Intravascular large B-cell lymphoma presenting with reticular telangiectasia on the trunk and panhypopituitarism: an autopsy case
- Midori Tokushima ,
- Masaki Tago ,
- Naoko E Katsuki and
- Shu-ichi Yamashita
- Department of General Medicine, Saga University Hospital, Saga, Japan
- Correspondence to Dr Masaki Tago; tagomas@cc.saga-u.ac.jp
Abstract
A 75-year-old woman developed redness and swelling on her truncal skin, spreading from the lower abdomen to left thigh, 2 months before being admitted to our hospital. She was urgently hospitalised because of her worsening respiratory condition. On admission, she had reticular telangiectasia, diffuse skin induration on the lower abdomen and panhypopituitarism. She was diagnosed with intravascular large B-cell lymphoma (IVLBCL) by the third random abdominal skin biopsy. After histopathological examination at autopsy, we made a final diagnosis of IVLBCL causing respiratory failure and panhypopituitarism. This is the rare case of IVLBCL-induced panhypopituitarism showing visible skin lesions.
Background
Infiltration by lymphoma cells of intravascular large B-cell lymphoma (IVLBCL) could be a rare cause of panhypopituitarism, which is caused by a wide range of pathophysiological conditions. Pathophysiology of IVLBCL results from impairment of blood flow and multiple small infarctions caused by obstruction of microvessels by infiltration of lymphoma cells. This can be difficult to detect by biopsy of the sites of infarction, making diagnosis of IVLBCL challenging.1 Definitive diagnosis of IVLBCL in patients with panhypopituitarism by visualising infiltration of lymphoma cells into the pituitary gland is difficult because of its rarity, and only a few cases have been reported.2
We report a rare case of IVLBCL that initially presented with skin lesions, including reticular telangiectasia, on the trunk, and subsequently developed severe respiratory failure and panhypopituitarism, which was definitively diagnosed by histopathological examination after autopsy.
Case presentation
A 75-year-old woman developed redness and swelling on her skin, from the lower abdomen to the left thigh, 2 months before being admitted to our hospital. She was diagnosed with bacterial cellulitis by her primary physician and prescribed oral tosufloxacin but this failed to improve perineal swelling. After referral to another hospital where abdominal computed tomography and skin biopsy showed no abnormalities, she was tentatively diagnosed with lymphedema. Two months later, she had shortness of breath with low percutaneous oxygen saturation level, without any improvement of skin lesions, and she was urgently transferred to our hospital (day 0).
On admission, the patient was alert and her body temperature was 36.3°C, blood pressure 100/60 mm Hg, pulse rate 84 beats/min regular and percutaneous oxygen saturation 88% in room air. Physical examination showed reticular telangiectasia and diffuse skin induration with mild tenderness and feeling of warmth in the lower abdomen, without any skin manifestations at other sites (figure 1). She had neither palpable lymph nodes nor any neurological abnormalities.
Skin findings on admission. Mild redness and diffuse skin induration were present on the lower abdomen (A, circle). Reticular telangiectasia was scattered around the midline of the abdomen (B, arrows).
Investigations
Laboratory examinations showed white blood cell count 3300/µL (with no abnormalities on complete blood count), haemoglobin 120 g/L, platelet count 17.6×104/ µL, C-reactive protein 0.61 mg/dL, aspartate aminotransferase 55 IU/L, alanine aminotransferase 12 IU/L, lactate dehydrogenase 472 IU/L, Na 127 mEq/L, K 4.1 mEq/L, Cl 98 mEq/L, soluble interleukin 2 receptor 1485 U/mL, plasma osmotic pressure 249 mOsm/L, d-dimer 9.97 µg/mL, urine osmotic pressure 384 mOsm/kg‧H2O and urinary sodium 62 mEq/L (table 1). Arterial blood gas analysis in room air showed type I respiratory failure with pH 7.438, PaO2 47.3 mm Hg, PaCO2 30.8 mm Hg, HCO3 20.5 mmol/L and alveolar-to-arterial oxygen difference 63.9 mm Hg (table 2). Transthoracic echocardiography revealed ejection fraction of 74% without any asynergy of cardiac wall movement or signs of right heart strain. Echo venography of the lower extremities showed no venous thrombosis. Thoracic and abdominal computed tomography with contrast enhancement revealed left pleural effusion, and ascites without lymphadenopathy or pulmonary thromboembolism. Laboratory examination of the pleural effusion fluid suggested the exudative nature of the effusion (lactate dehydrogenase 219 IU/L, protein 3.8 g/dL and albumin 2.0 g/dL). Cytological examination showed no signs of malignancy. Although we performed skin biopsies on the indurated abdominal skin lesions, which previously showed telangiectasia, histopathological examinations failed to show any malignant cells, with negative results for CD20 immunostaining.
Results of blood examination on admission
Results of blood examination on admission
Results of arterial blood gas analysis in room air
| pH | 7.438 |
| pO2 | 47.3 mm Hg |
| pCO2 | 30.8 mm Hg |
| HCO3 | 20.5 mmol/L |
| A-aDO2 | 63.9 mm Hg |
Outcome and follow-up
Hyponatraemia was not improved by restriction of fluid intake; therefore, we started oral administration of NaCl 3 g/day on day 3, without success. On day 20, the patient started to have hypoglycaemic attacks with disturbances of consciousness mainly at night and before each meal, which led us to suspect adrenal insufficiency. Hyponatraemia and hypoglycaemic both improved with administration of hydrocortisone 200 mg/day, which supported the tentative diagnosis. Measurement of basal hormone levels revealed growth hormone 0.4 ng/mL, thyroid-stimulating hormone 0.38 µIU/mL, adrenocorticotropic hormone 6.9 pg/mL, cortisol 4.7 µg/dL, luteinising hormone <0.10 mIU/mL and follicle-stimulating hormone 0.49 mIU/mL, which suggested panhypopituitarism and secondary adrenal failure. We could not perform endocrine stimulation tests because her disturbance of consciousness and hyponatraemia relapsed when the dose of hydrocortisone was reduced below 100 mg/day. Magnetic resonance imaging with contrast enhancement only showed an increased signal in the posterior pituitary gland on T1-weighted images, without any specific abnormality indicative of panhypopituitarism (figure 2). This was possibly caused by pathogenetic obstruction of microvessels nurturing the pituitary gland, without forming mass lesions, gross infarction or unequivocal atrophy.3
Pituitary magnetic resonance imaging with contrast enhancement. (A) T2-weigheted image and (B) T1-weighted image. Magnetic resonance imaging with contrast enhancement revealed no marked abnormalities in the pituitary gland, such as haemorrhage, cysts or mass lesion (A, B). High signal intensity usually detected in the posterior pituitary gland on T1-weighted images was unclear, although there was no apparent lesion that could have caused panhypopituitarism (B, arrow).
On admission, the patient had to receive 5 L/min of oxygen by face mask to keep percutaneous oxygen saturation above 90%. With increasing bilateral pleural effusions, the amount of oxygen was gradually increased to 7 or 15 L/min after day 40. Consequently, we were forced to initiate respiratory support on day 46 because of deterioration of respiratory failure. Meanwhile, reticular telangiectasia and diffuse skin induration spread from the lower abdomen to the chest wall. On day 46, we performed random skin biopsies at four sites on the abdomen and two sites on both thighs, which showed capillary dilatations, venous disconnections, purpura or normal findings. At that time, we highly suspected diagnosis of IVLBCL, despite failure to detect any lymphoma cells by two biopsies of the indurated skin lesions on the lower abdomen performed on admission. Histopathological examinations of the skin biopsies from sites with purpura on the abdomen and with normal findings on the abdomen and both thighs showed infiltration of CD20-positive, medium-to-large abnormal lymphoma cells in the microvasculature (figure 3). This enabled us to make a diagnosis of IVLBCL. A bone marrow biopsy, which the haematologist in our hospital failed to recommend prioritising on our consultation, was not performed because we had previously made a diagnosis of IVLBCL by pathohistological examinations of specimens gained by random skin biopsy. Despite definitive diagnosis, the patient was not able to undergo chemotherapy and was treated with 1000 mg/day prednisolone alone because of rapidly deteriorating performance status caused by complicated disseminated intravascular coagulation and worsening respiratory failure. These were considered to have been caused by systemic invasion and dissemination of malignant cells, producing progression of disseminated intravascular coagulation, pulmonary congestion, or increased pleural effusion. Because of the decision not to administer chemotherapy, we did not perform immunostaining to check for C-MYC/BCL2 double expression in our patient to predict more favourable therapeutic outcome with combination of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisolone (R-CHOP).4
Findings from third random skin biopsy from lower abdomen. (A) Medium-to-large abnormal lymphocytes aggregated in the dilated blood vessels (arrows; H&E staining). (B) Higher magnification of area indicated by left arrow in (A). (C,D) Immunohistochemical staining with anti-CD20 antibodies (C) and anti-CD3 antibodies (D) showing that abnormal lymphocytes in the small blood vessels were CD20-positive and CD3-negative, respectively.
Postmortem examination was performed after her death on day 56. Histopathological examination after autopsy revealed infiltration of large lymphoma cells in the small blood vessels throughout her body, including pituitary gland, lungs, brain, adrenal glands, kidneys, pancreas and skin. These findings confirmed the cause of hypopituitarism as infiltration of tumour cells into the anterior pituitary gland (figure 4).
Histopathological autopsy findings. (A) Medium-to-large abnormal lymphocytes aggregated in the blood vessels in the anterior pituitary gland (H&E staining, high power field). Abnormal lymphocytes mainly infiltrated the anterior lobe, sparing the posterior lobe (arrow). (B) Abnormal lymphocytes in the anterior pituitary gland were CD20 positive (immunohistochemical staining with anti-CD20 antibodies), whose surface was stained brown (outlined by dashed circles). (C) Medium-to-large abnormal lymphocytes similar to those seen in the pituitary gland aggregated in the blood vessels in both lungs (arrow, H&E staining, high power field). (D) Abnormal lymphocytes aggregated in the small blood vessels of both lungs were also CD20 positive (immunohistochemical staining with anti-CD20 antibodies), whose surface was stained brown (outlined by dashed circles).
Discussion
The most salient feature of our case was the presence of characteristic skin lesions, especially reticular telangiectasia. Even without panhypopituitarism, skin signs of IVLBCL were not popular in Japan. The incidence of skin manifestations in IVLBCL without panhypopituitarism in Japan is reported to be 8%, and reticular telangiectasia accounts for about 20% of those.5 6 The present case was a rare case of panhypopituitarism caused by IVLBCL with marked but non-specific skin lesions, which made timely, correct diagnosis difficult. Regrettably, it took us 2 months from admission of our patient to make a definitive diagnosis of IVLBCL, making it impossible to administer chemotherapy to this patient, which was finally decided by the department of haematology in our hospital on our consultation. The reticular telangiectasia and skin induration in our case are rare findings in IVLBCL. Nevertheless, the pathogenesis of such findings was similar to that of symptoms in previous cases of panhypopituitarism without skin lesions, namely, obstruction of arterioles, venules and capillaries by infiltration of lymphoma cells. Random skin biopsy was the key to making a correct diagnosis of IVLBCL of our patient, who shows visible skin lesions. The skin biopsy targeting the lesion failed to reveal her IVLBCL, because the lesions of telangiectasia of her abdomen was considered to be only the result of obstruction of vascular vessels by infiltration of malignant cells other parts than those showing telangiectasia. Hence, random skin biopsy is highly recommended to make a diagnosis of IVLBCL, even for cutaneous variants.7 Therefore, it is crucial to repeat random skin biopsy to make a timely diagnosis of IVLBCL complicated with panhypopituitarism, with or without skin lesions, to enable administration of appropriate, potentially life-saving chemotherapy. This is especially important when patients show non-specific symptoms, including so-called B symptoms such as fever, weight loss and drenching night sweat; neurological symptoms including consciousness disturbance, diplopia, and abducens nerve palsy; and dry mouth, polydipsia or polyuria.2 8–16
It can be a challenge to make a diagnosis of IVLBCL from the presence of panhypopituitarism, as in the present case. This is because panhypopituitarism caused by infiltration of tumour cells into the pituitary capillaries, especially by lymphoma cells of IVLBCL, is rare,2 in addition to the usual difficulty in making a diagnosis of IVLBCL itself.1 As far as we know, only 15 cases of panhypopituitarism caused by IVLBCL have been reported worldwide, among which, only two cases were found in Japan after 1986 (table 3).2 8–16 The median age of the previously reported 15 patients was 66.9 years, with the same incidence in men and women. No patients had skin lesions similar to our present case but they did present with some of the non-specific symptoms mentioned above. Imaging studies, including pituitary magnetic resonance imaging or computed tomography, revealed abnormal, though non-specific, findings in the pituitary gland in 6 (40%) cases. Nine of 10 fatal cases underwent postmortem examination.2 8–14 Autopsy reports of IVLBCL complicated with panhypopituitarism are of value because of the rarity of the condition.2 8–14 Although one case had a nodule of 7 mm in diameter in the pituitary gland,14 the others had infiltration of lymphoma cells into the microcirculation of the pituitary gland.3 9–11 The latter suggests that the mechanism of panhypopituitarism caused by IVLBCL was infiltration of lymphoma cells for most of the cases similar to that of lesions of other organs. Histopathological examination of our case showed similar findings (figure 4). Contrary to the autopsy findings, imaging studies often failed to reveal any abnormalities in the pituitary gland. As previously mentioned, among all 15 cases of panhypopituitarism caused by IVLBCL, only 6 had some abnormal findings in the pituitary gland revealed by imaging.8 12 14 Additionally, among the nine autopsy cases, only two had abnormal imaging findings in the pituitary gland.2 Although fluorodeoxyglucose-positron emission tomography was recently reported to be useful for diagnosis of IVLBCL,17 it appeared to be difficult to detect the lesion in the pituitary gland using this method.
Characteristics of 16 patients diagnosed with intravascular large B-cell lymphoma with pituitary infiltration
| Age | Sex | Symptoms | Sites of disease | Abnormalities of pituitary MRI | Sites of biopsy† | Therapy | Outcome | Autopsy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| *The present case. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 62 | M | Fever, skin leisions | Skin, kidney, lung, adrenal gland, urinary tract | + | NA | NA | Deceased | + | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 58 | M | Appetite loss, weight loss, fatigue | Lung, kidney, spleen, adrenal, thyroid, heart, pancreas | + | NA | Steroid, thyroxine, testosterone, DDAVP | Deceased | + | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 63 | F | Appetite loss, drowsiness | Lung, kidney, liver, spleen, heart, thyroid gland, uterus, ovaries | None | NA | Steroid | Deceased | + | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 69 | F | Fever, fatigue | Adrenal gland | NA | NA | NA | Deceased | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 77 | F | Fever, weight loss, drowsiness | Heart, liver, kidney, brain stem, cerebellum | None | Lips | NA | Deceased | + | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 68 | M | Fever, leg oedema | NA | NA | NA | NA | Deceased | + | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 59 | F | Fever, night sweat, leg oedema | NA | None | NA | NA | Deceased | + | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 65 | M | Fatigue, muscle weakness, dyspnoea | Lung | + | Pituitary gland, lung | CHOP-Bleo | Survived | – | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 63 | F | Fever, weight loss | Adrenal gland, uterus, liver, kidney, bone marrow | None | NA | NA | Deceased | + | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 67 | F | Fever, night sweat, weight loss | Bone marrow | + | Bone marrow | R-CHOP | Survived | – | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 69 | F | Fever, weight loss, dyspnoea | Breast, bone marrow | + | Breast | R-CHOP | Survived | – | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 70 | M | Paraplegia, constipation | Eyeball | None | Lacrimal gland | R-CHOP | Survived | – | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 68 | F | Fever, weight loss, fatigue | NA | + | Pituitary gland | NA | Deceased | – | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 75 | M | Weight loss, fatigue, syncope | Lung, kidney, adrenal gland | None | NA | NA | Deceased | + | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 71 | F | Diplopia, leg oedema | Bone marrow, skin | None | Cerebrospinal fluid | R-CHOP | Survived | – | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 75* | F | Fever, leg oedema, dyspnoea | Lung, adrenal gland, kidney, pancreas, skin | + | Skin | Steroid | Deceased | + | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Acknowledgments
The authors thank Shota Nakayama, Motosuke Tomonaga, Motoshi Fujiwara from Department of General Medicine, Saga University Hospital for their kindly support. We also thank Jane Charbonneau, DVM from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Footnotes
-
MT and MT contributed equally.
-
Correction notice This article has been corrected since it was published Online First. The spelling of Department has been corrected in the affiliation.
-
Contributors MidoriT was involved in literature search and drafting. MasakiT was involved in concept, literature search and drafting. NEK was involved in literature search and drafting. SY was involved in concept and revision of article.
-
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
-
Competing interests None declared.
-
Patient consent for publication Parental/guardian consent obtained.
-
Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
Use of this content is subject to our disclaimer