Delayed Recognition of Disorders of Sex Development (DSD): A Missed Opportunity for Early Diagnosis of Malignant Germ Cell Tumors

Abstract

Disorders of sex development (DSD) are defined as a congenital condition in which development of chromosomal, gonadal or anatomical sex is atypical. DSD patients with gonadal dysgenesis or hypovirilization, containing part of the Y chromosome (GBY), have an increased risk for malignant type II germ cell tumors (GCTs: seminomas and nonseminomas). DSD may be diagnosed in newborns (e.g., ambiguous genitalia), or later in life, even at or after puberty. Here we describe three independent male patients with a GCT; two were retrospectively recognized as DSD, based on the histological identification of both carcinoma in situ and gonadoblastoma in a single gonad as the cancer precursor. Hypospadias and cryptorchidism in their history are consistent with this conclusion. The power of recognition of these parameters is demonstrated by the third patient, in which the precursor lesion was diagnosed before progression to invasiveness. Early recognition based on these clinical parameters could have prevented development of (metastatic) cancer, to be treated by systemic therapy. All three patients showed a normal male 46,XY karyotype, without obvious genetic rearrangements by high-resolution whole-genome copy number analysis. These cases demonstrate overlap between DSD and the so-called testicular dysgenesis syndrome (TDS), of significant relevance for identification of individuals at increased risk for development of a malignant GCT.

Figure 1

Immunohistochemical staining and fluorescent in situ hybridization (FISH) of the gonadoblastoma and carcinoma in situ lesions of patient 1. (a) Representative hematoxylin and eosin staining. The germ cells present in the GB and CIS stain positive for (b) OCT3/4 (brown), (c) TSPY (red), and (d) SCF (brown). (e) The supportive cells in the CIS lesion are SOX9 positive (brown staining) and are negative for FOXL2. (f) In the GB, the supportive cells stain positive for FOXL2 (brown staining) and are negative for SOX9. (a–f) In every image the GB lesion is shown on the left side (embryonic germ cells intermixed with granulose-like supportive cells), CIS containing seminiferous tubules on the right side (CIS cells associated with Sertoli cells on the basal lamina). Magnification 200x and 400x for all. Slides (b)–(f) are counterstained with hematoxylin. (g) Representative FISH with Y-centromere-specific probe (shown in red) and X-centomere-specific probe (shown in green). Magnification 630x. (h) Schematic representation of the different moments in time of clinical intervention, blue arrow, identification of a malignant type II germ cell tumor, together with GB and CIS as precursor lesions at the age of 26 years. Review of the clinical history showed hypospadias and cryptorchid testes, signs of TDS/DSD which were not recognized at an early age. Grey-dashed arrows; early recognition of TDS/DSD could have allowed early detection and treatment of the malignancy, thereby, preventing the need for additional systemic treatment.

Figure 2

Immunohistochemical staining of the gonadoblastoma and carcinoma in situ lesions of patient 2. (a) Representative hematoxylin and eosin staining. Positive staining for (b) OCT3/4 (brown), (c) TSPY (red), and (d) SCF (brown) of the germ cells present in the GB and CIS. (e) In the GB the supportive cells stain positive for FOXL2 (brown). (f) The supportive cells in the CIS lesion are SOX9 positive (brown staining) and are negative for FOXL2. (a–d), (f) Again, both GB (embryonic germ cells intermixed with granulose-like supportive cells) and CIS (associated with Sertoli cells on the basal membrane of the tubules) are shown. Magnification 200x and 400x for all. Slides (b)–(f) are counterstained with hematoxylin. (g) Timeline showing the clinical history, histology, and actions taken.

Figure 3

Immunohistochemical staining of the carcinoma in situ lesion of patient 3 at three and twelve years of age. (a) Representative hematoxylin and eosin staining. Positive staining for (b) OCT3/4 (brown), (c) TSPY (red) of the germ cells present in the CIS. (a–c) Biopsy tissue at 3 years of age. (d) Representative hematoxylin and eosin staining. Positive staining for (e) OCT3/4 (brown), (f) TSPY (red), and (g) SCF (brown) of the CIS cells. (d–g) Gonadal tissue at 12 years of age. (e–g) Region indicated with a square in (d) is shown. Note the expression of OCT3/4, TSPY, and SCF in the CIS cell indicated by the arrow. Magnification 200x and 400x for all. Slides (b)–(g) are counterstained with hematoxylin. (h) Timeline showing the clinical history, histology, and actions taken.