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Contributed by John A Ozolek, MD and Jean C Dunn, MDFINAL DIAGNOSIS:
GRANULOCYTIC SARCOMA PRIMARILY INVOLVING THE UTERUS AND RETROPERITONEAL/MESENTERIC LYMPH NODES.
DISCUSSION:
The cause of death in this case is tumor burden secondary to extensive involvement of the uterus, retroperitoneal and mesenteric lymph nodes by granulocytic sarcoma (GS).
Granulocytic sarcoma was first linked to myeloid neoplasms in 1893 by Dock. This tumor has been referred to by a variety of names including myeloblastoma, chloroma, chloroleukemia. The latter two designations refer to the green color exhibited by this lesion secondary to the presence of myeloperoxidase within the cells (1). More recently the term extra-medullary myeloid tumor (EMMT) has been proposed to include all forms of extramedullary myeloid leukemic infiltrates (2). GS is a rare occurrence with an estimated incidence of 0.7 per million in children and 2 per million in adults (1). This tumor occurs in about 5% of myeloid leukemias in adults and 13% of children with myeloid leukemias. In autopsy series, granulocytic sarcoma occurs in two to eight percent of patients with acute and chronic myelogenous leukemia (2).
GS can occur in a diverse range of clinical situations with a variety of symptomatic presentations. They can occur in association with a known diagnosis of acute myelogenous leukemia (AML) either concurrently or as an isolated relapse, without a known diagnosis of AML, or in patients with a myelodysplastic syndrome (i.e. chronic myelogenous leukemia (CML), polycythemia vera, and myelofibrosis). They occur most commonly in bone, periosteum, soft tissues, lymph nodes and skin, but can occur virtually anywhere (3). In this case, this patient had a previously established diagnosis of AML status post bone marrow transplantation and was in remission for the last 21 months. She did not have evidence of recurrence of the AML based on her peripheral blood. The primary site of the tumor is probably the uterus or retroperitoneal/mesenteric lymph nodes. Both of these presentations would be somewhat unusual. GS in the female genital tract occurs more commonly in the ovary and also in the breast. Few cases have been reported arising from the uterus, vulva or vagina (4). GS occurring in the gastrointestinal tract represent approximately 6.5% of cases of GS with the ileum being the most common site of involvement. Clinical symptoms include abdominal pain and symptoms related to small bowel obstruction. These were the predominant presenting symptoms in this patient. Localized GS in the gastrointestinal tract can present with anemia, acute upper GI bleeding, and perforation (5). Although quite rare, this diagnosis should be considered in any woman presenting with menometrorrhagia, postcoital, and postmenopausal bleeding especially with a previous history of a myeloid malignancy or myelodysplastic syndrome.
GS is a tumor that is also frequently misdiagnosed especially in a negative clinical setting (i.e. no previous history of myeloid malignancy). In one series the initial diagnosis was correct in only 44% of 61 cases with the most common other histologic diagnoses including malignant lymphoma, small cell carcinoma, sarcoma (including Ewing's and primitive neuroectodermal tumor) and undifferentiated neoplasm (6). The distinction from other tumors especially other lymphomas can be critical since GS tumors can show well-differentiated, poorly differentiated, and blastic morphology. This distinction can have profound therapeutic implications and delay and interfere with the institution of appropriate chemo- and/or radiotherapy. Well-differentiated tumors will show various stages of maturation recognized as myeloid in origin. Eosinophilic myelocytes are heralded as a useful histologic feature noted in GS, however, they are present in approximately 50% of cases (7). The well-differentiated tumors will show variable cell size and lobulated nuclei with some cells showing eosinophilic granularity. Poorly differentiated and blastic tumors often resemble large cell (immunoblastic) lymphomas with large cells exhibiting vesicular nuclei and prominent nucleoli. Occasional cells will show cytoplasmic granularity. Subclassification into poorly differentiated or blastic subtypes can be difficult and generally is not of clinical significance (2). On the basis of morphology, the tumor presented in this case exhibits features consistent with a poorly differentiated GS.
Immunohistochemical stains are always necessary to confirm the diagnosis of GS. Generally markers are employed initially to establish the myeloid origin of the tumor. Chloroacetate esterase is a useful marker but may be show staining of 50% or less of cells in 56% of poorly differentiated/blastic and 25% of well-differentiated tumors in one series of 26 EMMT's reviewed by Menasce et al (2). Other myeloid markers such as myeloperoxidase, lysozyme, and CD68/PGM-1 can and should be employed especially in cases where the morphology suggests a poorly differentiated/blastic subtype. Since diagnostic confusion surrounds GS and other high-grade Non-Hodgkin's Lymphomas, stains to preclude B and T cell lineage neoplasms must be used. In the above series, 100% (8/8) of the well-differentiated and 89% (16/18) of the poorly differentiated/blastic tumors were CD43 positive. However, CD43 cannot be used singly to make the diagnosis of GS. CD43 positivity in the absence of other T-cell lineage markers should raise the possibility of a GS. Very rare GS can express B-cell lineage markers, but are generally negative and another diagnosis should be entertained if B-cell lineage markers are positive particularly CD79a. In this series of 26 tumors, all were CD3, CD20, CD30, and CD79a negative. In our case, the tumor was diffusely positive for Leucocyte Common Antigen (LCA) (Fig 10), CD43 (Fig. 12), moderately positive for myeloid marker lysozyme (Fig. 13) and negative for B and T cell lineage markers (Figs. 15, 16 and 17).
Most cases of GS that occur in nonleukemic patients will progress to AML within one year with a median survival of 22 months (6, 8).
This case presents a woman with a previous diagnosis of AML status post allogeneic bone marrow transplantation who develops granulocytic sarcoma involving the uterus and retroperitoneal and mesenteric lymph nodes. This diagnosis should be considered in the differential diagnosis of large cell lymphoma, with or without a history of previous myeloid malignancy. It is unclear whether the bone marrow transplantation contributed to the development of the granulocytic sarcoma.
REFERENCES:
Contributed by John A Ozolek, MD and Jean C Dunn, MD
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