1. Neoplastic vs. dysplastic vs. inflammatory (reactive lymphoid hyperplasia)
   
   
2. B-cell vs. T-cell process vs. other
   
   
3. Subtype of lymphoma.
   
   
4. Primary cutaneous vs. secondary lymphoma

Reactive Lymphoid Hyperplasia
Reactive Lymphoid Hyperplasia (RLH) is an inflammatory reaction composed primarily by lymphocytes to a known or unknown triggering stimulus. RLH may have architectural and cytological features that closely simulate a lymphoma. The term "pseudolymphoma" is often used for such cases. However, this term is misleading and confusing and its use is not recommended.

RLH, B-cell type: Patients are often young presenting with a solitary lesion often in the head and trunk with a predilection for sites like the forehead, ear, nose, nipple, and scrotum. The lesions are red non-ulcerated nodules covered by smooth skin. The treatment of choice is surgical excision, which at the same time will provide the pathologist with adequate material for a thorough evaluation. There are a number of distinct conditions that can present with a RLH, B-cell pattern. In order to reach the correct diagnosis, pertinent clinical history may be needed. Some of the conditions to be considered with this pattern are:

Kimura's disease Arthropod bite reaction (tick bite) Lupus erythematosus / Jessner's Ruptured cyst/ pseudolymphomatous folliculitis Reaction to foreign body (tattoo, vaccine, acupuncture, surgical site etc) Others (herpes, halo nevus, cancer, etc.)

RLH, B-cell type, or lymphocytoma cutis, maybe difficult to differentiate from a primary cutaneous follicular lymphoma. Both conditions display a follicular pattern at low magnification. RLH has sharply demarcated germinal centers with a distinct mantle zone, tingible body macrophages and a high mitotic activity. Some other clues favoring RLH include:

Polymorphous infiltrate (eosinophils, plasma cells, histiocytes) Paucity of intermediate cells Prominent endothelial cells, margination, edema and/or fibrosis Lack of light chain restriction (Kappa:Lambda between 4:1 and 1:2) Granulomatous changes Lack of adnexal destruction or "crush artifact"

In reality, the distinction between lymphocytoma and lymphoma is often difficult if not impossible. Furthermore, marginal zone lymphomas may have reactive germinal centers and conversely RLH with distorted dermal mesenchymal tissue may present with a diffuse pattern.

RLH, T-cells type: There are numerous dermatoses that can present with a dense infiltrate composed of reactive intermediate to large lymphocytes that can closely resemble a large cell T-cell lymphoma. Other dermatoses characterized by chronic epidermotropic reactive T-cells may resemble mycosis fungoides. Interestingly many of this entities display a CD8 T-cells phenotype, which is unusual for MF. Furthermore the large cell variants of RLH often express CD30. Once again, knowledge of the clinical presentation is of utmost importance.

T-cell lymphoma (large cell type) mimics   VZV reaction   Molluscum contagiosum   Nodular scabies   Some "pagetoid reticulosis" Mycosis fungoides mimics:   Actinic reticuloid   HIV photodermatitis   Drug hypersensitivity reaction (psycotropic drugs, antiepileptics, ACE-inhibitors, etc)   Others: lichenoid keratosis, lupus erythematosus and other interface dermatitis, contact dermatitis, erythema annulare centrifigum

Cutaneous lymphoid dysplasias (CLD )
In the last few years, we have also witnessed numerous studies reporting T-cell clonality (TCC) in a myriad of cutaneous conditions traditionally classified as benign dermatoses. This confusing trend has elicited some debate about the relevance of TCC in cutaneous infiltrates and the lack of specificity of TCC in the diagnosis of CTCL. However the detection of TCC in certain inflammatory dermatoses is probably a real event that should not be blamed to over sensitivity of the PCR based tests.

In my opinion, there are a number of well-defined skin conditions characterized by persistent cutaneous lymphoid infiltrates composed of a clonal population of T-cells with minimal cytologic atypia. Furthermore all of these conditions can transform into bona fide CTCL and hence should be considered precursor lesions. The defining criteria for CLD are:

1. Chronic dermatitis recalcitrant to steroids
   
   
2. Unknown triggering event
   
   
3. Small/intermediate lymphocytes without nuclear atypia
   
   
4. Persistentclone
   
   
5. Potential for malignant transformation

Hypopigmented interface variant Pigmented purpuric variant Atypical lobular panniculitis Syringolymphoid hyperplasia with alopecia Idiopathic follicular mucinosis Folliculotropic T-cell lymphocytosis Pityriasis lichenoides chronica Parapsoriasis en plaque Idiopathic erythroderma (Pre-Sézary)

Cutaneous T-cell lymphomas
Mycosis fungoides is the prototype of CTCL. There are approximately 0.3 new cases per 100,000 people diagnosed yearly with an estimated US prevalence of 18,000 to 20,000 cases. The majority of patients are 40 to 70 years of age with slight male and black predominance. MF is characterized by:

Low grade lymphomas Cutaneous homing features (CLA+) T helper cells (CD4) Mature & primed T-cells (CD45R0+) TH2 cytokine profile

The challenge in the diagnosis of CTCL is in the heterogeneity of clinical pathological presentation as well as the slow evolution of the disease. The classic histopathological features include:

1. Upper dermal band-like lymphocytic infiltrate with variable adnexal involvement.
   
   
2. Variable epidermal changes, often with parakeratosis.
   
   
3. Halo perinuclear effect with minimal spongiosis.
   
   
4. Epidermotropism (basal, Pautrier microabscesses, duplets/triplets).
   
   
5. Dermal fibroplasia (reticulated or laminar).
   
   
6. Nuclear atypia (small cerebriform cells--intermediate--large cells). Intraepidermal lymphocytic atypia.
   
   
7. Some eosinophils and plasma cells are frequently seen in advanced MF

Cutaneous T-cell lymphoma, large cell type
Diffuse, dense (superficial and deep) and mostly non-epidermotropic mononuclear cell infiltrate.

When a patient with a history of mycosis fungoides develops new tumor lesions the differential diagnosis includes:

Tumor progression commonly associated with large cell transformation (CD30 + or -) CD30 Lymphomas/lymphomatoid papulosis Other tumors: Patients with MF are prone to develop other malignancies including B-cell lymphoma and Hodgkin's disease. Pseudotumors (nodules without tumor cells) like picker's nodule (neurodermatitis) in follicular MF.

Large cell transformation (LCT) of mycosis fungoides carries a poor prognosis with a 5-year survival of 11 to 19% (Cerroni 1992, Diamandidou 1998). We must be careful not to confuse a primary cutaneous CD30 lymphoproliferative disorder with MF with LCT. This is particularly important since both conditions may coexist on the same patient and both entities can present with a dermal infiltrate composed of CD30+ large T-cells.

Primary cutaneous CD-30+ lymphoma (Ki-1 lymphoma, anaplastic large cell lymphoma)
This condition can present at any age with one or multiples often ulcerated nodules. The prognosis of tumors with limited skin involvement is excellent. However, some subsets of CD30+ LCL are particularly aggressive. These presentations include involvement of multiple skin regions, extensive single limb involvement, and associated pseudoepitheliomatous hyperplasia. The diagnosis of CD30+ lymphoma may also be difficult to differentiate from lymphomatoid papulosis (LyP). This is especially true with the type C variant of LyP which is characterized by large nodules with cohesive sheets of CD30+ large cells. The defining criteria will depend on the clinical behavior. LyP type C should undergo spontaneous regression which can take up to 8 weeks. A prudent approach by the clinician is to wait a few weeks prior to therapeutical intervention. In CD30+ anaplastic large cell lymphoma, unlike MF with LCT, the tumor cells show near-uniform expression of CD30 in more than 75% of the cells. The CD30 (Ki-1 antigen) is a marker of activated T and B cells and is not lineage specific. The antibody BER-H2 can be used in paraffin embedded tissue. Large CD30+ reactive lymphocytes have been reported in a variety of inflammatory conditions like arthropod bite or resolving ruptured cyst.

Medium and small cell variants of CD30+ anaplastic large cell lymphoma have been rarely described. Patients with multiple cutaneous nodules, especially children, should be worked up for possible systemic lymphoma with secondary skin involvement. Immune staining with ALK and EMA indicate a high likelihood of a secondary CD30 lymphoma. With rare exceptions, cutaneous CD30 lymphoproliferative lesions are t(2;5) negative.

Lymphomatoid papulosis
Lymphomatoid papulosis is characterized by recurrent crops of papulonecrotic lesions that histologically contain atypical lymphocytes. The term "Lymphomatoid" refers to the benign clinical course usually encountered, although approximately 10% of the patients may subsequently develop lymphoma (CTCL, CD30+ lymphomas). Histological features include: a superficial and deep perivascular and interstitial mononuclear cell infiltrate with epidermotropism, and the presence of atypical lymphocytes (Reed-Sternberg-like for Type A, small cerebriform for Type B). The vast majority of LyP cases are type A with large atypical cells. A variable number of eosinophils and extravasated RBC's can be found. Occasionally lymphocytic vasculitis is also noted. Most of the atypical large cells stain with T-cell markers and CD-30 (Ki-1). Differential diagnosis includes CD-30 positive lymphoma, which shows less non-specific inflammation and a more pure population of atypical cells. There are other entities that can present with multiple papules with an atypical CD30+ large cell population. Such entities include arthropod bite reactions (especially in children), dermal reactions associated with folliculitis, or molluscum contagiosum. Post-transplant and methotrexate-induced lymphoproliferative disorders can closely resemble LyP clinically and histopathologically.

Cutaneous B-Cell Lymphomas
The only trace of B-cells in normal skin is some secretory IgA cells present in eccrine and sebaceous glands. A B-cell skin immune system is probably acquired with recruitment of B-cells after an antigenic stimulus. This pool of reactive B-cells is probably the precursor of primary cutaneous B-cell lymphoma (PCBL). Because of the great similarities with mucosal-associated lymphoid tissue (MALT) lymphomas, PCBLs have also been called "SALT lymphomas".

Patients tend to present with a single or multiple red nodules or papules with smooth surface. The lesions tend to localize in one anatomical area, most commonly head, neck or back. Extracutaneous spread occurs in less than 10% of the cases, most commonly to the regional lymph node and rarely to the bone marrow (especially follicular cell lymphomas). Mortality rate of primary cutaneous B-cell lymphomas is low (4/133 patients). An uncommon subset of patients present with large tumor lesions on the legs. These patients are often elderly females and this variant carries a poor prognosis.

Immunohistochemistry
Immunophenotyping of cutaneous B cell lymphomas is more reliable with flow cytometry than immunohistochemistry. An adequate sample can be obtained by mincing a 4mm punch biopsy of fresh tumor specimen and then filtering the sample to create a cell suspension. The panel of immunomarkers available for flow cytometry is more comprehensive allowing for more precise tumor definition.

Initially, pan B-cell markers (CD79a, CD20) should be used. T-cell rich B-cell lymphomas and lymphomatoid granulomatosis may show only focal clusters of B-cells with a dominant T-cell or in some cases a histiocytic infiltrate. Conversely cases with a pure population of tumor B-cells with few reactive T-cells are likely to be secondary cutaneous lymphomas with a primary nodal or other systemic origin. Occasionally abnormal expression of CD43 and CD45RO has been reported in PCBL.

Infiltrates with a follicular pattern should be tested for bcl-2. Its expression is unusual on primary cutaneous follicular center cell (FCC) lymphomas. Primary cutaneous B-cell lymphomas expressing bcl-2 carries a poor prognosis even if a systemic lymphoma has not been detected (Grange Blood 2004).

Lymphomas composed of small/intermediate B-lymphocytes should be stained with CD5 and CD10. CD5 staining should alert us about a possible mantle cell lymphoma. Cyclin D1 can be used to confirm the diagnosis. Occasionally SLL/CLL can present with skin infiltrates with or without large cell transformation. CD23 can be used to identify this subtype. When the predominant cells are small cleaved (centrocytes) with variable centroblasts in a diffuse or nodular pattern, the likely diagnosis is a secondary FCC lymphoma. CD10 may be positive in this case. MUM-1 and Bcl-6 can be used for the evaluation of large cell B-cell lymphomas. Besides the cytologic features showing a pure population of intermediate to large cells with round nuclei, MUM-1 and strong bcl-2 expression will be helpful in the diagnosis of leg-type lymphoma. Bcl-6 will support a FCC origin, but it may also be expressed in the leg-type lymphoma.

Surface immunoglobulins (sIG) cannot be detected in formalin fixed sections. Hence the role of kappa and lambda is limited to cases suspicious for a plasmacytoma or a marginal zone lymphoma. mRNA in situ hybridization may be helpful when cytoplasmic immunoglobulins cannot be detected. In approximately 25% of cases, light chain expression is absent. Cases with negative results may include early lymphomas with many tumor-infiltrating lymphocytes, advanced large cells lymphomas that have lost their surface immunoglobulins, and pre-B cell or null phenotype lymphomas. In addition, necrosis or linkage of plasma proteins may lead to a loss of sIGs.

Follicular center cell lymphoma
This is the most common type of PCBL. Histologically it is characterized by an ill-defined follicular pattern with centrocytes and centroblasts. The mantle zone is reduced or absent and there is a confluence of the follicles, a lack of polarization and tingible bodies, and a low proliferative index. Over time the infiltrate tends to become diffuse, often with large cell transformation. Large cell transformation in primary cutaneous FCC lymphoma has no prognostic or therapeutic implications.

The phenotype is as follows: CD5 negative, CD10 often positive (negative on diffuse lesions), bcl-6 positive, MUM-1 usually negative. Bcl-2 is usually negative or weakly positive but occasionally positive in primary skin lesions and especially in secondary skin tumors. In early FCC lymphomas, CD21 stains dendritic reticulum cells (follicular dendritic cells) and outlines an irregular network pattern that tends to disappear with time. The karyotype often includes t(14:18).

The distinction between a primary cutaneous and a secondary cutaneous lymphoma should be determined on the clinical grounds. When a patient presents with multiple lesions in different anatomical areas, a systemic lymphoma should be suspected. Rarely primary cutaneous FCC lymphomas can involve multiple anatomical regions. The individual lesions are indistinguishable from PCBL. Approximately 5-10% of advanced follicular lymphomas will involve the skin. Histopathological clues to suggest a systemic lymphoma include a deep follicular or diffused infiltrate with a monomorphous infiltrate and relatively few reactive cells. BCL-2 is often expressed.

Marginal zone lymphomas
Patients are often young adults with one or several deeply seated nodules in the extremities. The prognosis is excellent prognosis with persistent lesions and high frequency of cutaneous recurrences. The 5-year survival rate is 98%. Patients have no evidence of a paraproteinemia and are not at increased risk of an autoimmune disorder. Rarely transformation into a large cell lymphoma can occur.

Vertically oriented infiltrates often tracing adnexal structures. Centrocyte-like/monocytoid cells with ample pale cytoplasm "Monotypic" lymphoplasmacytoid/plasma cells at periphery in most cases Occasionally with deep dermal reactive germinal centers which can be colonized by tumor cells. Light chain restriction on plasmacytoid cells even on paraffin sections. CD5- and CD10- Elderly patients ( average.76 y.o.) Women (M:F, 2:7)(M Vermeer et al., Arch Derm 1996) Multiple or solitary nodules in the lower legs although it may occur in other areas. Radiotherapy or chemotherapy; CR in 16/18 pts. Relapse 9/18. 5 died of their lymphoma Activated B-cell phenotype with MUM1 expression Diffuse pattern with intermediate to large round cells (centroblasts/immunoblasts) Necrotic areas, destructive pattern and minimal stromal reaction Bcl-2 ++; staining is typically strong and in most neoplastic cells, Bcl-6: +/-, CD10: -/+

Lymphoblastic lymphoma presenting in the skin
Extremely rare cutaneous presentation. Report of 6 patients with skin involvement (head/neck) at the time of presentation. Frequently patients have bone marrow involvement and ALL.(C Sander et al., JAAD 1991)

Uniform dermal infiltrate composed of small-medium size cells with blastic nuclear chromatin. Many mitosis and apoptotic cells. CD10 (CALLA) +/-, CD20 +/-, TdT+, cytoplasmic Ig+, sIg- Most cases reported, unlike mediastinal tumors, are pre-B-cell Differential diagnosis: Burkitt's, small non-cleaved MZL This is a high grade lymphoma that often responds to chemotherapy

Cutaneous plasmacytoma
Primary (very rare) or spread from bone (multiple myeloma). Extraosseous lesions more common in IgD secreting tumors (63%). Monomorphous infiltrate composed of plasma cells. Suspect myeloma if there is nuclear atypia or multinucleated cells, mitosis and/or cytoplasmic IgD. Differential diagnosis: Immunocytoma/marginal zone lymphoma (less maturity with more plasmacytoid cells).

Intravascular large B-cell lymphoma (malignant angioendotheliomatosis)
Elderly patients (F>M) present with CNS changes, dementia, fever, skin changes, etc.

Indurated hemorrhagic plaques (>50% pts.). Rarely confined to skin only Large B-cells in blood vessels with fibrin Differential diagnosis: "inflammatory carcinoma" and reactive angioendotheliomatosis MUM-1+ , Bcl-2+, CD10-/+, CD5-

Cytotoxic lymphomas

Subcutaneous panniculitis-like T-cell lymphoma
(SPTL) SPTL is characterized by the presence of primarily subcutane­ous infiltrates of small, medium or large pleomorphic T-cells with many histiocytes, predominantly involving the legs. Necrosis, karyorrhexis and cytophagocytosis are com­mon findings. Recent studies suggest that at least two groups of SPTL with different histologies, phenotypes and prognosis can be distinguished. Cases with α/β+ T-cell phenotype are usually CD8-positive, are restricted to the subcutaneous tissue with minimal dermal or epidermal involvement, and often run an indolent clinical course. In contrast, SPTL with γ/δ T-cell phenotype, are typically CD4-, CD8-, and often co-express CD56. The neoplastic infiltrates are not confined to the subcutaneous tissue, but may involve the epidermis and/or dermis as well. This subtype invariably has a very poor prognosis.

The disease may be complicated by a hemop­hagocytic syndrome, which is generally associated with a rapidly progressive cour­se. However, the hemop­hagocytic syndrome is probably less common than in cutaneous γ/δ+ T-cell lymphomas with panniculitis-like lesions. Dissemination to extracutaneous sites is rare. SPTCL may be preceded for years or decades by a more indolent panniculitis. In the early stages the neoplastic infiltrates may lack significant atypia and a heavy inflammatory infiltrate may predominate. EBV is absent.

Extranodal NK/T-cell lymphoma, nasal type
After the nasal cavity/nasopharynx, the skin is the second most common site of involvement of extranodal NK/T-cell lymphoma; skin involvement may be a primary or secondary manifestation of the disease. Patients are predominantly adult males. This lymphoma is more common in Asia, Central America and South America. Patients generally present with multiple hemorrhagic and ulcerated plaques or tumors and sometimes with central facial destructive features also designated lethal midlinegranuloma.

The infiltrate often involves dermis and often extends to the subcutis. Prominent angiocentricity and angiodestruction are often accompanied by extensive necrosis. In most cases the infiltrate is mostly composed of medium sized cells with a spectrum from small to large lymphocytes. The cells may have irregular hyperchromatic nuclei with scant pale cytoplasm. In some cases a heavy inflammatory infiltrate of small lymphocytes, histiocytes, plasma cells and eosinophils can complicate the diagnosis. The neoplastic cells express CD2, CD56, cytoplasmic CD3ε and cytotoxic proteins (TIA-1, granzyme B, perforin), but lack surface CD3. In rare cases CD56 is negative and detection of EBV by in-situ hybridization and expression of cytotoxic proteins are required for diagnosis. LMP-1 is inconsistently expressed.Hydroa vacciniforme-like CTCL is a rare type of EBV-associated lymphoma of CD8+ cytotoxic T-cells which affects children almost exclusively in Latin America and Asia. In my opinion, this variant is very closely related to nasal type, NK lymphoma.

Primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T-cell lymphoma
Clinically, these lymphomas are characterized by the presence of localized or disseminated eruptive papules, nodules and tumors showing central ulceration and necrosis or by superficial, hyperkeratotic patches and plaques.The clinical features are very similar to those observed in patients with a cutaneous γ/δ T-cell lymphoma and cases described as generalized pagetoid reticulosis (Ketron-Goodman type) in the past. These lymphomas may disseminate to other visceral sites (lung, testis, central nervous system, oral mucosa), but lymph nodes are often spared.

The epidermis shows a pagetoid infiltrate of atypical lymphocytes with prominent necrotic changes. Invasion and destruction of adnexal skin structures are commonly seen. Angiocentricity and angioinvasion may be present. Tumor cells are small-medium-large with pleomorphic or blastic nuclei. The phenotype is as follows: CD3+, CD8+, TIA-1+, CD45RA+, CD2-, CD4-, CD5-, EBV-.

Cutaneous gamma/delta T-cell lymphoma can present with a similar manner with extensive cutaneous and even mucosal necrosis. The prognosis is also poor.

CD4+/CD56+ Hematodermic neoplasm (formally Blastic type, NK lymphoma)
The blastic cytological appearance and CD56 expression initially suggested an NK-precursor origin of these lymphomas. More recent studies suggest derivation from a plasmacytoid dendritic cell precursor. CD4+/CD56+ hematodermic neoplasm commonly presents in the skin with multiple nodules or tumors with or without concurrent extracutaneous localizations. Most patients presenting with only skin lesions rapidly develop involvement of bone marrow, peripheral blood, lymph nodes and extranodal sites. Only about half of the patients have nodal or bone marrow involvement at presentation. The prognosis is poor. Some of these cases may have been diagnosed in the past as "aleukemic leukemia cutis". The infiltrate is non-epidermotropic, monotonous and is composed of medium-sized cells with finely dispersed chromatin and absent or indistinct nucleoli resembling lymphoblasts or myeloblasts. There is a high mitotic index and often some hemorrhage. The phenotype is as follows: CD4+, CD56+, CD3-, CD8-, myeloperoxidase-, CD45RA+, CD123+, germline TCR, EBV-

Proposed WHO/EORTC classification of primary cutaneous lymphomas

Cutaneous T-cell and NK-cell lymphomas

Mycosis fungoides Mycosis fungoides variants and subtypeso Folliculotropic MF   Pagetoid reticulosis   Granulomatous slack skin Sézary syndrome Adult T-cell leukemia/lymphoma Primary cutaneous CD30-positive lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, unspecified Primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma (provisional) Cutaneous γ/δ T-cell lymphoma (provisional) Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

Cutaneous B-cell lymphomas

Primary cutaneous marginal zone B-cell lymphoma Primary cutaneous follicle center lymphoma Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, other Primary cutaneous intravascular large B-cell lymphoma

Precursor hematologic neoplasm

CD4+/CD56+ hematodermic neoplasm (formerly blastic NK cell lymphoma)

WHO-EORTC Classification	Number	Frequency (%)	Disease-specific5-year survival (%)
CUTANEOUS T-CELL LYMPHOMAS Indolent clinical behavior
Mycosis fungoides	800	44	88
Folliculotropic MF	86	4	80
Pagetoid reticulosis	14	<1	100
Granulomatous slack skin	4	<1	100
Primary cutaneous anaplastic large cell lymphoma	146	8	95
Lymphomatoid papulosis	236	12	100
Subcutaneous panniculitis-like T-cell lymphoma	18	1	82
Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma	39	2	75
Aggressive clinical behavior
Sézary syndrome	52	3	24
Primary cutaneous NK/T-cell lymphoma, nasal-type	7	<1	NR
Primary cutaneous aggressive CD8+ T-cell lymphoma	14	<1	18
Primary cutaneous γ/δ T-cell lymphoma	13	<1	NR
Primary cutaneous peripheral T-cell lymphoma, unspecified	47	2	16
CUTANEOUS B-CELL LYMPHOMAS Indolent clinical behavior
Primary cutaneous marginal zone B-cell lymphoma	127	7	95
Primary cutaneous follicle center lymphoma	207	11	99
Intermediate clinical behavior
Primary cutaneous diffuse large B-cell lymphoma, leg type	78	4	55
Primary cutaneous diffuse large B-cell lymphoma, other	11	<1	50
Primary cutaneous intravascular large B-cell lymphoma	6	<1	65