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Hematopathology / LYMPHADENOPATHY ASSOCIATED WITH CUTANEOUS T-CELL LYMPHOMA

Fine-Needle Aspiration Biopsy in the Evaluation of Lymphadenopathy Associated With Cutaneous T-Cell Lymphoma (Mycosis Fungoides/Sézary Syndrome) Lorenzo M. Galindo, MD,1 Fernando U. Garcia, MD,1 Cheryl A. Hanau, MD,1 Stuart R. Lessin, MD,2 Nirag Jhala, MD,1 Robert D. Bigler, MD,1 and Eric C. Vonderheid, MD3 Key Words: Mycosis fungoides; Cutaneous T-cell lymphoma; Cytology; Fine-needle aspiration; Lymphadenopathy; Sézary syndrome; T-cell gene rearrangement

Abstract We studied the role of fine-needle aspiration (FNA) in the evaluation of lymphadenopathy associated with cutaneous T-cell lymphoma (CTCL) in 11 patients with lymphadenopathy and compared findings with corresponding histologic material. Molecular genetic analysis for T-cell clonality by polymerase chain reaction (PCR) was performed on all aspirates. Immunophenotyping was successful in 4 of 7 cases in which flow cytometry was attempted from the aspirated material. Cytologic evaluation of FNA samples correlated strongly with histologic rating of involvement based on numbers of atypical cerebriform lymphocytes in the nodal specimen. Of 7 nodal specimens with scattered or small groups of atypical cells in the background of dermatopathic lymphadenopathy (LN1-2), the cytologic diagnosis was interpreted as reactive in all instances. Of 4 specimens with highly suspect (LN3) or definite histologic involvement (LN4), the cytologic diagnosis was likewise suspect or malignant. The correlation between molecular genetic studies on FNA samples and studies on tissue was not significant; in 2 cases, a T-cell clone was detected in the nodal tissue sample but not in the FNA sample, suggesting undersampling. A T-cell clone was detected by PCR in 5 of 7 nodal specimens judged reactive by FNA biopsy or histologic assessment. FNA for cytologic and molecular genetic analysis is a useful method to evaluate lymphadenopathy associated with CTCL and may obviate the need for surgical biopsy.

© American Society of Clinical Pathologists

Despite a large and growing volume of literature supporting the use of fine-needle aspiration (FNA) in the evaluation and diagnosis of lymphadenopathies, much skepticism exists among clinicians about its usefulness for the diagnosis and subtyping of lymphomas. Opinions vary about its accuracy and reliability compared with surgical biopsies.1-16 The application of new ancillary techniques, such as flow cytometry, laser scanning cytometry, polymerase chain reaction (PCR), and others, to cytologic material can aid greatly in reaching a definitive diagnosis. With the advent of the revised European-American lymphoma classification that emphasizes the combination of clinical features, immunophenotype, and cytomorphology, we believe that the role of FNA in the primary diagnosis and classification of lymphomas has expanded greatly.17 Mycosis fungoides and Sézary syndrome are neoplasms classified under the general category of cutaneous T-cell lymphomas (CTCL). The neoplastic T cells typically express a CD3+CD4+CD8–CD7– surface phenotype, although exceptions may occur. The histologic diagnosis of CTCL in the skin is based on the presence of atypical lymphocytes with convoluted or cerebriform nuclei (mycosis or Sézary cells) within a bandlike subepidermal infiltrate with exocytosis into the epidermis (epidermotropism). The diagnosis of Sézary syndrome requires that patients have generalized erythroderma (T4 skin rating), Sézary cells on blood smears, and evidence of an expanded abnormal T-cell population in circulation by flow immunophenotyping, molecular genetics, or chromosome analysis. The prognosis of patients with CTCL correlates with the extent of skin involvement (T rating), lymph node status (N rating), and evidence of blood or visceral involvement (M rating).18-20 Patients with enlarged lymph nodes often undergo Am J Clin Pathol 2000;113:865-871

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Galindo et al / LYMPHADENOPATHY ASSOCIATED WITH CUTANEOUS T-CELL LYMPHOMA

a lymph node biopsy for staging of the disease and to determine prognosis. The characteristic cytologic findings of dermatopathic lymphadenopathy and mycosis fungoides have been described recently.21-24 In the present study, we compared the cytologic diagnosis obtained by FNA, a less invasive technique, with the histopathologic diagnosis of the excised lymph nodes using the standard National Cancer Institute–Veterans Administration (NCI-VA) classification ❚Table 1❚ in conjunction with newer ancillary techniques, such as flow immunophenotyping and PCR amplification of the T-cell receptor gamma-chain gene.

Materials and Methods Patients Eleven patients (3 men, 8 women) who underwent lymph node biopsy constitute the basis of this study ❚Table 2❚. Lymph node specimens were obtained from 8 patients at the time of initial staging and from 3 patients at the time of clinical evidence of disease progression. The median age was 69 years (range, 35-89 years). Four patients had mycosis fungoides, and 7 patients had Sézary syndrome. The size of palpable lymph nodes ranged from 1.5 to 4 cm in maximum diameter (Table 2). Preoperative FNA of the enlarged node was

performed in 5 cases, while in 6 cases, FNA of the excised lymph node was performed on the fresh intact specimen in the surgical pathology laboratory. To obtain enough cells for studies, 2 to 5 passes with a 23- or 25-gauge needle were done. Air-dried and alcohol-fixed smears were prepared for each case and stained with rapid Romanowsky and Papanicolaou stains, respectively. The majority of the aspirated material was rinsed onto 10 mL of cold RPMI 1640 solution with 1% bovine serum albumin (Cellgro, Washington, DC). All cytologic smears were reviewed independently by 2 pathologists (L.M.G., F.U.G.) without knowledge of the clinical history or the final histopathologic results. The smears were interpreted according to the criteria outlined in ❚Table 3❚ and compared with the histopathologic interpretation using the criteria outlined in Table 1. The PCR–denaturing gradient gel electrophoresis, which has a sensitivity on the order of 1 in 105 cells, was used to detect a clonal expansion of the T-cell receptor gamma-chain gene as described by Wood et al.25 Flow cytometry analysis was performed with a flow cytometer (FACScan, Becton Dickinson, San Jose, CA) equipped with a doublet discrimination module. Monoclonal antibodies used in the 2-color flow cytometry included CD3, CD4, CD8, and CD7 as the minimal panel when the number of available cells for analysis was limited. All antibodies used for flow immunophenotyping were purchased from Becton Dickinson.

❚Table 1❚ National Cancer Institute–VA Classification for Lymph Node Histology in Cutaneous T-Cell Lymphoma Classification

Description

LN0 LN1 LN2 LN3 LN4

Reactive lymph node hyperplasia without atypical lymphocytes Dermatopathic lymphadenopathy with occasional atypical lymphocytes Dermatopathic lymphadenopathy with atypical lymphocytes singly or in small clusters (15 cells) Partial or complete effacement by mycosis fungoides/Sézary syndrome with or without dermatopathic lymphadenopathy

❚Table 2❚ Patient Characteristics Patient No./ Sex/Age (y) 1/F/83 2/F/72 3/M/57 4/M/82 5/M/77

Clinical Diagnosis

Lymph Node Site/Size (cm)

Stage

Histologic Diagnosis

Axilla/2 Groin/2.4 Axilla/3 Groin/2 Groin/2

III IIa IIb III III

LN1 LN1 LN1 LN2 LN1

Grade I, reactive Grade I, reactive Grade I, reactive Grade I, reactive Grade I, reactive

Groin/3 Neck/1.5

III IIa

LN1 LN2

Axilla/4

IVa

LN3

Grade I, reactive Grade II, atypical favor reactive Grade III, “suspicious,” favor NHL Grade III, “suspicious,” favor NHL Grade III, suggestive of NHL Grade IV, NHL

8/F/66

SS (T4 N1 B1 M0) MF patch (T2 N1 B0 M0) MF tumor (T3IIb B0 M0) SS (T4 N1 B1 M0) Erythrodermic MF (T4 N1 B2 M0) SS (T4 N1 B1 M0) MF plaque (unilesional) (T1 N1 B0 M0) SS (T4 N3 B1 M0)

9/F/84

SS (T4 N3 B1 M0)

Axilla/2

IVa

LN3

10/F/70 11/F/35

SS (T4 N3 B1 M0) SS (T4 N3 B1 M0)

Axilla/2 Neck/3

IVa IVa

LN4 LN4

6/F/89 7/F/45

Cytologic Diagnosis

NHL, non-Hodgkin lymphoma.

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Hematopathology / ORIGINAL ARTICLE

Statistical Analysis The Fisher exact test and Pearson chi-square test were used to test for significant association between histologic, cytologic, and molecular genetic findings. Software used for these tests was StatXact, version 2.11 from CYTEL Software, Cambridge, MA.

Results The patient’s clinical characteristics and results of the various studies on the lymph node samples are summarized in Table 2. An adequate number of cells was obtained by FNA for cytomorphologic assessment and molecular genetics in all cases. However, flow immunophenotyping was performed in only 5 of 7 FNA samples because of an insufficient number of cells. A 100% diagnostic concordance was found between the 2 reviewing pathologists using the cytologic classification

scheme shown in Table 3. When the results of the FNA cytologic interpretation were compared with the histologic diagnosis based on the NCI-VA grading scheme ❚Table 4❚, a highly significant correlation was found (chi-square, P = .008). Discrepant results were observed in 2 cases: the lymph node from patient 4 was classified as LN2 by histologic examination and as grade I by FNA, and the lymph node from patient 10 was classified as LN4 by histologic examination and as grade III by FNA. Both of these lymph nodes were involved by CTCL by flow immunophenotyping and molecular genetics. Thus, in both instances, the assessment based on the number of atypical cerebriform lymphocytes resulted in a lower classification score on the FNA sample compared with the corresponding histologic interpretation. By contrast with the strong positive correlation between FNA cytologic and histologic grading, a poor correlation was found between either FNA or histopathologic findings and PCR results ❚Table 5❚ (chi-square, P = .382). The explanation seems to be related to the high sensitivity of PCR testing

❚Table 3❚ Cytologic Criteria for Diagnosis of Lymph Node Involvement by Cutaneous T-Cell Lymphoma (CTCL) Grade

Description

I: Reactive pattern including dermatopathic lymphadenopathy II: Atypical, favor reactive pattern III: Suggestive of CTCL

Lymphocytes in all stages of maturation, melanophages, plasma cells, eosinophils, absent or very rare atypical lymphocytes* Same as grade I with occasional scattered atypical lymphocytes Same as grade I admixed with a larger number of atypical lymphocytes (4-6 per high-power field†), or frequent but dispersed atypical lymphocytes, occasional melanophages Predominant population of atypical lymphocytes or transformation to non-Hodgkin lymphoma

IV: Definite for CTCL * †

Atypical cerebriform lymphocytes. ×40.

❚Table 4❚ Summary of Cytologic/Histologic Correlation Grade I II III IV Total

LN1

LN2

LN3

5 – – – 5

1 1 – – 2

– – 2 – 2

LN4

Total

– – 1 1 2

6 1 3 1 11

❚Table 5❚ T-Cell Gene Rearrangement Studies: Cytologic/Histologic Correlation Patient No. 1 2 3 4 5 6 7 8 9 10 11

FNA/TCR

Tissue/TCR

Clonal Polyclonal Polyclonal Polyclonal Clonal Clonal Polyclonal Clonal Clonal Clonal Clonal

Clonal Clonal Clonal Polyclonal Clonal Clonal Polyclonal Clonal Clonal Clonal Clonal

Histologic Diagnosis LN1 LN1 LN1 LN2 LN1 LN1 LN2 LN3 LN3 LN4 LN4

FNA, fine-needle aspiration; TCR, T-cell receptor.


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because a dominant T-cell clone was shown in 9 of 11 nodal specimens irrespective of histologic or cytologic grading. This finding underscores the difficulty of recognizing small numbers of malignant T cells in a dermatopathic lymph node by histologic or cytologic examination. Furthermore, the correlation between PCR results on FNA samples and tissue samples was not statistically significant (Fisher exact test, P = .109) because of a discordant result in 2 samples (patients 2 and 3). Both cases were polyclonal on the FNA sample and clonal on the larger piece of tissue. In each case, histologic and cytologic assessment showed only reactive changes, ie, LN1 histology and grade I cytology, and flow immunophenotyping did not show evidence of an abnormality. The correlation between flow immunophenotyping on FNA samples and tissue seemed to be good, but the small number of samples available for comparison limited the assessment ❚Table 6❚ . However, the difference in the CD4/CD8 ratio (10.8 vs 20.7) and level of CD7 expression (36% vs 13%) observed between the FNA and tissue samples, respectively, for patient 8, indicated a problem with adequate sampling by FNA. The high CD4/CD8 ratio with low level of CD7 expression by flow immunotyping provides additional evidence of involvement in this LN3-rated specimen.

Discussion Mycosis fungoides is typically an indolent form of CTCL with a protracted clinical course. This entity is characterized clinically by the sequential appearance of patches that progress to plaques and finally to tumors. Overt lymph node involvement occurs in 20% to 25% of patients with plaque phase mycosis fungoides and 50% to 60% of patients with tumor phase mycosis fungoides. Sézary syndrome is an erythrodermic and leukemic expression of CTCL with a high

frequency of lymph node involvement. If lymph node involvement is evident histologically with mycosis fungoides or Sézary syndrome, the prognosis is poor, with median survival of about 3 years. At the time of diagnosis, almost 70% of patients with CTCL have palpably enlarged lymph nodes, particularly in the axillary and inguinal regions.26 The decision of when or which lymph nodes to biopsy is not always straightforward. The risk of wound infection, development of a seroma, and chronic edema of the extremity are complications that occur not infrequently in patients with extensive skin involvement with CTCL. Moreover, more than 80% of the lymph nodes in CTCL will be classified as LN0 or LN1, ie, dermatopathic lymphadenopathy with or without scattered atypical lymphocytes with cerebriform nuclei in the paracortical regions of the node. Results of the study show that FNA cytology combined with ancillary techniques is a useful method to evaluate lymphadenopathy in patients with CTCL and that FNA may obviate the need for a surgical procedure. The correlation between the FNA cytology and the histologic assessment of the same node was excellent. All 7 cases classified as reactive or probably reactive, ie, grade I or II, had a similar histologic grade, ie, LN1 or LN 2 ❚Image 1❚ and ❚Image 2❚. Likewise, the 4 cases with an FNA cytologic profile that was suggestive of or definite for malignant neoplasm, ie, grade III or IV ❚Image 3❚, had an LN3 or LN4 histologic grade. However, FNA cytology grades were lower than the corresponding histologic grades in 2 instances, suggesting that undersampling may occasionally occur. This impression was supported by molecular genetic studies in which a T-cell clone was detected in 2 tissue nodal specimens but not in the corresponding FNA samples. For staging purposes, lymph nodes interpreted histologically as LN1 to LN2 are considered not to be involved with

❚Table 6❚ Summary of Histologic, Cytologic, and Flow Cytometric Correlation Flow Cytometry* Patient No. 1 2 3 4 5 6 7 8 9 10 11

Diagnosis (Histologic/FNA) LN1/Gr I LN1/Gr I LN1/Gr I LN2/Gr I LN1/Gr I LN1/Gr I LN2/Gr II LN3/Gr III LN3/Gr III LN4/Gr III LN4/Gr IV

Tissue 48/43/5/40 64/63/8/65 46/21/7/49 89/91/8/13 91/87/10/82 68/69/4/27 54/45/10/52 92/62/3/13 92/87/2/93 51/65/12/11 24/15/4/14

FNA 57/63/6/49 Quantity of cells insufficient for analysis Quantity of cells insufficient for analysis ND 87/85/11/81 ND ND 91/86/8/36 ND 79/71/ND/17 Quantity of cells insufficient for analysis

FNA, fine-needle aspiration; Gr I-IV, grading of the lymph node cytology according to criteria given in the “Materials and Methods” section; LN 1-4, grading of lymph node histologic features according to the National Cancer Institute–Veterans Administration classification; ND, not done. * Flow cytometry data given as percentage of lymphocytes expressing CD3/CD4/CD8/CD7.

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❚Image 1❚ Fine-needle aspiration smear showing a polymorphic population of reactive lymphocytes and macrophages, some containing melanin characteristic of a grade I reactive pattern/dermatopathic lymphadenopathy (Papanicolaou, ×60).

❚Image 3❚ Morphologic appearance of a smear showing a predominant monotonous population of lymphocytes as evidence of transformation to non-Hodgkin lymphoma. Rare atypical lymphocytes are also present. This corresponds to grade IV of the cytologic classification (rapid Romanowsky, ×200).

CTCL, whereas lymph nodes interpreted as LN3 and LN4 are considered to be involved. In this regard, assessment of lymph nodes by FNA cytology compares quite favorably with histologic examination in our series, a result that indicates that grade III or IV cytology can obviate a surgical procedure. Moreover, most patients with an LN1 or LN2 © American Society of Clinical Pathologists

❚Image 2❚ High-power magnification showing several atypical lymphocytes with convoluted cerebriform nuclei. This corresponds to grade III of the cytologic classification. If these atypical lymphocytes are found only infrequently in an otherwise reactive lymph node, the smear would be classified as grade II (Papanicolaou, ×500).

histologic grade and evidence of early involvement that is detectable by PCR or flow cytometry would receive a correct diagnosis by FNA. Our experience indicates that it is easier to perform PCR than flow cytometry on FNA samples because PCR can be performed on smaller samples. However, in 2 instances (patients 2 and 3), a T-cell clone was found only in excised tissue but not in the FNA sample. The clinical course was favorable for patient 2 and unfavorable for patient 3, who ultimately died of advanced CTCL. Our results on a small series of cases support the finding of others that excised lymph nodes from patients with clinically advanced CTCL frequently are involved with malignant T cells before histologic detection.27-29 By using the Southern blot technique, which is less sensitive than PCR, Lynch et al30 found that the frequency of detecting T-cell clones increased from 0% (0/5) for specimens classified as LN2 to 47% (8/17) for LN3 specimens and 91% (10/11) for LN4 cases.30 More recently, Kern et al31 found a T-cell clone in 12% (4/34) of clinically normal lymph nodes defined as soft nodes of less than 1 cm in diameter vs 52% (11/21) of enlarged nodes studied by Southern blot technique. They also found that the frequency of detecting a clone increased according to the lymph node score from 0% (0/18) for LN1 to 12% (3/24) for LN2, 83% (5/6) for LN3, and 100% (7/7) for LN4 nodes. By contrast, in our small series, a T-cell clone was detectable by PCR amplification of the T-cell receptor gamma-chain gene in 100% (4/4) of lymph nodes Am J Clin Pathol 2000;113:865-871

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classified as LN1, 33% (1/3) classified as LN2 nodes, and 100% (4/4) classified as LN3 and LN4 nodes. Thus, PCR seems to show a higher frequency (4/4) of T-cell clonality in LN1 to LN2 nodes compared with the Southern blot technique, but definite conclusions require study of a larger number of cases by both methods. The clinical significance of T-cell clones demonstrated by PCR in lymph nodes with an LN1-LN2 grade in patients with CTCL remains to be determined. Several investigators have reported that detection of T-cell clonality by using the Southern blot technique in enlarged lymph nodes without definite histologic involvement (LN2 or less) is associated with a worse prognosis than for patients without clonality.2729,32,33 However, it has not been shown that the same adverse connotations also apply to patients without enlarged lymph nodes or LN1 to LN2 nodes with T-cell clones demonstrated only by the more sensitive PCR technique. It seems likely that malignant T cells circulate through regional lymph nodes in virtually all patients with CTCL and that their detection by the very sensitive PCR technique may have no special importance in the setting of early skin involvement. A T-cell clone was detected in the lymph nodes obtained from all 7 patients with Sézary syndrome irrespective of the fact that 3 of these patients had lymph nodes scored as LN1 or LN2. Nevertheless, at our institution, we often opt to administer relatively well-tolerated systemic agents, such as interferon alfa or methotrexate, in combination with a topical therapy to patients with detectable T-cell clones in enlarged lymph nodes even though such systemic treatments have not been shown to be helpful.18,27-29,34,35 Because it is free of the morbidity associated with a lymph node excision, FNA combined with PCR may offer a feasible approach for prospective study of this issue in patients with early CTCL. From the Departments of 1Pathology, MCP-Hahnemann University, 2Dermatology, University of Pennsylvania, and 3Dermatology, MCP-Hahnemann University, Philadelphia, PA. Address reprint requests to Dr Galindo: Dept of Pathology, MCP-Hahnemann University, Mail Stop 435, 245 N 15 St, Philadelphia, PA 19102.

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