CASE REPORT Extramammary Paget’s Disease of the Vulva: Metastases to the Bone Marrow in the Absence of an Underlying Adenocarcinoma — Case Report and Literature Review

A case of Paget’s disease of the vulva is presented which, over a period of 6 years, was characterized by local recurrences and Patient E.R. para metastases to the bone marrow. Detailed examination of multiple sections of the primary tumor and of the bone marrow biopsy com-specimen failed to demonstrate an underlying adenocarcinoma in any of the sites. The routine histologic staining and immunohisto-raised chemical staining demonstrated that the metastatic cells strongly disease. correlated with cells from the vulvar lesion. Speciﬁcally, immuno-patient histochemical staining of the specimens from the primary and metastatic sites was positive for the gross cystic disease ﬂuid pro-a tein-15, which has been associated with extramammary Paget’s was also disease uncomplicated by underlying malignancies. Finally, during performed. Figure 1 is a diagramatic representation of the several years of close follow-up, no other primary site of Paget’s right vulvar surgical specimen. The pathology revealed in- disease declared itself clinically or was found by radiographic studies or analysis of serum tumor markers.


dure. A superficial right inguinal lymphadenectomy was also
disease uncomplicated by underlying malignancies. Finally, during performed. Figure 1 is a diagramatic representation of the several years of close follow-up, no other primary site of Paget's right vulvar surgical specimen. The pathology revealed indisease declared itself clinically or was found by radiographic studies or analysis of serum tumor markers. ᭧ 1997 Academic Press traepidermal Paget's disease of the vulva. The lesion was totally embedded for histology (34 blocks) and no invasion into the dermis or subcutaneous soft tissues was identified (Fig. 2). The margins of resection were free of tumor and INTRODUCTION seven of seven lymph nodes were without evidence of disease. She was without complaints until June 1990, when she Extramammary Paget's disease of the vulva (EMPD) was presented with recurrent noninvasive disease in the right first described by Dubrewilh in 1901 as a variant of mampericlitoral region measuring 3 1 4 cm (23 tissue blocks mary Paget's carcinoma [1]. The lesion is found most comexamined). She underwent a skinning vulvectomy without monly in postmenopausal Caucasian women, and when assoa skin graft. ciated with an underlying adenocarcinoma (0-25% of She was followed in the office periodically, and in Novemcases), is very agressive with metastases to the lymph nodes ber 1990 physical examination was notable for a 2 1 3 cm and other sites [2,3]. The natural history of the disease palpable, nontender left inguinal lymph node. A fine needle involves multiple local recurrences over a period of many aspiration was performed and EMPD was demonstrated. She years, requiring multiple surgical procedures. We report a underwent a bilateral inguinal lymph node dissection with unique case of EMPD of the vulva with numerous recur-3 of 11 lymph nodes in the left groin found to be positive rences, progression to invasive disease, and metastates to for metastatic extramammary Paget's disease (Fig. 3); two the bone marrow without evidence of an underlying adenoof two nodes sampled on the right side were benign. The carcinoma.
patient received whole pelvis external beam radiation therapy for a total dose of 50.4 Gy in 25 fractions. She was bone marrow biopsy of the left posterior iliac crest was performed with histologic findings consistent with metastatic extrammary Paget's disease (Fig. 5). Interestingly, no hematopoietic elements were identified in the specimen. A serum CEA level was obtained and found to be elevated at 115 ng/ ml. The patient's serum electrophoresis study was within normal limits as were bilateral breast mammography and serum cancer antigen 125. From October 1991 to January 1992, the patient completed four courses of vincristine (1 mg/m 2 , total dose 1.6 mg/course) and cisplatin chemotherapy (75 mg/m 2 , total dose 120 mg/course). Prior to each course the patient required blood transfusion for severe anemia. She tolerated this therapy well except for moderate nausea and vomiting. Although there was no evidence of progressive disease in the vulva, because of worsening metastases based on bone marrow metabolic assays and increasing serial serum CEA levels (238-281 ng/ml), a decision was made to change chemotherapy to a second-line agent consisting of a continous infusion of 5-fluorouracil (5FU) at 500 mg/m 2 /day for 5 days, totaling 3750 mg/cycle. The patient completed one cycle of 5FU in March 1992 and subsequently expired at the right vulvar surgical specimen obtained at the time of partial vulvectomy in November 1986. The disease is depicted as the hypopigmented region measuring 6.5 1 2.3 cm. The entire specimen measured 11 1 3.2 cm.

DISCUSSION
The clinical manifestations of EMPD are varied and with-tigen (CEA) levels, both of which remained within normal limits for nearly 1 year.
out an observed pattern of progression. This has led some investigators to speculate that a disease spectrum exists The patient presented in October 1991 with her second vulvar recurrence in the right periclitoral area, measuring which involves several separate pathologic entities. Extramammary Paget's disease may be confined to the epidermis approximately 0.5 cm 2 within the radiation field. In addition, she gave a history of 3 months of persistent and progressive (noninvasive Paget's disease) or it may be associated with a contiguous invasive adenocarcinoma considered to have a low back pain without radiation. An initial series of lumbarsacral radiologic films had revealed disk space narrowing cutaneous adnexal gland nature (invasive Paget's disease).
A third category of patients with EMPD has been reported and associated spondylosis with no blastic or lytic lesions. A bone scan was abnormal with increased uptake of radioactive showing a variety of types of carcinomas arising in nearby internal as well as distant organs (e.g., rectum, prostate, tracer in the lumbar-sacral vertebral levels. Serum antinuclear antibody titer, rheumatoid factor, and treponemal anti-bladder, bile duct) [4,5]. Cases in this third category of EMPD with noncutaneous ''underlying carcinomas'' are gen studies were negative and the sedimentation rate was only slightly elevated. The differential diagnosis at the time somewhat heterogeneous, with invasive malignancies sometimes only tenuously associated with the cutaneous Paget's included sacral ileitis versus spondylosis, although a rare case of metastatic disease could not be ruled out.
disease phenomenon. Perhaps cases in this category should be considered separately from the first two groups in terms A follow-up series of lumbar-sacral films demonstrated a compression fracture in the lumbar region and magnetic of pathogenesis, prognosis, and treatment.
The most striking feature which distinguishes Paget's dis-resonance imaging (MRI) of the spine showed diffuse replacement of the normal fatty marrow by foreign tissue (Fig. ease of the vulva from Paget's disease arising in other sites is the low association with underlying adenocarcinoma. In-4). An MRI of the abdomen and pelvis revealed mild left periaortic lymphadenopathy but no evidence of any ovarian deed, in the majority of cases of nonvulvar Paget's disease, an adenocarcinoma is present. This association approaches or other pelvic or intra-abdominal masses.
During this period, the patient's complete blood count 100% when the disease arises in the breast, while among the 200 cases of vulvar EMPD which exist in the literature, was notable for anemia (hematocrit, 22%) and leukopenia (white blood cell count, 3.8 K/ml) with a differential sugges-the incidence of underlying adenocarcinoma ranges from 0-25% [2]. tive of bone marrow involvement (4% metamyelocytes, 2% myelocytes, target cells, and nucleated red blood cells). A In our patient, the opinion that the tumor cells in the thelial Paget's cells and the metastatic tumor cells were positive for CA 15-3, CAM 5.2, Her-2-neu, and gross cystic disease fluid protein-15 (GCDFP-15); both groups of cells were negative for Ca 19-9, CEA, S-100, and HMB-45. Interestingly, Kohler and Smoller reported 16 of 20 cases of extramammary Paget's disease without associated internal malignancies which were strongly reactive to GCDFP-15; only one of six cases with concomitant underlying carcinoma showed reactivity to . Finally, despite careful clinical follow-up of up to 6 years, no other primary tumor site declared itself, either by symptomatology, clinical findings, or imaging studies. A few foci in the original excision site showed piling up of cells at the dermal-epidermal interface in the region of the clitoris. However, unequivocal dermal invasion was never documented despite histologic sectioning of the entire original lesion (34 tissue blocks) and of the recurrent lesion (23 tissue blocks). It seems likely that subtle invasive tumor was, in fact, present and was not recognizable as such despite extensive histologic sectioning and repeated reviews on occasion of recurrences. This case, then, may be an example of minimally invasive Paget's disease, as described by Kodama et al. [6]. Another possibility that must be considered is that a few tumor cells were mechanically introduced into lymphatics at the time of surgical manipulation and that some of these cells were capable of growth at the site of ultimate vascular lodgment. Whatever the mechanism of metastasis, both the delayed presentation and the pattern of metastasis with ultimate spread to the bone are unusual.
Fine et al. reported a case of minimally invasive vulvar Paget's disease (1 mm depth of invasion) which developed extensive inguinofemoral lymph node metastases [7]. Hart and Millman described the sequential progression from intraepithelial Paget's disease, which had persisted after a simple vulvectomy, infiltrating the dermis and permeating the lymphatic FIG. 4. Magnetic resonance image of the spine demonstrating diffuse channels with metastases to regional lymph nodes. No underlyreplacement of the normal fatty marrow constituent by some other foreign ing primary adenocarcinoma had been present, thus establishing tissue. the invasive potential of the disease. Our case represents another report of vulvar EMPD, which over a 5-year interval lymph nodes and bone marrow originated from the vulvar progressed from an intraepithelial lesion to invasive disease Paget's disease is based upon several lines of evidence. First, with distant metastases. In addition, this is the first report of both the primary and metastatic tumor cells appeared similar bone marrow metastases from what appeared to have originally at the H&E level of light microscopy. The tumor cells stained been noninvasive intraepithelial disease. equivocally with mucicarmine. Additionally, the immunohistochemical findings demonstrated that both the intraepi-Bone involvement by metastatic vulvar Paget's disease  (Fig. 2) and were interpreted to represent metastatic carcinoma originating from extramammary Paget's disease of the vulva.
FIG. 5. Metastatic carcinoma was found in the left posterior iliac crest bone marrow. In this biopsy section, the bone marrow is entirely replaced by fibrosis with numerous large pleomorphic epithelial cells with prominent nucleoli; these malignant cells are surrounded by desmoplastic stroma. As in the inguinal lymph nodes (Fig. 3), the cells in the bone marrow were similar to the intraepidermal tumor cells and were interpreted to represent metastatic carcinoma originating from the Paget's disease of the vulva. has been described previously, but such reports involved Because the disease is a multifocal entity, local recurrences are common even when the margins of resection lesions known to be invasive and associated with underlying are negative, as occurred in our case. In addition, our carcinoma. Parmley and colleagues reported seven cases of group has documented two cases of recurrent vulvar Paginvasive extramammary Paget's disease of the vulva, three et's disease in a split-thickness skin graft with simultaneof which had metastases to the vertebrae, ribs, and bones of ous occurrence of disease outside the grafted area; this the pelvis [9]. Curtin et al. reviewed 36 cases of vulvar may occur via ''retrodissemination'' or a migratory be-Paget's disease and found five patients with an associated havior of Paget's cells into the skin graft from a peripheral invasive adenocarcinoma, one of whom died of widespread occult metastatic site [14]. bony metastases [10]. Finally, of the 11 patients with EMPD The disease without underlying adenocarcinoma remains, of the vulva and underlying carcinoma reported recently by for the most part, as an intraepithelial lesion and has only Kodama et al., one had bone metastases and died 18 months occasionally been reported to become invasive and metastaafter initial diagnosis [6].
size. We believe that the development of low back pain An alternative explanation would be that the bone metastain our patient heralded the development of bone marrow ses represented either a new primary site for EMPD in the metastases. Patients with vulvar Paget's disease are at risk bone or that the bone was the site for metastases from a for the development of metastatic disease and second prisecond primary EMPD from elsewhere in the body where mary tumors. In every patient, close follow-up is prudent there may have been an associated underlying carcinoma. and all symptoms should be thoroughly investigated. Breast carcinoma is the malignancy most often occuring along with vulvar Paget's disease [11] and is known to de-REFERENCES velop metastases to the bone. In addition, the urogenital area has a strong potentital for developing a second primary bladder, and the ovary (3 to 10 cases per site); they noted 2549,1977 one case each of a cancer involving the urethra, the vagina,