Mammary Carcinoma with Osteoclast-like Giant Cells

Mammary Carcinoma with Osteoclast-like Giant Cells A Study of Eight Cases with Follow-up Data NIKI T. AGNANTIS, M.D., AND PAUL PETER ROSEN, M.D.

THE PRESENCE of benign osteoclast-like multinucleated giant cells in extraskeletal neoplasms arising in the various organs has puzzled clinicians and pathologists for many years. 1,2,5,9-12,19,20_23 The significance of this phenomenon is poorly understood due to the rarity of such cases and the limited follow-up data available. This type of mammary carcinoma is especially rare. 3-6,8,1517 In the past few years, we have had an opportunity to examine eight cases of infiltrating carcinoma of the breast with benign multinucleated giant cells, which constitute the basis of this report. Materials and Methods Six of the eight cases were identified at varying times in the course of several retrospective studies of patients treated at Memorial Hospital. The cases span 34 years (1944-1978) in terms of date of diagnosis, but do not represent the result of a consecutive review of all patients with mammary carcinoma treated during that interval. Slides of specimens from two patients treated in other hospitals were submitted for consultation. Received August 21, 1978; received revised manuscript and accepted for publication September 28, 1978. Address reprint request to Dr. Rosen: Department of Pathology, Memorial Hospital, 1275 York Avenue, New York, New York 10021.

Departments of Pathology of Memorial Sloan-Kettering Cancer Center and the Hellenic Anti-cancer Institute of Athens, St. Savvas Hospital, Athens, Greece (Dr. Agnantis)

Histologic examination of the tumors was done by light microscopy. Polarization was performed in all the histologic slides. Follow-up data were obtained in all cases. Results The results are presented in detail in Table 1. The patients were all women, 43 to 84 years old (median age 49 years). Laterality of the primary tumor is known in seven cases. The right breast was involved in five and the left in two instances. The primary tumors were mainly located in the upper outer quadrant of the mammary gland. They ranged from 0.5 to 5.0 cm in diameter and were largely ill-defined. Three patients had metastases in Level I axillary lymph nodes. Follow-up

Status

Three of the eight patients were alive and well when last seen. Two of them were treated in 1978, and the third was free of disease four years after treatment. Three women are known to have died of mammary carcinoma. Patient 5 had widespread metastases when her mammary tumor was found and died in the same year. Patients 6 and 3 died one and six years, respectively, after primary treatment. Patient 1 died of unknown cause 11 years after treatment, and Patient 2 had metastases two years after treatment when last seen. Histologic

Findings

Five of the tumors were infiltrating ductal carcinomas. Two were mainly infiltrating lobular carcinomas with a less prominent infiltrating ductal pattern. Areas of intraductal and lobular carcinoma in situ were found in both cases. Finally, one tumor was of the pure infiltrating lobular type (Fig. 1). There were solid areas and pleomorphic forms of

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Agnantis, Niki T., and Rosen, Paul Peter: Mammary carcinoma with osteoclast-like giant cells. A study of eight cases with follow-up data. Am J Clin Pathol 72:383-389,1979. Eight cases of a rare, distinctive variant of infiltrating mammary carcinoma featuring benign multinucleated osteoclast-like giant cells are reported. The multinucleated giant ceils were associated with ductal carcinoma in five cases and with infiltrating lobular carcinoma in three cases. Although three patients had lymph nodal metastases in level one, none of the nodal metastases contained giant cells. From the limited followup data of this report, it seems likely that the prognosis for patients who have this type of adenocarcinoma is not especially favorable. The observation that the giant cells generally occurred in areas of prominent angiogenesis suggests that the angiogenesis may be induced by some chemical substance produced by the tumor cells. Biochemical and immunologic investigations may eventually provide an explanation for this unusual morphologic manifestation of host reaction to mammary carcinoma. (Key words: Mammary carcinoma; Tumor; Giant cells).

AGNANTIS AND ROSEN

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Table 1. Summary of Year of Diagnosis

Patient's Age (years)

Right (R) or Left (L) Breast

Size of Tumor (cm)

Site of Tumor*

Gross Tumor's Margin

Nodal Status No. Positive and Level

—

—

—

—

Circumscribed

—

—

45

R

1.0

UOQ

Circumscribed

—

Factor el a/.8

1972 1975

40 45

R R

10.0 1.5

UH LH

III defined III defined

1 Negative

Karas el al.15

1974

66

L

6.0

LOQ

111 defined

—

Present series Patient 1 Patient 2

1944 1960

57 50

R

1.5 0.5

— —

Patient 3 Patient 4

1965 1975

43 84

L R

3.6 4.0

Patient 5

1976

48

L

Patient 6

1976

53

Patient 7

1978

Patient 8

1978

Circumscribed Circumscribed

3, Level I Negative

UOQ UOQ

Moderately circumscribed 111 defined

Negative Negative

5.0

UOQ

111 defined

4, Level I

R

4.0

UOQ

Moderately circumscribed

Negative

46

R

3.6

UOQ

111 defined

1, Level I

49

R

2.0

UOQ

111 defined

Negative

* UH = upper half: LH = lower half; UOQ = upper outer quadrant; LOQ = lower outer quadrant, t 1C = intraductal carcinoma; LC = lobular carcinoma; IDC = infiltrating ductal

carcinoma; 1LC = infiltrating lobular carcinoma: t O.M.G.C. = osteoclast-like multinucleated giant cells; T.G.C. = tumor giant cells.

tumor cells in five cases and squamous or spindle cell metaplasia in three cases. We detected a focus of osseous metaplasia in only one case. Vascular or lymphatic invasion were not evident. The inflammatory lymphoid reaction was generally moderate and in some areas intensive. Focal areas of increased vascularity and hemorrhage were present either at the periphery of the primary lesion (six cases) or in metastases (two cases). Generally, there was evidence of past and recent bleeding. The most unusual characteristic of these tumors was the presence of multinucleated osteoclast-like giant cells (Fig. 2). These histologically benign cells were abundant in the primary tumor in six cases. In two other tumors, numerous giant cells were found only in visceral metastases (Fig. 3). After careful examination of the latter cases, we detected only two to four multinucleated giant cells in sections of the primary tumors. This probably reflects the limitations of the samples available. Giant cells were not observed in any axillary lymph nodal metastases. The benign giant cells were found only in limited areas within any one tumor, rather than dispersed

throughout the lesion. Most were located in the cellular portions of the tumors, where they were apparently associated with the areas of increased vascularity and hemorrhage. In some sections we observed areas of infiltrating carcinoma free of giant cells adjacent to moderately well-defined foci with abundant multinucleated giant cells (Fig. 4). Because of the vascularity in areas with giant cells, these regions could sometimes be appreciated grossly on the slide. Polarization of all the histologic slides did not show any birefringent crystals within the multinucleated giant cells, and they did not contain hemosiderin or intact erythrocytes. In two cases, there were two populations of giant cells. In addition to osteoclast-type cells, there were multinucleated cells with features otherwise identical to those of the mononuclear tumor cells. These have been interpreted as being multinucleated tumor giant cells. Discussion Although undoubtedly extremely unusual, examples of mammary tumors with epulis-type giant cells have been mentioned in isolated cases for more than 70


—

Duboucheref al."

Leroux"

MAMMARY CARCINOMA WITH GIANT CELLS

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Cases and Results

Metastases to Organs

Last Follow-up Status and Cause of Death

Many "myeloplaxique"

No

Unknown

Many "myeloplaxique"

No

Unknown

No No

Many osteoclast-like Many osteoclast-like

No No

Unknown Alive 1975

Osteoplastic

Many osteoclast-like

No

Alive 1978

No Eye; many O.M.G.C.

Died 1955; cause unknown Alive with metastases 1962

Characteristics of the Primary Tumor Adenocarcinomat

Metaplasia

IDC

No

IDC

No

IDC IDC IDC and papillary

Primary

Spindle cell and squamous No

ManyO.M.G.C. + T.G.C. Few O.M.G.C.

No Squamous and focus of bone

Many O.M.G.C. Many O.M.G.C.

No No

Died 1972 of the disease Alive 1978

No

Few O.M.G.C.

Liver; many O.M.G.C.

Died 1975 of the disease

ManyO.M.G.C. + T.G.C.

No

Died 1976 of the disease

No

Many O.M.G.C.

No

Alive 1978

No

ManyO.M.G.C.

No

Alive 1978

Spindle cell and squamous

years. Lecene1" described two cases of "Tumeurs mixtes du sein" with "epulis-like" multinucleated giant cells, or "myeloplaxes," and Fry9 recorded a case of "osteoclastoma (myeloid sarcoma) of the human female breast," characterized by the same type of giant cells and simulating a giant cell tumor of bone. Others have since described similar giant cells associated with bone and cartilage in metaplastic carcinoma25 and malignant tumor of the breast with bone formation."18 The only similarity between the tumors described above and the lesions presented in this report appears to be the presence of histologically similar osteoclastlike giant cells. However, we have been able to find only seven reports of this distinctive type of adenocarcinoma which described similar giant cells in the absence of sarcomatous features. Two such cases were reported more than 40 years ago,617 and another two were described in 1977 (Table l). 8 A fifth case was presented at the VI Congress of the European Society of Pathology in 1977, by Karas and associates.15 Binkley and Stewart3 described the histologic features in two such tumors, but provided no clinical information.

Clinical Features To the extent that information is available in prior reports, 6,81517 the clinical features in previously reported cases did not differ appreciably from those in our series of eight cases. For example, laterality of the primary tumor and age at diagnosis are known for four patients described after 1931. Seventy-one per cent of our patients (5/7) and 75 per cent of those in prior cases (3/4) had right-sided primary tumors. The average age at diagnosis in our series was 52 years, and in the four previously reported cases it was 49 years. Factor8 speculated on the potential significance of the osteoclast-like giant cell as a prognostic feature, but was unable to draw any conclusion because of limited follow-up data. The only appreciable followup data available for a previously reported case is that for a woman described by Karas and co-workers,13 who is now free of disease 3Vi years after treatment of her primary tumor. While the data presented in this report are limited and probably not conclusive, it seems likely that the prognosis for patients with this type of


IDC LC ILC IDC ILC IDC ID ILC LC + IC IDC IDC IC IDC IC LC IDC ID

Presence of Multinucleated Giant Cellst

386

AGNANTIS AND ROSEN

mammary cancer is not especially favorable when compared with that for patients who have more ordinary infiltrating lesions. In this regard it is interesting that carcinomas arising in organs with malignant giant cells, notably the thyroid, lung, and pancreas, as well as sarcomas of the heart, uterus, skin and soft parts with osteoclast-like giant cells,1,5,11!'21'23 generally have had relatively poor prognoses. The prognosis for rare examples of adenocarcinoma of the thyroid, lung or pancreas with osteoclast-type giant cells is not well defined.2'19'20

carcinoma cells to the osteoclast-type giant cells. The latter cells lacked the cytologic features observed in the obviously malignant multinucleated cells found in two instances, and therefore appeared to be a distinct cellular element not readily traceable to the carcinomas. It seems likely that the giant cells are formed as a result of an unusual stromal reaction, rather than by metaplasia from altered neoplastic cells. In ultrastructural,711,18-22-26 tissue culture,27 and autoradiographic24 studies regarding the development of the benign multinucleated giant cells, it is generally accepted that they originate from undifferentiated stromal cells by fusion of histiocytes."•'4-18'24,26'27 Repeated mitotic division of the latter or amitotic division of the nucleus without cytoplasmic division and endoreduplication followed by endomitosis have been proposed,24 although the mechanism by which stromal cells undergo giant-cell transformation is still unsettled.7'8,26'27 Factor,8 in his electron microscopic study of one case of mammary carcinoma with reactive multinucleated giant cells, confirmed Leroux's17

FIG. 1. Infiltrating lobular carcinoma with abundant osteoclast-like multinucleated giant cells. Hematoxylin and eosin. x320. Inset: Giant cell, x800.


Pathologic Features On the basis of the very small number of cases available for study, we cannot determine precisely how these tumors may be related to typical examples of metaplastic mammary carcinoma. Since inconspicuous foci of squamous and osseous metaplasia were found in a few of our cases, it is possible that this group represents an extreme form of metaplasia limited almost entirely to osteoclast-like giant cells. However, we were unable to observe transitional forms from

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original concept of their benign histiocytic nature, and suggested that these giant cells may be reacting to antigenic stimulation associated with the tumor. As in our case, hemorrhage and marked vascularity were described in previous publications concerning mammary tumors with osteoclast-like giant cells.3 This observation suggests that giant cell formation may be part of a more complex stromal reaction. A series of experimental studies by Gullino and co-workers41013 led them to conclude that mammary carcinoma elicits a strong angiogenic response. An assay of angiogenic effect has been studied by them as a marker of preneoplastic lesions of the human breast by transplantation of tissue fragments onto the rabbit iris at the time of biopsy or mastectomy.413 Conceivably, in the rare instances we have reported, the tumor cells might elaborate substances capable of eliciting a giant cell reaction, as well as marked stromal angiogenesis. It is to be hoped that future biochemical or immunologic investigations will provide a better understanding of this unusual morphologic manifestation of host reaction to carcinoma. Acknowledgment. Dr. Edward Petrus, Resurrection Hospital, Chicago, Illinois, provided histologic sections and follow-up information for Case 6.

References I. Andreev VC, Raitchev R, Nikolova D: Malignant osteoclastoma of the skin. Br J Dermatol 76:40-44, 1964. 2. Berkheiser SW: Malignant giant-cell tumors of the thyroid gland. Am J Clin Pathol 24:166-171, 1954 3. Binkley JS, Stewart FW: Morphogenesis of extraskeletal osteogenic sarcoma and pseudosarcoma. Arch Pathol 29: 42-56, 1940 4. Brem SS, Jensen HM, Gullino PM: Angiogenesis as a marker of preneoplastic lesions of the human breast. Cancer 41:239244, 1978 5. Dorney P: Osteoclastoma of the heart. Br Heart J 29:276-278, 1967 6. Duboucher H, Montpellier J, Laffarque F: Epithelioma mammaire avec reaction de type myeloplaxique. Ann Anat Pathol 70:787-791, 1933 7. Elias PM, Epstein WL: Ultrastructural observations on experimentally induced foreign body and organized epithelioidcell granulomas in man. Am J Pathol 52:1207-1223, 1968 8. Factor FM, Biempica L, Ratner I, et al: Carcinoma of the breast with multinucleated reactive stromal giant cells (A light and electron microscopic study of two cases). Virchow's Arch A Pathol Anat 374:1-12, 1977 9. Fry HJB: Osteoclastoma (myeloid sarcoma) of the human female breast. J Pathol Bacteriol 30:529-536, 1927 10. Gimbrone MA Jr, Gullino PM: Neovascularization induced by intraocular xenografts of normal, preneoplastic and neoplastic mouse mammary tissues. J Natl Cancer Inst (USA) 56: 305-318, 1976 II Gonzalez-Licea A, Yardley JH, Hartmann WH: Malignant tumor of the breast with bone formation. Studies by light and electron microscopy. Cancer 20:1234-1247, 1967


FIG. 2. Intimate mingling of carcinoma and giant cells is evident. Notice the micropapillary intraductal carcinoma in the lower left corner. Hematoxylin and eosin. x80. Inset x320.

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FIG. 3 {upper). Metastasis of mammary carcinoma in the liver with epulis-type giant cells. Hepatic parenchyma is shown at the lower right. Hematoxylin and eosin. x200. Inset shows giant cell from center of picture, x800. FIG. 4 {lower). Separate areas Of infiltrating ductal carcinoma with giant cells (upper right; without these cells, lower left). Hematoxylin and eosin. x80.

20. Ryoichi O, Battifora HA, Buckingham WB, et al: Metaplastic squamous cell carcinoma of bronchus simulating giant cell tumor of bone. Cancer 39:1119-1128, 1977 21. Salm R, Sissons HA: Giant-cell tumours of soft tissues. J Pathol 107:27-39, 1972 22. Sapp JP: Ultrastructure and histogenesis of peripheral giant cell reparative granuloma of the jaws. Cancer 30:1119-1129, 1972 23. Schmaman A, Penn I, Sorour V: Giant-cell tumours of the soft tissues. S Afr Med J 37:819-820, 1963 24. Silverman L, Shorter RG: Histogenesis of the multinucleated giant cell. Lab Invest 12:985-990, 1963 25. Smith BH, Taylor HB: The occurrence of bone and cartilage in mammary tumours. Am J Clin Pathol 51:610-618, 1969 26. Soskolne WA: Peripheral giant cell granulomas. An ultrastructural study of three lesions. J Oral Pathol 1:133-143,1972 27. Sutton JS, Weiss L: Transformation of monocytes in tissue culture into macrophages, epithelioid cells, and multinucleated giant cells. An electron microscope study. J Cell Biol 28: 303-332, 1966


12. Guccion JG, Enzinger FM: Malignant giant-cell tumor of soft parts. An analysis of 32 cases. Cancer 29:1518-1529, 1972 13. Gullino PM: Natural history of breast cancer. Progression from hyperplasia to neoplasia as predicted by angiogenesis. Cancer 39:2697-2703, 1977 14. Haythorn SR: Multinucleated giant cells; with particular reference to the foreign body giant cell. Arch Pathol 7:651713, 1929 15. Karas M, Zafiridou H, Karai'ossifides C: Unusual stromal response in a malignant breast tumor. Presented at the VI Congress of the European Society of Pathology, 1977 16. Lecene P: Les tumeurs mixtes du sein. Rev Chir 33:434439, 1906 17. Leroux R: Reaction giganto cellulaire du stroma dans un epithelioma mammaire. Bull Cancer 20:692-697, 1931 18. Llombart-Bosch A, Peydro A: Malignant mixed osteogenic tumours of the breast. An ultrastructure study of two cases. Virchows Arch A Pathol Anat 366:1-14, 1975 19. Rosai J: Carcinoma of pancreas simulating giant cell tumor of bone. Cancer 22:333-343, 1968