungoides begins with persistent scaly patches (Fig. 46-1A) that respond poorly to topical therapy with emollients and topical steroids. In the early stages, skin biopsy is frequently not diagnostic. The average time from onset of skin lesions to diagnosis is 7 years. In this early phase of the disease, a diagnosis of parapsoriasis en plaque is often made. In time, the patches thicken and become plaques. Eventually, skin tumors develop (Fig. 46-1B,C) and the lymph nodes can become involved. Visceral disease is a late occurrence in this low-grade lymphoma. Median survival for persons with patch- and plaque-stage disease is 12 years; for tumor-stage disease, it is 5 years; and for nodal or visceral disease, it is 3 years.
6. What is parapsoriasis?
The skin diseases included under this diagnosis are poorly understood and encompass a morass of confusing terms. The “splitters” have described over a dozen varieties of parapsoriasis, while the “lumpers” limit this designation to only a few types. This discussion supports the “lumpers” viewpoint.
Large-plaque parapsoriasis presents as palm-sized or larger lesions located most frequently on the thighs, buttocks, hips, lower abdomen, and shoulder girdle areas (Fig. 46-2). The lesions may be pink, red-brown, or salmon-colored. They often have fine scale and show epidermal atrophy with cigarette-paper wrinkling. Some patients may have lesions with a netlike or reticular pattern with telangiectasia and fine scale. This clinical type of lesion is referred to as retiform parapsoriasis or poikiloderma atrophicans vasculare. Between 15% and 20% of patients with large-plaque parapsoriasis eventually develop mycosis fungoides.
Figure 46-2. Large-plaque parapsoriasis. The lesion was unresponsive to topical treatment.
(Courtesy of the Fitzsimons Army Medical teaching files.)
Sehgal VN, Srivastava G, Aggarwal AK: Parapsoriasis: a complex issue, Skinmed 6:280–286, 2007.
7. What type of skin lesions are seen in patients with mycosis fungoides?
Although the classic skin lesions are scaly patches, plaques, and tumors, a wide variety of skin lesions have been reported, such as follicular papules and pustules with or without alopecia (alopecia mucinosa). Bullous, erythrodermic, hypopigmented, vasculitic, and hyperkeratotic lesions also have been described.
A rare variant of mycosis fungoides is granulomatous slack skin disease (Fig. 46-3). This disorder is characterized by the slow development of lax erythematous skin that eventually develops large pendulous folds of redundant integument. Histologic examination shows a dense atypical granulomatous infiltrate with destruction and phagocytosis of elastic tissue.
8. Describe the three subtypes of mycosis fungoides.
• Sézary syndrome (Fig. 46-4) presents with the classic triad of erythroderma, lymphadenopathy, and atypical circulating mononuclear cells (Sézary cells). These cells are moderately large mononuclear cells with hyperconvoluted nuclei. They resemble activated T cells, and when >15% of circulating lymphocytes are atypical, it is considered significant, with 10% to 15% being considered borderline. However, the finding of circulating Sézary cells must be evaluated in context with the clinical picture and skin biopsy. Severe pruritus, ectropion, nail dystrophy, peripheral edema, alopecia, and keratoderma of the palms and soles are common associated features. The disease tends to wax and wane and generally progresses faster and is more resistant to treatment than typical mycosis fungoides.
• Pagetoid reticulosis (Woringer-Kolopp disease) is characterized by single or grouped hyperkeratotic skin lesion(s). Skin biopsy shows striking epidermotropism, with numerous atypical mononuclear cells, both singly and in clusters, scattered through all levels of the epidermis. The disease tends to be slowly progressive and responds well to local radiation.
• The tumor d’emblee form was initially thought to be a type of mycosis fungoides that began with skin tumors without the usual progression through a patch-and-plaque stage. Recent reports suggest that some of these cases are B-cell primary cutaneous lymphomas and some represent Ki-1–positive primary cutaneous T-cell lymphomas.
9. What is the TNM classification of mycosis fungoides?
• Combination chemotherapies
• EPOCH
National Cancer Institute. Mycosis fungoides and the Sézary syndrome treatment. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/mycosisfungoides/healthprofessional/allpages. Accessed December 6, 2006.
11. Describe topical nitrogen mustard (HN2) therapy.
This treatment is one of the most common for mycosis fungoides in the United States, and it has been used extensively in this disease since the early 1960s. It is easy to learn, can be applied by the patient at home, and has few side effects. The treatment consists of the topical application of 10 mg of nitrogen mustard in 60 mL of water every day to the entire skin surface except the eyelids and genitalia. Complete response rates for stage 1 disease are >50%. The treatment is well tolerated with few side effects and no severe systemic side effects. Over 50% of patients will develop allergic contact dermatitis to the topical medication, and there is a long-term risk for basal and squamous cell carcinoma. Some physicians prefer to use the medication in an ointment base.
12. If a patient develops allergic contact dermatitis to topical nitrogen mustard, does the treatment have to be permanently discontinued?
No. The medication should be temporarily discontinued, and the dermatitis treated with either topical or systemic steroids. When the dermatitis has cleared, the patient can then be restarted on dilute HN2. Usually, the patient will tolerate 10 mg of HN2 in 1 gallon of water. The concentration of the HN2 can be slowly increased over several months without a flare of the dermatitis. On a rare occasion, a patient may develop immediate contact urticaria to topical HN2, requiring discontinuation of treatment.
13. Is photochemotherapy an effective treatment of mycosis fungoides?
Yes. The response rates to psoralen plus ultraviolet A (PUVA) are at least equal to those with topical nitrogen mustard. Ultraviolet light irradiation required special instruments for whole skin irradiation of UVA light. Adding psoralens potentiates the effects of UVA light (PUVA). A study from Sweden, where PUVA is the treatment of choice, showed a 50% decrease in mortality from mycosis fungoides after the introduction of PUVA. UVB therapy may work in some patients with early patches and plaques. Newer NBUVB (311- to 313-nm range) phototherapy has certain advantages over PUVA: no oral premedication required, eliminating systemic side effects, and long-term skin carcinogenic effects may be decreased. Small studies of PUVA and oral and topical bexarotene (Targretin) indicate a combination treatment of light and retinoids may have synergistic benefit.
14. What are the major side effects of bexarotene in the treatment of patients with cutaneous T-cell lymphoma?
Bexarotene (Targretin) is a synthetic retinoid that selectively activates retinoid X receptors. The drug is given orally at a recommended dose of 300 mg/m2. Partial response rate (50% improvement) was 67% and complete response occurred in 7% of patients. Like other retinoid drugs, Targretin is teratogenic and should not be given to pregnant women. In a study of 58 patients with patch and plaque stage disease, side effects included hyperlipidemia in 83%, neutropenia in 47%, central hypothyroidism in 74%, and hypercholesteremia in 47% of patients.
15. How does one manage the side effects of bexarotene?
Hypothyroidism caused by bexarotene (Targretin) results in a low thyroid-stimulating hormone level because the drug stops RNA transcription. Central hypothyroidism is managed with levothyroxine replacement. It is recommended that one start and stop levothyroxine and bexarotene together. Measure free T4 at baseline, at 2 weeks, then monthly. Normalizing free T4 helps clear plasma lipids.
16. Are interferons effective in treating mycosis fungoides?
Yes. Of the interferon group of drugs, recombinant interferon-α has been the most promising. Both complete remissions and partial remissions have been reported. Low-dose treatment protocols are as effective as high-dose protocols and have fewer side effects. The recommended dose is 3 million units, given subcutaneously, three times weekly.
17. Is chemotherapy an effective treatment of mycosis fungoides?
Yes. Both partial and complete remissions can be achieved with both single-drug and multidrug chemotherapy protocols. However, the remissions are short-lived, and no one drug or combination of drugs appears to be superior. In a large blinded study, 103 patients randomized to 3000 cGy of electron-beam therapy followed by chemotherapy with cyclophosphamide, daunorubicin, etoposide, and vincristine were compared to a group of patients treated with topical HN2 progressing to PUVA if necessary. After a median follow-up of 75 months, there was no difference in response rates or survival in the two groups.
18. What is extracorporeal photophoresis?
Extracorporeal photopheresis (ECP) is a treatment in which peripheral blood is exposed in an extracorporeal circuit to UVA following administration of 8-methoxypsoralen. Response rates of 50% to 80% have been observed in CTCL. ECP is also used as a treatment for chronic graft-versus-host disease (GVHD) in allogeneic stem cell transplant recipients. The mechanism of action is thought to be activation of cellular apoptosis and possible immunomodulatory effects. The treatment is expensive, requires the availability of specialized equipment, and is administered on an outpatient basis in a hospital setting. It is the only Food and Drug Administration (FDA)–approved treatment for mycosis fungoides.
19. Are there any other FDA-approved treatments for cutaneous T-cell lymphoma?
Yes. Denileukin diftitox (Ontak) is interleukin-2 (IL-2) conjugated to diphtheria toxin. The drug is given intravenously only to patients whose malignant cells express CD25, the IL-2 receptor. The drug can be associated with significant toxicity, including capillary leak syndrome, acute hypersensitivity–type reactions, hypoalbuminemia, and hypotension. Flulike symptoms for several weeks following infusion are frequently noted. Partial responses are reported in 30% and complete responses in 10% of patients.
20. Outline the Ann Arbor clinical staging system for Hodgkin’s disease.
• Stage II: Two or more lymph node regions on the same side of the diaphragm or nodal involvement with a contiguous extralymphatic site
21. What is a Reed-Sternberg cell?
It is a large cell with two mirror-image nuclei with large distinct nucleoli, often with surrounding halos (owl’s eye cells). It is considered to be the malignant cell of Hodgkin’s disease, and its presence confirms the histologic diagnosis. The origin of the cell is debated, with marker studies having shown both T- and B-cell immunoenzymatic staining.
22. What are the histologic classes of Hodgkin’s disease?
• Nodular sclerosis is the most common type, accounting for 35% of all patients with Hodgkin’s disease. It is more common in women and has a relatively good prognosis. It is characterized by a particular type of Reed-Sternberg cell, called the lacunar cell, which is a large cell with a hyperlobulated nucleus and multiple nucleoli surrounded by a clear space (lacunae).
• Mixed cellularity represents a histologic type that is intermediate between lymphocyte-predominance and lymphocyte-depletion types. It is the second most common type. Reed-Sternberg cells are prominent.
• Lymphocyte-predominance type has a diffuse or slightly nodular histologic pattern (popcorn pattern). Reed-Sternberg cells are rare. It is the most common pattern found in young men, and the prognosis is excellent. The anti–CD20 monoclonal antibody, rituximab, which is usually used in non–Hodgkin’s lymphoma, has been shown to produce over a 50% complete response rate for this subtype of Hodgkin’s disease.
• Lymphocyte-depletion pattern is characterized by a paucity of lymphocytes and numerous Reed-Sternberg cells or their variants. There is a diffuse fibrotic and a reticular variant of the lymphocyte-depleted subtype. This type tends to occur in older patients, with disseminated involvement and a poor prognosis.
23. Does Hodgkin’s disease occur in the skin?
Yes, but very rarely. One series of 1800 cases reported a <5% incidence of specific skin lesions in patients with Hodgkin’s disease. Many of the early reports of Hodgkin’s disease presenting with skin lesions with no nodal involvement probably represent Ki-1–positive, T-cell lymphomas. Nonspecific skin lesions are common and include pruritus, pigmentation, prurigo, ichthyosis, alopecia, and herpes zoster.
24. How are cells immunophenotyped? What does the CD nomenclature mean?
“CD” stands for cluster designation and is a nomenclature for identification of specific cell surface antigens defined by monoclonal antibodies. The procedure can be applied to both formalin-fixed and frozen tissue. It is very helpful in identifying subpopulations of T- and B-cell lymphocytes (Table 46-2).
25. What is lymphomatoid papulosis?
This chronic recurrent skin eruption is characterized by papules and/or nodules that frequently crust or ulcerate and self-heal, often with atrophic scars (Fig. 46-5). There are three histopathologic types. Type A has large Reed-Sternberg–like cells, which are often CD30 (Ki-1) positive. Type B has moderately large atypical cells with cerebriform nuclei similar to the cell type found in mycosis fungoides. These cells are usually CD30 negative. Type C is composed of sheets of cells that resemble the cells of anaplastic T-cell lymphoma. About 15% to 20% of patients with lymphomatoid papulosis will develop a lymphoma.
Table 46-2. Cells Marked by CD Antigens
| CD2 | T cells (E rosette receptor) |
| CD3 | T-cell receptor |
| CD4 | Helper T cells |
| CD5 | Mature thymocytes, some B-cell subsets |
| CD7 | T cells, natural killer (NK) cells |
| CD8 | T cells, NK cells |
| CD10 | Pre-B cells, lymphoblastic leukemia cells |
| CD14 | Monocytes |
| CD15 | Reed-Sternberg cells, myeloid cells |
| CD19 | Pan-B cells |
| CD20 | Pan-B cells, dendritic cells |
| CD21 | Receptor for complement 2 and Epstein-Barr virus |
| CD23 | Activated B cells, monocytes, eosinophils, and platelets |
| CD25 | Activated T and B cells, monocytes (interleukin-2 receptor) |
| CD30 | Ki-1–related cells, Reed-Sternberg cells, T-cell NHL |
| CD34 | Lymphoid and myeloid precursor cells |
| CD43 | T cells, myeloid cells |
| CD45 | Leukocytes |
| CD45R | T cells, myeloid cells |
| CD56 | NK cells |
| CD74 | HLA-invariant chain |
| CD75 | Follicular center cells |
CD, Cluster of differentiation; HLA, histocompatibility locus antigen; NHL, non-Hodgkin’s lymphoma.
26. Are CD30-positive cells specific for lymphomatoid papulosis?
No. The monoclonal antibody CD30 (Ki-1) was first described in 1982 with positive staining of Reed-Sternberg cells of Hodgkin’s disease. Positive staining was also found in the paracortical cells of reactive lymph nodes. Ki-1 positivity can be seen in primary T-cell lymphomas, anaplastic large-cell lymphomas, regressing atypical histiocytosis, and occasionally pityriasis lichenoides et varioliformis acuta (Mucha-Habermann disease). Ki-1–positive primary cutaneous lymphomas have a better prognosis than Ki-1–negative primary cutaneous lymphomas.
27. What is HTLV-1 virus? What is its significance?
HTLV-1 is a type C retrovirus associated with T-cell lymphoma and leukemia. It was initially isolated from a patient diagnosed with mycosis fungoides. The virus is endemic in Japan, the Caribbean, and northeastern South America; a few cases have been reported in the United States. It can be transmitted by blood transfusions, intravenous drug abuse, breast feeding, and, less commonly, sexual contact. A small subset of patients who are HTLV-1–antibody positive (<5%) will develop lymphoma or lymphocytic leukemia. The disease is characterized by immunosuppression, lymphadenopathy, cutaneous lesions, and hypercalcemia.
28. Can multiple myeloma present with skin lesions only?
Yes. However, it is extremely rare for myeloma to begin with only skin lesions. Extraosseous lesions in association with osseous myeloma are common, and the skin is one of the extraosseous sites. There are many skin diseases associated with monoclonal gammopathy, including pyoderma gangrenosum, scleromyxedema, scleroderma adultorum, leukocytoclastic vasculitis, collagen-vascular disease, xanthomas, Waldenström’s macroglobulinemia, subcorneal pustular dermatosis, pustular psoriasis, and even urticaria. The diagnosis of multiple myeloma is confirmed when there are lytic bone lesions, anemia, hypercalcemia, elevated serum and/or urine monoclonal protein spike, and bone marrow plasma cells exceeding 10%. Subcutaneous myeloma is much more common during late-stage, relapsed disease.
29. What is pseudolymphoma of the skin?
This term represents several clinical entities that probably have multiple etiologies. Included are lymphocytoma, Spiegler-Fendt sarcoid, lymphadenosis benigna cutis, and Jessner’s benign lymphocytic infiltrate. In most cases, the etiology is unknown, although chronic arthropod bite reactions are an etiologic stimulus in some cases. The lesions present as indolent single or grouped, red or purple nodules or plaques on the head, neck, and upper trunk, and other anatomic sites can be involved (Fig. 46-6). The infiltrate may show either B- or T-cell predominance. Some cases can be difficult to differentiate from lymphoma, and the patient must be followed before a definite diagnosis can be made.
30. Can B-cell lymphomas present with skin lesions?
Yes. Most benign and malignant cutaneous lymphocytic infiltrates are predominantly T cell in origin. Cutaneous involvement occurs in >5% of patients with B-cell nodal lymphoma. Also, an entity termed SALT (skin-associated lymphoid tissue) lymphoma, or primary cutaneous B-cell lymphoma (PCBCL) may present as solitary or multiple, red to violaceous nodules or plaques (Fig. 46-7). The treatment of choice is local radiation therapy.
31. What is the most common type of leukemia in adults?
Chronic lymphocytic leukemia. It is the most common cause of specific leukemic skin lesions, which are usually multiple and may present with papules, nodules, plaques, erythema, and, rarely, bullae (Fig. 46-8A). This neoplastic proliferation of lymphocytes is usually B cell in origin.
32. Can leukemia present with specific skin lesions?
Yes. Although uncommon, skin infiltration with neoplastic leukemia cells can be a presenting finding and precede the leukemic phase of the disease by several months. This is most common with acute myeloid leukemia (AML). Often, this phenomenon is preceded by a myelodysplastic or myeloproliferative syndrome. The skin lesions may present as red or purple papules, nodules, or plaques.
33. What are some nonspecific skin lesions seen in patients with leukemia?
Nonspecific skin lesions are quite common in patients with all types of leukemia and preleukemia. The most common skin findings are petechiae, purpura, pruritus, papular eruptions, vasculitis, urticaria, herpes zoster, and erythroderma. Approximately 5% to 10% of patients with pyoderma gangrenosum have or will develop leukemia, usually of the myelocytic type. Gingival hyperplasia is a common association with acute myelomonocytic leukemia (FAB subtypes M4 and M5) (Fig. 46-8B).
