Other lymphoproliferative Disorders (chapter 121)

Lymphocytic Infiltrate of Jessner
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Lymphocytic Infiltrate of Jessner
Lymphocytic Infiltrate of Jessner

Epidemiology
This entity occurs primarily in middle-aged adults. There is no gender predilection.

Pathogenesis
Benign lymphocytic infiltrate of the skin remains a controversial entity. Some authors believe it is a variant of either lupus erythematosus (primarily LE tumidus) or polymorphic light eruption2 versus a form of cutaneous lymphoid hyperplasia (pseudolymphoma). There are cases of co-occurrence with LE and with polymorphic light eruption, while in Europe, it has been associated with Borrelia burgdorferi infection3. Lastly, rare cases of drug-induced disease (e.g. angiotensin-converting enzyme [ACE] inhibitors, glatiramer acetate) have been described4,5 as have familial cases6.

Clinical features
Cutaneous lesions appear primarily on the head, neck and upper back as one or several asymptomatic, erythematous papules, plaques, and less commonly nodules, with an absence of secondary epidermal changes such as scale (Fig. 121.1). Annular plaques with central clearing are commonly observed and individual lesions last several weeks to months. There are no associated systemic manifestations. Although spontaneous resolution occurs, recurrences are common.

Pathology
The epidermis is unremarkable, with little evidence of interface dermatitis. There is a superficial and deep, primarily perivascular, lymphocytic infiltrate that may surround hair follicles (Fig. 121.2). A mild increase in dermal mucin may be seen. By immunohistochemistry, a mixed T-cell infiltrate with a predominance of CD8+ lymphocytes is observed7, admixed with CD123+ plasmacytoid dendritic cells. The distribution of plasmacytoid dendritic cells is identical to that seen in LE tumidus, further supporting a close relationship8.
Lymphocytic Infiltrate of Jessner
Differential diagnosis
The differential diagnosis includes the plaque form of polymorphic light eruption, LE tumidus, cutaneous lymphoid hyperplasia (pseudolymphoma), reticular erythematous mucinosis, and cutaneous lymphoma (Fig. 121.3). Subacute and chronic cutaneous LE are distinguished by the presence of secondary changes, including scale, follicular plugging and central hypopigmentation, along with interface changes
histologically. Because interface changes are sparse, if present at all, in LE tumidus, distinction from LIJ may prove impossible. Reticular erythematous mucinosis, which is considered by some as synonymous with LE tumidus, has abundant dermal mucin.
Polymorphic light eruption is associated with sun exposure and usually has a self-limited clinical course. Histologically, papillary dermal edema is often seen and usually there are no clusters of CD123+ plasmacytoid dendritic cells. For some patients, phototesting may provide additional helpful information
Cutaneous lymphomas can have significant clinical and histopathologic overlap with LIJ. If the dermal lymphocytic infiltrate is extensive, immunophenotypic analyses may help to distinguish between the two entities (see Chs 119 & 120). Although individual lesions of borderline lepromatous leprosy may resemble LIJ, these patients have a greater number of widespread lesions.

Treatment
The cutaneous manifestations of LIJ may resolve spontaneously within months to years, without scarring. Oral antibiotics and topical or intralesional corticosteroids have been used with limited success. Up to 50% of patients may improve with hydroxychloroquine. In general, the disorder is resistant to radiation therapy. A crossover study of oral thalidomide (100 mg/day) versus placebo in 25 patients resulted in a clinical response of 76% for thalidomide and 16% for placebo. In isolated case reports, improvement following pulsed dye (595 nm) laser treatment or chemotherapy (for an unrelated malignancy) has been described
Cutaneous Lymphoid Hyperplasia
(Pseudolymphoma of the Skin)
History
Cutaneous lymphoid hyperplasia (pseudolymphoma) was first reported by Spiegler in 1894. He described patients who presented with clinical features of a malignant neoplasm but experienced a benign clinical course. Although a characteristic feature is the resemblance to cutaneous lymphoma, there is a spectrum of clinical and histologic findings, reflecting its heterogeneous nature10.

Epidemiology
Precise data regarding incidence, prevalence, and geographic distribution are lacking. Both children and adults can be affected.
Pathogenesis

Cutaneous lymphoid hyperplasia (CLH) does not represent a single disease, but rather reflects an exaggerated local immunologic reaction to a stimulus, often unrecognized. The possibility of a hapten-driven immunologic response to cells damaged by a direct toxic effect of stimuli has been suggested11. Inciting agents include arthropod bites (including ticks and mites), tattoos, metal implants, contact allergens, vaccinations, and medications (Table 121.1)10,11,12,13. In addition, several infections such as herpes zoster and Lyme borreliosis have been associated with CLH1

Clinical features
CLH usually presents as a single, 1-3 cm, firm, erythematous to violaceous plaque or nodule located on the head, neck or upper extremities (Fig. 121.4A,B). That said, presentations can vary from multiple clustered papules to larger panniculitis-like nodules10. The vast majority of lesions lack surface changes such as scale.
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Pathology
The histopathological features are variable and the pattern may resemble either a low-grade B-cell lymphoma (follicle center lymphoma, marginal zone lymphoma) or a T-cell lymphoma, in particular mycosis fungoides, lymphomatoid papulosis (LyP), cutaneous anaplastic large cell lymphoma (cALCL), or subcutaneous T-cell lymphoma10,14.
In CLH with B-cell predominance, there is typically a superficial and deep nodular or diffuse infiltrate of lymphocytes, admixed with histiocytes and occasional plasma cells and eosinophils. In florid cases, germinal centers with prominent tingible-body macrophages may be observed (Fig. 121.5). Distinction from follicle center lymphoma can be made on routine histologic sections or with the addition of immunohistochemical stains (Table 121.2). Clonality, based upon IgH gene rearrangements or restricted κ or λ expression, is usually not seen in pseudolymphomas (see Fig. 119.10)10,15. PCR analysis for Borrelia burgdorferi DNA is positive in Borrelia-associated lymphocytoma cutis and pseudolymphomatous acrodermatitis chronica atrophicans10,15.
In T-cell-predominant infiltrates, CD4+ T helper lymphocytes are commonly observed within the dermis, admixed with a minority of CD8+ cytotoxic/suppressor T cells. A mycosis fungoides-like pattern is most often encountered in drug-induced pseudolymphomas (see Table 121.1). Histologically, epidermotropism, spongiosis, vacuolar degeneration of the basal layer, papillary dermal edema, and red cell extravasation may be seen. Prominent papillary dermal fibrosis, which can be seen in mycosis fungoides, is absent, but T-cell clonality may be present. CD30+ pseudolymphomas include persistent arthropod bite reactions, drug reactions, and the atypical lymphoid infiltrates associated with cutaneous poxvirus infections (e.g. molluscum contagiosum, orf). Additional findings related to the underlying disorder can aid in diagnosis, and there is polyclonal rearrangement of the TCR10,14.

Treatment
CLH is a benign, reactive condition and it should be treated conservatively. Spontaneous resolution may occur without scarring. For persistent lesions, topical and/or intralesional corticosteroids may lead to improvement. Simple excision, cryosurgery, laser ablation, and radiation therapy are other options. Thalidomide has been utilized with success in recalcitrant cases24. Performance of a biopsy, even if partial, can be followed by spontaneous regression. For Borrelia-associated pseudolymphoma, appropriate antibiotics are administered
Extramedullary hematopoiesis
Epidemiology
Extramedullary hematopoiesis (EMH) is a reflection of bone marrow dysfunction and is most commonly seen in neonates. It may occur in adults with myelofibrosis and less often myelodysplasia or after splenectomy10,25.

Pathogenesis
Cutaneous EMH occurs normally during early embryogenesis and abates prior to birth. Thereafter, it occurs only as a secondary phenomenon in response to altered bone marrow function. Rarely, in otherwise healthy individuals, primary cutaneous neoplasms such as pilomatricomas, nevus sebaceus, hemangiomas, and pyogenic granulomas may be associated with localized EMH10,26.

Clinical Features
The clinical presentation consists of erythematous to violaceous papules and nodules which may ulcerate. When widely disseminated in neonates, it leads to the classic "blueberry muffin baby" (Fig. 121.6)25. This can be seen in association with congenital viral infections and prenatal anemias (Table 121.4). Dermal hematopoiesis is most often seen with rubella and cytomegalovirus, and serologic titers for TORCH infections can aid in diagnosis.

Pathology
EMH is characterized by a dermal infiltrate of immature red and white blood cell precursors and megakaryocytes, centered around vessels of the superficial vascular plexus. It may also extend into the deeper reticular dermis and exhibit a diffuse pattern. All three hematopoietic cell lines are present in varying ratios, depending upon the underlying disease process.

Differential Diagnosis
Histologically, the differential diagnosis is limited. Distinguishing EMH from disseminated congenital leukemia cutis and neonatal neuroblastoma is important. Whereas all three hematopoietic cell lines (erythrocytes, leukocytes and megakaryocytes) are represented in EMH, there is an atypical infiltrate of immature leukocytes in leukemia cutis. Patients with overwhelming marrow involvement by leukemia may have both EMH and leukemic involvement of the skin, further complicating the diagnosis.

Treatment
Treatment of the underlying bone marrow dysfunction results in reversal of the cutaneous process. Spontaneous resolution can occur with some viral infections.
Leukemia Cutis
Epidemiology
Multiple types of leukemia exist, each with its own epidemiologic characteristics. Acute lymphoblastic leukemia (ALL) tends to be a neoplasm of childhood. Acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) occur primarily in adults, and chronic lymphocytic leukemia (CLL) and hairy cell leukemia are most common in elderly patients. Development of CML-associated leukemia cutis can be a harbinger of blast transformation10, while the development of leukemia cutis in a patient with myelodysplastic syndrome points to progression to AML27.

Pathogenesis
Specific chromosomal abnormalities are associated with particular subtypes of leukemia. The Philadelphia chromosome, the primary diagnostic feature of CML, represents a translocation between chromosomes 9 and 22 [t(9;22)]. This translocation results in fusion of the two genes BCR and ABL, with constitutive activation of the tyrosine kinase activity of the fusion oncoprotein. It is this kinase activity that is selectively inhibited by imatinib mesylate (Gleevec®). Additionally, 95% of patients with promyelocytic leukemia have a t(15;17) translocation, which leads to abnormal expression of a fusion retinoic acid receptor that is the target of all-trans retinoic acid therapy. A variety of non-random chromosomal abnormalities exists in ALL and AML that can influence prognosis, and in AML mutations in particular genes can be favorable (e.g. CEBPA) or unfavorable (e.g. FLT3-ITD). Table 121.5 outlines the relationship between specific abnormalities and prognosis in CLL28.

Clinical features
Leukemia can lead to nonspecific reactive skin lesions (Table 121.6) or specific infiltrates. The latter most commonly present as firm papules and nodules that often become hemorrhagic; thrombocytopenia usually plays a role in this associated hemorrhage. Ulcerative and rarely bullous lesions occur. Leukemia cutis can develop in any location, but the head, neck and trunk are most commonly involved (Fig. 121.7A). Leukemic infiltrates may arise at sites of trauma or scars.
Rarely, myelogenous leukemias may present with dermal nodules known as chloromas, granulocytic sarcomas, or extramedullary myeloid tumors. Granulocytic sarcomas may precede the development of systemic leukemia by months. Gingival hyperplasia, secondary to leukemic infiltrates, favors acute monocytic or acute myelomonocytic leukemia.
In one series, cutaneous eruptions of leukemia accounted for 30% of all skin biopsy specimens in patients with leukemia29. Other diagnoses included GVHD, drug eruptions, infectious processes, purpura, and small vessel vasculitis. In most patients with acute leukemia, cutaneous lesions are present at the time of diagnosis or recurrence, but occasionally, skin involvement precedes the appearance of leukemia in the peripheral smear ("aleukemic" leukemia cutis). Rarely, leukemia cutis predates apparent bone marrow involvement by months or even years. Of note, asymptomatic dermal leukemic infiltrates of CLL may be evident in biopsy specimens of primary cutaneous neoplasms (e.g. squamous cell carcinoma) and inflammatory or infectious disorders, indicating that these neoplastic cells retain the capability to respond to chemotactic stimuli and migrate into tissues30,31.
The characteristics of the different forms of leukemia cutis are summarized in
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Pathology
Histologic features of leukemia cutis vary with the type of leukemia. The neoplastic infiltrate may be perivascular, interstitial, nodular and/or diffuse; occasionally, they densely surround the eccrine glands29-31. Diagnosis is more difficult when the perivascular and periadnexal infiltrates are sparse and mimic inflammatory disorders31 AML represents a neoplastic proliferation of immature myeloid cells and encompasses multiple subtypes28. In general, the neoplastic cells recapitulate myeloid precursor cells in their immature stages of development (Fig. 121.7B). In many cases, cytoplasmic granules can be found. A chloroacetate esterase stain is helpful in detecting myeloid differentiation, but in very immature precursor cells, granules may not be present. The most common forms of AML that involve the skin and present de novo (without previous evidence of systemic disease) are the more mature subtypes - acute myelomonocytic and acute monocytic leukemia. Immunohistochemically, the infiltrates of AML are positive for myeloid markers such as myeloperoxidase, CD13, CD33 and CD6810.
ALL represents a clonal expansion of immature lymphocytes, most commonly of B-cell lineage and less commonly T-cell lineage. Rarely, cytoplasmic granularity may be present, and this corresponds with a precursor B-cell immunophenotype. Cells of ALL may be difficult to identify in skin biopsy specimens and immunostaining for terminal deoxytransferase may prove helpful10.
CML demonstrates a range of myeloid precursors, including promyelocytes, metamyelocytes, bands, and mature neutrophils. Although cutaneous lesions of CML are rare, they are typically seen in patients with chronic myelomonocytic leukemia and are associated with blast transformation and a poor prognosis10.
Cutaneous CLL is characterized by a dense infiltrate of uniform-appearing, small, round lymphocytes of B-cell lineage (Fig. 121.8). The infiltrating cells appear mature, but the monomorphous nature and paucity of other cell types within the infiltrate suggest a leukemic infiltrate. The lymphocytes often surround adnexal and vascular structures with the infiltrates having prominent crush artifact. Immunohistochemically, CLL shows positivity for CD5, CD20, and CD4310,30,32.
Differential diagnosis
The clinical differential diagnosis includes lymphoma cutis, infectious emboli, vasculitis, and drug eruptions. The histologic differential diagnosis of leukemia cutis depends upon the type of leukemia present. Distinguishing some cases of leukemia cutis from lymphomas involving the skin can be difficult. For myeloid leukemias, the differential diagnosis includes extramedullary hematopoiesis (see above), Sweet syndrome, cutaneous small vessel vasculitis, and other neutrophilic dermatoses. In general, recognizing immature and atypical granulocytic precursors within leukemic infiltrates allows the distinction from reactive neutrophilic infiltrates. However, in histiocytoid Sweet syndrome, the infiltrate is composed mostly of immature cells of myeloid lineage and may be misinterpreted as leukemia cutis32a.
Treatment
No specific treatment for leukemia cutis currently exists. The cutaneous eruptions typically resolve following successful treatment of the leukemia
Cutaneous hodgkin lymphoma
Epidemiology
Cutaneous involvement by Hodgkin lymphoma (HL) is rare10,33,34. In one large study, only 0.5% of patients with HL had cutaneous involvement35, primarily in the setting of advanced disease and serving as a marker of poor prognosis. The existence of true primary cutaneous HL is debatable10.
The incidence of HL peaks during early adulthood, with a second, smaller peak in the sixth decade. Of note, compared to the general population, mycosis fungoides and LyP occur at higher rates in patients with HL34,36. This reflects the increased incidence of non-Hodgkin lymphomas in general in HL patients. The underlying reason for this phenomenon is not known.
Pathogenesis
Approximately 30-40% of patients with classic HL (see below) have EBV DNA within the pathognomonic Reed-Sternberg tumor cells. The precise role of EBV in HL pathogenesis is not known37. In classic HL, the Reed-Sternberg cells represent the malignant population and are usually derived from B-cell lymphocytes.
Clinical features
Classic HL includes the nodular sclerosing (most common), mixed cellularity, and lymphocyte-depleted forms of the disease, and it is characterized histologically by the presence of Reed-Sternberg cells. A small minority of patients have a non-classic, more indolent form of the disease, referred to as nodular lymphocyte-predominant HL.
Cutaneous involvement usually consists of multiple papulonodules or plaques in a patient with known, advanced disease. The trunk is the most common site of involvement (Fig. 121.9)35, and lesions often appear in sites distal to affected lymph nodes. Lymphadenopathy, splenomegaly, and constitutional symptoms (e.g. fevers, chills, night sweats) are additional signs and symptoms.
In 20-50% of patients with HL, paraneoplastic cutaneous disorders can develop. These include primary pruritus, acquired ichthyosis, persistent dermatitis, hyperpigmentation, and occasionally, erythema nodosum34
Cutaneous hodgkin lymphoma
Pathology
The histologic features of cutaneous HL are similar to those of affected lymph nodes. A nodular or diffuse dermal infiltrate consisting of lymphocytes admixed with eosinophils and plasma cells is present; epidermotropism is not seen. Depending upon the histologic subtype, Reed-Sternberg cells (or mononuclear variants) (Fig. 121.10) and lacunar cells may be present. The latter, most common in the nodular sclerosing subtype of HL, are large cells with abundant eosinophilic cytoplasm. The retraction of this cytoplasm from adjacent cells during fixation gives rise to a giant cell residing within a clear space. Areas of dermal sclerosis may be seen and extension into the subcutaneous fat is common.
Reed-Sternberg cells express CD30 (Ki-1), fascin and CD15, but not CD45RB (leukocyte common antigen) or CD20. They are positive for PAX-5, MUM-1, and in some cases, EBV (EBER-1). The background infiltrate of lymphocytes is composed predominantly of T cells31. In lymphocyte-predominant HL, the malignant cells stain positively for CD2010,28.
Differential diagnosis
The histologic differential diagnosis of HL includes cALCL and LyP, both of which have cells that stain positively for CD30 (see Ch. 120). Clinicopathologic correlation is important in differentiating between these entities. Both LyP and cALCL can present with variably ulcerated papules and nodules, but patients with LyP do not have evidence of systemic involvement and crops of their lesions appear and then spontaneously resolve. Sheets of atypical CD30+ cells are usually seen in cALCL, and the cells in LyP and cALCL do not stain positively for CD15 or PAX-510.
Treatment
Patients with stage IV HL, who may have secondary cutaneous disease, have a cure rate of approximately 60-70% following combination chemotherapy38. Treatments for recurrent disease include salvage chemotherapy, autologous HSCT, and anti-CD30 (brentuximab) and anti-PD-1 antibodies.
Blastic plasmacytoid dendritic cell neoplasm
History and epidemiology
In 1994, blastic plasmacytoid dendritic cell neoplasm (BPDCN) was described by Adachi et al.39 as a CD4+/CD56+ lymphoma presenting predominantly in the skin. Initially classified as blastic NK-cell lymphoma due to its CD56 expression, this rare tumor was subsequently reclassified, first as a hematodermic neoplasm and then as a neoplasm of plasmacytoid dendritic cells40. In the revised World Health Organization (WHO) 2017 classification, it is a distinct entity and is grouped with AML-related precursor neoplasms40a,40b.
BPDCN is a disease of adults, usually those >50 years of age, but pediatric cases have been reported. The male-to-female ratio is 3 : 1.

Pathogenesis
BPDCN represents a malignant proliferation of plasmacytoid dendritic cells. These cells produce large amounts of type I interferons (IFN), specifically IFN-α, and they express several Toll-like receptors (e.g. TLR7, TLR9), making them critical in the defense against viruses and other pathogens28.

Clinical features
Clinically, BPDCN presents as solitary or multiple, non-tender, variably pruritic, erythematous to violaceous papules, plaques or nodules that can resemble bruises (Fig. 121.11). Ulceration is uncommon. In most patients, the skin is the presenting site of involvement. However, further evaluation usually reveals subclinical regional lymph node, peripheral blood, and bone marrow involvement in the majority of patients. Those individuals with initial negative staging eventually develop hematologic involvement. Symptoms of fevers, chills, night sweats or weight loss are uncommon at presentation but may develop with disease progression
Pathology A diffuse dermal infiltrate of monotonous, atypical, medium-sized mononuclear cells is seen (Fig. 121.12A). These cells have fine blastic chromatin, indistinct nucleoli, and scant agranular eosinophilic cytoplasm. Intratumoral hemorrhage is common. In early lesions, the infiltrate may be perivascular and periadnexal. A grenz zone is almost always present and the infiltrate commonly extends into the subcutis10,41,42. Immunohistochemical studies are necessary to establish the diagnosis. The cells are CD4+, CD56+, CD123+, TCL1+, BDCA2+/CD303+, and myeloperoxidase- and EBV-negative (Fig. 121.12B). Expression of CD123 reflects the presence of plasmacytoid dendritic cells; TdT is variably positive. There are descriptions of aberrant CD4−, CD56−, or CD123− cases10,41,43. The tumor cells have germline configurations of Ig (H and L) and TCR, i.e. lack rearrangement. Abnormalities of several chromosomes including 12p13 (CDKN1B), 13q13 (RB1), and 9p21 (CDKN2A) have been detected leading to alterations in the proteins involved in cell-cycle checkpoint regulation, e.g. p27/Kip1, pRb, p1644. These same genes can be altered in non-Hodgkin lymphoma, ALL, and hairy cell leukemia Differential diagnosis The differential diagnosis includes AML and other cutaneous lymphomas. BPDCN, however, lacks IgH and TCR gene rearrangements and has a characteristic immunohistochemical profile (see above). There are subtypes of AML that may express CD4, CD56 and CD123, but expression of TCL1, BDCA2 and CD2-associated protein (CD2AP) points to the diagnosis of BPDCN10,45. Of note, there are isolated reports of patients with BPDCN developing AML28. Treatment Initial treatment of BPDCN usually consists of multidrug chemotherapeutic regimens. Although response rates are high (up to 80%), invariably patients relapse followed by progression, with one year being the median overall survival. For that reason, eligible patients are offered allogeneic HSCT. Patients with primary cutaneous BPDCN should be treated in the same aggressive manner10. Aberrant activation of the NF-κB pathway may represent a therapeutic target.Angioimmunoblastic T cell lymphomaHistory This disease was initially described in 1974 as angioimmunoblastic lymphadenopathy with dysproteinemia, and its features included generalized lymphadenopathy, hepatosplenomegaly, polyclonal hypergammaglobulinemia, and a hemolytic anemia46,47. Epidemiology Angioimmunoblastic T-cell lymphoma (AITCL) is a rare disease of the middle-aged and elderly, with a nearly equal incidence in men and women47. Pathogenesis Formerly, AITCL was considered to be an atypical reactive process or an abnormal immunologic reaction, until non-random chromosomal abnormalities, clonal rearrangements of the TCR, and progression to an aggressive lymphoma were frequently noted. Currently, in the WHO Classification of Haematopoietic Tumours, it is considered a mature T-cell neoplasm whose cells of origin are follicular T helper cells28. Clinical features Patients with AITCL usually present at an advanced stage with fever, weight loss, night sweats, generalized lymphadenopathy, and hepatosplenomegaly28,47,48. Approximately one-half of the patients have cutaneous manifestations. The most common presentation is a widespread morbilliform eruption that resembles a viral exanthem. Other cutaneous findings include petechiae (often associated with thrombocytopenia), urticaria, purpura, papulonodules, and rarely, erythroderma. Generalized pruritus may be a presenting symptom. AITCL has an aggressive behavior, with a median survival of <3 yearsPathology The histopathologic features vary, with five patterns described to date. These include: (1) a superficial perivascular infiltrate composed of eosinophils and lymphocytes that lack atypia (most common pattern); (2) a sparse perivascular infiltrate with atypical lymphocytes; (3) a dense superficial and deep infiltrate of pleomorphic lymphocytes; (4) a vasculitis, with or without atypical lymphocytes; and (5) necrotizing granulomas28,47,48. A presentation with necrotizing granulomas resembling an infectious process has been reported49. Similar to involved lymph nodes, the skin may have increased numbers of venules with a prominent endothelial lining ("high endothelial venules"). By immunohistochemistry, the neoplastic cellular phenotype corresponds to follicular T helper cells (CD3+, CD4+, CD8−, CD10+, PD-1+, ICOS+, Bcl-6+, chemokine ligand CXCL13+) plus clusters of CD21+ follicular dendritic cells50. Although EBV-positive B cells are frequently seen, EBV DNA and EBV proteins are not detected in the neoplastic T-cells. Molecular analysis demonstrates a monoclonal TCR rearrangement and a polyclonal immunoglobulin pattern. The most frequently mutated gene in AITCL is TET2 (on 4q24) whose protein product is tet methylcytosine dioxygenase 2, which is involved in DNA methylation and is also implicated in peripheral T-cell lymphoma51. Differential diagnosis The morbilliform nature of the eruption belies its malignant nature. Consequently, confusion with a drug eruption or viral exanthem is common. As cutaneous histologic changes are subtle, a specific diagnosis often cannot be rendered. Treatment Few prognostic factors exist and the majority of patients present with stage III-IV disease47,48. In a prospective, randomized clinical trial, in which most of the 157 patients received various intensive anthracycline-based chemotherapeutic regimens, there were no observable differences amongst the varying regimens, even with the addition of HSCT48. Despite achieving a complete response in 46% of patients following induction therapy, the 5- and 7-year survival rates were 33% and 29%, respectivelyLymphomatoid granulomatosisHistory Lymphomatoid granulomatosis (LG) was first described in 1972 as a pulmonary angiitis/granulomatosis mimicking Wegener granulomatosis. Initially thought to represent a reactive process, subsequent studies demonstrated a malignant clonal B-cell population admixed with an abundant, polyclonal, reactive T-cell population28. Epidemiology LG is a rare disease of adults, usually presenting in the fifth to sixth decade of life. The male-to-female ratio is approximately 2 : 1. The disease can affect children, most commonly in the setting of immunodeficiency syndromes28,52. Pathogenesis The pathogenesis of LG is often related to EBV infection, occasionally in combination with immunosuppression. Based upon case reports, immunosuppressive factors associated with LG include renal transplantation, Wiskott-Aldrich syndrome, HIV infection, and X-linked lymphoproliferative syndrome26. Clinical features Patients with LG present with symptoms related to pulmonary involvement, such as cough, dyspnea and chest pain. Constitutional symptoms include fever, weight loss, malaise, arthralgias and myalgias. Cutaneous lesions develop in 25-50% of patients and usually present as nodules or ulcerated plaques (Fig. 121.13). Rarely, LG may present as a maculopapular exanthem. The kidney, brain and gastrointestinal tract may be affected. In contrast to angioimmunoblastic T-cell lymphoma, the lymph nodes and spleen are rarely involved.Pathology In LG, there are three histopathologic grades: (1) grade 1 - polymorphous lymphoid infiltrate without cytologic atypia, along with a few large cells, and few cells are positive for Epstein-Barr virus-encoded RNA 1 (EBER-1) and latent membrane protein via in situ hybridization and immunohistochemistry, respectively; (2) grade 2 - polymorphous inflammatory background with scattered large cells and more abundant EBER-1+ cells; and (3) grade 3 - sheets of large B-cells and numerous EBER-1+ cells predominate over the inflammatory background. The amount of necrosis increases with the grade and angiocentricity/angiodestruction is consistently present. Granulomatous changes are often present. The neoplastic cells stain positively for CD20 and CD79a, and in some cases, a monoclonal rearrangement of the JH gene10,28. Differential diagnosis The clinical differential diagnosis includes various forms of cutaneous lymphoma, as well as infectious and inflammatory disorders (e.g. medium vessel vasculitis, pyoderma gangrenosum). The histopathologic differential diagnosis is broad and encompasses most of the lymphoproliferative disorders mentioned above, including B-cell and T-cell lymphomas. Other disorders with histologic evidence of granulomatosis include granulomatosis with polyangiitis (Wegener granulomatosis), sarcoidosis, and infectious processes. Diagnosis is based upon histopathologic findings plus immunohistochemical and molecular analyses. Treatment LG follows an aggressive course, with the 5-year mortality ranging from 60% to 90%. For higher-grade disease, treatment commonly involves multidrug chemotherapy and/or rituximab (anti-CD20 monoclonal antibody), and, for grade 1 disease, IFN-α. Reversal of exogenous immunosuppression may also lead to clinical improvement2 patients