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Antemortem diagnosis of pulmonary tumor thrombotic microangiopathy in a patient with recurrent breast cancer: a case report

  • Yui Takahashi1Email author,
  • Hironori Uruga1,
  • Takeshi Fujii2, 4,
  • Sayaka Mochizuki1,
  • Shigeo Hanada1,
  • Hisashi Takaya1,
  • Atsushi Miyamoto1,
  • Nasa Morokawa1,
  • Atsuko Kurosaki3 and
  • Kazuma Kishi1, 4
BMC Cancer201616:666

https://doi.org/10.1186/s12885-016-2721-3

Received: 28 January 2016

Accepted: 14 August 2016

Published: 22 August 2016

Abstract

Background

Pulmonary tumor thrombotic microangiopathy (PTTM), a rare complication of advanced cancer, is histologically characterized by tumor embolisms and fibrocellular intimal proliferation of small pulmonary arteries and arterioles. PTTM usually has an extremely poor prognosis, and antemortem diagnosis is very difficult.

Case presentation

A 65-year-old woman with a 5-year history of clinical stage IIA (T2N0M0) invasive ductal carcinoma of the left breast was hospitalized for worsening shortness of breath, hemoptysis, and cough since 2 months. She had previously received neoadjuvant chemotherapy and left mastectomy. Because the cancer cells were positive for human epidermal growth factor receptor 2 (HER2), four cycles of trastuzumab had been administered as adjuvant chemotherapy. On admission, chest computed tomography (CT) showed peripheral consolidations in both the lower lobes and a mediastinal mass. Specimens obtained on video-assisted thoracoscopic surgical biopsy revealed tumor cell embolism, intimal fibrocellular proliferation of small arteries, fibrin thrombi, recanalization, and infarction in the left lower lobe, as well as metastasis to the mediastinal pleura. Immunohistochemical staining of the tumor cells revealed positivity for HER2, and a diagnosis of recurrent breast cancer with PTTM was made. Four cycles of trastuzumab resulted in rapid improvement of her symptoms and CT findings of peripheral consolidations and the mediastinal mass.

Conclusion

An antemortem diagnosis of PTTM was made in a patient with HER2-positive recurrent breast cancer. Trastuzumab was effective for not only breast cancer but also PTTM.

Keywords

Pulmonary tumor thrombotic microangiopathy Breast cancer Tumor embolism Trastuzumab Human epidermal growth factor receptor 2

Background

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare complication of advanced cancer; it is histologically characterized by tumor embolisms and fibrocellular intimal proliferation of small pulmonary arteries and arterioles [1]. PTTM causes rapidly progressive pulmonary hypertension, right heart failure, and death in a few days. It is usually diagnosed on autopsy and is rarely diagnosed antemortem [28]. The most frequent underlying malignancy is gastric adenocarcinoma, while breast cancer is an infrequent cause of PTTM [1, 9, 10]. Herein, we report a patient with human epidermal growth factor receptor 2 (HER2)-positive recurrent breast cancer with accompanying PTTM without pulmonary hypertension; the diagnosis was made antemortem, and the patient responded well to trastuzumab therapy.

Case presentation

A 65-year-old woman with a 5-year history of clinical stage IIA (T2N0M0) invasive ductal carcinoma of the left breast was hospitalized for worsening shortness of breath, hemoptysis, and cough since 2 months. Her breast carcinoma was 32 mm in diameter at diagnosis, with a histologic grade of 3 and nuclear grade of 3. Immunostaining for the estrogen receptor and progesterone receptor revealed negativity for both, but the tumor cells were positive for HER2. The patient had received neoadjuvant chemotherapy with four cycles of epirubicin and cyclophosphamide, followed by four cycles of trastuzumab and paclitaxel. A left mastectomy had been performed, and the surgical specimen showed no residual cancer. After the operation, four cycles of trastuzumab had been administered as adjuvant chemotherapy; however, trastuzumab had been discontinued because of heart failure. Echocardiography showed diffuse and moderate impairment of left ventricular contraction and a decrease in ejection fraction from 65.8 % to 36 %. Seven months after stopping trastuzumab administration, a repeat echocardiography revealed that her ejection fraction had recovered. Since then, she had been followed-up without treatment for breast carcinoma until this readmission.

On admission, the patient showed normal auscultation findings. A chest radiograph showed faint infiltrates at the base of both the lungs. Arterial blood gas analysis using room air indicated minimal hypoxemia: pH, 7.42; PaCO2, 42 mmHg; and PaO2, 78 mmHg. D-dimer levels were slightly increased to 1.2 μg/mL (normal, <1.0 μg/mL). Serum levels of carcinoembryonic antigen and HER2 were elevated to 57.0 μg/L (normal, 0.8–4.8 μg/L) and 64.9 ng/mL (normal, <15.2 ng/mL), respectively. Contrast-enhanced computed tomography (CT) scans revealed peripheral consolidation with ground-glass opacity in both the lower lobes and a heterogeneous mediastinal mass (Fig. 1). 18F-fluorodeoxyglucose (FDG)-positron emission tomography demonstrated increased FDG uptake in the peripheral consolidation and the mass. Echocardiography revealed normal contractions without any finding suggestive of pulmonary hypertension. Because transbronchial lung biopsy did not lead to any diagnosis, video-assisted thoracoscopic surgery (VATS) lung biopsy was performed. The surgical specimens of the peripheral area of the left lower lobe and the mediastinal mass revealed tumor cell embolism, intimal fibrocellular proliferation of small arteries, fibrin thrombi, recanalization, and infarction in the left lower lobe, as well as metastasis to the mediastinal pleura (Fig. 2). Immunohistochemical staining of tumor cells revealed positivity for mammaglobin, gross cystic disease fluid protein 15, HER2 (3+), and vascular endothelial growth factor. Accordingly, a diagnosis of recurrent breast cancer with PTTM was made.
Fig. 1

Chest computed tomography scans on admission. a, b Irregular shaped peripheral consolidations in both the lower lobes. c A heterogeneously enhanced mediastinal mass

Fig. 2

Histopathological findings of the surgical specimens. a Widespread infarction (hematoxylin and eosin staining, ×2); b Tumor fibrin embolism in a pulmonary arteriole (hematoxylin and eosin staining, ×10); c Fibrocellular intimal proliferation (elastic van Gieson staining, ×10); d Tumor cells (at increased magnification, hematoxylin and eosin staining, ×60); and e Tumor cells demonstrating HER2 positivity (immunohistochemical staining, ×60)

Retreatment with trastuzumab therapy rapidly improved the symptoms and CT findings of peripheral consolidation and the mass, resulting in partial remission (Fig. 3). After four cycles of trastuzumab therapy, it was stopped owing to heart failure. The patient visited another hospital and is alive more than 2 years after the diagnosis of PTTM.
Fig. 3

Chest computed tomography scans after trastuzumab therapy showing improvements of (a) consolidations in both the lower lobes and (b) the mediastinal mass.

Discussion

We report a patient with recurrent breast cancer to the left lung accompanied by PTTM, which was diagnosed antemortem. The onset was subacute, and respiratory failure was absent. Although transbronchial lung biopsy could not help in making a diagnosis, the results obtained with VATS lung biopsy led to the diagnosis. Treatment with trastuzumab, a humanized monoclonal antibody that targets the extracellular domain of HER2, rapidly resolved the patient’s symptoms and CT findings.

Because PTTM is usually diagnosed postmortem, the clinical manifestations are not fully understood. Unlike in the present patient, the prognosis is known to be extremely poor. The incidence of PTTM is 0.9–3.3 % in autopsy patients with carcinoma, and the most common origin was gastric carcinoma, followed by lung and breast carcinoma [1, 9, 10]. The proposed mechanism of PTTM is that tumor cells activate the coagulation systems and release inflammatory mediators and growth factors including vascular endothelial growth factor, resulting in thrombosis, fibrocellular intimal proliferation, and luminal stenosis [5]. Elevated serum levels of D-dimer and fibrin degradation products have been reported [10]. Patients with PTTM frequently develop severe pulmonary hypertension and disseminated intravascular coagulation, but our patient did not have either.

PTTM differs from tumor emboli in terms of accompanying activation of the coagulation system and intimal proliferation in small arteries [1]. Clinically, patients with PTTM usually show rapid worsening of respiratory function, with or without pulmonary hypertension. Unlike tumor emboli, the proximal pulmonary arteries do not show defects on contrast-enhanced CT scans of patients with PTTM.

In the present patient, a prominent CT finding was the peripheral consolidation in both the lower lobes, which was pathologically correlated with infarction. After breast cancer treatment, chest CT can show abnormalities due to various causes including radiation pneumonitis, chemotherapy-induced interstitial changes, pulmonary infection under immunosuppressed condition, cancer related thromboembolic events including PTTM, and pulmonary metastasis [11]. Among them, CT findings of PTTM include consolidations, ground-glass opacities, small nodules, and tree-in-bud appearance [2, 5, 7, 10, 12]. We should consider breast cancer recurrence with PTTM as a differential diagnosis if a patient presents with respiratory symptoms and abnormalities on chest CT images, after breast cancer treatment.

To our knowledge, only 10 patients have been successfully diagnosed with PTTM antemortem (Table 1) [28, 12, 13]. The primary site was the upper gastrointestinal tract (n = 4), breasts (n = 3), unknown (n = 2), and lungs (n = 1). The diagnostic methods for PTTM were transbronchial lung biopsy in five patients and VATS in three. Pulmonary hypertension was detected in five patients. All but one patient received treatment with anti-cancer drug and seven patients survived for more than 3 months. Among them, only the present patient received a molecular-targeted drug trastuzumab that acts against known molecular abnormalities. Trastuzumab therapy was effective for not only breast cancer but also PTTM.
Table 1

Previously reported antemortem diagnoses of PTTM

Year

Author

Primary site

Diagnostic method of PTTM

CT findings

PH

Treatment

Survival time

2007

Miyano et al. [5]

Stomach

VATS

Multiple tiny nodules

-

S-1 + dexamethasone

+ warfarin, aspirin

9 months

2008

Noguchi et al. [12]

Stomach

TBLB

Tiny nodules

+

No treatment

10 days

2008

Uruga et al. [8]

Lung

CT guided biopsy

Consolidation, ground glass attenuation

-

Carboplatin, paclitaxel

7 months

2011

Ishiguro et al. [2]

Unknown

TBLB

Mild interlobular septal thickening, ground glass opacities

+

CHOP(cyclophosphamide, doxorubicin, vincristine, prednisolone)

4 months

2011

Ueda et al. [7]

Esophagus

TBLB

Multiple bilateral diffuse interstitial infiltrative shadows

+

Fluorouracil, nedaplatin

9 days

2012

Kayatani et al. [3]

Unknown

VATS

Centrilobular ultrafine granular shadows

-

S-1, cisplatin

15 months

2013

Ogawa et al. [6]

Gastroduodenum

TBLB

A nodular shadow and septal thicken with a slight amount of pleural effusion

+

Bosentan, epoprostenol

+ imatinib

+ S-1, 5-fluorouracil

9 months

2013

Kitamura et al. [4]

Breast

TBLB

Ground glass opacities around the bronchovascular bundles

-

Irinotecan + warfarin

3 months

2014

Higo et al. [13]

Breast

Pulmonary wedge aspiration

Mosaic pattern

+

Bosentan, tadalafil

+ imatinib, bevacizumab + S-1

12 months

2015

Takahashi et al. (present case)

Breast

VATS

Peripheral consolidation in both lower lobes

-

Trastuzumab

32 months

PTTM Pulmonary tumor thrombotic microangiopathy, PH pulmonary hypertension, TBLB transbronchial lung biopsy, VATS Video-assisted thoracoscopic surgery, S-1 tegafur, gimeracil oteracil potassium

Although von Herbay et al. first reported PTTM [1], almost all previous reports have been from Japan. Although we do not know the exact reason for this, there are several possibilities. First, the prevalence of gastric cancer is high in Japan. Second, Japanese patients can access hospital care easily owing to a national insurance system. Lastly, teaching hospitals, including ours, understand the importance of autopsy, and we try to perform autopsy as often as possible.

Conclusions

PTTM should be included in the differential diagnosis when breast cancer patients exhibit progressive respiratory symptoms with lung infiltrations without pulmonary infection or heart failure. When tumor cells are positive for an oncogenic driver such as HER2, genotype-directed therapy seems promising for the treatment of both cancer and PTTM.

Abbreviations

CT: 

Computed tomography

FDG: 

18F-fluorodeoxyglucose

HER2: 

Human epidermal growth factor receptor 2

PTTM: 

Pulmonary tumor thrombotic microangiopathy

VATS: 

Video-assisted thoracoscopic surgery

Declarations

Acknowledgements

We thank Dr. Toshimi Takano (Department of Medical Oncology, Toranomon Hospital) for his advice regarding the treatment of breast cancer.

Funding

The research has no sources of funding.

Availability of data and material

Data are available on request due to privacy.

Authors’ contributions

YT is the first and corresponding author of the manuscript. HU, SM, SH, HT, AM, and NM collected the patient’s data and provided figures. HU and TF performed pathologic evaluation. AK evaluated CT findings. KK gave final approval of the version to be published. The final version of the manuscript was seen and approved by all authors.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

The patient provided written informed consent for publication of this case report and the associated images.

Ethics approval and consent to participate

The patient provided written informed consent for publication of this case report and the associated images.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Respiratory Medicine, Respiratory Center, Toranomon Hspital
(2)
Department of Pathology, Toranomon Hospital
(3)
Department of Diagnostic Radiology, Fukujuji Hospital
(4)
Okinaka Memorial Institute for Medical Research

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Copyright

© The Author(s). 2016