Methotrexate and actinomycin D chemotherapy in a patient with porphyria: a case report

A 49-year-old Japanese woman (gravida 4, para 3) was diagnosed with AIP at the age
of 27. Our patient had repeatedly visited the hospital for stomachaches beforehand;
however, approximately 2 years of consultations passed before she was accurately diagnosed.
Afterwards, she avoided elements known to precipitate acute attacks, and had not experienced
an acute porphyria attack since she was 33 years of age. In addition, she began hypertension
treatment with amlodipine besylate at the age of 40 years, and her last pregnancy
had spontaneously aborted 4 years prior to the present event. In July 2011, this patient
visited a local private clinic for atypical vaginal bleeding and was referred to a
general hospital because of suspected spontaneous abortion. She was subsequently diagnosed
with a acute intermittent porphyria hydatidiform mole via dilatation and curettage
(DC).

One month after DC, our patient presented with an elevated serum human chorionic
gonadotropin (hCG) level (Fig. 1). As fertility preservation was deemed impossible, she underwent an abdominal total
hysterectomy. Pathological study of the resected specimen revealed an invasive mole,
but no metastasis was observed. However, our patient’s serum hCG level was again elevated
1 month after hysterectomy, and she was referred to Saitama Medical Center for chemotherapy
to address expected AIP-associated complications. An X-ray computed tomography scan
of her chest, performed at our institution, revealed a lung metastasis. The FIGO 2000
staging and risk factor scoring system indicated a stage III:41 gestational trophoblastic
neoplasia (GTN) (Tables 1 and 2), and our patient was accordingly diagnosed with a low-risk GTN. Her treatment strategy
included intramuscular MTX administration at a dose of 20 mg/day for 5 days every
2 weeks.

Fig. 1. Changes in serum human chorionic gonadotropin (hCG) levels, urinary 8-carboxyl porphyrin (URO) and urinary 4-carboxyl porphyrin (COPRO) during treatment. ACT-D actinomycin D, ATH abdominal total hysterectomy, DC dilatation and curettage, MTX methotrexate

Table 1. FIGO 2000 risk factor scoring system for gestational trophoblastic neoplasia

Table 2. FIGO 2000 staging for gestational trophoblastic neoplasia (GTN)

MTX chemotherapy was initiated after our patient provided informed consent, which
included an understanding that MTX had not been implicated as either porphyrinogenic
or nonporphyrinogenic. Our patient experienced small eruptions on the hands and epigastric
region on day 3 of chemotherapy. However, a dermatologist did not interpret these
eruptions as drug-related, and thus treatment was continued. On day 5, the eruptions
expanded over her whole body and worsened, with ulcers developing on the oral mucosa
(Fig. 2). Our patient was unable to eat or drink owing to the severe pain caused by mucosal
erosion; moreover, she complained of painful micturition because of a sore on her
vulva. A skin biopsy revealed drug eruption instead of a porphyric skin lesion. In
particular, microabscesses had formed under the stratum corneum, with neutrophilic
and eosinophilic invasion, and neutrophilic exocytosis was observed in the epidermis.
Liquefaction was also observed between the epidermis and dermis, and eosinophilic,
neutrophilic, and lymphocytic invasion from the layer between the epidermis and dermis
to the superficial layer of the dermis was noted (Fig. 3). No changes in our patient’s urinary coproporphyrin or uroporphyrin levels were
observed despite the appearance of skin lesions (Fig. 1). She received intravenous prednisolone at 60 mg/day beginning on day 5 to treat
the drug eruption.

Fig. 2. Progress of eruption. On day 6, erythema with infiltration appeared on the trunk (upper panel); blisters containing bloody serum developed on our patient’s hands (middle panel), and erosive lesions and a furred tongue were observed in her mouth (lower panel). On day 8, the erythema became brown (upper panel); bullous lesions were observed on her hands (middle panel), and mucosal erosion of her mouth continued (lower panel). On day 18, the erythema improved, leaving only pigmentation (upper panel); the bullous rash was epithelialized with scaling (middle panel), and some erosive lesions became blood-filled blisters (lower panel)

Fig. 3. Abdominal skin biopsy. Microabscesses formed under the stratum corneum, with neutrophilic
and eosinophilic invasion, and neutrophilic exocytosis was observed in the epidermis
(hematoxylin and eosin staining, ×20 and ×40 magnification)

On day 11, our patient experienced febrile neutropenia (absolute neutrophil count
[ANC] on day 8 was 1,380/?L but decreased to 12/?L on day 11) and was treated subcutaneously
with 75 ?g/day of granulocyte-colony stimulating factor (G-CSF) for 3 days beginning
on day 11. However, as she was unable to recover from neutropenia (ANC remained at
12/?L on day 13), additional subcutaneous G-CSF at 150 ?g/day was administered for
2 days beginning on day 13, and her neutropenia finally resolved on day 15 (ANC, 1598/?L).
During that time, her skin lesions and stomatitis also began to improve, and the prednisolone
dose was reduced to 40 mg/day. As she was able to eat on day 17, oral prednisolone
administration at 20 mg/day was started on day 20 and tapered on day 24. She was discharged
on day 25.

Although our patient’s serum hCG level decreased with MTX treatment, it became elevated
during treatment interruption. Chemotherapy with ACT-D was therefore considered. After
providing informed consent to ACT-D treatment and acknowledging that ACT-D was not
implicated as either porphyrinogenic or nonporphyrinogenic, our patient received intravenous
ACT-D at a dose of 1.5 mg/day on days 1–5 of every 2-week period, starting on day
70 of her clinical course. As shown in Fig. 1, her serum hCG level effectively decreased, and the lung metastasis disappeared without
any porphyric attacks. After five cycles of ACT-D, her serum hCG level stabilized
at 3.2 mIU/mL. Although other chemotherapeutic drugs were considered, a negative serum
hCG level was achieved and maintained for the following 3 years.