Cutaneous Lymphoid Hyperplasia, Cutaneous T-Cell Lymphoma, Other Malignant Lymphomas, and Allied Diseases Rick Lin, DO, MPH March 18, 2003

Cutaneous Lymphoid Hyperplasia Collection of lymphocytes with other inflammatory cells on the skin Maybe monoclonal or mixed with both T or B cells Caused by unknown stimuli Medications, infections, insect bites

Cutaneous Lymphoid Hyperplasia AKA Pseudolymphoma May progress to lymphoma Immunosuppression may aggravate the infiltrate and may regress with immunosuppression is removed

Cutaneous B-Cell Lymphoid Hyperplasias Knowns as Speigler-Fendt sarcoid Caused by Borrelia, infections, herpes zosters scars, tatoo, drugs Appears as discrete firm of doughy cutaneous papules or nodules Most lesions are asymptomatic, treatment not required If caused by medication, medication should be removed

Cutaneous T-Cell Lymphoid Hyperplasias Maybe idiopathic Aka actinic reticuloid and chronic actinic dermatitis Patient resembles mycosis fungoides Histologically, dermal infiltrate that is band-like with no grenz zone.

Cutaneous lymphoid hyperplasia Pseudolymphoma has to be distinguished from cutaneous lymphomas by the combination of clinicopathological correlation, histochemical studies, and, in selected cases, gene rearrangement studies T cell lymhoma can be usually distinguished from T cell pseudolymphoma by the presence of prominent epidermotropism, large and atypical lymphocytes, and T cell gene rearrangements up to 90%

Cutaneous lymphoid hyperplasia The lack of acanthosis, "bottom-heavy" infiltrates, light-chain expression of monotypical B-cells, and immunoglobulin gene rearrangements (75%) provide strong evidence for the diagnosis of B-cell lymphoma A careful monitoring of these patients for the development of lymphoma is necessary

Coalescing erythematous follicular papules and raspberry-like nodules on the right shoulder.

Histological examination of the skin The microscopic examinations revealed dense and diffuse infiltrates of cytologically benign-appearing lymphocytes and scattered histiocytes in the upper and mid dermis

Immunohistochemical examination of skin Immunohistochemical examination of skin. Antibody against CD3+ (T-lymphocytes).

Cutaneous T Cell Lymphomas Primary Cutaneous T-Cell Lymphomas Not synonymous with MF Up to 30% of primary CTCLs are not MF Primary Cutaneous T-Cell Lymphomas other than Mycosis Fungoides

Primary Cutaneous T-Cell Lymphomas Mycosis Fungoides Pagetoid Reticulosis Sezary Syndrome Granulomatous Slack Skin Lymphomatoid papulosis

Mycosis Fungoides Malignancy of T-lymphocytes, almost always MEMORY T-CELL Black>white M:F = 2:1 Race: MF is more common in black than in white patients (incidence ratio 1.6). Sex: MF occurs more frequently in men than in women (male-to-female ratio of 2:1). Age: The most common age at presentation is 50 years; however, MF also can be diagnosed in children and adolescents with apparently similar outcomes.

Mycosis Fungoides Patch Stage – premycotic, severe pruritis. Plaque Stage – infiltrated plaque Tumore stage – when de novo, called d’ emblee form Erythroderma – Rare

MF Staging TNMB system on skin (T) node (N), viscera (M), and blood (B) T1 – Skin involvement <10% T2 – Skin involvement >10% T3 – Tumor T4 – Erythroderma

MF Staging N0 – normal nodes N1 – palpable but not pathologically MF N2 – not palpable but pathologically MF N3 – clinically and pathologically involved M0 B0 - Viscera and blood not involved M1 B1 - Viscera and blood involved

MF Staging Stage IA – T1, N0, M0 – 8-9% progress Stage IB – T2, N0, M0 – 11-16 years surv Stage IIA – T1-2, N1, M0 – 7.7 years Stage IIB – T3, N0-1, M0 – 3-8 years surv Stage IIIA – T4, N0, M0 – 1.8-3.7 years Stage IIIB – T4, N1, M0 – 1.8-3.7 years Stage IVA – T1-4, N2-3, M0 Stage IVB – T1-4, N0-3, M1

Lymph nodes in MF Extracutaneous involvement is more clinically evident as the stage and extent of MF increases Peripheral lymphadenopathy is the most frequent site of extracutaneous involvement in MF Evaluate palpable lymphadenopathy by obtaining a biopsy because the result influences the patient’s stage, prognosis, and treatment.

MF Workup CBC – to review the buffy coat smear for Lymph nodes CMP Liver Function to include LDH (aggressive) and transaminase (liver involvement) values CXR If lymph nodes are palpable CT to access abdominal and pelvic nodes Lymph node biopsy

Histologic Findings The criteria for diagnosis include the following: A bandlike upper dermal infiltrate of lymphocytes and other inflammatory cells, with no grenz zone, is present. Epidermotropism of mononuclear cells occurs. When a clear halo surrounds an intraepidermal mononuclear cell singly or in clumps, this is called a Pautrier microabscess. Its presence is suggestive of MF, but it is not necessary for diagnosis. Little spongiosis of the epidermis is found. Lymphocytes have nuclei that are hyperchromatic and convoluted or cerebriform.

Pagetoid Reticulosis Localized epidermotropic reticulosis Woringer-Kolopp disease Acral mycoses fungoides Mycosis fungoides palmaris et plantaris

Pagetoid Reticulosis 0.6% of all MF cases Woringer-Kolopp variant: solitary lesion Ketron-Goodman variant: multiple lesions Long durantion without progression to frank lymphoma is the clincal hallmark of Woringer-Kolopp Local excision and radiation therapy maybe curative.

Scan power view. Hyperkeratosis is associated with papillomatosis

Medium power view. Keratinocyte enlargement is seen, and this can occur whenever there is an abnormal cell population in the lower epidermis. Clusters of  dark mononuclear cells are in all levels of the epidermis.

High power view. It would be difficult to distinguish between abnormal T cells and small, dark, lymphocytoid melanocytes in this field.

Scattered plaque-like lesions on both lower extremities Scattered plaque-like lesions on both lower extremities. Ketron-Goodman disease

Band-like infiltration of lymphoid cells in lower epidermis and upper dermis. Intraepidermal infiltrate were medium- to large-sized atypical cells. Lymphoid cells infiltrating upper dermis revealed no overt atypicality.

Sezary Syndrome Leukemic phase of mycosis fungoides Generalized erythroderma, superficial lymphadenopathy, atypical cells in circulating blood Erythroderma from onset with leonine facies, eyelid edema, ectropion, alopecia, palm and sole hyperkeratosis Pruritis, burning, chill and profuse sweating

Prognosis Difficult to treat Median survival is 3 years Low dose methotrexate has reasonable response rate of 50% Photophoresis Retinoid, interferon alfa, lowdose chlorabucil, prednisone, systemic chemo

Granulomatous Slack Skin Rare variant of CTCL Middle-age adult and gradually progress Erythematous atrophic pendulous redundant plaque Multinucleated giant cells replaces fat lobules histologically.

Lymphomatoid Papulosis LyP has a chronic indolent course in most patients; estimates indicate that as many as 10-20% of LyP patients have a history of associated malignant lymphoma (ALCL, HD, or mycosis fungoides [MF]) prior to, concurrent with, or subsequent to the diagnosis of LyP. Race: Black persons may be less affected than other racial groups. Sex: No consistent sex predominance is found in studies. Age: LyP may develop at any age, usually in the third to fourth decade

Presentation Primary lesion: Each erythematous papule evolves into a red-brown, often hemorrhagic, papulovesicular or papulopustular lesion over days to weeks. Some lesions develop a necrotic eschar before healing spontaneously. Occasionally, noduloulcerative lesions may be present Each papule heals within 2-8 weeks, leaving a hypopigmented or hyperpigmented depressed oval varioliform scar. Large nodules and plaques may take months to resolve. Distribution: Characteristically, lesions appear on the trunk and extremities, although the palms and/or soles, face, scalp, and anogenital area also may be involved.

Lymphomatoid Papulosis Type A: Characterized by large (25-40 mm) CD30+ atypical cells with polymorphic convoluted nuclei and a minimum of 1 prominent nucleolus. These large cells resemble Reed-Sternberg cells when binucleate. Type A LyP is the most common histologic variant. Type B: Characterized by smaller (8-15 mm) atypical cells with hyperchromatic cerebriform nuclei resembling the atypical lymphocytes in MF. CD30+ large cells are rare, but epidermotropism is more common in this variant.

Lymphomatoid Papulosis Type C (diffuse large cell type): Characterized by sheets of CD30+ anaplastic large cells

Treatment of LyP mid-to-high potency topical steroids to hasten resolution. Low-dose weekly methotrexate is a safe and effective treatment for suppressing LyP; however, the disease recurs within 1-2 weeks after ending medication. Oral psoralen plus UV-A phototherapy (PUVA) also effectively treats and suppresses the disease. carmustine, topical nitrogen mustard, intralesional interferon, low-dose cyclophosphamide, chlorambucil, and dapsone help disease suppression.

Primary CTCL other than Mycosis Fungoides CD30-positive cutaneous T-Cell Lymphoma Secondary Cutaneous CD30 positive large-cell lymphoma Non-MF CD30-negative cutaneous large T-cell lymphoma Non-MF CD30-negative cutaneous pleomorphic small or medium sized cell lymphoma Subcutaneous (Panniculitis-Like) T-Cell Lymphoma Nasal/Nasal Type T/NK Cell Lymphoma

CD30-positive cutaneous T-Cell Lymphoma Present as solitary or localized skin lesions with tendency to ulcerate and have spontaneous regression Rare in children, occur more frequesntly in males 5 year survival rate 90% Highly responsive to ratiotherapy Lesions can be surgically excised

Secondary CD30-positive cutaneous T-Cell Lymphoma CD30 Positive CTCL arise from MF Poor prognosis

Non-MF CD 30 Negative Cutaneous Large T-Cell lymphoma Solitary or generalized plaque or tumor of short duration, no patch stage Prognosis is poor, 15% 5 year survival Malignant cells are pleomorphic large or medium cell types

Non-MF CD 30 Negative Cutaneous Small or Medium Size Cell T-Cell lymphoma Differentiate from large-cell type by having less than 30% large pleomorphic celll. Similar to large type clinically Prognosis is better than large cell type. 50% 5 year survival. Radiation tx, interferon alfa, or cyclophosphamide are effective

Subcutaneous (Panniculitis-Like) T-Cell Lymphoma Clinically presents with subcutaneous nodules Usually on lower extremities Frequently diagnosed as having erythema nodosum or other forms of panniculitis Poor prognosis

A, Marked edema of right calf at time of presentation A, Marked edema of right calf at time of presentation. B, Erythematous nodules with associated vascular ectasia on abdominal wall.

High-power view of infiltrate showing random atypical lymphocytes

Cutaneous B-Cell Lymphoma Primary Cutaneous Follicular Center Cell Lymphoma Primary Cutaneous Immunocytoma Intravascluar Large B-Cell Lymphoma Plasmacytoma (Multiple Myeoloma)

Primary Cutaneous Follicular Center Cell Lymphoma AKA B-Cell lymphoma of follicular center cell origin AKA Reticulohistiocytoma of the dorsum Multiple papules and nodules in one anatomic region. 2/3 of case on the trunk, 1/5 on the head and neck 15% on the leg

Primary Cutaneous Follicular Center Cell Lymphoma M:F = 2:1 Prognosis: Head and neck 100% 5 yr surv. Leg lesion of people over 70, 50% 5 yr surv. Stains with B-Cell marker CD 20, monotypic for immunoglobulin production of kappa or lambda chain, not both

Primary Cutaneous Immunocytoma AKA Marginal Zone B-Cell Lymphoma AKA MALT Type Lymphoma SubQ nodule or tumor primaroily of the extremities or trunk CD79, CD 20, and bcl-2 positive 5 years survival near 100%

Plasmacytoma Multiple Myeloma Spectrum of solitary plasmacytoma to multiple plasmacytoma to multiple myeloma. Neoplasm of B lymphcytes Multiple myeloma is most common characterized by lytic bone lesions and infiltration of bone marry by plasma cells

Plasmacytoma Multiple Myeloma Cutaneous plasmacytomas seen most commonly a secondary lesion in the setting of primary myeloma. Prognosis is poor. When bone film and bone biopsy are normal but cutaneous lesions present, these are primary cutaneous plasmacytoma. Excellent prognosis.

Dense mononuclear infiltrate within entire dermis Dense mononuclear infiltrate within entire dermis. This represent a primary cutaneous plasmacytoma

Neoplastic plasma cells, some with atypical features, are visible J Am Acad Dermatol 2000;43:962-5.)  

Plasmacytoma Multiple Myeloma Numerous nonspecific skin lesions occurs in patient with multiple myeloma. Amyloidosis Cutaneous vasculitis alopecia Raynaud’s Pyoderma gangrenosum

Hodgkin’s Disease Vast majority of cutaneous Hodgkin’s disease report are type A lymphomatoid papulosis with Reed-Sternberg Difficult to prove cutaneous disease

Malignant Histiocytosis Rare, fatal occur in men in second to fourth decade of life Solitary lesion or wide spread papule occur in 10% of cases Onset of acute fever, hepatosplenomegly, and painful lymphadenopathy

Malignant histiocytosis Malignant histiocytosis. Extensive superior orbital involvement in a young adult male.

Extensive erythrophgocytosis by histiocyte in marrow, liver, spleen

Leukemia Cutis 30% of Leukemia patient will have leukemia cutis Vast majority of derm manifestation are from AML Morphology: 60% multiple papules and nodules, 26% of infiltrated plaques Subtypes and variants: Granulocytic Sarcoma Hairy-cell Leukemia Nonspecific Condition associated with Leukemia

Cutaneous Myelofibrosis Overproduction and premature death of atypical megakaryocytes in bone marrow Inrease in platelet-derived growth factor Extramedullary hematopoesis is the hallmark Blast cells escape marrow and enter circulation and form tumor Cutaneous EMH reported in 20 cases

Hypereosinophilic Syndrome Icrease Eos with more than 1500 eos per cubit millimeter for 6 month or more. Cardiac disease most frequent complication 90% patient are men between 20 to 50 Angioedema and urticaria lesions most common. Sometimes papules.

Angioimmunoblastic T-Cell Lymphoma AKA Angioimmunoblastic T-Cell Lymphoma Uncommon, affect middle age and elderly Unspecific skin finding (pruritis, skin rash) Unspecific histology finding (patchy perivascular dermal infiltrate) Lymph node biopsy required for diagnosis

Polycythemia Vera Increase hermatocrite to 55% to 80% Associated with aquagenic pruritis in 50% of the patients. Elevation of blood and skin histamine Tx – control of pruritis by antihistamin or PUVA. Referral to HemOnc