Leukemoid Reaction A Diagnostic Clue in Metastatic Carcinoma Mimicking Classic Hodgkin

Sanjay Mukhopadhyay, MD; Surabhi Mukhopadhyay, MD; Katalin Banki, MD; Shirish Mahajan, MD

● We report on 2 patients who were initially suspected to at bronchoscopy revealed RS cells (Figure 1), suspicious for clas- have classic because of lymphadenop- sic Hodgkin lymphoma. Staging for Hodgkin lymphoma was performed. Complete blood count at diagnosis revealed a total athy and the presence of Reed-Sternberg–like cells. Both ␮ patients had an associated leukemoid reaction (using a leukocyte count of 52 000/ L, with 92% , 3% bands, ␮ 4% , and 1% . There was no middle bulge threshold leukocyte count of 50 000/ L) and were even- or . biopsy revealed a hypercellular mar- tually diagnosed with metastatic carcinoma. Disseminated row with no evidence of malignancy. The hematologic picture carcinoma can mimic Hodgkin lymphoma clinically, radio- was suggestive of a leukemoid reaction. Computed tomographic logically, and histologically. Reed-Sternberg–like cells may scan of the abdomen showed bilateral 5-cm hypodense adrenal be found in carcinomas, and they represent a particularly masses lacking contrast enhancement (Figure 2). The patient de- challenging diagnostic pitfall for the unwary. When these veloped superior vena cava syndrome for which radiotherapy cells lead to a suspicion of Hodgkin lymphoma, the pres- was planned. In view of the need for a definitive diagnosis prior ence of a leukemoid reaction should prompt the patholo- to radiotherapy, a bronchoscopic biopsy was performed, which gist to question the diagnosis. Misdiagnosis can be avoided showed a non–small cell carcinoma with RS-like cells. The atyp- by the use of cytokeratin whenever a leukemoid reaction ical cells stained positively for cytokeratin (CK) and negatively for CD15 and CD30. The diagnosis was revised to carcinoma of is present in a suspected case of Hodgkin lymphoma. the lung with metastases to the adrenals. The patient died 4 (Arch Pathol Lab Med. 2004;128:1445–1447) weeks after diagnosis despite treatment with carboplatin, pacli- taxel, and radiation therapy. eed-Sternberg (RS) cells, when found on a background Case 2 R of lymphocytes, plasma cells, and , sug- A 37-year-old man presented with worsening abdominal pain gest a diagnosis of classic Hodgkin lymphoma. However, and a 50-pound weight loss during a 3-month period. Exami- RS-like cells can be seen in carcinomas and can lead to nation revealed left posterior cervical lymphadenopathy and he- misdiagnosis. Leukemoid reactions (using a threshold leu- patomegaly. Complete blood count at diagnosis revealed a total kocyte count of 50 000/␮L) are relatively far more likely leukocyte count of 50 000/␮L, with 94% neutrophils and without to be encountered in the setting of metastatic carcinoma a middle bulge or basophilia, which is consistent with a leuke- rather than in Hodgkin lymphoma. We report here on 2 moid reaction. Computed tomographic scans of the abdomen re- patients with leukemoid reactions in a setting of dissem- vealed a right-sided abdominal mass, which appeared to be aris- inated malignancy. The presence of RS-like cells histolog- ing from the kidney, with involvement of the retroperitoneal lymph nodes (Figure 3). The clinicoradiologic differential diag- ically led to an initial impression of Hodgkin lymphoma, nosis was lymphoma versus metastatic carcinoma. Excision bi- but both patients were eventually diagnosed as having opsy of cervical lymph nodes showed extensive infiltration by metastatic carcinomas. dyscohesive sheets of large RS-like cells (Figure 4). The back- ground consisted of neutrophils and occasional plasma cells. The REPORT OF CASES histologic picture was considered suspicious for classic Hodgkin Case 1 lymphoma. However, immunohistochemical stains showed the RS-like cells to be positive for pan-CK, CK CAM 5.2, and CK A 78-year-old man presented with cough, shortness of breath, AE1/AE3 (focal). The cells were negative for leukocyte common and weight loss for several months. Radiologic investigations re- antigen, CD20, CD3, CD30, and CD15. A diagnosis of metastatic vealed a 5-cm right lung mass with enlarged hilar and medias- carcinoma was made. The results of additional immunostains tinal lymph nodes. Cytologic examination of brushings obtained (CK7 and CK20 negative, vimentin positive) suggested a renal primary. The patient developed painful scrotal swelling, which was thought to be caused by progressive retroperitoneal adenop- Accepted for publication August 16, 2004. athy. Radiotherapy was administered to the retroperitoneum. De- From the Departments of Pathology (Drs Sanjay Mukhopadhyay and spite therapy with paclitaxel and carboplatin, the patient died 6 Banki) and Medicine (Drs Surabhi Mukhopadhyay and Mahajan), State weeks after diagnosis. University of New York Upstate Medical University, Syracuse. The authors have no relevant financial interest in the products or COMMENT companies described in this article. Reprints: Sanjay Mukhopadhyay, MD, Department of Pathology, State The presence of RS-like cells in several conditions other University of New York Upstate Medical University, 750 E Adams St, than classic Hodgkin lymphoma is well documented in Syracuse, NY 13210 (e-mail: [email protected]). the literature.1–4 These conditions include several subtypes Arch Pathol Lab Med—Vol 128, December 2004 Leukemoid Reaction: A Diagnostic Clue—Mukhopadhyay et al 1445 Figure 1. Reed-Sternberg–like cells in bronchoscopic brushings from case 1 (Diff-Quik, original magnification ϫ400). Figure 2. Computed tomographic scan of the abdomen (case 1) showing bilateral adrenal masses (arrows). Figure 3. Computed tomographic scan of the abdomen (case 2) showing a renal mass (short arrow) and involvement of retroperitoneal lymph nodes (long arrow). Figure 4. Binucleate Reed-Sternberg–like cell in lymph node in case 2. Note that background cells are exclusively neutrophils (hematoxylin- eosin, original magnification ϫ400).

of non-Hodgkin lymphoma, carcinomas of the lung and munohistochemistry in virtually all cases at the time of breast, melanoma, thymoma, inflammatory myxohyaline initial diagnosis. tumor of distal extremities, , and Leukemoid reaction is defined as a reactive rubeola.1–4 The ability of metastatic carcinoma, in partic- in excess of 50 000/␮L.6 It is usually seen in response to ular, to simulate classic Hodgkin lymphoma has been de- infection, inflammation, or therapeutic agents such as scribed previously.5 A cytologic or histologic diagnosis of growth factors and is less commonly caused by malignan- classic Hodgkin lymphoma must be made only in the con- cy. Milder elevations in leukocyte count are common both text of the appropriate cellular background (eosinophils, in carcinoma and Hodgkin lymphoma. White cell counts plasma cells, and small lymphocytes). The absence of this in excess of 10 000/␮L have been found in 14.5% of 227 typical milieu should prompt confirmation of the diag- patients with lung carcinoma7 and in 27% of 100 patients nosis with a panel of immunohistochemical stains. The with Hodgkin lymphoma.8 other situation in which immunohistochemistry becomes However, although mild leukocytosis is common in imperative is when large numbers of neoplastic cells are Hodgkin lymphoma, leukemoid reactions are rare. In the seen (such as in case 2), such that excluding the possibility series of 100 cases of Hodgkin lymphoma just cited, not a of metastatic carcinoma, large cell non-Hodgkin lympho- single case had a total leukocyte count of more than ma, or melanoma would be especially important. For these 50 000/␮L.8 A review of the literature reveals only a hand- reasons, among several others, there is a widespread ac- ful of documented cases of Hodgkin-associated leukemoid ceptance among hematopathologists of the need to con- reactions, most of which involve eosinophilia. On the con- firm the diagnosis of classic Hodgkin lymphoma by im- trary, leukemoid reaction is a well-documented paraneo- 1446 Arch Pathol Lab Med—Vol 128, December 2004 Leukemoid Reaction: A Diagnostic Clue—Mukhopadhyay et al plastic syndrome in primary lung , with a frequency 2. Iacobuzio-Donahue CA, Clark DP, Ali SZ. Reed-Sternberg–like cells in 7,9,10 lymph node aspirates in the absence of Hodgkin disease: pathologic significance of 1.8% to 2.6%. A review of 47 cases of malignancy- and differential diagnosis. Diagn Cytopathol. 2002;27:335–339. associated leukemoid reaction revealed only 1 case asso- 3. Montgomery EA, Devaney KO, Giordano TJ, Weiss SW. Inflammatory my- ciated with Hodgkin lymphoma, in contrast to 18 cases xohyaline tumor of distal extremities with virocyte or Reed-Sternberg–like cells: associated with lung cancer and 6 cases associated with a distinctive lesion with features simulating inflammatory conditions, Hodgkin renal carcinoma.9 disease, and various sarcomas. Mod Pathol. 1998;11:384–391. 4. Camilleri-Broet S, Molina T, Audouin J, Tourneau AL, Diebold J. Morpho- Thus, although leukemoid reaction may occur in Hodg- logical variability of tumour cells in T-cell–rich B-cell lymphoma: a histopatho- kin lymphoma, it is far more common in carcinomas. logical study of 14 cases. Virchows Arch. 1996;429:243–248. Reed-Sternberg–like cells constitute a well-known diag- 5. Bacchi CE, Dorfman RF, Hoppe RT, Chan JK, Warnke RA. Metastatic car- nostic pitfall, and their occurrence in a tumor causing a cinoma in lymph nodes simulating ‘‘syncytial variant’’ of nodular sclerosing leukemoid reaction should be a clue that one is not dealing Hodgkin disease. Am J Clin Pathol. 1991;96:589–593. 6. Curnutte JT, Coates TD. Disorders of phagocyte function and number. In: with classic Hodgkin lymphoma. This should prompt the Hoffman R, Benz EJ Jr, Shattil SJ, eds. : Basic Principles and Practice. use of CK in an immunohistochemical panel, helping to 3rd ed. Philadelphia, Pa: Churchill Livingstone; 2000:740. prevent potential misdiagnosis. It has been suggested that 7. Kasuga I, Makino S, Kiyokawa H, Katoh H, Ebihara Y, Ohyashiki K. Tumor- the appearance of leukemoid reaction in patients with car- related leukocytosis is linked with poor prognosis in patients with lung carcino- cinoma is a poor prognostic sign.7 The demise of both our ma. Cancer. 2001;92:2399–2405. 8. Kaplan HS. Clinical evaluation. In: Kaplan HS, ed. Hodgkin Disease. 2nd patients soon after diagnosis appears to support this hy- ed. Cambridge, Mass: Harvard University Press; 1980:125–130. pothesis. 9. McKee LC Jr. Excess leukocytosis (leukemoid reactions) associated with ma- References lignant diseases. South Med J. 1985;78:1475–1482. 1. Strum SB, Park JK, Rappaport H. Observations of cells resembling Sternberg- 10. Fahey RJ. Unusual leukocyte responses in primary carcinoma of the lung. Reed cells in conditions other than Hodgkin disease. Cancer. 1970;26:176–190. Cancer. 1951;4:930–935.

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