H to be a relatively infrequent and late manifestation

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1 Hodgkin s Disease Involving the Breast and Chest Wall JEANNE M. MEIS, MD,* JAMES J. BUTLER, MD, AND BARBARA M. OSBORNE, MD Eighteen patients with Hodgkin s disease involving the breast or chest wall were identified from the M. D. Anderson Hospital and Tumor Institute pathology files from 1962 through All of these cases were nodular sclerosing Hodgkin s disease. Nine of the 18 patients had Hodgkin s disease involving the breast or chest wall at initial presentation. The remaining nine cases represented recurrences involving the breast or chest wall. Breast or chest wall involvement represented extranodal extension and/or involvement of another supradiaphragmatic lymph node group. No marked difference in survival was found between the initial and recurrent groups. Those patients with breast involvement had a better prognosis than those with chest wall involvement. Hodgkin s disease involving the breast or chest wall as an initial presentation or a recurrence does not necessarily indicate an accelerated phase of the disease. Breast or chest wall involvement is probably due to Hodgkin s disease involving the intramammary or internal mammary, or is due to direct mediastinal extension into the chest wall. Cancer 57: , ODGKIN S DISEASE involving the breast is considered H to be a relatively infrequent and late manifestation of disease. Even though such lesions have been shown to respond to radiation therapy or chemotherapy, they are allegedly associated with a grave prognosis. No well documented series of cases of Hodgkin s disease involving the breast and chest wall has been previously reported to support or refute this contention. This study was undertaken to document the occurrence of Hodgkin s disease in the breast and chest wall, and to evaluate the clinical and prognostic significance of this occurrence. Materials and Methods From 1962 through 1983,2365 cases of Hodgkin s disease were diagnosed and treated at M. D. Anderson Hospital and Tumor Institute. Eighteen cases of Hodgkin s disease involving the breast or chest wall were reviewed from the pathology files of the M. D. Anderson Hospital and Tumor Institute from 1962 through Fourteen of the 18 cases were treated at M. D. Anderson Hospital; the remaining 4 cases were seen in consultation by one of the authors (J.J.B.). Follow-up information was obtained by reviewing the patients charts in 14 of the cases From the Department of Anatomic Pathology, M. D. Anderson Hospital and Tumor Institute, Houston, Texas. Supported in part by the American Cancer Society. * American Cancer Society Fellow, Department of Anatomic Pathology. Address for reprints: James J. Butler, MD, Department of Anatomic Pathology, M. D. Anderson Hospital, 6723 Bertner Avenue, Houston, TX Accepted for publication July 22, and by contacting the referring pathologist or clinician in the remaining four cases. On review, all of these cases were classified as nodular sclerosing Hodgkin s disease. Six of these involved the breast and 12 involved the chest wall. Four of the six cases involving the breast contained surrounded by or associated with breast parenchyma in the microscopic sections. Another case consisted of a needle biopsy of a located in the other breast by mammography, which was discrete and noncontiguous with the axillary. Nodal involvement could not be ascertained on this specimen. The remaining breast case was a discrete located in the lower inner quadrant of the breast and consisted of a lymph node on microscopic section, unassociated with breast parenchyma (Fig. 1). Those 12 cases which invaded the chest wall contained bone, skeletal muscle, cartilage and/or dense fibrous tissue. Subcutaneous involvement alone did not qualify as chest wall or breast involvement. The patients were divided into two groups. The first group included nine patients with Hodgkin s disease involving the breast or chest wall at initial presentation, along with mediastinal and/or supradiaphragmatic lymph node involvement. These cases were all at least Stage I1 disease and therefore not considered to be primary Hodgkin s disease of the breast or chest wall. The second group included nine patients with recurrent Hodgkin s disease involving the chest wall or the breast. For further analysis, the patients were divided into those with breast involvement and those with chest wall involvement, regardless of initial presentation or recurrence (see Fig. 2). 1859

2 I860 CANCER May VOl. 57 FIG. 1. Lymph node with nodular sclerosing Hodgkin s disease, lower inner quadrant of breast (H & E, original magnification X20). Hesults In the first group with initial involvement of the breast or chest wall, the patients ranged from 11 to 37 years of age (median, 24 years) and included 5 females and 4 males. The stages at presentation ranged from clinical and pathologic Stages I1 through IV. All of the patients received radiation therapy and/or chemotherapy. Two of the cases had breast involvement at initial presentation and seven had chest wall involvement. Of the seven with chest wall disease, five had radiographic evidence (chest x-ray, tomograms or CT scan) of destruction of the chest wall or sternum associated with an enlarged mediastinum (Table 1; Patients 1, 2, 4, 5, and 9). The size of the mediastinal was recorded in only two of the five cases: one was 5.2 cm in maximum diameter in a 15-year-old girl, and the other was 15 cm in an adult man. In one of the two cases with breast involvement at initial presentation, the patient was stated to have a huge mediastinal. No chest wall erosion was documented, however. This patient had nodular sclerosing Hodgkin s disease involving lactating breast (Table 1, Patient 7). The other patient had no apparent mediastinal disease. This patient had involvement of a lymph node in the lower inner quadrant of the breast (Table 1, Patient 6). GROUP I GROUP II RECURRENT (9) 2 (g) I 2 BREAST 7 CHEST WALL 4 BREAST 5 CHEST WALL l=--i 6 BREAST 12 CHEST WALL FIG. 2 Group 1 and Group I1 division of patients with Hodgkin s disease involving breast and chest wall. The second group of patients with recurrent Hodgkin s disease in the breast or chest wall ranged from 21 to 34 years of age (median, 25 years) and included 6 females and 3 males. Stages at initial presentation ranged from pathologic and clinical Stages I through 111. All of the patients received radiation therapy and chemotherapy. Four involved the breast and five involved the chest wall as recurrences. The duration from initial diagnosis to breast or chest wall recurrence ranged from 13 to 119 months (mean, 71 months; median, 81 months). None of the cases with breast involvement were associated with radiographic evidence of chest wall destruction or mediastinal widening. Two of the four breast es were located in the outer aspect of the breast by mammography, ranging from 2 cm to confluent es greater than 16 cm in size. The biopsy of the smaller of these two es contained breast parenchyma microscopically (Table 2, Patient 9). In the case with the larger, a needle biopsy was performed (Table 2, Patient 8). The was reported to be discrete and noncontiguous with the axillary lymph. No breast parenchyma was identified in the needle biopsy specimen. The location of the remaining two es was not mentioned. These latter two cases, however, were associated with breast parenchyma microscopically (Table 2, Patients 1 and 2). In three of the five chest wall recurrences, there was lytic destruction of the sternum or costochondral junction. In two of these cases, the mediastinum was not significantly widened, clinically suggesting the probability of internal mammary lymph node involvement (Table 2, Patients 4 and 6). In the remaining case with radiographic evidence of chest wall destruction, a 10 cm anterior mediastinal eroded the anterior chest wall and eventually protruded into the abdominal cavity (Table 2, Patient 7). In the remaining two cases

3 No. 9 HODGKIN S DISEASE IN BREAST AND CHEST WALL * MeiS d. TABLE 1. Summary of Patients With Involvement of Breast/Chest Wall at Initial Diagnosis 1861 Breastichest Mediastinal status Age/ Stage and wall Other organs involved at time of breast/ Patient sex subtype involvement at initial diagnosis chest involvement FoIIow-u~ I/M 27/M 31/F 24/F 15/F 34/F 22/F 26/M 23lM CS IIe B CS IIe B PS IIe PS IIe A PS IVe A PS Ile A CS IV A (34 wks gestation) CS IV B CS IV 4.5 x 5.5 cm sternal 5X5cm sternal 2 cm left anterior chest wall 4.5 cm left chest wall 2 cm left chest wall 2.5 cm left breast Left breast : no size reported 1 1 th posterior rib & adjacent soft tissue Chest wall ; no size reported Mediastinal, paratracheal & left Mediastinum & left lung, bilateral axillary & right scalene lymph Lymph in neck Mediastinal & right Mediastinum, apex of lung, right axillary & left Left axillary lymph node Mediastinum, cervical & para-aortic : blastic changes in lower thoracic & upper lumbar spine Lytic lesions of T9 & TI I; lytic destruction of right pedicle of TI I & compression fracture of T9 Mediastinum with chest wall invasion & pleural effusions Enlarged mediastinum with sternal destruction Mediastinal invading chest wall Not mentioned Enlarged mediastinum with sternal destruction 5.2 cm mediastinal with sternal destruction Negative chest x-ray Huge mediastinal Minimal widening of mediastinum 15 X 14 cm mediastinal with chest wall destruction Developed left lung involvement. Four courses of MOPP to date after radiation therapy Developed bilateral lung involvement after standard mantle radiation therapy. One course of CHOP-Bleo; one course of MOPP-ABVD Died 3 years and 3 months after diagnosis; presumably dead of disease Complete remission for seven years Expired 1 year and 6 months after diagnosis with disseminated disease; no autopsy Complete remission for 12 years 13 year follow-up; complete remission last 3 years: mastectomy I year ago foi adenocarcinoma of breast Seven year follow-up; complete remission for 5 years, then recurrence in mediastinum, right hilum and right cervical lymph node: currently in remission Died in 10 months with bilateral lung infiltrates; no autopsy MOPP: Nitrogen mustard, vincristine, prednisone, and procarbazine; MOPP-ABVD: Doxorubicin, bleomycin, vinblastine, and DTIC (dimethyltriazenoimidazole carboxamide); CHOP-Bleo: Cyclophosphamide, hydroxydaunomycin, vincristine, prednisone, and bleomycin. with histologic evidence of chest wall invasion, there was no radiographic documentation of chest wall destruction (Table 2, Patients 3 and 5). Three of the nine with initial chest or breast involvement died 10 to 39 months from the initial diagnosis of Hodgkin s disease (mean, 22 months; median, 18 months). The remaining six patients are alive 4 months to 155 months after initial presentation (mean 80 months; median, 85 months). Seven of the nine patients with chest wall or breast recurrence died 7 months to 96 months after the initial recurrence (mean, 44 months; median, 2 1 months). The remaining two are alive 3 1 months and 204 months, respectively, after recurrence (mean and median, 118 months). There was not a significant difference in survival between the initial and recurrent groups (P = 0.26). Of the six patients with breast involvement, including those with initial and recurrent disease, only one had clinical evidence of significant mediastinal disease at the time of breast involvement, and none had radiographic evidence of chest wall destruction. In contrast, 8 of the 12 patients with chest wall involvement had radiographic evidence of chest wall destruction. Six had mediastinal es eroding the chest wall. Five of these were in the initial group (see Table I, Patients 1, 2, 4, 5 and 9). The remaining two cases with radiographic evidence of chest wall destruction had clinically suspected involvement of the internal mammary (Table 2, Patients 4 and 6); neither of these had concurrent mediastinal disease. In the remaining four cases, there was no radiographic documentation of chest wall destruction. One of these had a left hilar involving the anterior fifth rib

4 1862 CANCER May I 1986 VOl. 57 TABLE 2. Summary of Patients With Involvement of Breast/Chest Wall as a Recurrence of Hodgkm s Disease Breast/chest Interval from Mediastinal status at Age/ Stage and wall Other organs involved diagnosis to time of breast/chest PT sex subtype involvement at initial diagnosis recurrence recurrence FOIIOW-UP 2 l/f 34/F 24/F 32/F 25/M CS IIB CS IA cs I1 PS IIA PS IIB Three breast recurrences: right breast once: left breast twice Left breast Left 5th rib, anterior Two chest wall recurrences: (I) 3 X 3 cm at right costochondral junction; (2) 2 chest wall es, 6-7th right intercostal spaces 17X 15X2cm chest wall Mediastinum & right cervical lymph node Left cervical lymph node Mediastinum & left Mediastinum & supradiaphragmatic Mediastinum & left 6 28/M CSIIA 13 X I1 cm left Mediastinum & left 8 yr chest wall cervical lymph 7 30/M PS I vs I1 Right chest wall Mediastinum 9 Yr 8 25/F CS IIIA 9 23fF CS IIIA Right breast, 16 cm (confluent es) 2 cm left breast Mediastinal, bilateral & left submaxillary ; upper lobe of left lung Mediastinal, neck & para-aortic lymph Right breast 6 yr; left breast 9 & I4 yr Unknown 14 yr, 10 mo No mediastinal disease 6 yr, 8 mo Left hilar with erosion of 5th rib found at surgery Destruction of right costochondral cartilage (2nd recurrence) & soft tissue on left side of aortic arch. No mediastinal disease 23 yr follow-up; alive I7 yr after first breast recurrence: remission for 10 yr; recent recurrence in cervical lymph 17 yr, 5 mo followup; alive with disease 2 yr, 7 mo after breast recurrence 7 yr., 3 mo follow-up; died with disseminated disease 7 mo after chest wall recurrence; no autopsy 3 yr, 8 mo follow-up; died 3 mo after 2nd chest recurrence with E. culi. sepsis: no autopsy 13 mo Not mentioned yr, 8 mo follow-up, died 7 mo after chest wall recurrence with bilateral lung infiltrates; no autopsy 3 yr, 1 mo Minimal mediastinal disease; left sternal lytic lesion 10 crn mediastinal with anterior chest wall erosion No mediastinal disease No mediastinal disease 6 yr follow-up; died 8 yr after chest wall recurrence; no autopsy 10 yr follow-up; died 11 mo after chest wall recurrence with bilateral pulmonary infiltrates, mediastinal & E. culi sepsis; 9 yr, 2 mo follow-up: expired 6 yr, 1 mo after breast recurrence with diffuse skin eruptions, retroperitoneal & lumbar spine involvement 9 yr, 9 mo follow-up; died 7 yr, 9 mo after breast recurrence: no residual Hodgkin s disease at autopsy

5 No. 9 HODGKIN S DISEASE IN BREAST AND CHEST WALL - MeiS et d at thoracotomy (Table 2, Patient 3). Another had Hudgkin s disease presenting in the posterior eleventh rib with lytic destruction of the pedicle of T 1 1 and a compression fracture of T9 (Table 1, Patient 8). This patient also had no concurrent mediastinal disease. In the remaining two patients with chest wall involvement, the clinical information concerning mediastinal disease was incomplete (Table 1, Patient 3 and Table 2, Patient 5). No mention of mediastinal disease was made, despite the fact that one of the patients had a palpable chest wall measuring up to 17 cm in maximum diameter (Table 2, Patient 5). Eight of the 12 patients with chest wall involvement have died 7 to 96 months after chest wall invasion (mean, 26 months; median, 15 months). Only two of the six patients with Hodgkin s disease in the breast have died; these were at 73 months and 94 months, respectively, after breast involvement (mean and median, 84 months). The four surviving are alive 31 to 204 months after breast involvement (mean, 134 months; median, 15 1 months), as compared to 4 to 90 months (mean, 45 months; median, 42 months) for the remaining four chest wall survivors. There was a significant difference in survival between those patients with breast involvement versus those with chest wall involvement (P = 0.015). Discussion Hodgkin s disease involving the breast was first described by Kuckens in Since that time, there have been several case reports of primary Hodgkin s disease of the brea~t.~-~ In a review of localized primary extranodal Hodgkin s disease, Wood et al. found only eight authentic cases of primary breast involvement. In several of the aforementioned cases, however, there was a reliance on patients histories that the breast or chest wall had appeared first, with development of axillary lymphadenopathy or disseminated disease shortly thereafter. While we acknowledge that Hodgkin s disease may have been primary in the breast in these cases with subsequent involvement of axillary or development of disseminated disease, this point remains unproven for several reasons. All of these cases, with the exception of that of Sanyal et af., were reported between 1928 and Most, if not all, of these cases were inadequately staged, primarily due to technical limitations. Well defined histologic criteria to diagnose and uniformly classify Hodgkin s disease were not in use prior to the development of the Lukes-Butler classification in Some of the alleged cases involving the breast were not even biopsied to verify the clinical impression of Hodgkin s disease6 or the breast biopsy did not contain histologic evidence of Hodgkin s disease. With these factors taken into consideration, the diagnosis of primary Hodgkin s disease of the breast (Le., with no evidence of disease elsewhere in the body) has never been well documented. This current series includes six cases of nodular sclerosing Hodgkin s disease involving the breast over a 22-year period. None of these were considered to be primary in the breast. All 18 cases of breast and chest wall involvement in the current series were at least Stage I1 disease at the time of breast or chest wall involvement. We conclude that primary Hodgkin s disease of the breast has never been well documented and is an extremely rare occurrence, if it occurs at all. The relatively few number of cases of biopsyproven involvement of the breast and chest wall support the statement that this phenomenon is a rare occurrence, at least at a tertiary care institution. The statement that involvement of the breast or chest wall is a late manifestation of disease is not supported by this study. In both the initial and recurrent groups, there is a wide range of survival, suggesting that these may be heterogeneous groups and that there are other factors contributing to survival. In the first group with initial breast or chest wall involvement, three of nine patients died in 10 to 39 months (median, 18 months) compared to seven of nine in the second group with breast or chest wall recurrence, who died in 7 months to 8 years (median, 21 months). On the other hand, the survivors in both groups have survived from 14 months to 13 years in the first group (median, 85 months) and from 3 to 17 years (median, 1 18 months) in the second group. The data suggests that there is not a significant difference in survival between the initial and recurrent groups (P = 0.26). Division of disease into that involving the breast or chest wall in this study is somewhat arbitrary, since the same tissues are involved with disease. Breast or chest wall involvement is probably due to Hodgkin s disease involving intramammary or internal mammary lymph, or is the result of direct mediastinal extension into the chest wall. Further analysis of the entire group of patients, when divided into those involving the breast versus those involving the chest wall, regardless of initial or recurrent disease, suggests that those with breast involvement have a better prognosis than those with chest wall involvement (P = ). The median survival of those surviving with breast involvement is 15 1 months, as compared to the median survival of those with chest wall involvement and a median survival of 45 months. Those with breast involvement who died had a median survival of 84 months, compared to those with chest wall involvement and a median survival of 15 months. The difference in survival between the breast and the chest wall groups may be attributable, at least in part, to the presence of a large erosive mediastinal in the chest wall group. Eight of the 12 patients with chest wall involvement had radiographic evidence of chest wall destruction. Six of these eight had mediastinal es which eroded the chest wall. Five of these six patients were in the group with initial breast or

6 I864 CANCER May I 1986 VOl. 57 FIG. 3. Chest wall with skeletal muscle containing an infiltrate of cells resembling large cell lymphoma (H & E, original magnification X200). chest wall involvement. Three of the six with erosive mediastinal es died within 10 to 18 months of chest wall invasion (median, 11 months). The remaining three patients are alive 4 months to 7 years later. In the other two cases with radiographic chest wall destruction, involvement ofthe internal mammary was clinically suspected; there was erosion of the left sternum in one case, and the costochondral cartilage in the remaining case. In the group with initial breast or chest wall involvement, only one patient received multiple chemotherapeutic agents and radiation therapy for refractory disease. The other patients with initial breast or chest wall involvement responded to the initial therapeutic approach. In the group with recurrent disease involving the breast and the chest wall, three patients who had received previous radiation therapy received chemotherapy at the time of recurrence; two patients who had received previous radiation therapy and chemotherapy received different chemotherapeutic agents; one who received previous radiation therapy underwent local radiation therapy followed by a radical lymph node dissection and new chemotherapeutic agents. In the remaining three patients, the available clinical information was incomplete. Clinical and pathologic recognition of Hodgkin s disease is imperative to prevent delay in diagnosis and treatment. Some of the cases had relatively unusual features that could contribute to such a delay. One of the patients had unilateral breast swelling, which could arouse clinical suspicion of adenocarcinoma of the breast, particularly if FIG. 4. Chest wall containing diagnostic Reed-Sternberg cell and lacunar cells (H & E. original magnification X400).

7 No. 9 HODGKIN S DISEASE IN BREAST AND CHEST WALL * Meis et Uf FIG. 5. Immunoperoxidase stain of formalin-fixed specimen demonstrating Leu MI positivity in cytoplasm of Reed-Sternberg cell (original magnification X400). there is no previous diagnosis of Hodgkin s disease. Asymmetry may be secondary to axillary lymph node involvement. An 1 1-year-old boy was the youngest patient in the series, presenting with a palpable sternal 5.5 X 4.5 cm. Two patients presented during pregnancy causing a delay in diagnosis and pathologic staging. Finally, two of the cases had histologic features not commonly seen in Hodgkin s disease. In one of the cases, the primary diagnosis of nodular sclerosing Hodgkin s disease was made in a segmental resection of the I 1 th rib and surrounding soft tissue. Five years later, there was a recurrence in a right cervical lymph node and the mediastinurn. A biopsy of the cervical lymph node contained extensive areas of necrosis surrounded by lacunar cells. This appearance is occasionally seen in lacunar cell predominant nodular sclerosing Hodgkin s disease.13 In the remaining case which involved the chest wall at initial presentation, the biopsy contained skeletal muscle infiltrated by a population of cells which morphologically resembled a large cell lymphoma (Fig. 3); other areas contained diagnostic Reed-Sternberg cells and lacunar cells (Fig. 4). Some of the Reed-Sternberg cells were positive for Leu M 1 by immunoperoxidase in formalin fixed tissue sections, confirming the histologic impression of Hodgkin s disease14 (Fig. 5). In summary, Hodgkin s disease involving the breast or chest wall as an initial presentation or a recurrence does not necessarily indicate an accelerated phase of the disease. Breast or chest wall involvement may be due to Hodgkin s disease involving the intramammary or internal mammary with extranodal extension, or to direct mediastinal extension into the chest wall. Those patients with breast involvement at presentation or recurrence, may have a better prognosis than those with chest wall involvement. Clinical and pathologic recognition of this relatively unusual presentation of Hodgkin s disease is important to prevent delay in diagnosis and treatment. REFERENCES I. Kaplan HS. Hodgkin s Disease. ed. 2. Cambridge, MA: Harvard University Press, 1980; Kiickens H. Ein lokales Lymphogranulom der Brust in furm eines Mammatumors. Beitr Pathol 1928; 80: McGregor JK. Hodgkin s disease of the breast. Am J Surg 1960; 90: Lawler MR Jr, Riddell DH. Hodgkin s disease of the breast. Arch Surg 1966; 93: Randall KJ, Spalding JE. Primary Hodgkin s disease of the breast: Reportofacaseand acommentary. Guy s Hosp Rep 1945;94: Adair FE, Carver LF, Hermann JB. Hodglun s disease of the breast. Surg Gynecol Obstet 1945; 80: Petrignani R. Lymphogranulomatose maligne primitive du sein. Ann Anat Pathol (Paris) 1930; 7: Gendreav JE, Pinsonneault G. Un cas de lymphogranulomatose maligne du sein: Union Med Can 1939; 68: Wray S. Hodgkin s disease of the breast. J Pa athol Bacteriol 1943; 55:JS Wood NL, Coltman CA Jr. Localized primary extranodal Hodgkin s disease. Ann Intern Med 1973; 78:l I. Sanyal B, Pant GC, Subrahmanyam K, Dhanna NN, Rastogi BL. Hodgkin s disease of the breast. Indian J Cancer 1974; 11: Lukes RJ, Butler JJ. The pathology and nomenclature of Hodgkin s disease. Cancer Re7 1966; 26: Butler JJ: The Lukes-Butler classification of Hodgkin s disease revisited, In: Bennett, JM, ed. Lymphoma 11: Controversies in the Management of Lymphomas. Boston: Martinus Nijhoff Publishers, 1984; Hsu SM, Jaffe ES. Leu M1 and peanut agglutinin stain the neoplastic cells of Hodgkin s disease. Am J Clin Pathof 1984;