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Anaplastic large cell lymphoma involving the breast: a clinicopathologic study of 6 cases and review of the literature.

Nonepithelial neoplasms involving the breast are uncommon. (1) The most common nonepithelial breast neoplasms are of hematologic origin, with non-Hodgkin lymphomas being most frequent. Non-Hodgkin lymphomas involving the breast account for 1.7% to 2.2% of extranodal lymphomas, and 0.38% to 0.7% of all non-Hodgkin lymphomas. (2-4) Similar to non-Hodgkin lymphomas in general, lymphomas involving the breast are mainly of B-cell lineage; T-cell neoplasms represent less than 10% of neoplasms, most of which are unspecified peripheral T-cell lymphomas. Anaplastic large cell lymphoma (ALCL) of the breast is rare; only a subset of these neoplasms have been further specified as systemic versus cutaneous with dissemination, or as anaplastic lymphoma kinase positive ([ALK.sup.+]) versus [ALK.sup.-]. Fifteen cases of ALCL involving the breast and associated with breast implants have been reported. (5)

In this study, we describe 6 cases of ALCL involving the breast identified during 21 years at our institution. We show that all types of ALCL as defined in the World Health Organization classification can occur in the breast and report 3 additional cases of ALCL associated with breast implants, including 1 patient with a history of cutaneous ALCL who subsequently developed [ALK.sup.-] ALCL surrounding a breast implant.

MATERIALS AND METHODS

Clinical Information

The files of The University of Texas M. D. Anderson Cancer Center (Houston) were searched for patients with lymphoid neoplasms involving the breast that were biopsied or excised during the course of their disease. Among all patients with breast lymphoma identified from January 1986 to the time of writing, 6 cases of ALCL involving the breast were identified. These patients were either referred to our institution for treatment, or their slides were submitted for consultation. All cases were reviewed and classified using the criteria of the World Health Organization classification. Clinical data, which included age, sex, side of involvement, clinical stage, treatment, and clinical follow-up were available for all patients, although follow-up was very short for one recently diagnosed patient. The criteria for breast involvement by lymphoma were described previously. (6)

Histologic and Immunohistochemical Techniques

Hematoxylin-eosin--stained slides and unstained slides for immunohistochemical analysis were prepared from fixed, paraffin-embedded tissue blocks. Immunohistochemical stains were performed using heat-induced epitope retrieval, an avidin-biotin complex method, and an automated immunostainer (Ventana Medical Systems, Tucson, Arizona) as described previously. (7) The antibody panel used to assess these cases included the following antibodies (and dilutions): CD3 (1:150), CD20 (1:700), CD45 (1:300), CD45RO (1:100), and ALK1 (1:30;all from DAKO, Carpinteria, California); CD43 (1:120; Becton-Dickinson Biosciences, San Jose, California); and CD30 (1:20; Signet, Dedham, Massachusetts).

Molecular Analysis

T-cell receptor--chain gene rearrangement studies were performed using polymerase chain reaction-based methods on DNA extracted from fixed, paraffin-embedded tissue. A mixture of 4 family-specific, multicolored, fluorescently labeled variable region primers and 4 unlabeled joining primers was used in a multiplex assay as has been described. (8)

RESULTS

Clinical Features

The clinical features are summarized in Table 1. All patients were women, with a median age of 52 years (range, 21-65 years). Complete blood counts at the time of breast tumor diagnosis were available for 4 patients (cases 1-3 and 6). All patients had normal white blood cell and differential counts. Hemoglobin and platelet counts were within normal range, except for one patient (case 3) who had mild anemia and one patient (case 6) who had mild thrombocytosis. All patients had a palpable breast mass. The left breast was involved in 3 patients and the right in 3 patients; no patients had bilateral involvement. The surgical procedures that patients underwent included 3 excisional biopsies, 2 needle-core biopsies, and 1 capsulectomy.

Four patients had [ALK.sup.-] neoplasms (cases 1-4) involving the breast, and 2 patients had [ALK.sup.+] neoplasms (cases 5 and 6) with breast involvement as a part of clinical stage IV disease. The [ALK.sup.-] neoplasms can be further divided into 2 subgroups. Two patients had a history of cutaneous ALCL 1 year and 4 years, respectively, before the diagnosis of ALCL in the breast. One patient (case 1), who also had a history of breast carcinoma 8 years earlier, had cutaneous ALCL involving the wrist, hip, and vagina. The ALCL involving the breast was associated with a breast implant that had been inserted 8 years earlier. The neoplasm also was associated with 80 mL of seroma-like fluid. The second patient (case 2) had cutaneous ALCL with lesions mainly involving the left lower extremity, abdomen, shoulder, and contralateral breast. This patient did not have breast implants.

Two patients (cases 3 and 4) had [ALK.sup.-] ALCL involving the breast and did not have a history of cutaneous ALCL. Both tumors were associated with breast implants. In one patient (case 3), the implant was placed 9 years earlier, and the ALCL was not associated with a seroma. In the other patient (case 4), the length of time the patient had implants is not known, and the neoplasm was associated with 720 mL of seroma-like fluid. One patient (case 3) had a history of focal involvement of an axillary lymph node by a lymphoid tumor that expressed CD15 and CD30 and was initially interpreted as classic nodular sclerosis Hodgkin lymphoma. This tumor was diagnosed 2.5 years before breast ALCL. The patient had clinical stage II disease and was treated with doxorubicin, bleomycin, vincristine, and dacarbazine chemotherapy. Subsequently, 0.5 years before breast ALCL, the patient had cervical and supraclavicular lymph nodes involved by [ALK.sup.-] ALCL. In retrospect, the initial axillary lymph node was probably also involved by [ALK.sup.-] ALCL, because these tumors can express CD15 in a subset of cases.

Two patients had [ALK.sup.+] ALCL (cases 5 and 6). In both, breast involvement occurred as a part of clinical stage IV disease. Neither patient had breast implants.

Clinical Follow-up

Clinical follow-up (Tables 2 and 3) after diagnosis of the breast ALCL was available for all patients, but one patient (case 4) was diagnosed recently. The follow-up interval for 5 patients ranged from 1.2 to 9 years (mean, 3.5 years). Four patients are alive. One patient (case 1) with a history of cutaneous ALCL and subsequent [ALK.sup.-] ALCL in breast was treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and is disease free 10 years after diagnosis of skin lesions and 9 years after diagnosis of breast ALCL. The other patient (case 2) with a history of cutaneous ALCL and subsequent [ALK.sup.-] ALCL involving the breast was treated with rituximab (R)-CHOP and subsequently anti-CD30 antibody, and she went into partial remission. R-CHOP was employed because a biopsy specimen of a skin lesion showed T-cell lineage with aberrant expression of CD20. This patient is alive with disease 5.5 years after diagnosis of skin disease and 2 years after diagnosis of breast ALCL, but she developed contralateral breast carcinoma. For the 2 patients with ALKALCL without a history of cutaneous ALCL, one patient (case 3) was treated with a number of chemotherapy regimens and is disease free at 4 years. The recently diagnosed patient (case 4) has had only 1 month of follow-up at time of writing, and details of the chemotherapy plan are unknown.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

For the 2 patients with [ALK.sup.+] ALCL, one patient (case 5) died with disease 1.2 years after diagnosis, despite being treated with various chemotherapeutic regimens. The other patient (case 6) is alive with disease 9.5 years after initial diagnosis of [ALK.sup.+] ALCL and 1.5 years after biopsy showed breast involvement. She has been treated with local radiation and multiple chemotherapy regimens.

Histologic and Immunohistochemical Features

Cases 1 and 2 occurred in patients with a history of cutaneous ALCL who subsequently developed [ALK.sup.-] ALCL of the breast. In case 1, the breast neoplasm was a 1-cm mass around the breast implant that was associated with fluid. Aspiration and cytologic examination of the fluid revealed neoplastic cells. The biopsy specimen showed a monotonous infiltrate of pleomorphic cells with rare hallmark cells admixed with neutrophils, eosinophils, and a background of sclerosis and necrosis. In case 2, the neoplasm was a 1.2-cm mass composed of a monotonous, diffuse infiltrate of large cells with prominent central nucleoli (immunoblastic morphology) and a background of sclerosis (Figure 1). Both cases were positive for CD3 and CD30 and were negative for ALK. Case 1 was granzyme [B.sup.+]. Previous skin lesions but not the breast ALCL of case 2 coexpressed CD20. Molecular studies showed monoclonal T-cell receptor [gamma]-chain gene rearrangements in both neoplasms.

Cases 3 and 4 were denovo [ALK.sup.-] ALCL. Case 3 was a 1.5-cm mass around a breast implant that was composed of a monotonous infiltrate of pleomorphic cells with frequent hallmark cells and sclerosis. Necrosis as well as neutrophils and eosinophils were present (Figure 2). In case 4, no distinct tumor was identified grossly. Histologically, the neoplasm appeared to lie within a fibrinous exudate and penetrate or become trapped in a thick fibrous capsule (Figure 3, A). The neoplastic cells were large and pleomorphic with vesicular nuclei, prominent nucleoli, and numerous mitoses. The neoplastic cells were focally admixed with abundant neutrophils when surrounded by the fibrinous exudate (Figure 3, B), or they were distributed in large clusters when immersed in the fibrous capsule (Figure 3, C). Chronic inflammation was present at the periphery of the fibrous capsule. In both cases, the neoplastic cells were positive for CD30 (Figure 3, D) and negative for CD20 and ALK. In case 3, the neoplastic cells were also positive for CD4, CD43 (Figure 4), EMA, and granzyme B.

Cases 5 and 6 were [ALK.sup.+] ALCL. Case 5 was a 1.5-cm tumor that infiltrated breast parenchyma, and the neoplastic cells were monotonous with centroblast-like nuclei. No hallmark cells were identified (Figure 5). Case 6 was a 4.0-cm mass. A needle-core biopsy showed neoplastic cells arranged in a nested pattern, and the cells were large and pleomorphic, including hallmark cells (Figure 6, A). Mitotic figures were numerous. Both tumors were positive for CD30, granzyme B, and ALK (Figure 6, B), and were negative for CD3. Both neoplasms had a nuclear and cytoplasmic pattern of ALK expression, consistent with the t(2;5)(p23;q35). Case 5 was [CD43.sup.+], and case 6 was [EMA.sup.+].

COMMENT

We report 6 cases of ALCL involving the breast. Four cases were [ALK.sup.-], including 2 patients who had a history of cutaneous ALCL, and 2 cases were [ALK.sup.+]. Three patients, all with [ALK.sup.-] ALCL, including one patient with a history of cutaneous ALCL, had tumors associated with breast implants. Two implant-associated tumors had fluid accumulation or "seromas."

ALCL rarely involves the breast (Tables 2 and 3). Including the 6 cases of breast ALCL we report, 21 cases have been reported in the literature, and these cases are heterogeneous. Seventeen cases were [ALK.sup.-], or ALK status was not reported, (4,5,9-12) including 4 cases occurring in patients with a history of cutaneous ALCL. (9,10) A review of several case series of breast lymphomas published within the past 10 years (13-18) did not disclose additional cases of ALCL.

A total of 15 cases of ALCL associated with breast implants are now reported in the literature, of which 10 had seromas or concomitant fluid accumulation. (5,9,19-21) The association between breast implants and lymphoma involving the breast has been reported rarely, not only associated with ALCL, but rarely with other lymphomas, such as follicular lymphoma and lymphoplasmacytic lymphoma. (9,19,22,23) However, it is intriguing that ALCL, a relatively uncommon type of lymphoma representing approximately 2% of all non-Hodgkin lymphomas in North America, seems to be particularly associated with breast implants. If chance alone were the explanation, one would expect to observe more cases of common lymphoma types, such as diffuse large B-cell lymphoma or follicular lymphoma, to be associated with implants. The frequency of [ALK.sup.-] ALCL in this clinical setting suggests a pathogenetic relationship with implants, as has been suggested by others. (5)

Clinically, reported cases of ALCL associated with a breast implant have arisen from 3 to 19 years (median, 8 years) after implant, placed for either cosmetic or reconstructive surgery reasons in 7 cases each. The reason for implant is unknown for one patient. Seroma or fluid accumulation is commonly but not invariably associated with these neoplasms. The amount of fluid has ranged from 80 to 720 mL. Fluid obtained via fine-needle aspiration was analyzed in 7 cases; 6 were diagnosed as positive for malignant cells, and 1 was diagnosed as suspicious for malignancy. Thirteen patients had clinical stage IE and 2 had clinical stage IIE disease. Ten patients received therapy: 6 patients received local radiation and chemotherapy (most often the CHOP regimen), 3 patients received chemotherapy alone, and 1 patient received local radiation only. Two patients did not receive therapy, and the status is unknown in 3 patients. Adequate clinical follow-up was reported for 9 patients and ranged from 0.8 to 9 years (median, 1 year). No lymphadenopathy or systemic disease developed during the follow-up interval.

Grossly, a tumor mass was identified in only 6 cases and ranged from 1 to 3 cm. In the remaining 9 cases, the tumors were contained in fibrous tissue, not identified grossly, and presented as thickening or nodularity in the capsule around the breast implant. In these cases, the tumor was only identified by histologic examination of extracted fibrous capsule. Seven implants were filled with saline, and 7 were filled with silicone; the type of implant is unknown in one case. In all cases, these tumors have been composed of large and pleomorphic cells. Twelve cases had a T-cell immunophenotype, and 3 had a null-cell immunophenotype. (20) When performed, monoclonal T-cell receptor gene rearrangements have been identified. In aggregate, these clinical and pathologic findings suggest that ALCL associated with breast implants is a distinctive entity, associated with clinically indolent behavior and a good prognosis, as has been suggested previously by others. (5)

[FIGURE 3 OMITTED]

Including 2 cases we report, there are 4 cases of cutaneous ALCL with secondary involvement of the breast parenchyma (Table 2) reported in the literature. (9,10) All patients were women, with an age range of 50 to 72 years (median, 61 years). In the 2 cases we report, the skin biopsy specimens were initially interpreted as cutaneous [CD30.sup.+] T-cell lymphoproliferative disorder, to be correlated with clinical data. In retrospect, the skin lesions were involved by cutaneous ALCL that disseminated to the breast after 1 and 4 years, respectively. Three patients reported receiving chemotherapy; the one patient who did not receive chemotherapy was lost to follow-up. (10) A 63-year-old patient with breast mass and fluid accumulation is alive and is disease free 9 years after diagnosis of the breast tumor; the other 2 patients were alive with disease at 1 and 2 years of follow-up (Table 2). Cutaneous ALCLs are [ALK.sup.-], and many affected patients have a protracted course or even spontaneous regression. (24) It is reported that cutaneous ALCLs may occasionally progress and rarely affect viscera, (25) but cutaneous ALCL cases disseminating to breast have been described rarely in the literature. The 63-year-old patient associated with breast implant and fluid accumulation we report is alive 10 years after initial diagnosis of cutaneous ALCL. This case is similar to the other cases with breast implants, and ALCL associated with fluid accumulation in that the tumor mass was small, [ALK.sup.-], and was associated with an excellent outcome. (5,9,19-21) Roden and colleagues5 have suggested that [ALK.sup.-] ALCL associated with breast implants, which they refer to as seroma-associated ALCL, may be closely related to cutaneous ALCL based on its clinicopathologic features. The 2 patients with a history of cutaneous ALCL we report, as well as the other 2 cases reported in the literature, provide support for the suggestion of Roden and colleagues. (5)

[ALK.sup.+] ALCL results from cytogenetic abnormalities involving ALK, of which the t(2;5)(p23;q35) is most common. (26) The t(2;5) fuses the ALK gene on 2p23 to the nucleophosmin (NPM) gene on 5q35, resulting in the constitutive activation of ALK kinase. (26-28) Including the 2 cases we report, 4 cases of [ALK.sup.+] ALCL involving breast (Table 3) are reported in the literature. (29,30) All patients were women, with an age range of 13 to 36 years (mean, 26 years). All presented with a breast mass ranging from 1.5 to 6 cm (mean, 3.5 cm); one tumor was partially cystic. (30) All patients had extramammary involvement, and only one patient (30) had localized disease involving breast and regional lymph nodes (stage IIE). The 2 patients we report received chemotherapy (Table 3). Therapy is not reported for the other 2 cases in the literature. In 3 cases with follow-up, 2 died of disease at 0.5 and 1.2 years; one is alive with disease 9.5 years after initial diagnosis of ALCL and 1.5 years after diagnosis of breast ALCL. Thus, it is apparent that [ALK.sup.+] ALCL involving the breast usually occurs as a part of disseminated disease and with a variable outcome, similar to what is described for patients affected by [ALK.sup.+] ALCL involving other anatomic sites. (26)

In summary, we describe 6 cases of ALCL involving the breast. Our cases, in addition to 15 cases described in the literature, highlight the clinical and pathologic spectrum of ALCL affecting the breast. This study also highlights 3 distinct groups. The first group includes patients with a history of cutaneous ALCL who subsequently develop [ALK.sup.-] ALCL of the breast. Although we have not sequenced the neoplasms in the skin and breast, presumably the cutaneous and breast lesions are related. The second group includes cases of [ALK.sup.-] ALCL associated with breast implants. The first and second groups are not mutually exclusive, because patients with a history of cutaneous ALCL can subsequently develop implant-associated ALCL of the breast. The association of [ALK.sup.-] ALCL, an uncommon lymphoma type, with breast implants suggests an etiologic relationship. These lesions are commonly but not invariably associated with seromas. The third and last group includes patients with [ALK.sup.+] ALCL involving the breast. Patients with [ALK.sup.+] ALCL usually have widespread systemic disease, of which breast involvement is only one site of dissemination.

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References

(1.) Tavassoli FA, Devilee P. Malignant Lymphoma and Metastatic Tumors: WHO Classification of Tumours of Breast. Lyon, France: IARC; 2003:107-109.

(2.) Brogi E, Harris NL. Lymphomas of the breast: pathology and clinical behavior. Semin Oncol. 1 999;26:357-364.

(3.) Wiseman C, Liao KT. Primary lymphoma of the breast. Cancer. 1 972;29: 1705-1712.

(4.) Wong AK, Lopategui J, Clancy S, Kulber D, Bose S. Anaplastic large cell lymphoma associated with a breast implant capsule: a case report and review of the literature. Am J Surg Pathol. 2008;32:1265-1268.

(5.) Roden AC, Macon WR, Keeney GL, Myers JL, Feldman AL, Dogan A. Seroma-associated primary anaplastic large-cell lymphoma adjacent to breast implants: an indolent T-cell lymphoproliferative disorder. Mod Pathol. 2008;21:455-463.

(6.) Talwalkar SS, Valbuena JR, Abruzzo LV, et al. MALT1 gene rearrangements and NF-kappaB activation involving p65 and p50 are absent or rare in primary MALT lymphomas of the breast. Mod Pathol. 2006;19:1402-1408.

(7.) Sun X, Medeiros LJ, Lu D, Rassidakis GZ, Bueso-Ramos C. Dysplasia and high proliferation rate are common in acute myeloid leukemia with inv(16)(p13q22). Am J Clin Pathol. 2003;120:236-245.

(8.) Vega F, Medeiros LJ, Jones D, et al. A novel four-color PCR assay to assess T-cell receptor gamma gene rearrangements in lymphoproliferative lesions. Am J Clin Pathol. 2001;116:17-24.

(9.) Gaudet G, Friedberg JW, Weng A, Pinkus GS, Freedman AS. Breast lymphoma associated with breast implants: two case-reports and a review of the literature. Leuk Lymphoma. 2002;43:115-119.

(10.) Fritzsche Fr, Pahl S, Petersen I, et al. Anaplastic large-cell non-Hodgkin's lymphoma of the breast in periprosthetic localisation 32 years after treatment for primary breast cancer--a case report. Virchows Arch. 2006;449:561-564.

(11.) Pereira EM, Maeda SA, Reis-Filho JS. Sarcomatoid variant of anaplastic large cell lymphoma mimicking a primary breast cancer: a challenging diagnosis. Arch Pathol Lab Med. 2002;126:723-726.

(12.) Keech JA Jr, Creech BJ. Anaplastic T-cell lymphoma in proximity to a saline-filled breast implant. Plast Reconstr Surg. 1997;100:554-555.

(13.) Aviles A, Delgado S, Nambo MJ, Neri N, Murillo E, Cleto S. Primary breast lymphoma: results of a controlled clinical trial. Oncology 2005;69:256-260.

(14.) Ganjoo K, Advani R, Mariappan MR, McMillan A, Horning S. Non-Hodgkin lymphoma of the breast. Cancer. 2007;110:25-30.

(15.) Lin Y, Guo XM, Shen KW, Wang JL, Jiang GL. Primary breast lymphoma: long-term treatment outcome and prognosis. Leuk Lymphoma. 2006;47:2102-2109.

(16.) Wong WW, Schild SE, Halyard MY, Schomberg PJ. Primary non-Hodgkin lymphoma of the breast: The Mayo Clinic Experience. J Surg Oncol. 2002;80:19-25.

(17.) Topalovski M, Crisan D, Mattson JC. Lymphoma of the breast: a clinico-pathologic study of primary and secondary cases. Arch Pathol Lab Med. 1999; 123:1208-1218.

(18.) Cao YB, Wang SS, Huang HQ, et al. Primary breast lymphoma--a report of 27 cases with literature review. Ai Zheng. 2007;26:84-89.

(19.) Sahoo S, Rosen PP, Feddersen RM, Viswanatha DS, Clark DA, Chadburn A. Anaplastic large cell lymphoma arising in a silicone breast implant capsule: a case report and review of the literature. Arch Pathol Lab Med. 2003;12 7:e115-e118.

(20.) Olack B, Gupta R, Brooks GS. Anaplastic large cell lymphoma arising in a saline breast implant capsule after tissue expander breast reconstruction. Ann Plast Surg. 2007;59:56-57.

(21.) Newman MK, Zemmel NJ, Bandak AZ, Kaplan BJ. Primary breast lymphoma in a patient with silicone breast implants: a case report and review of the literature. J Plast Reconstr Aesthet Surg. 2008;61:822-825.

(22.) Kraemer DM, Tony HP, Gattenlohner S, Muller JG. Lymphoplasmacytic lymphoma in a patient with leaking silicone implant. Haematologica. 2004;89: ELT01.

(23.) Cook PD, Osborne BM, Connor RL, Strauss JF. Follicular lymphoma adjacent to foreign body granulomatous inflammation and fibrosis surrounding silicone breast prosthesis. Am J Surg Pathol. 1995;19:712-717.

(24.) Ralfkiaer E, Willemze R, Paulli M, Kadin ME. Primary Cutaneous CD30 positive T-cell lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008:300-301.

(25.) Bekkenk MW, Geelen FA, van Voorst Vader PC, et al. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of219 patients and guidelines for diagnosis and treatment. Blood. 2000;95:3653-3661.

(26.) Medeiros LJ, Elenitoba-Johnson KS. Anaplastic large cell lymphoma. Am J Clin Pathol. 2007;127:707-722.

(27.) Delsol G, Falini B, Muller-Hermelink HK, et al. Anaplastic large cell lymphoma (ALCL), ALK-positive. In: Swerdlow SH, Campo E, Harris NL, et al, eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008:312-316.

(28.) Ioachim HL, Medeiros LJ. loachim's Lymph Node Pathology. 4th ed. Philadelphia, PA: Wolters Kluver; 2009:504-516.

(29.) Aguilera NS, Tavassoli FA, Chu WS, Abbondanzo SL. T-cell lymphoma presenting in the breast: a histologic, immunophenotypic and molecular genetic study of four cases. Mod Pathol. 2000;13:599-605.

(30.) Iyengar P, Reid-Nicholson M, Moreira AL. Pregnancy-associated anaplastic large-cell lymphoma of the breast: a rare mimic of ductal carcinoma. Diagn Cytopathol. 2006;34:298-302.

Roberto N. Miranda, MD; Lin Lin, MBBS; Sameer S. Talwalkar, MD; John T. Manning, MD; L. Jeffrey Medeiros, MD

Accepted for publication November 19, 2008.

From the Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Roberto N. Miranda, MD, Department of Hematopathology, Unit 072, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: roberto.miranda@ mdanderson.org).
Table 1. Anaplastic Large Cell Lymphoma (ALCL) Involving the
Breast: Clinical Features

Diagnosis        Age y   Clinical Presentation

Cutaneous ALCL
  Case 1          63     Skin lesions in hip, wrist,
                           and vagina

  Case 2          61     Skin lesions in leg, shoulder,
                           and abdomen
ALK- ALCL
  Case 3          40     Supraclavicular and neck
                           ALCL 6 mo before
"Seroma"-associated ALK-ALCL
  Case 4          65     Breast swollen

ALK+ ALCL
  Case 5          21     Nodal inguinal, mediastinal,
                           and lung
  Case 6          35     Shoulder soft tissue, axillary
                           and pleural mass

Diagnosis        History

Cutaneous ALCL
  Case 1         Breast cancer T1N1M0. Chemotherapy and
                   mastectomy. Implant after surgery. Smoker
                   x 10 y.
  Case 2         Left breast reduction. Family history of
                   breast cancer. Smoker x 48 y.
ALK- ALCL
  Case 3         ALK- ALCL 2 y before. Chemotherapy and
                   radiation. Implant, cosmetic, 9 y before.
"Seroma"-associated ALK-ALCL
  Case 4         NA

ALK+ ALCL
  Case 5         NA

  Case 6         ALCL 8 y before. Astrocytoma 16 y before.
                   Seizures.

Diagnosis        Breast Presentation          Tumor Size

Cutaneous ALCL
  Case 1         Mass effect. Fluid around    1 cm
                   implant.

  Case 2         Mass effect. Contralateral   1.2 cm
                   breast cancer.
ALK- ALCL
  Case 3         Pain and swelling. Scar;     1.5 cm
                   no fluid.
"Seroma"-associated ALK-ALCL
  Case 4         Swelling. Fluid around       NA
                 implant.
ALK+ ALCL
  Case 5         Mass effect.                 1.5 cm

  Case 6         Swelling.                    4 cm

Diagnosis         Side    Specimen   Implant   Stage (a)

Cutaneous ALCL
  Case 1          Right   Excision     Yes       T1a

  Case 2          Left    Core         No        T3b

ALK- ALCL
  Case 3          Left    Excision     Yes       IIE

"Seroma"-associated ALK-ALCL
  Case 4          Left    Capsule      Yes       NA

ALK+ ALCL
  Case 5          Right   Excision     No        IV

  Case 6          Right   Core         No        IV

Diagnosis         Therapy                   Outcome (b)

Cutaneous ALCL
  Case 1          Chemotherapy              DFS 9 y

  Case 2          Chemotherapy              AWD 2 y, Breast cancer 2 y
                                              later.

ALK- ALCL
  Case 3          Chemotherapy, radiation   DFS 4 y

"Seroma"-associated ALK-ALCL
  Case 4          None                      NA

ALK+ ALCL
  Case 5          Chemotherapy              DOD 1.2 y

  Case 6          Chemotherapy, radiation   AWD 1.5 y

Abbreviations: ALK, anaplastic lymphoma kinase; AWD, alive with
disease; DFS, disease-free survival; DOD, dead of disease; NA,
not available.

(a) TNM staging for cutaneous lymphomas; Ann Arbor staging for
nodal or extranodal lymphomas.

(b) Here, y indicates years after diagnosis of breast tumor.

Table 2. Cutaneous Anaplastic Large Cell Lymphoma (ALCL) and
Anaplastic Lymphoma Kinase-Negative ([ALK.sup.-]) ALCL Involving
the Breast: Clinicopathologic Features and Review of the
Literature

Diagnosis                      Age, y   Presentation

Cutaneous ALCL
  Case 1                       63       Mass effect. Seroma 80 mL.
  Case 2                       61       Mass effect. Contralateral
                                          breast CA.
  Gaudet et al, (9) 2002       50       Subcutaneous nodules.
  Fritzche et al, (10) 2006    72       Skin ulcer.
ALK-ALCL
  Case 3                       40       Pain and swelling. Scar;
                                          no fluid.
  Pereira et al, (11) 2002     92       Mass.
  Keech and Creech, (12)
    1997                       41       Mass. No fluid.
  Wong et al, (4) 2008         40       Scarring. No fluid.

Diagnosis                      Tumor Size    Side     Implant

Cutaneous ALCL
  Case 1                       1 cm          Right      Yes
  Case 2                       1.2 cm        Left       No

  Gaudet et al, (9) 2002       NA            Right      Yes
  Fritzche et al, (10) 2006    2.5 cm        Left       Yes
ALK-ALCL
  Case 3                       1.5 cm        Left       Yes
  Pereira et al, (11) 2002     2.7 cm        Left       No
  Keech and Creech, (12)
    1997                       2 cm          Right      Yes
  Wong et al, (4) 2008         0.2 cm        Right      Yes

                               Reason for    Material of
Diagnosis                       Implant        Implant

Cutaneous ALCL
  Case 1                       CA            Saline
  Case 2                       NA            NA

  Gaudet et al, (9) 2002       CA            Silicone
  Fritzche et al, (10) 2006    CA            Silicone
ALK- ALCL
  Case 3                       Cosmetic      Silicone
  Pereira et al, (11) 2002     NA            NA
  Keech and Creech, (12)
    1997                       Cosmetic      Saline
  Wong et al, (4) 2008         Cosmetic      Silicone

                               Time implant                 Type of
Diagnosis                     to ALCL, y (a)   Stage (b)   Specimen

Cutaneous ALCL
  Case 1                           8            T1a/IE      Positive
  Case 2                          NA            T3b/IE      NA
  Gaudet et al, (9) 2002           9            IE          NA
  Fritzche et al, (10) 2006       16            T1a         NA

ALK- ALCL
  Case 3                           9            IIE         NA
  Pereira et al, (11) 2002        NA            IIIE        NA
  Keech and Creech, (12)           5            Excision    NA
    1997
  Wong et al, (4) 2008            19            Capsule     NA

Diagnosis                        Immunophenotype      PCR (c)

Cutaneous ALCL
  Case 1                             T-cell           Clonal
  Case 2                             T-cell           Clonal
  Gaudet et al, (9) 2002             T-cell           NA
  Fritzche et al, (10) 2006          T-cell           NA

ALK- ALCL
  Case 3                             T-cell           NA
  Pereira et al, (11) 2002           T-cell           NA
  Keech and Creech, (12)             T-cell           NA
    1997
  Wong et al, (4) 2008               T-cell           Clonal

Diagnosis                       Therapy                   Outcome (d)

Cutaneous ALCL
  Case 1                      Chemotherapy              DFS 9y
  Case 2                      Chemotherapy              AWD 2 y Breast
                                                          CA 2 y later
  Gaudet et al, (9) 2002      Chemotherapy              AWD 1 y
  Fritzche et al, (10) 2006   Chemotherapy              NA

ALK- ALCL
  Case 3                      Chemotherapy, radiation   DFS 4y
  Pereira et al, (11) 2002    Chemotherapy              DOD 0.3 y
  Keech and Creech, (12)      Chemotherapy, radiation   DFS, unknown
    1997
  Wong et al, (4) 2008        Chemotherapy, radiation   NA

Abbreviations: AWD, alive with disease; CA, breast cancer; DFS,
disease-free survival; DOD, dead of disease; NA, not available.

(a) Here, y indicates years after initial diagnosis of lymphoma.

(b) TNM Staging for cutaneous lymphomas; Ann Arbor staging for
nodal or extranodal lymphomas.

(c) PCR indicates polymerase chain reaction for T-cell
receptor--chain gene rearrangement.

(d) Here, y indicates years of follow-up after diagnosis.

Table 3. Breast Implant Associated With Anaplastic Large Cell
Lymphoma (ALCL) and Anaplastic Lymphoma  Kinase-Positive
([ALK.sup.+]) ALCL Involving the Breast: Clinicopathologic
Features and Review of the Literature

                                           Breast
Diagnosis                     Age, y    Presentation     Tumor Size

Breast implant and "seroma"-associated ALCL
  Case 4                        65     Seroma 720 mL    Not detected
  Roden et al, (5) 2008         45     Seroma           Not detected
  Roden et al, (5) 2008         59     Seroma           NA
  Roden et al, (5) 2008         34     Seroma 700 mL    NA
  Roden et al, (5) 2008         44     Seroma           NA
  Sahoo et al, (19) 2003        33     Seroma           1 mm
  Gaudet et al, (9) 2002        87     Seroma           NA
  Newman et al, (21) 2008       52     Seroma 200 mL    3 cm
  Olack et al, (20) 2007        64     Seroma           NA
[ALK.sup.+] ALCL
  Case 5                        21     Mass effect      1.5 cm
  Case 6                        35     Swelling         4 cm
  Aguilera et al, (29) 2000     13     Fungating mass   6 cm
  Iyengar et al, (30) 2006      36     Mass cystic      3.5 cm

                                                Reason for
Diagnosis                     Side    Implant    Implant     Material

Breast implant and "seroma"-associated ALCL
  Case 4                      Left    Yes       NA           NA
  Roden et al, (5) 2008       Right   Yes       CA           Saline
  Roden et al, (5) 2008       Left    Yes       CA           Silicone
  Roden et al, (5) 2008       Left    Yes       Cosmetic     Saline
  Roden et al, (5) 2008       Left    Yes       Cosmetic     Saline
  Sahoo et al, (19) 2003      Left    Yes       Cosmetic     Silicone
  Gaudet et al, (9) 2002      Right   Yes       CA           Saline
  Newman et al, (21) 2008     Right   Yes       Cosmetic     Silicone
  Olack et al, (20) 2007      Right   Yes       CA           Saline
[ALK.sup.+] ALCL
  Case 5                      Right   No        NA           NA
  Case 6                      Right   No        NA           NA
  Aguilera et al, (29) 2000   Left    No        NA           NA
  Iyengar et al, (30) 2006    Left    No        NA           NA

                              Time Implant
Diagnosis                      to ALCL, y    Stage   Specimen

Breast implant and "seroma"-associated ALCL
  Case 4                      NA             IE      Capsule
  Roden et al, (5) 2008       7              IE      Capsule
  Roden et al, (5) 2008       3              IE      Capsule
  Roden et al, (5) 2008       4              IE      Capsule
  Roden et al, (5) 2008       NA             IE      Capsule
  Sahoo et al, (19) 2003      9              IE      Capsule
  Gaudet et al, (9) 2002      8              IE      NA
  Newman et al, (21) 2008     14             IE      Core
  Olack et al, (20) 2007      7              IE      Capsule
[ALK.sup.+] ALCL
  Case 5                      NA             IV      Excision
  Case 6                      NA             IV      Core
  Aguilera et al, (29) 2000   NA             IV      Excision
  Iyengar et al, (30) 2006    NA             IIE     Core

Diagnosis                      Cytology    Immunophenotype   PCR (a)

Breast implant and "seroma"-associated ALCL
  Case 4                      Positive     T-cell            NA
  Roden et al, (5) 2008       Positive     T-cell            Clonal
  Roden et al, (5) 2008       Positive     T-cell            Negative
  Roden et al, (5) 2008       NA           T-cell            Clonal
  Roden et al, (5) 2008       Positive     T-cell            Clonal
  Sahoo et al, (19) 2003      NA           T-cell            Clonal
  Gaudet et al, (9) 2002      NA           T-cell            Clonal
  Newman et al, (21) 2008     Suspicious   NA                NA
  Olack et al, (20) 2007      Positive     T-cell            NA
[ALK.sup.+] ALCL
  Case 5                      NA           T-cell            NA
  Case 6                      NA           Null-cell         NA
  Aguilera et al, (29) 2000   NA           T-cell            Clonal
  Iyengar et al, (30) 2006    Positive     T-cell            NA

Diagnosis                           Therapy (b)         Outcome (c)

Breast implant and "seroma"-associated ALCL
  Case 4                      None                      NA
  Roden et al, (5) 2008       None                      DFS 1.7 y
  Roden et al, (5) 2008       Radiation                 DFS 0.8 y
  Roden et al, (5) 2008       Chemotherapy, radiation   DFS 0.8 y
  Roden et al, (5) 2008       NA                        NA
  Sahoo et al, (19) 2003      Chemotherapy, radiation   DFS 1 y
  Gaudet et al, (9) 2002      NA                        NA
  Newman et al, (21) 2008     Chemotherapy              DFS 1.5 y
  Olack et al, (20) 2007      Chemotherapy, radiation   DFS 1 y
[ALK.sup.+] ALCL
  Case 5                      Chemotherapy              DOD 1.2 y
  Case 6                      Chemotherapy, radiation   AWD 1.5 y
  Aguilera et al, (29) 2000   NA                        DOD 0.5 y
  Iyengar et al, (30) 2006    NA                        NA

Abbreviations: AWD, alive with disease; DFS, disease-free
survival; DOD, dead of disease; CA, breast cancer; NA, not
applicable or not available.

(a) PCR indicates polymerase chain reaction for T-cell receptor
[gamma]-chain gene rearrangement.

(b) None indicates no therapy in addition to surgery.

(c) Here, y indicates years of follow-up after diagnosis.
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Title Annotation:Original Articles
Author:Miranda, Roberto N.; Lin, Lin; Talwalkar, Sameer S.; Manning, John T.; Medeiros, L. Jeffrey
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:1USA
Date:Sep 1, 2009
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