Mycosis fungoides (MF) is the most common type of cutaneous lymphoma. In most cases, the disease is indolent and slowly progressive over a period of years or decades. Three main stages of the lymphoma are recognized: patch, plaque, and tumor stages. In the patch stage of mycosis fungoides, patients typically present with broad pink or tan oval-shaped patches with a predilection for the bathing trunk area. The patches may be asymptomatic or pruritic. Both clinically and histopathologically, distinction from eczematous dermatitis is sometimes difficult in the earliest stages of the lymphoma. In the evaluation of patch stage mycosis fungoides, multiple shave biopsies are often helpful, since the shave technique provides a broad area of epidermis for examination. The typical immunophenotype is CD3+, CD4+, CD8−, CD30−. Aberrant immunophenotypes (with loss of normal T-cell markers, such as CD7) can frequently be demonstrated. Clonal rearrangement of the T-cell receptor gene is helpful in supporting the diagnosis, although the earliest cases may sometimes not have a detectable clone.

Differential Diagnosis

• Dermatitis generally has more spongiosis and fewer intraepidermal lymphocytes

• Lichenoid drug eruption typically has more apoptotic keratinocytes

• Lymphomatoid drug eruption may look nearly identical. Pautrier’s microabscesses favor mycosis fungoides

Fig 24-1 Patch stage mycosis fungoides

Fig 24-2 Patch stage mycosis fungoides

Primary cutaneous CD30+ lymphoproliferative disorders

Lymphomatoid papulosis

Clinicopathologic correlation is particularly important in the diagnosis of lymphomatoid papulosis (LyP). Patients present with crops of ulcerated nodules and papules most frequently involving the trunk and limbs. Lesions regress spontaneously, while new lesions erupt at other sites. Three histologic subtypes (A, B, and C) are recognized in the 2008 WHO classification, and two additional cytotoxic variants (types D and E) have subsequently been described in the literature. Different lesions from an individual patient may simultaneously demonstrate a single or multiple histologic subtypes. Type A is the most common and characteristic type of LyP; type B is uncommon.

LyP is a spontaneously regressing lymphoproliferative disorder. Clonal rearrangement of the T-cell receptor genes is detectable in many cases. LyP itself is a non-fatal disease, but it can be associated with other more aggressive lymphoproliferative disorders. In 10–20% of cases, it is associated with mycosis fungoides, cutaneous or systemic anaplastic large cell lymphoma, or Hodgkin’s lymphoma. These associated lymphomas may precede, accompany, or follow the diagnosis of LyP.

Pearls

Type B LyP may histologically mimic mycosis fungoides. The clinical features distinguish the two entities. Spontaneously regressing papules or nodules favor LyP. Persistent patches or plaques favor MF.

Type C LyP may be histologically indistinguishable from anaplastic large cell lymphoma (ALCL). Crops of spontaneously regressing papules or nodules favor LyP. Persistent, solitary or localized nodules or tumors favor ALCL. The two are closely related and may in fact represent a spectrum of a single disorder.

Type D LyP histologically mimics primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, but is CD30 positive and has the typical course of LyP with crops of self-resolving ulcerative papulonodules.

Type E LyP histologically mimics extranodal NK/T-cell lymphoma, nasal type, which is similarly angioinvasive and angiodestructive. The two entities are distinguished by the clinical course and the presence or absence of Epstein–Barr virus (EBV) within the tumor cells. NK/T-cell lymphoma has an aggressive clinical course; lesions of type E LyP regress spontaneously. The tumor cells of NK/T-cell lymphoma are Epstein–Barr virus (EBV) positive by in situ hybridization and usually CD56 positive by immunohistochemistry; the cells of type E LyP are EBV negative and usually CD56 negative.

Fig 24-15 Lymphomatoid papulosis

Fig 24-16 Lymphomatoid papulosis, type A

Fig 24-17 Lymphomatoid papulosis, type B

Fig 24-18 Lymphomatoid papulosis, type B

Fig 24-19 Lymphomatoid papulosis, type C

Fig 24-20 Lymphomatoid papulosis

Primary cutaneous anaplastic large cell lymphoma

Key features

• Sheets of large Reed–Sternberg-like cells in dermis ± subcutaneous fat

• Reactive small lymphocytes, histiocytes, and eosinophils in background

• CD30 expression by >75% of large cells in infiltrate

Primary cutaneous anaplastic large cell lymphoma (ALCL) most often presents with solitary or localized tumors or nodules. Spontaneous regression occasionally occurs. Extracutaneous dissemination is uncommon. The prognosis is generally favorable with 5-year survival rates of ≥90%.

Pearl

ALCL may also originate in lymph nodes and spread secondarily to the skin. By routine microscopy, primary cutaneous ALCL is virtually indistinguishable from nodal ALCL. The distinction is important since nodal ALCL has a much worse prognosis. Immunohistochemistry can provide useful clues in this situation. Nodal ALCL has a chromosomal translocation t(2;5), which results in expression of anaplastic lymphoma-related tyrosine kinase (ALK-1). ALK-1 expression can be demonstrated by immunohistochemistry in most cases of nodal ALCL, but ALK-1 is generally absent in primary cutaneous ALCL. Nevertheless, staging is mandatory in all cases and is ultimately more important than immunohistochemistry in distinguishing primary cutaneous ALCL from its nodal counterpart.

Fig 24-21 Primary cutaneous anaplastic large cell lymphoma

Fig 24-22 Primary cutaneous anaplastic large cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma

Patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) typically present with deep indurated nodules and plaques. The legs are a common site of involvement. Survival rates are approximately 80% at 5 years. SPTCL is sometimes associated with a potentially fatal hemophagocytic syndrome, consisting of pancytopenia, hepatosplenomegaly, and fever. In hemophagocytic syndrome, blood cells are engulfed by macrophages in the bone marrow and lymphoid organs.

Differential Diagnosis

Lupus panniculitis may be very difficult to distinguish from early SPTCL. Interface vacuolization, dermal mucin, and hyaline necrosis are all typical of lupus panniculitis but may sometimes be seen in SPTCL. Clonal rearrangement of T-cell receptor genes generally supports the diagnosis of SPTCL.

Fig 24-23 Subcutaneous panniculitis-like T-cell lymphoma

Fig 24-24 Subcutaneous panniculitis-like T-cell lymphoma

Fig 24-25 Subcutaneous panniculitis-like T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Key features

• Dense lymphoid infiltrates in dermis, subcutaneous fat, ± epidermis

• Angiocentricity, angiodestruction, and zonal necrosis

• CD2+ CD3epsilon+, usually CD56+ (NK-cell marker)

• CD3 expression variable

• Cytotoxic phenotype: granzyme B+ TIA-1+ perforin+

• Epstein–Barr virus detected within lymphoma cells by in situ hybridization

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL) develops within the nasal cavity or skin. It is most commonly seen in Asia and Latin America. The nasal cavity and palate can be infiltrated and destroyed by the lymphoma. Cases previously described as lethal midline granuloma included some examples of ENKTCL. This lymphoma is associated with a very aggressive clinical course. Hemophagocytic syndrome occurs in a subset of patients. In most cases, no clonal rearrangement of the T-cell receptor can be demonstrated. The oncogenic role of Epstein–Barr virus is an important feature of this lymphoma.

Fig 24-26 Extranodal NK/T-cell lymphoma, nasal type

Fig 24-27 Extranodal NK/T-cell lymphoma, nasal type

Fig 24-28 Extranodal NK/T-cell lymphoma, nasal type

Primary cutaneous peripheral T-cell lymphoma

Peripheral T-cell lymphoma is a heterogeneous category of lymphomas. Several distinctive, rare cutaneous variants are recognized:

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (provisional entity)

Key features

• Band-like, lichenoid lymphoid infiltrate with marked epidermotropism

• Beta F1+ CD3+ CD8+

• Cytotoxic phenotype: granzyme B+ TIA-1+ perforin+

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma presents with patches, papules, nodules, or tumors. Ulceration and hemorrhage are frequent. As the name implies, the clinical course is rapidly progressive.

Differential Diagnosis

Distinguished from the rare CD8+ variant of mycosis fungoides, Pagetoid reticulosis, and type D LyP by the clinical features (especially the aggressive clinical course).

Fig 24-29 Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma

Fig 24-30 Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma

Fig 24-31 Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma

Cutaneous gamma–delta T-cell lymphoma

Key features

• Location of infiltrate: subcutaneous, dermal, epidermal

• TCR gamma–delta+ Beta F1− CD3+ CD56+ CD4−

• Cytotoxic phenotype: granzyme B+ TIA-1+ perforin+

• Clonal rearrangement of T-cell receptor genes

Patients with cutaneous gamma/delta T-cell lymphoma develop plaques, ulcerated nodules, and tumors, most frequently involving the extremities. This lymphoma is sometimes associated with hemophagocytic syndrome. The clinical course is usually rapidly progressive.

Pearl

Subcutaneous cases of gamma–delta T-cell lymphoma may be histologically similar to subcutaneous panniculitis-like T-cell lymphoma, but the gamma–delta lymphomas have a much worse prognosis. Distinguishing the two entities is important. In contrast to SPTCL, gamma–delta lymphomas often extend into the dermis and sometimes into the epidermis. By immunohistochemistry, SPTCL is Beta F1 positive and TCR gamma–delta negative. Gamma–delta lymphoma is Beta F1 negative and TCR gamma–delta positive.

Fig 24-32 Primary cutaneous gamma–delta T-cell lymphoma

Fig 24-33 Primary cutaneous gamma–delta T-cell lymphoma

Fig 24-34 Primary cutaneous gamma–delta T-cell lymphoma

Primary cutaneous CD4+ small/medium T-cell lymphoma (provisional entity)

Key features

• Dermal infiltrate ± involvement of subcutaneous fat and epidermis

• CD3+ CD4+ CD8− CD30−

• Aberrant immunophenotype with loss of some T-cell markers

• Clonal rearrangement of T-cell receptor genes

Primary cutaneous CD4+ small/medium T-cell lymphoma is a provisional entity in the 2008 WHO classification. The lymphoma is remarkable for its localized distribution and relatively good prognosis. Patients usually present with a solitary plaque, nodule, or tumor. Diagnosis requires clinical correlation to exclude mycosis fungoides. In contrast to mycosis fungoides, no preceding patches are noted by history. By histology, epidermotropism is less conspicuous than that seen in early mycosis fungoides.

Some reports suggest that this provisional category may represent a heterogeneous group of lymphomas. A recently described entity termed primary cutaneous follicular helper T-cell lymphoma may partially overlap with primary cutaneous CD4+ small/medium T-cell lymphoma. Follicular helper T cells commonly express CD10, BCL-6, and CXCL-13. Expression of these markers has been variable in reported cases of primary cutaneous CD4+ small/medium T-cell lymphoma.

Fig 24-35 Primary cutaneous CD4+ small/medium T-cell lymphoma

Fig 24-36 Primary cutaneous CD4+ small/medium T-cell lymphoma

Hydroa vacciniforme-like lymphoma

Hydroa vacciniforme-like lymphoma is an Epstein–Barr virus-associated lymphoproliferative disease of childhood. Early in the course, the clinical presentation mimics hydroa vacciniforme, although the disease activity is often independent of sun exposure. Disordered immune regulation confers severe sensitivity to mosquito bites. Over a period of years, the lymphoma progresses to systemic involvement. Systemic associations include fever, lymphadenopathy, and organomegaly. When systemic involvement occurs, the clinical course is aggressive.

Precursor hematologic neoplasm

Blastic plasmacytoid dendritic cell neoplasm

Fig 24-37 Hydroa vacciniforme-like lymphoma

Fig 24-38 Hydroa vacciniforme-like lymphoma

Fig 24-39 Hydroa vacciniforme-like lymphoma

Fig 24-40 Hydroa vacciniforme-like lymphoma

Previous names for this entity include CD4+/CD56+ hematodermic neoplasm and blastic NK-cell lymphoma. The cell of origin is a precursor of CD123-positive plasmacytoid dendritic cells. Patients present with solitary or multiple nodules or tumors. Tumor cells rapidly disseminate to the lymph nodes, bone marrow, and blood. The prognosis is poor. T-cell markers are negative, and there is no clonal rearrangement of the T-cell receptor genes. In the 2008 WHO classification, this tumor is classified as a precursor neoplasm related to acute myeloid leukemia (AML). An association with AML occurs in about 10–20% of patients.

Fig 24-41 Blastic plasmacytoid dendritic cell neoplasm

Fig 24-42 Blastic plasmacytoid dendritic cell neoplasm

Myeloid leukemia

Cutaneous infiltrates of leukemic cells occur commonly in acute myeloid leukemia and rarely in chronic myelogenous leukemia. Direct involvement of the skin is particularly common in M5 (acute monocytic) and M4 (acute myelomonocytic) leukemia. Infiltration of the gingivae is also common in these two subtypes. Patients present with papules, nodules, plaques, purpura, or ulcers. Unusual presentations include a generalized maculopapular eruption clinically resembling an allergic drug eruption or viral exanthem. In skin biopsy specimens, acute myeloid leukemia and chronic myelogenous leukemia may have similar morphologic features. Some types of acute leukemia are associated with specific chromosomal translocations, such as t(15;17) in promyelocytic leukemia (M3).

Pearl

Myeloid leukemia may be indistinguishable from lymphoma in H&E sections. CD43 is commonly used as a T-cell marker but is also expressed in myeloid cells. Myeloid leukemia should be considered when a CD43-positive infiltrate does not express the T-cell marker CD3 or the B-cell marker CD20. Lysozyme, myeloperoxidase, and chloroacetate esterase (Leder stain) may then be performed to confirm myeloid lineage.