Morphologic alteration of metastatic neuroblastic tumor in bone marrow after chemotherapy

Abstract

Background: The aim of this study is to evaluate the histologic features of metastatic neuroblastic tumors (NTs) in bone marrow (BM) before and after chemotherapy in comparison with those of primary NTs.

Methods: A total of 294 biopsies from 48 children diagnosed with NTs with BM metastasis were examined. There were 48 primary neoplasm biopsies, 48 BM biopsies before chemotherapy, 36 primary neoplasm excisional biopsies after chemotherapy, and 162 BM biopsies after chemotherapy.

Results: Metastatic NTs in BM before chemotherapy were composed of undifferentiated and/or differentiating neuroblasts, but had neither ganglion cells nor Schwannian stroma. Metastatic foci of BM after chemotherapy were found to have differentiated into ganglion cells or Schwannian stroma, which became more prominent after further cycles of chemotherapy. Persistence of NTs or tumor cell types in BM after treatment did not show statistically significant correlation to patients' outcome. However, three out of five patients who newly developed poorly differentiated neuroblasts in BM after treatment expired due to disease progression.

Conclusions: Metastatic NTs in BM initially consist of undifferentiated or differentiating neuroblasts regardless of the primary tumor subtype, and become differentiated after chemotherapy. Newly appearing poorly differentiated neuroblasts after treatment might be an indicator for poor prognosis.

Keywords: Bone marrow; Drug therapy; Histology; Neoplasm metastasis; Neuroblastoma.

Fig. 1

The histological subtypes of metastatic tumor subtypes in bone marrow according to the subtypes of the primary tumors. Regardless of the primary tumor subtype, poorly differentiated or differentiating subtypes predominated at the time of diagnosis. NBU, neuroblastoma undifferentiated subtype; NBP, neuroblastoma poorly differentiated subtype; NBD, neuroblastoma differentiating subtype; GNBN, ganglioneuroblastoma nodular; GNBI, ganglioneuroblastoma intermixed; GNMI, ganglioneuroma maturing.

Fig. 2

The histological features of primary and metastatic neuroblastic tumors in a representative case. (A) Primary tumor initially diagnosed as neuroblastoma (Schwannian stroma-poor), poorly differentiated subtype. (B) Primary tumor after multiple cycles of chemotherapy showing maturation evidenced by scattered differentiating neuroblasts in Schwannian stroma and fibrosis. (C) Metastatic tumor in bone marrow at initial diagnosis composed of undifferentiated neuroblasts in neuropil. (D) Metastatic tumors in bone marrow after chemotherapy showing differentiating neuroblasts or ganglion cells in Schwannian stroma.

Fig. 3

Time course of histological maturation of metastatic foci in bone marrow in a single case. (A) Metastatic neuroblastic tumor (NT) in bone marrow at initial diagnosis comprised of undifferentiated neuroblasts with neuropil. (B) Metastatic NT in bone marrow after nine cycles of induction chemotherapy two months after diagnosis. Differentiating neuroblasts are seen in a background of Schwannian stroma. (C) Ganglion cells appear in a background of Schwannian stroma ten months after the initial diagnosis without additional chemotherapy.

Fig. 4

Newly developed poorly differentiated neuroblastic tumor (NT) in bone marrow after multi-cycle chemotherapy in a single case. (A) Poorly differentiated neuroblasts in the background of neuropil in bone marrow at the initial diagnosis. (B, C) Metastatic NT in bone marrow after multiple cycles of chemotherapy reveal progressive differentiation of tumor cells with Schwannian stroma at three months (B) and 19 months (C) after the initial diagnosis. (D) Newly developed metastatic NTs in bone marrow composed of poorly differentiated neuroblasts approximately five years after the initial diagnosis. This patient eventually died 2.5 months after the diagnosis of recurrence.